title: Feasibility study of a randomised controlled trial of pre and postoperative nutritional supplementation in major lung surgery.

abstract:
ObjectivesMalnutrition and weight loss are important risk factors for complications after lung surgery. However, it is uncertain whether modifying or optimising perioperative nutritional state with oral supplements results in a reduction in malnutrition, complications, and quality of life.

DesignA randomised, open label, controlled feasibility study was conducted to assess the feasibility of carrying out a large multicentre randomised trial of nutritional intervention. The intervention consisted of preoperative carbohydrate-loading drinks (4x 200mls evening before surgery and 2x 200mls the morning of surgery), and early postoperative nutritional protein supplement drinks twice a day for 2 weeks following surgery compared to the control group receiving an equivalent volume of water. Qualitative interviews were conducted with participants to help determine the acceptance of the study.

SettingSingle adult thoracic centre in the UK.

ParticipantsAll patients admitted for major lung surgery. Participants were included if were able to take nutritional drinks prior to surgery and were able to give written informed consent. Patients were excluded if they were likely unable to comply with completion of the study questionnaires, they had a body mass index (BMI) < 18.5 kg/m2, were receiving parenteral nutrition or known pregnancy.

ResultsAll patients presenting for major lung surgery were screened over a 6-month period, with 163 patients screened, 99 excluded and 64 (41%) patients randomised. Feasibility criteria were met and the study completed recruitment 5 months ahead of target. The 2 groups were well balanced, and tools used to measure outcomes were robust. 97% of patients were compliant with pre-surgery nutritional drinks and 89% of the questionnaires at 3 months were returned fully completed. The qualitative interviews demonstrated that the trial and the intervention were acceptable to patients. Patients felt the questionnaires used captured their experience of recovery from surgery well.

ConclusionA large multicentre randomised controlled trial of nutritional intervention in major lung surgery is feasible. It is possible to randomise eligible patients and follow up with high fidelity. A pre-op carbohydrate-loading and post-surgery supplementation is highly acceptable to patients with good compliance to both intervention and trial measures. A large multi-centre clinical trial is required to test clinical efficacy in improving outcomes after surgery.

Trial registration numberISRCTN16535341

Strengths and limitation of this studyO_LIThis randomised, feasibility study had pre-planned feasibility to assess whether a larger randomised trial would be feasible.
C_LIO_LIThe study included a large regional thoracic surgical centre and cohort of patients undergoing major lung surgery predominantly for cancer, which would be representative of full trial national recruitment.
C_LIO_LIThe study was not designed and powered to be large enough to provide conclusive evidence to support the use of nutritional intervention in major lung surgery, but provided evidence that a larger, substantive randomised controlled trial is feasible.
C_LI

category: surgery


title: Molecular Stratification of Chronic Kidney Disease

abstract:
Current classification of chronic kidney disease (CKD) into stages based on the indirect measures of kidney functional state, estimated glomerular filtration rate and albuminuria, is agnostic to the heterogeneity of underlying etiologies, histopathology, and molecular processes. We used genome-wide transcriptomics from patients kidney biopsies, directly reflecting kidney biological processes, to stratify patients from three independent CKD cohorts. Unsupervised Self-Organizing Maps (SOM), an artificial neural network algorithm, assembled CKD patients into four novel subgroups, molecular categories, based on the similarity of their kidney transcriptomics profiles. The unbiased, molecular categories were present across CKD stages and histopathological diagnoses, highlighting heterogeneity of conventional clinical subgroups at the molecular level. CKD molecular categories were distinct in terms of biological pathways, transcriptional regulation and associated kidney cell types, indicating that the molecular categorization is founded on biologically meaningful mechanisms. Importantly, our results revealed that not all biological pathways are equally activated in all patients; instead, different pathways could be more dominant in different subgroups and thereby differentially influencing disease progression and outcomes. This first kidney-centric unbiased categorization of CKD paves the way to an integrated clinical, morphological and molecular diagnosis. This is a key step towards enabling precision medicine for this heterogeneous condition with the potential to advance biological understanding, clinical management, and drug development, as well as establish a roadmap for molecular reclassification of CKD and other complex diseases.

One sentence summaryUnbiased grouping of patients based on kidney biopsy transcriptomics profiles generated a novel molecular categorization of chronic kidney disease.

category: nephrology


title: Relationship between eye movements and freezing of gait during turning in individuals with Parkinson disease

abstract:
BackgroundIndividuals with Parkinsons disease can experience freezing of gait: "a sudden, brief episode of an inability to move their feet despite the intention to walk". Since turning is the most sensitive condition to provoke freezing-of-gait episodes, and the eyes typically lead turning, we hypothesize that disturbances in saccadic eye movements are related to freezing-of-gait episodes.

ObjectivesThis study explores the relationship between freezing-of-gait episodes and saccadic eye movements for gaze shift and gaze stabilization during turning.

MethodsWe analyzed 277 freezing-of-gait episodes provoked among 17 individuals with Parkinsons disease during two conditions: self-selected speed and rapid speed 180-degree turns in alternating directions. Eye movements acquired from electrooculography signals were characterized by the average position of gaze, the amplitude of gaze shifts, and the speed of gaze stabilization. We analyzed these variables before and during freezing-of-gait episodes occurring at the different phase angles of a turn.

ResultsSignificant off-track changes of the gaze position were observed almost one 180-degree-turn time before freezing-of-gait episodes. In addition, the speed of gaze stabilization significantly decreased during freezing-of-gait episodes.

ConclusionsWe argue that off-track changes of the gaze position could be a predictor of freezing-of-gait episodes due to continued failure in movement-error correction or an insufficient preparation for eye-to-foot coordination during turning. The decline in the speed of gaze stabilization is large during freezing-of- gait episodes given the slowness or stop of body turning. We argue that this could be evidence for a healthy compensatory system in individuals with freezing-of-gait.

category: neurology


title: Explainable Brain Disease Classification and Relevance-Guided Deep Learning

abstract: Deep neural networks are increasingly used for neurological disease classification by MRI, but the networks decisions are not easily interpretable by humans. Heat mapping by deep Taylor decomposition revealed that (potentially misleading) image features even outside of the brain tissue are crucial for the classifiers decision. We propose a regularization technique to train convolutional neural network (CNN) classifiers utilizing relevance-guided heat maps calculated online during training. The method was applied using T1-weighted MR images from 128 subjects with Alzheimers disease (mean age=71.9{+/-}8.5 years) and 290 control subjects (mean age=71.3{+/-}6.4 years). The developed relevance-guided framework achieves higher classification accuracies than conventional CNNs but more importantly, it relies on less but more relevant and physiological plausible voxels within brain tissue. Additionally, preprocessing effects from skull stripping and registration are mitigated. With the interpretability of the decision mechanisms underlying CNNs, these results challenge the notion that unprocessed T1-weighted brain MR images in standard CNNs yield higher classification accuracy in Alzheimers disease than solely atrophy.


title: Interpretable Brain Disease Classification and Relevance-Guided Deep Learning


title: In silico cancer immunotherapy trials uncover the consequences of therapy-specific response patterns for clinical trial design and outcome

abstract:
BackgroundLate-stage cancer immunotherapy trials strive to demonstrate the clinical efficacy of novel immunotherapies, which is leading to exceptional responses and long-term survival in subsets of patients. To establish the clinical efficacy of an immunotherapy, it is critical to adjust the trials design to the expected immunotherapy-specific response patterns.

MethodsIn silico cancer immunotherapy trials are virtual clinical trials that simulate the kinetics and outcome of immunotherapy depending on the type and treatment schedule. We used an ordinary differential equation model to simulate (1) cellular interactions within the tumor microenvironment, (2) translates these into disease courses in patients, and (3) assemble populations of virtual patients to simulate in silico late-stage immunotherapy, chemotherapy, or combination trials. We predict trial outcomes and investigate how therapy-specific response patterns affect the probability of their success.

ResultsIn silico cancer immunotherapy trials reveal that immunotherapy-derived survival kinetics - such as delayed curve separation and plateauing curve of the treatment arm - arise naturally due to biological interactions in the tumor microenvironment. In silico clinical trials are capable of translating these biological interactions into survival kinetics. Considering four aspects of clinical trial design - sample size calculations, endpoint and randomization rate selection, and interim analysis planning - we illustrate that failing to consider such distinctive response patterns can significantly reduce the power of novel immunotherapy trials.

ConclusionIn silico trials have three significant implications for immuno-oncology. First, they provide an economical approach to verify the robustness of biological assumptions underlying an immunotherapy trial and help to scrutinize its design. Second, the biological basis of these trials facilitates and encourages communication between biomedical researchers, doctors, and trialists. Third, its application as an educational tool can illustrate design principles to scientists in training, contributing to improved designs and higher success rates of future immunotherapy trials.

category: oncology


title: Identification of Highly Frequent TP53 Germline Variations in a Cohort of Head and Neck Cancer Cases

abstract: TP53 is a tumour suppressor gene. Its inactivation plays a significant role in the molecular pathology of cancers. TP53 germline mutations increase the risk of developing multiple primary cancers. However, the role of alterations in TP53 germline DNA in head and neck cancers (HNCs) is not well-established. HNCs comprise one of the most frequent cancers in South Asia. The present discovery study reports the investigation of germline variations in the TP53 gene in a cohort of 30 HNC patients from Karachi, Pakistan. Blood samples were collected and genomic DNA was extracted from white blood cells. TP53 has 11 exons, where exon 1 is not transcribed. After quality control of DNA, amplification of seven selected exons along with their splice sites, two intronic regions (introns 2-3 and 3-4), and 3UTR were carried out. Sanger sequencing was carried out in order to identify germline variations. Comparison with wild type sequence revealed rs1642785 G>C (intron 2-3) variation in 63.2%, PIN3 duplication (rs17878362) in intron 3-4 in 94.7%, and rs1042522 G>C in exon 4 (p.R72P) in 66.6% of the cases. In 3UTR, 13.4% of the analyzed cases carried either one of two variants, i.e., 17:7669567_8delCA or 17:7669560C>G. The latter variations are reported for the first time in literature. In conclusion, we report three highly frequent germline variations and two newly discovered variations in 3UTR of TP53 germline DNA in HNC patients from Pakistan. These results shall contribute to delineating the genetic component of HNCs with potential translational implications.


title: Frequencies of TP53 Germline Variations and Identification of Two Novel 3'UTR Variants in a Series of Head and Neck Cancer Cases


title: Trends in Covid-19 hospital mortality in women and men

abstract:
IntroductionIt remains unclear if the development of health services, clinical management, and scientific evidence, during the pandemic is associated with better medical outcomes, sustained in the long term, for Covid-19 patients of each gender. This study presents the trends in mortality associated with Covid-19 for women and men during the first year of the pandemic.

MethodsThis study was based in 17 Spanish hospitals. Sociodemographic, clinical, and mortality data from all patients with Covid-19, who had been discharged alive, or had died after being admitted, between March 2020 and February 2021, were used.

The association between time of admission and mortality was examined with multivariate logistic regression models.

Results3390 Covid-19 patients were included in the study, of which 1330 were women, the age was M(SD): 66.55(16.55) Death was reported for 451 patients. There was a significant decreasing trend in mortality by time of admission for the whole year with an OR: 0.86(0.77-0.96) p=0.005. No significant trend in mortality for women was observed OR: 1.00(0.85-1.19) p=0.959, while there was a significant decreasing trend for men OR: 0.78 (0.68-0.90) p=0.001

DiscussionThe health policies put in place, the scientific evidence developed by researchers, and the experienced acquired by clinicians, are likely to explain this improvement in mortality. More epidemiological and clinical studies addressing trends of mortality in patients with different sociodemographic and clinical profile and the improvement of clinical outcomes are required. Future research may address the safety and efficacy of interventions specifically in female patients.

category: infectious diseases


title: A simple, sensitive and quantitative FACS-based test for SARS-CoV-2 serology in humans and animals

abstract:
Serological tests are important for understanding the physiopathology and following the evolution of the Covid-19 pandemic. Assays based on flow cytometry (FACS) of tissue culture cells expressing the spike (S) protein of SARS-CoV-2 have repeatedly proven to perform slightly better than the plate-based assays ELISA and CLIA (chemiluminescent immuno-assay), and markedly better than lateral flow immuno-assays (LFIA).

Here, we describe an optimized and very simple FACS assay based on staining a mix of two Jurkat cell lines, expressing either high levels of the S protein (Jurkat-S) or a fluorescent protein (Jurkat-R expressing m-Cherry, or Jurkat-G, expressing GFP, which serve as an internal negative control). We show that the Jurkat-S&R-flow test has a much broader dynamic range than a commercial ELISA test and performs at least as well in terms of sensitivity and specificity. Also, it is more sensitive and quantitative than the hemagglutination-based test HAT, which we described recently. The Jurkat-flow test requires only a few microliters of blood; thus, it can be used to quantify various Ig isotypes in capillary blood collected from a finger prick. It can be used also to evaluate serological responses in mice, hamsters, cats and dogs. Whilst the Jurkat-flow test is ill-suited and not intended for clinical use, it offers a very attractive solution for laboratories with access to tissue culture and flow cytometry who want to monitor serological responses in humans or in animals, and how these relate to susceptibility to infection, or re-infection, by the virus, and to protection against Covid-19.

NoteThis manuscript has been refereed by Review Commons, and modified thanks to the comments and suggestions from two referees. Those comments, and our replies, are provided at the end of the manuscripts pdf, and can also be accessed by clicking on the box with a little green number found just above the "Abstract " tab in the medRXiv window.


title: Distinguishing Incubation and Acute Disease Stages of Mild-to-Moderate COVID-19

abstract:
ObjectiveWhile numerous studies have already compared the immune responses against SARS-CoV-2 in severely and mild-to-moderately ill COVID-19 patients, longitudinal trajectories are still scarce. We therefore set out to analyze serial blood samples from mild-to-moderately ill patients in order to define the immune landscapes for differently progressed disease stages.

MethodsTwenty-two COVID-19 patients were subjected to consecutive venipuncture within seven days after diagnosis or admittance to hospital. Flow cytometry was performed to analyze peripheral blood immune cell compositions and their activation as were plasma levels of cytokines and SARS-CoV-2 specific immunoglobulins. Healthy donors served as controls.

ResultsIntegrating the kinetics of plasmablasts and SARS-CoV-2 specific antibodies allowed for the definition of three disease stages of early COVID-19. The incubation phase was characterized by a sharp increase in pro-inflammatory monocytes and terminally differentiated cytotoxic T cells. The latter correlated significantly with elevated concentrations of IP-10. Early acute infection featured a peak in PD-1+ cytotoxic T cells, plasmablasts and increasing titers of virus specific antibodies. During late acute infection, immature neutrophils were enriched whereas all other parameters returned to baseline.

ConclusionOur findings will help to define landmarks that are indispensable for the refinement of new anti-viral and anti-inflammatory therapeutics, and may also inform clinicians to optimize treatment and prevent fatal outcome.


title: State-wide Genomic Epidemiology Investigations of COVID-19 Infections in Healthcare Workers: Insights for Future Pandemic Preparedness

abstract:
BackgroundCOVID-19 has resulted in many infections in healthcare workers (HCWs) globally. We performed state-wide SARS-CoV-2 genomic epidemiological investigations to identify HCW transmission dynamics and provide recommendations to optimise healthcare system preparedness for future outbreaks.

MethodsGenome sequencing was attempted on all COVID-19 cases in Victoria, Australia. We combined genomic and epidemiologic data to investigate the source of HCW infections across multiple healthcare facilities (HCFs) in the state. Phylogenetic analysis and fine-scale hierarchical clustering were performed for the entire Victorian dataset including community and healthcare cases. Facilities provided standardised epidemiological data and putative transmission links.

FindingsBetween March and October 2020, approximately 1,240 HCW COVID-19 infection cases were identified; 765 are included here. Genomic sequencing was successful for 612 (80%) cases. Thirty-six investigations were undertaken across 12 HCFs. Genomic analysis revealed that multiple introductions of COVID-19 into facilities (31/36) were more common than single introductions (5/36). Major contributors to HCW acquisitions included mobility of staff and patients between wards and facilities, and characteristics and behaviours of individual patients including super-spreading events. Key limitations at the HCF level were identified.

InterpretationGenomic epidemiological analyses enhanced understanding of HCW infections, revealing unsuspected clusters and transmission networks. Combined analysis of all HCWs and patients in a HCF should be conducted, supported by high rates of sequencing coverage for all cases in the population. Established systems for integrated genomic epidemiological investigations in healthcare settings will improve HCW safety in future pandemics.

FundingThe Victorian Government, the National Health and Medical Research Council Australia, and the Medical Research Future Fund.


title: The 1st year of the COVID-19 epidemic in Estonia: an interrupted time series of population based nationwide cross-sectional studies.

abstract:
BackgroundDecisions about the continued need for control measures and the effect of introducing COVID-19 vaccinations rely on accurate and population-based data on SARS-CoV-2 positivity and risk factors for testing positive.

MethodsIn this interrupted time series of population-based nationwide cross-sectional studies, data from nasopharyngeal testing and questionnaires were used to estimate the SARS-CoV-2 RNA prevalence and factors associated with test positivity over the 1st year of the COVID-19 epidemic.

The study is registered with the ISRCTN Registry, ISRCTN10182320.

ResultsBetween April 23, 2020 and February 2, 2021, results were available from 34,915 individuals and 27,870 samples from 11 consecutive studies. The percentage of people testing positive for SARS-CoV-2 decreased from 0.27% (95% CI 0.10% - 0.59%) in April to 0.04% (95% CI 0.00% - 0.22%) by the end of May and remained very low (0.01%, 95% CI 0.00% - 0.17%) until the end of August, followed by an increase since November (0.37%, 95% CI 0.18% - 0.68%) that escalated to 2.69% (95% CI 2.08% - 2.69%) in January 2021. In addition to substantial change in time, an increasing number of household members (for one additional OR 1.15, 95% CI 1.02-1.29), reporting current symptoms of COVID-19 (OR 2.21, 95% CI 1.59-3.09), and completing questionnaire in the Russian language (OR 1.85, 95% CI 1.15-2.99) were associated with increased odds for SARS-CoV-2 RNA positivity.

ConclusionsSARS-CoV-2 population prevalence needs to be carefully monitored as vaccine programmes are rolled out in order to inform containment decisions.

Strengths and limitations of this studyO_LIOur study relies upon nation-wide and population-based data on SARS-CoV-2 prevalence, and presents changes in prevalence over the whole 1st year of the Covid-19 epidemic.
C_LIO_LIOur analysis of SARS-CoV-2 infection risk factors is not limited to notification or health care-based case data.
C_LIO_LISelection bias may have been introduced as a result of low response rate. The direction of bias is unclear, but most likely operates rather uniformly over the period of observation, though this presents less of a threat to the SARS-CoV-2 prevalence trend analysis.
C_LIO_LIOur data could be used to adequately project the future course of the SARS-CoV-2 epidemic and the effect of control measures.
C_LI


title: Serosurvey in two rural areas evidences recent and previously undetected WNV and SLEV circulation in Costa Rica

abstract:
West Nile virus (WNV) and Saint Louis encephalitis virus (SLEV) share similar virus transmission cycles that involve birds as amplifiers and mosquitoes as vectors. Mammals, including humans, are dead-end-hosts that may be asymptomatic or develop more severe symptoms. Costa Rica is a hyperendemic country for several flaviviruses such as Dengue (DENV) and Zika (ZIKV) and previous research showed limited and restricted SLEV and WNV circulation in horses, sloths, and monkeys. Nevertheless, actual seroprevalence and high transmission areas are not yet identified. To determine putative WNV and SLEV circulation, we sampled peri-domestic and domestic animals, humans, wild birds, and mosquitoes in rural households located in two DENV and ZIKV hyperendemic regions during the rainy and dry seasons of 2017-2018 and conducted PRNT assays for serology and RT-PCR for virus detection. At Cuajiniquil, serological evidence of WNV and SLEV was found in equines, humans, chickens, and wild birds. Also, 5 seroconversion events were recorded for WNV (2 equine), SLEV (1 human), and DENV-1 (2 humans). At Talamanca, a lack of WNV circulation was found, but evidence of SLEV circulation was recorded in equines, humans, and wild birds. No evidence of active viral infection was found in any mosquitoes or wild bird samples. This seroconversion evidence supports the active and recent circulation of SLEV and WNV in these two regions. This study provides clear-cut evidence of WNV and SLEV circulation and should be considered by the health and epidemiology authorities for future prevention and differential diagnostics.

Author summaryMosquitoes serve as vectors for the transmission of infectious diseases such as WNV and SLEV. The natural virus cycle of these viruses is maintained between birds and mosquitoes. Yet, humans and horses are dead end-hosts and can develop severe diseases such as encephalitis. We aimed to elucidate if WNV or SLEV were silently circulating in two regions of the country that historically report numerous cases of other arboviruses such as Dengue and Zika. Eight households were sampled at each region twice during the rainy (high number of arbovirus related infections are reported) and dry season (lower number of infections reported) to record seroconversion events. Serum samples from different species were analyzed using serology and virus presence was detected through molecular methods for wild bird and mosquito pools samples. We found serological evidence of WNV and SLEV infection in horses, humans, wild birds, and chicken samples, but did not detect actual virus in any tissue or mosquito sample. Taken together, our result shows the active but silent circulation of those viruses at both sampling sites. Action to include these arboviruses into diagnostics and public health measures must be taken.


title: Investigating the biological and technical origins of unknown bases in the S region of the SARS-CoV-2 Delta variant genome sequences

abstract: We are reporting on the observation of a large, under-sequenced region of the S gene of the SARS-CoV2 Delta variant genomes, identified in sequences originating from various sequencing centres worldwide (e.g. USA, India, England, Switzerland, France, Germany). This poorly sequenced region was identified from the early phases of the Delta variant spread and the phenomenon is still ongoing. As many commonly-used protocols rely on amplicon-based sequencing procedures, we investigated the likely origin of the issue. We established its biological origin as resulting from mutations in the viral genomes at primer binding sites. We designed and evaluated new PCR primers to circumvent this issue in order to complement the ARTIC v3 set, and validated their performance for the sequencing of circulating Delta variants.


title: Professional practice for COVID-19 risk reduction among health care workers : a Cross-Sectional Study with Matched Case-Control Comparison

abstract:
BackgroundHealth care workers (HCWs) are particularly exposed to COVID-19 and therefore it is paramount to study preventive measures in this population.

AimTo investigate socio-demographic factors and professional practice associated with the risk of COVID-19 among HCWs in health establishments in Normandy, France

MethodsA cross-sectional and 3 case-control studies were conducted in order to explore the possible risk factors that lead to SARS-CoV2 transmission within HCWs, based on an online questionnaire. The case-control studies focused on risk factors associated with care of COVID-19 patients, care of non COVID-19 patients and contacts between colleagues.

FindingsAmong 2,058 respondents, respectively 1,363 (66.2%) and 695 (33.8%) in medical and medico-social establishments, 301 (14.6%) reported having been infected by SARS-CoV2. When caring for COVID-19 patients, HCWs who declared wearing respirators, either for all patient care (ORa 0.39; 95% CI: 0.29-0.51) or only when exposed to aerosol-generating procedures (ORa 0.56; 95% CI: 0.43-0.70), had a lower risk of infection compared with HCWs who declared wearing mainly surgical masks. During care of non COVID-19 patients, wearing mainly a respirator was associated with a higher risk of infection (ORa 1.84; 95% CI: 1.06-3.37). An increased risk was also found for HCWs who changed uniform in workplace changing rooms (ORa 1.93; 95% CI: 1.63-2.29).

ConclusionCorrect use of PPE adapted to the situation and risk level is essential in protecting HCWs against infection.


title: Analysis of 2.1 million SARS-CoV-2 genomes identifies mutations associated with transmissibility

abstract:
Repeated emergence of SARS-CoV-2 variants with increased fitness necessitates rapid detection and characterization of new lineages. To address this need, we developed PyR0, a hierarchical Bayesian multinomial logistic regression model that infers relative prevalence of all viral lineages across geographic regions, detects lineages increasing in prevalence, and identifies mutations relevant to fitness. Applying PyR0 to all publicly available SARS-CoV-2 genomes, we identify numerous substitutions that increase fitness, including previously identified spike mutations and many non-spike mutations within the nucleocapsid and nonstructural proteins. PyR0 forecasts growth of new lineages from their mutational profile, identifies viral lineages of concern as they emerge, and prioritizes mutations of biological and public health concern for functional characterization.

One Sentence summaryA Bayesian hierarchical model of all SARS-CoV-2 viral genomes predicts lineage fitness and identifies associated mutations.

category: epidemiology


title: Analysis of 6.4 million SARS-CoV-2 genomes identifies mutations associated with fitness


title: Predicting the Effectiveness of the Pfizer-BioNTech BNT162b2 Vaccine from SARS-CoV-2 Variants Neutralisation Data

abstract: Rapid and accurate prediction of Covid-19 vaccine effectiveness is crucial to response against SARS-CoV-2 variants of concern. Despite intensive research, several prediction tasks are not well supported, such as predicting effectiveness of partial vaccination, of vaccine boosters and in vaccinated subpopulations. This paper introduces a novel predictive framework to accommodate such tasks and improve prediction accuracy. It was developed for predicting the symptomatic effectiveness of the BNT162b2 (Comirnaty) and ChAdOx1 nCoV-19 (Vaxzevria) vaccines but could apply to other vaccines and effectiveness types. Direct prediction within the framework uses levels of vaccine-induced neutralising antibodies against SARS-CoV-2 variants to fit efficacy and effectiveness estimates from studies with a given vaccine. Indirect prediction uses a model fitted for one vaccine to predict the effectiveness of another. The directly predicted effectiveness of Comirnaty against the Delta variant was 44.8% (22, 69) after one and 84.6% (64, 97) after two doses, which is close to 45.6% and 85.5%, the average estimates from effectiveness studies with the vaccine. The corresponding direct predictions for Vaxzevria were 41.6% (18, 68) and 63.2% (37, 86); and the indirect predictions, from the model fitted to Comirnaty data, were 45.5% (23, 70) and 61.2% (37, 83). Both sets of predictions are comparable to the average estimates, 42.5% and 66.3%, from effectiveness studies with Vaxzevria. Further results are presented on age subgroups; prediction biases and their mitigation; and implications for vaccination policies.


title: Predicting the Effectiveness of Covid-19 Vaccines from SARS-CoV-2 Variants Neutralisation Data


title: The tiered restrictions enforced in November 2020 did not impact the epidemiology of the second wave of COVID-19 in Italy.

abstract:
In the attempt to counter the second COVID-19 wave in autumn 2020, the Italian government introduced a unique countrywide system of physical distancing measures organized in progressively restrictive tiers (coded as yellow, orange, and red) imposed on a regional basis according to epidemiological risk assessments. This followed a set of other scattered or limited measures described in full detail by Manica et al.1.

This paper concerns the introduction of the tiered restrictions. The data used to evaluate the impact of the restriction system on SARS-CoV-2 transmissibility and hospitalization burden in Italy is from the Italian COVID-19 integrated surveillance system.

The reproduction number R(t) estimated on the onset of COViD-19 symptoms constantly decreased during most of the observation period 04 October 2020 - 06 December 2020 than is centered on the date of introduction of the measures and includes the expected latency to reach an effect. The fastest decrease of R(t) occurred in the period preceding the introduction of the tiered restrictions. There was no evidence that introducing the tiered restrictions determined the reduction of R(t). An alternative analysis using the daily growth rate of the epidemic curve confirms these conclusions. Similar considerations are made concerning the health system burden, analyzing hospitalizations at country level.

The trend of R(t) tending to increase shortly after the measures became effective does not allow to exclude that the enforcement of such restrictions might have been counterproductive.

These results are instrumental in informing public health efforts aimed at attempting to manage the epidemic efficiently. Planning further use of the tiered restrictions and the associated containment measures should be carefully and critically revised to avoid a useless burden to the population with no advantage for the containment of the epidemic or a possible worsening.


title: The thalamus and its subnuclei: a gateway to obsessive-compulsive disorder findings from the ENIGMA-OCD Working Group

abstract:
ObjectiveHigher thalamic volume has been found in children with obsessive-compulsive disorder (OCD) and children with clinical-level symptoms within the general population. Particular thalamic subregions may drive these differences. The ENIGMA-OCD working group conducted mega- and meta-analyses to study thalamic subregional volume in OCD across the lifespan.

MethodStructural T1-weighted brain magnetic resonance imaging (MRI) scans from 2,649 OCD patients and 2,774 healthy controls across 29 sites (50 datasets) were processed using the FreeSurfer built-in ThalamicNuclei pipeline to extract five thalamic subregions. Volume measures were harmonized for site effects using ComBat before running separate multiple linear regression models for children, adolescents, and adults to estimate volumetric group differences. All analyses were preregistered (https://osf.io/73dvy) and adjusted for age, sex and intracranial volume.

ResultsUnmedicated pediatric OCD patients (< 12 years) had larger lateral (d = 0.46), pulvinar (d = 0.33), ventral (d = 0.35) and whole thalamus (d = 0.40) volumes at unadjusted p-values <0.05. Adolescent patients showed no volumetric differences. Adult OCD patients compared with controls had smaller volumes across all subregions (anterior, lateral, pulvinar, medial, and ventral) and smaller whole thalamic volume (d = -0.15 to -0.07) after multiple comparisons correction, mostly driven by medicated patients and associated with symptom severity. The anterior thalamus was also significantly smaller in patients after adjusting for thalamus size.

ConclusionOur results suggest that OCD-related thalamic volume differences are global and not driven by particular subregions and that the direction of effects are driven by both age and medication status.

category: psychiatry and clinical psychology


title: Genome-wide association study of REM sleep behavior disorder identifies novel loci with distinct polygenic and brain expression effects

abstract: Rapid eye movement (REM) sleep behavior disorder (RBD), enactment of dreams during REM sleep, is an early clinical symptom of alpha-synucleinopathies. RBD also defines more severe forms of alpha-synucleinopathies. The genetic background of RBD and its underlying mechanisms are not well understood. Here, we performed the first genome-wide association study of RBD, identifying five RBD risk loci. Expression analyses highlight SNCA-AS1 and SCARB2 differential expression in different brain regions in RBD, with SNCA-AS1 further supported by colocalization analyses. Genetic risk score and other analyses provide further insights into RBD genetics, highlighting RBD as a unique subpopulation that will allow future early intervention.

category: genetic and genomic medicine


title: Association between COVID-19 vaccination, infection, and risk of Guillain-Barre syndrome, Bell's palsy, encephalomyelitis and transverse myelitis: a population-based cohort and self-controlled case series analysis

abstract:
OBJECTIVEWe aimed to study the association between COVID-19 vaccines, SARS-CoV-2 infection, and the risk of immune-mediated neurological events.

METHODSO_ST_ABSDesignC_ST_ABSPopulation-based historical rate comparison study and self-controlled case series (SCCS) analysis.

SettingPrimary care records from the United Kingdom.

ParticipantsIndividuals who received the first dose of ChAdOx1 or BNT162b2 between 8 December 2020 and 6 March 2021. A cohort with a first positive RT-PCR test for SARS-CoV-2 between 1 September 2020 and 28 February 2021 was used for comparison.

Main outcome measuresOutcomes included Guillain-Barre syndrome (GBS), Bells palsy, encephalomyelitis, and transverse myelitis.

Incidence rates were estimated in the 28 days post first-dose vaccine, 90 days post-COVID-19, and between 2017 to 2019 for the general population cohort for background rates. Indirectly standardised incidence ratios (SIRs) were estimated. Adjusted incidence rate ratios (IRR) were estimated from the SCCS when sufficient statistical power was reached.

ResultsWe included 1,868,767 ChAdOx1 and 1,661,139 BNT162b2 vaccinees; 299,311 people infected with COVID-19; and 2,290,537 from the general population. SIRs for GBS were 1.91 [95% CI: 0.86 to 4.26] after ChAdOx1, 1.29 [0.49 to 3.45] after BNT162b2, and 5.20 [1.95 to 13.85] after COVID-19. In the same cohorts, SIRs for Bells palsy were 1.34 [1.05 to 1.72], 1.15 [0.88 to 1.50], and 1.23 [0.80 to 1.89], and for encephalomyelitis 1.62 [0.61 to 4.31], 0.86 [0.22 to 3.46], and 11.05 [5.27 to 23.17], respectively. Transverse myelitis was too rare to analyse (n<5 in all cohorts). SCCS analysis was only conducted for Bells palsy due to limited statistical power. We found no association between either vaccine and Bells palsy, with an IRR of 1.10 [0.81 to 1.46] and 1.15 [0.87 to 1.49] for BNT162b2 and ChAdOx1, respectively.

ConclusionsWe found no consistent association between either vaccine and any of the studied neuroimmune adverse events studied. Conversely, we found a 5-fold increase in risk of GBS and an 11-fold of encephalomyelitis following COVID-19.


title: Vaccinations or Non-Pharmaceutical Interventions:Safe Reopening of Schools in England

abstract: With high levels of the Delta variant of COVID-19 circulating in England during September 2021, schools are set to reopen with few school-based non-pharmaceutical interventions (NPIs). In this paper, we present simulation results obtained from the individual-based model, JO_SCPLOWUNEC_SCPLOW, for English school opening after a prior vaccination campaign using an optimistic set of assumptions about vaccine efficacy and the likelihood of prior-reinfection. We take a scenario-based approach to modelling potential interventions to assess relative changes rather than real-world forecasts. Specifically, we assess the effects of vaccinating those aged 16-17, those aged 12-17, and not vaccinating children at all relative to only vaccinating the adult population, addressing what might have happened had the UK began teenage vaccinations earlier. Vaccinating children in the 12-15 age group would have had a significant impact on the course of the epidemic, saving thousands of lives overall in these simulations. In the absence of such a vaccination campaign our simulations show there could still be a significant positive impact on the epidemic (fewer cases, fewer deaths) by continuing NPI strategies in schools. Our analysis suggests that the best results in terms of lives saved are likely derived from a combination of the now planned vaccination campaign and NPIs in schools.


title: Vaccinations or Non-Pharmaceutical Interventions: Safe Reopening of Schools in England


title: Citizens' Attitudes Under Covid19: a cross-country panel survey of public opinion in 11 democracies

abstract: This article introduces data collected in the Citizens Attitudes Under Covid-19 Project (CAUCP), which surveyed public opinion throughout the Covid-19 pandemic in 11 countries between March to December 2020. In this paper, we present a unique cross-country panel survey of citizens attitudes and behaviors during a worldwide unprecedented health, governance, and economic crisis. This dataset allows to examine the behavioral and attitudinal consequences of crisis across time and contexts. In this paper, we describe the set-up of the CAUCP and the main features of the dataset and we present promising research prospects.

category: public and global health


title: Wound Complications Following Surgery to the Lymph Nodes: A protocol for a systematic review and meta-analysis

abstract:
BackgroundMalignancies that spread to the lymph nodes may be identified through surgical biopsy, and treatment of metastatic disease may be through lymph node dissection. These surgeries, however, may be associated with significant adverse outcomes, particularly wound complications, the true incidence of which remains unknown. Multiple studies have reported their individual rates of complications in isolation. The aim of this study will be to systematically evaluate data that presents the incidence of wound complications in patients undergoing these surgeries.

MethodsWe have designed and registered a protocol for a systematic review and meta-analysis of studies presenting incidence data. We will search MEDLINE, EMBASE and CENTRAL for relevant articles published before March 30th, 2021. Meta-analysis will be undertaken to synthesise an overall incidence of surgical site infection, wound dehiscence, haematoma and seroma. Subgroup analyses will investigate the effects of anatomical location, primary malignancy and study design on pooled incidence. Risk of bias will be evaluated for each included study using bespoke tools matched to the study design.

DiscussionThe results of this study will provide the incidence of wound complications and secondary complications following lymph node surgery. This will directly impact upon the consent process, and may influence the nature of future research studies aimed at reducing post-operative complications.


title: Provisional research criteria for the behavioral variant of Alzheimer disease: A systematic review and meta-analysis

abstract:
ImportanceThe behavioral variant of Alzheimers disease (bvAD) is characterized by early and predominant behavioral deficits caused by AD pathology. This AD phenotype is insufficiently understood and lacks standardized clinical criteria, limiting reliability and reproducibility of diagnosis and scientific reporting.

ObjectiveTo perform a systematic review and meta-analysis of the bvAD literature, and use the outcomes to propose provisional research criteria for this syndrome.

Data sourcesA systematic literature search in PubMed/Medline and Web-of-Science databases (from inception through April 7th, 2021, performed in duplicate) led to the assessment of 83 studies, including 13 suitable for meta-analysis.

Study selectionStudies reporting on behavioral, neuropsychological or neuroimaging features in bvAD, and, when available, providing comparisons with "typical" amnestic-predominant AD (tAD) or behavorial variant frontotemporal dementia (bvFTD).

Data extraction and synthesisWe performed random-effects meta-analyses on group-level study results of clinical data, and systematically reviewed the neuroimaging literature.

Main outcome and measuresBehavioral symptoms (neuropsychiatric symptoms and bvFTD core clinical criteria), cognitive function (global cognition, episodic memory and executive functioning) and neuroimaging features (structural MRI, [18F]FDG-PET, perfusion SPECT, amyloid-PET and tau-PET).

ResultsData were collected for 591 patients with bvAD. There was moderate-to-substantial heterogeneity and moderate risk of bias across studies. bvAD showed more severe behavioral symptoms compared to tAD (standardized mean difference [SMD, 95% confidence interval]: 1.16[0.74-1.59], p<0.001), and a trend towards less severe behavioral symptoms compared to bvFTD (SMD:-0.22[-0.47-0.04], p=0.10). Meta-analyses of cognitive data indicated worse executive performance in bvAD versus tAD (SMD:-1.03[-1.74--0.32], p<0.01), but not compared to bvFTD (SMD:-0.61[-1.75-0.53], p=0.29). bvAD showed a trend towards worse memory performance compared to bvFTD (SMD:-1.31[-2.75-0.14], p=0.08), but did not differ from tAD (SMD:0.43[-0.46-1.33], p=0.34). The neuroimaging literature revealed two distinct bvAD neuroimaging-phenotypes: an "AD-like" posterior-predominant pattern and a "bvFTD-like" anterior-predominant pattern, with the former being more prevalent.

Conclusions and relevanceOur data indicate that bvAD is clinically most similar to bvFTD, while it shares most pathophysiological features with tAD. Based on these insights, we propose provisional research criteria for bvAD aimed at improving the consistency and reliability of future research and aiding the clinical assessment of this AD phenotype.

KEY POINTSO_ST_ABSQuestionC_ST_ABSHow does the behavioral variant of Alzheimers disease (bvAD) relate to typical AD (tAD) and to behavioral variant frontotemporal dementia (bvFTD) in terms of clinical presentation and neuroimaging signatures?

FindingsIn this systematic review and meta-analysis, we found that, at time of diagnosis, bvAD showed more severe neuropsychiatric symptoms and other behavioral deficits compared to tAD. Two distinct neuroimaging phenotypes were observed across reported bvAD cases: an "AD-like" posterior-predominant pattern and a "bvFTD-like" anterior-predominant pattern, with the posterior-predominant neuroimaging phenotype being the most prevalent across reported bvAD cases.

MeaningbvAD is clinically most reminiscent of bvFTD, while it shares most pathophysiological features with tAD. The provisional research criteria are aimed at improving the consistency and reliability of future research, and potentially aid in the clinical assessment of bvAD.


title: Intact corticostriatal and altered subcortical circuits in chronic pain

abstract:
Previous research has demonstrated the importance of the corticostriatal circuit in chronic pain. By focusing on nucleus accumbens (NAcc) circuits related to reward, we aimed to clarify how altered brain reward systems contribute to chronic pain. Using resting-state functional magnetic resonance imaging, we compared NAcc-medial prefrontal cortex (MPFC) functional connectivity in patients with fibromyalgia vs. healthy controls. Among patients, we analyzed the extent to which functional connectivity correlated with clinical measures. We also examined NAcc functional connectivity to subcortical regions. Lastly, we compared our results to a separate dataset of patients with chronic back pain. We identified robust NAcc-MPFC functional connectivity among patients with fibromyalgia and healthy controls, with no significant group differences. We found a positive correlational trend between NAcc-MPFC functional connectivity and total mood disturbance. Notably, patients with fibromyalgia showed significantly reduced functional connectivity of the right NAcc with mesolimbic circuit regions compared to controls. These results were largely similar to the results from the separate dataset. Our results provide novel evidence of intact corticostriatal but altered subcortical functional connectivity of the NAcc during resting-state in chronic pain and suggest that measured connectivity may relate to changes in mood and the level of cognitive demand during fMRI-based measurement.

PerspectiveThis article indicates complex brain valuation system alterations associated with chronic pain. Our findings expand our understanding of the valuation system and its relationship to clinical presentation in patients with fibromyalgia.

category: pain medicine


title: Genetic underpinnings of the transition from alcohol consumption to alcohol use disorder: shared and unique genetic architectures in a cross-ancestry sample

abstract: Recent GWAS of alcohol-related traits have uncovered key differences in the underlying genetic architectures of alcohol consumption and alcohol use disorder (AUD), with the two traits having opposite genetic correlations with psychiatric disorders. Understanding the genetic factors that underlie the transition from heavy drinking to AUD has important theoretical and clinical implications. We utilized longitudinal data from the cross-ancestry Million Veteran Program sample to identify 1) novel loci associated with AUD and alcohol consumption [measured by the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C)] and 2) genetic variants with direct effects on AUD not mediated through alcohol consumption. We identified 26 loci associated with AUD, including 5 ancestry-specific and 6 novel loci and 22 loci associated with AUDIT-C, including 3 ancestry-specific and 8 novel loci. In secondary GWAS that excluded individuals who report abstinence, we identify 7 additional loci for AUD and 8 additional loci for AUDIT-C. We demonstrate that, although the heterogeneity of the abstinent group biases the GWAS findings, unique variance between alcohol consumption and disorder remains after the group is excluded. Finally, using mediation analysis, we identified a set of variants with effects on AUD that are not mediated through alcohol consumption. The distinct genetic architectures of alcohol consumption and AUD suggest different biological contributions to the traits. Genetic variants with direct effects on AUD are potentially relevant to understanding the transition from heavy alcohol consumption to AUD and targets for translational prevention and treatment efforts.


title: Indirect effects of peaks in COVID admissions on access to surgery in the English NHS, differential effects by operation type, ethnicity and socio-economic status: a database study

abstract:
ObjectivesDuring the COVID pandemic the UK saw two peaks in the prevalence of hospital admissions resulting in disruption of routine hospital services in the English National Health Service. This study aimed to track the effect of these peaks on various types of surgery representing differences in urgency, importance, and complexity.

DesignDatabase study using the Hospital Episode Statistics database and surgical operations selected purposively, to represent different combinations of urgency, importance and complexity.

SettingAll hospitals within England that carried out procedures funded by the National Health Service.

Main Outcome MeasuresNumber of emergency routine surgeries; cancer-removal surgeries; transplant surgeries; renal transplants Deceased and living donors); and elective routine surgeries carried out prior to and during the COVID pandemic.

ResultsWhile all surgeries declined, emergency or urgent operations held up better than elective cases. There was rapid rebound between peaks. Among emergency cases, coronary angioplasty for acute myocardial infarction held up well in contrast to appendectomy, where indications for surgery are more elastic. Among urgent cancer and transplant operations, those with the most complex pathways were the most severely affected. The pandemic affected socio-economic and ethnic groups similarly. Disruption during the second peak was slightly less than during the first peak despite even greater COVID admission rates.

ConclusionThe NHS titrated its response appropriately to the pandemic by prioritising emergency and urgent cases over elective cases. However, complex time critical conditions like organ transplants and certain cancers are also disrupted with implications for third peaks in hospital admissions that many countries are experiencing.

category: health systems and quality improvement


title: Low levels of Fe and Se with high IL-6/IL-10 likely influence nutritional immunity in tuberculosis patients.

abstract: Tuberculosis (TB) patients present dysregulated immunity, iron metabolism and anaemia of inflammation. In this study, circulatory cytokines, trace metals, and iron-related proteins (hepcidin, ferroportin, transferrin, DMT1, Nramp1, ferritin, ceruloplasmin, hemojuvelin, aconitase, transferring receptor) were monitored in case (active tuberculosis patients: ATB) and control (non-tuberculosis: NTB and healthy) study populations (n=72, male, 42.94 mean age (16-83)). Using serum elemental and cytokine levels, a partial least square discriminate analysis model (PLS-DA) was built and variables with a VIP score of >0.6 were selected as important markers. A biosignature of IL-13, IL-12(p70), IFN-{gamma}, IL-10, IL-5, IL-18, IL-4, Selenium, and Aluminium clustered ATB away from controls. Interestingly, low iron and selenium levels, while high copper and aluminum levels were observed in ATB subjects. All the important serum cytokines were positively correlated in ATB subjects. A low abundance of transferrin, ferroportin, and hemojuvelin, while higher ferritin and ceruloplasmin levels explained an altered iron metabolism in ATB subjects which partially resolved upon completion of treatment. Further, the identified biosignature in TB patients, that explained anemia of inflammation, along with perturbed iron homeostasis could be useful targets for the development of host-directed adjunct therapeutics.


title: Determinants of hospital outcomes for COVID-19 infections in a large Pennsylvania Health System

abstract:
There is growing evidence that racial and ethnic minorities bear a disproportionate burden from COVID-19. Temporal changes in the pandemic epidemiology and diversity in the clinical course require careful study to identify determinants of poor outcomes.

We analyzed 6255 individuals admitted with PCR-confirmed COVID-19 to one of 5 hospitals in the University of Pennsylvania Health System between March 2020 and March 2021, using electronic health records to assess risk factors and outcomes through 8 weeks post-admission. Discharge, readmission and mortality outcomes were analyzed in a multi-state model with multivariable Cox models for each transition.

Mortality varied markedly over time, with cumulative incidence (95% CI) 30 days post-admission of 19.1% (16.9, 21.3) in March-April 2020, 5.7% (4.2, 7.5) in July-October 2020 and 10.5% (9.1,12.0) in January-March 2021; 26% of deaths occurred after discharge. Average age (SD) at admission varied from 62.7 (17.6) to 54.8 (19.9) to 60.5 (18.1); mechanical ventilation use declined from 21.3% to 9-11%.

Compared to Caucasian, Black race was associated with more severe disease at admission, higher rates of co-morbidities and low-income resident zip code. Between-race risk differences in mortality risk diminished in multivariable models; while admitting hospital, increasing age, admission early in the pandemic, and severe disease and low blood pressure at admission were associated with increased mortality hazard. Hispanic ethnicity was associated with fewer baseline co-morbidities and lower mortality hazard (0.57, 95% CI: 0.37, .087).

Multi-state modeling allows for a unified framework to analyze multiple outcomes throughout the disease course. Morbidity and mortality for hospitalized COVID-19 patients varied over time but post-discharge mortality remained non-trivial. Black race was associated with more risk factors for morbidity and with treatment at hospitals with lower mortality. Multivariable models suggest there are not between-race differences in outcomes. Future work is needed to better understand the identified between-hospital differences in mortality.


title: Molecular point-of-care testing for SARS-CoV-2 using the ID NOW(TM) System in Emergency Department: Prospective Evaluation and Implementation in the Care Process

abstract:
BackgroundThe increasing number of cases and hospital admissions due to COVID-19 created an urgent need for rapid, reliable testing procedures for SARS-CoV-2 in Emergency Departments (ED) in order to effectively manage hospital resources, allocate beds and prevent nosocomial spread of infection. The ID NOW COVID-19 assay is a simple, user-friendly, rapid molecular test run on an instrument with a small footprint enabling point-of-care diagnostics.

MethodsIn the first wave, outsourced RT-PCR testing regularly required 36-48 hours before results were available. This prospective study was conducted in the second wave (October 2020-April 2021) and evaluated the impact the implementation of the ID NOW COVID-19 test in the ED had on clinical care processes and patient pathways. 710 patients were recruited upon arrival at the ED which included those presenting clinical symptoms, asymptomatic individuals or persons fulfilling epidemiological criteria. The first anterior nasal swab was taken by trained nurses in the ambulance or a separate consultation room. The ID NOW COVID-19 test was performed in the ED in strict compliance with the manufacturers instructions and positive or suspected cases were additionally tested with RT_PCR (cobas SARS-COV-2 RT-PCR, Roche) following collection of a second nasopharyngeal NP specimen.

ResultsSwabs directly tested with the ID NOW COVID-19 test showed a diagnostic concordance of 98 % (sensitivity 99.59 %, specificity 94.55 %, PPV 97.6 %, NPV 99.05 %) compared to RT-PCR as reference. The 488 patients that tested positive with the ID NOW COVID-19 had a Ct range in RT-PCR results between 7.94 to 37.42 (in 23.2 % > 30). Two false negative results (0.28%) were recorded from patients with Ct values > 30. 14 (1.69%) discordant results were reviewed case-by-case and usually associated with either very early or very advanced stages of infection. Furthermore, patients initially negative with the ID NOW COVID-19 test and admitted to the hospital were tested again on days 5 and 12: no patient became positive.

DiscussionThe ID NOW COVID-19 test for detection of SARS-CoV-2 demonstrated excellent diagnostic agreement with RT-PCR under the above-mentioned patients pathways implemented during the second wave. The main advantage of the system was the provision of reliable results within a few minutes. This not only allowed immediate initiative of appropriate therapy and care for COVID-19 (patient benefit) but provided essential information on isolation and thus available beds. This drastically helped the overall finances of the department and additionally allowed more patients to be admitted including those requiring immediate attention; this was not possible during the first wave since beds were blocked waiting for diagnostic confirmation. Our findings also show that when interpreting the results, the clinical condition and epidemiological history of the patient must be taken into account, as with any test procedure. Overall, the ID NOW COVID-19 test for SARS-CoV-2 provided a rapid and reliable alternative to laboratory-based RT-PCR in the real clinical setting which became an acceptable part of the daily routine within the ED and demonstrated that early patient management can mitigate the impact of the pandemic on the hospital.

category: emergency medicine


title: The Gut Microbiome of Youth Who Have Behavioral and Mental Health Problems: A Scoping Review

abstract:
BackgroundMental health conditions have increased over the past several decades. While there is growing evidence that the gut microbiome affects mental health, there are limited studies focused on children, adolescents, and young adults. This scoping review examined the existing literature and compared findings on the relationships between the gut microbiome with mental health across these younger age groups.

MethodsA literature search using PubMed, PsycINFO, and CINAHL was performed, and bibliographies were manually searched. Eighteen articles met eligibility for our scoping review. Findings from each study were evaluated, focusing on bacterial composition and diversity among children/adolescents and young adults.

ResultsThere were no studies specifically on the adolescent age group, so data was synthesized comparing the child/adolescent (2 to <18 years of age) and young adult (18-25 years of age) groups. Studies utilized several different methods for gut microbiome analysis and examined various mental health conditions. Findings for both age groups were mostly inconsistent. However, Bifidobacteria seems to be associated with better mental health. Alpha diversity was lower for children/adolescents with ADHD and high stress but higher for young adults with ADHD and Major Depressive Disorder.

LimitationsThere were inconsistencies across studies, likely due to differences in mental health problems examined, populations assessed, and research designs or measurements used.

ConclusionsFuture research should replicate studies to confirm findings, examine lower taxonomic levels, consider longitudinal designs to assess for directionality, and consider clinical trials to examine the effects of probiotics with the same strains to manage mental health symptoms.


title: Pre-conceptional maternal vitamin B12 supplementation improves offspring neurodevelopment at 2 years of age: PRIYA trial

abstract:
BackgroundNutritional interventions during the first 1000 days of life improves lifelong health. Better pre-conceptional maternal nutrition improves the nutrition of the early embryo. Vitamins B12 and folate are important for fetal neural development. Vitamin B12 deficiency is common in India.

MethodsIn the Pune Rural Intervention in Young Adolescents (PRIYA) adolescents (N=557, 226 females) were provided with vitamin B12 (2{micro}g/day) with or without multiple micronutrients, or a placebo, from preconception until delivery. All groups received mandatory iron and folic acid. We used the Bayleys Scale of Infant Development (BSID-III) at 24-42 months of age to investigate effects on offspring neurodevelopment. We examined cord blood concentrations of brain-derived neurotropic factor (BDNF).

ResultsParticipants in the three groups had similar baseline B12 levels. These improved in the B12 supplemented groups at pre-conceptional and pregnancy (28 weeks gestation) measurements, reflected in higher cord holo-TC levels compared to the placebo. Neurodevelopmental outcomes are available for 74 children. Offspring in the B12 alone group (n=21) performed better than the placebo (n=27) on cognition (p=0.044) and language (p=0.020) domains (adjusted for maternal baseline B12 levels). There were no differences between the B12+MMN (n=26) and placebo group. Cord blood BDNF levels were highest in the B12 alone group (not statistically significant).

ConclusionPre-conceptional vitamin B12 supplementation improved maternal B12 status and offspring neurodevelopment at 2 years of age. The usefulness of cord BDNF as a marker of brain development needs further investigation. Our results highlight the importance of intervening in the pre-conceptional period.


title: Rapid realist review: Anxiolytic effects of music therapy on mechanically ventilated patients

abstract:
AimsTo review the literature focusing on anxiety and music therapy as a non-pharmacological anxiolytic for patients receiving mechanical ventilation and to determine the contexts, mechanisms and outcomes of what works for whom and under what circumstances.

BackgroundMechanical ventilation is one of the numerous processes that a critically ill patient requiring single or multi organ support may experience. This is often frightening and perplexing for the patient, particularly when mechanically ventilated. The abundance of interventions, monitoring and unfamiliar noises can precipitate feelings of stress and anxiety which is common within this population of patients leading to prolonged hospital stay and increases in mortality and morbidity.

MethodsA rapid realist review (Abrahamson et al. 2020) was undertaken applying the realist methodology to a search of the literature using CINHAL, MEDLINE and Cochrane library, PsycIFNO, PubMed and EMBASE along with searching for the grey literature using an experience library technician, Google Scholar, Google, OpenGrey and the British Library ETHOS.

ResultsTwenty-one studies were included in the review. From the heterogeneity amongst the literature and the poor quality of evidence it was ascertained what worked for whom and under what circumstances. No negative outcomes for patients were noted in the review thus suggesting that music may have a place within critical care to help reduce anxiety. Given the heterogeneity of the evidence there is scope to review this topic further.

ConclusionThe overarching conclusion was that music could help reduce anxiety in the critically ill mechanically ventilated patient. Thematic analysis helped identify what quantifies the markers of anxiety; furthermore, it noted alternative themes that could be explored through more research. Theories could be developed and implemented into a protocol for practice; however, it would be based on the researchers own experience due to the poor-quality heterogeneous evidence.

category: nursing


title: Long-term Services and Supports, Cognitive Impairment, and Disease Management among Older Chinese Adults

abstract: Rapid population aging elevates burden of chronic and non-communicable diseases among older adults. Despite the critical role of self-management in disease prevention and control, effective management of diseases can be cognitively demanding and may require additional supports from family, friends and social services. Using nationally representative data from China, this paper documents the gradient relationship between cognitive impairment and disease management, and characterizes the differential effects of long-term care services and supports (LTSS) on disease management among older adults in different stages of cognitive impairment. In specific, we examine preventive care use and the management of hypertension, a highly prevalent but inadequately addressed chronic disease in China. We find that a severer stage of cognitive impairment is associated with poorer performance in disease prevention, hypertension awareness and management. While some of the LTSS offered by spouse, friends or community significantly facilitate active disease management behaviors, the effects are only evident among older adults with no cognitive impairment. By contrast, we find no significant effect of LTSS among cognitively impaired individuals. These findings reveal the vulnerability of older adults with cognitive impairment in disease management, and point to the importance of promoting targeted interventions to reduce barriers of receiving and utilizing LTSS, especially among cognitively impaired population.

category: health policy


title: Clinical Trial Data Sharing: A Cross-Sectional Study of Outcomes Associated with Two NIH Models

abstract:
BackgroundThe impact and value of clinical trial data sharing, including the number and quality of publications that result from shared data - "shared data publications" - may differ depending on the data sharing model used.

MethodsWe characterized the outcomes associated with two data sharing models previously used by Institutes of the U.S. National Institutes of Health (NIH): NHLBIs centralized model, which uses a repository to manage data sharing requests, and NCIs decentralized model, which entrusted research groups to independently manage data sharing requests. We identified trials completed in 2010 that met NIH data sharing criteria and matched studies sponsored by each Institute based on cost or size, determining whether trial data were shared and the frequency of shared data publications.

ResultsWe identified 14 NHLBI-funded trials and 48 NCI-funded trials that met NIH data sharing criteria. We matched 14 NCI-funded trials to the 14 NHLBI-funded trials; among these, 4 NHLBI-sponsored trials (29%) and 2 NCI-sponsored trials (14%) shared data. From the 2 NCI-sponsored trials sharing data, we identified 2 shared data publications, one per trial, both of which were meta-analyses. From the 4 NHLBI-sponsored trials sharing data, we identified 7 shared data publications, all using data from 1 trial, 5 of which were pooled analyses and 2 reported secondary outcomes.

ConclusionWhen characterizing the outcomes associated with two NIH data sharing models, both the NHLBI and the NCI models resulted in only 21% of trials sharing data and few shared data publications. There are opportunities to optimize clinical trial data sharing efforts both to enhance clinical trial data sharing and increase the number of shared data publications.


title: Successful Application of Wastewater-Based Epidemiology in Prediction and Monitoring of the Second Wave of COVID-19 in India with Fragmented Sewerage Systems- A Case Study of Jaipur (India)

abstract:
The present study tracked the city-wide dynamics of severe acute respiratory syndrome-corona virus 2 (SARS-CoV-2) RNA in the wastewater from nine different wastewater treatment plants (WWTPs) in Jaipur during second wave of COVID-19 out-break in India. A total of 164 samples were collected weekly between February 19th and June 8th, 2021. SARS-CoV-2 was detected in 47.2% (52/110) influent samples and 37% (20/54) effluent samples. The increasing percentage of positive influent samples correlated with the citys increasing active clinical cases during the second wave of COVID-19 in Jaipur. Furthermore, WBE based evidence clearly showed early detection of about 20 days (9/9 samples reported positive on April 20th, 2021) prior to the maximum cases & maximum deaths reported in the city on May 8th, 2021. The present study further observed the presence of SARS-CoV-2 RNA in treated effluents at the time window of maximum active cases in the city even after tertiary disinfection treatments of UV & Chlorine. The average genome concentration in the effluents and removal efficacy of six commonly used treatments; Activated Sludge Treatment + Chlorine disinfection (ASP + Cl2), Moving Bed Biofilm Reactor (MBBR) with Ultraviolet radiations disinfection (MBBR + UV), MBBR + Chlorine (Cl2), Sequencing Batch Reactor (SBR) and SBR + Cl2 were compared with removal efficacy of SBR + Cl2 (81.2%)> MBBR + UV (68.8%) > SBR (57.1%) > ASP (50%) > MBBR + Cl2(36.4%). The study observed the trends & prevalence of four genes (E, RdRp, N, and ORF1ab gene) based on two different kits and found that prevalence of N> ORF1ab >RdRp> E gene, suggested that the effective genome concentration should be calculated based on the presence/absence of multiple genes. Hence, it is imperative to say that using a combination of different detection genes (E, N, RdRp & ORF1ab genes) reduce false positives in WBE.

Graphical Abstract

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=131 SRC="FIGDIR/small/21263417v1_ufig1.gif" ALT="Figure 1">
View larger version (40K):
org.highwire.dtl.DTLVardef@156126corg.highwire.dtl.DTLVardef@1d39404org.highwire.dtl.DTLVardef@19a9dcdorg.highwire.dtl.DTLVardef@1ee3a0c_HPS_FORMAT_FIGEXP  M_FIG C_FIG HighlightsO_LISuccessful application of WBE with prediction of 14-20 days for COVID-19 in Jaipur
C_LIO_LIA comparison of SARS-CoV-2 RNA removal efficacy of 9 WWTPs was investigated
C_LIO_LISBR showed better performance than MBBR with SARS-CoV-2 RNA removal from wastewater
C_LIO_LIPresence of SARS-CoV-2 in effluents even after UV and Chlorine disinfection
C_LIO_LIUsing a combination of different detection genes reduce false positives in WBE
C_LI


title: Second wave of the Covid-19 pandemic in Delhi, India: high seroprevalence not a deterrent?

abstract:
BackgroundWe report the findings of a large follow-up community-based serosurvey and correlating it with the COVID-19 test-positivity rate and the case load observed during the peak of the second wave of the Covid-19 pandemic in Delhi, India.

MethodsIndividuals of age [≥]5 years were recruited from 274 wards of the state (population [~] 19.6 million) during January 11 to January 22 2021. A total of 100 participants each were included from all the wards for a net sample size of [~]28,000. A multi-stage sampling technique was applied for selection of participants for the household serosurvey. Anti SARS CoV-2 IgG antibodies were detected by using the VITROS assay (90% Sn, 100% Sp).

ResultsAntibody positivity was observed in 14,298 (50.76%) of the 28,169 samples. The age, sex and district population weighted seroprevalence of the IgG SARS-CoV-2 was 50.52% (95% C.I. 49.94-51.10) and after adjustment for assay characteristics was 56.13% (95% C.I. 55.49-56.77). On adjusted analysis, participants aged [≥]50 years, of female gender, housewives, having ever lived in containment zones, urban slum dwellers, and diabetes or hypertensive patients had significantly higher odds of SARS-CoV-2 antibody positivity.

The peak infection rate and the test positivity rate since October 2020 were initially observed in mid-November 2020 with a subsequent steep declining trend, followed by a period of persistently low case burden lasting until the first week of March 2021. This was followed by a steady increase followed by an exponential surge in infections from April 2021 onwards culminating in the second wave of the pandemic.

ConclusionsThe presence of infection induced immunity from SARS-CoV-2 even in more than one in two people can be ineffective in protecting the population.


title: The clinically extremely vulnerable to COVID: Identification and changes in health care while self-isolating (shielding) during the coronavirus pandemic

abstract:
BackgroundIn March 2020, the government of Scotland identified people deemed clinically extremely vulnerable to COVID due to their pre-existing health conditions. These people were advised to strictly self-isolate (shield) at the start of the pandemic, except for necessary healthcare. We examined who was identified as clinically extremely vulnerable, how their healthcare changed during isolation, and whether this process exacerbated healthcare inequalities.

MethodsWe linked those on the shielding register in NHS Grampian, a health authority in Scotland, to healthcare records from 2015-2020. We described the source of identification, demographics, and clinical history of the cohort. We measured changes in out-patient, in-patient, and emergency healthcare during isolation in the shielding population and compared to the general non-shielding population.

ResultsThe register included 16,092 people (3% of the population), clinically vulnerable primarily due to a respiratory disease, immunosuppression, or cancer. Among them, 42% were not identified by national healthcare record screening but added ad hoc, with these additions including more children and fewer economically-deprived.

During isolation, all forms of healthcare use decreased (25%-46%), with larger decreases in scheduled care than in emergency care. However, people shielding had better maintained scheduled care compared to the non-shielding general population: out-patient visits decreased 35% vs 49%; in-patient visits decreased 46% vs 81%. Notably, there was substantial variation in whose scheduled care was maintained during isolation: younger people and those with cancer had significantly higher visit rates, but there was no difference between sexes or socioeconomic levels.

ConclusionsHealthcare changed dramatically for the clinically extremely vulnerable population during the pandemic. The increased reliance on emergency care while isolating indicates that continuity of care for existing conditions was not optimal. However, compared to the general population, there was success in maintaining scheduled care, particularly in young people and those with cancer. We suggest that integrating demographic and primary care data would improve identification of the clinically vulnerable and could aid prioritising their care.


title: Multidimensional Data Integration Identifies Tumor Necrosis Factor Activation in Nephrotic Syndrome: A Model for Precision Nephrology

abstract:
BackgroundClassification of nephrotic syndrome relies on clinical presentation and descriptive patterns of injury on kidney biopsies. This approach does not reflect underlying disease biology, limiting the ability to predict progression or treatment response.

MethodsSystems biology approaches were used to categorize patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) based on kidney biopsy tissue transcriptomics across three cohorts and assessed association with clinical outcomes. Patient-level tissue pathway activation scores were generated using differential gene expression. Then, functional enrichment and non-invasive urine biomarker candidates were identified. Biomarkers were validated in kidney organoid models and single nucleus RNA-seq (snRNAseq) from kidney biopsies.

ResultsTranscriptome-based categorization identified three subgroups of patients with shared molecular signatures across independent North American, European and African cohorts. One subgroup demonstrated worse longterm outcomes (HR 5.2, p = 0.001) which persisted after adjusting for diagnosis and clinical measures (HR 3.8, p = 0.035) at time of biopsy. This subgroups molecular profile was largely (48%) driven by tissue necrosis factor (TNF) activation and could be predicted based on levels of TNF pathway urinary biomarkers TIMP-1 and MCP-1 and clinical features (correlation 0.63, p <0.001 for predicted vs observed score). Kidney organoids confirmed TNF-dependent increase in transcript and protein levels of these markers in kidney cells, as did snRNAseq from NEPTUNE biopsy samples.

ConclusionsMolecular profiling identified a patient subgroup within nephrotic syndrome with poor outcome and kidney TNF pathway activation. Clinical trials using non-invasive biomarkers of pathway activation to target therapies are currently being evaluated.

Significance StatementMechanistic, targeted therapies are urgently needed for patients with nephrotic syndrome. The inability to target an individuals specific disease mechanism using currently used diagnostic parameters leads to potential treatment failure and toxicity risk. Patients with focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) were grouped by kidney tissue transcriptional profiles and a subgroup associated with poor outcomes defined. The segregation of the poor outcome group was driven by tumor necrosis factor (TNF) pathway activation and could be identified by urine biomarkers, MCP1 and TIMP1. Based on these findings, clinical trials utilizing non-invasive biomarkers of pathway activation to target therapies, improve response rates and facilitate personalized treatment in nephrotic syndrome have been initiated.


title: Development of a novel startle response task in Duchenne muscular dystrophy

abstract:
Duchenne muscular dystrophy (DMD), an X-linked childhood-onset muscular dystrophy caused by loss of the protein dystrophin, can be associated with neurodevelopmental, emotional and behavioural problems. A DMD mouse model also displays a neuropsychiatric phenotype, including increased startle responses to threat which normalise when dystrophin is restored in the brain.

We hypothesised that startle responses may also be increased in humans with DMD, which would have potential translational therapeutic implications. To investigate this, we first designed a novel discrimination fear-conditioning task and tested it in six healthy volunteers, followed by male DMD (n=11) and Control (n=9) participants aged 7-12 years. The aims of this methodological task development study were to: i) confirm the task efficacy; ii) optimise data processing procedures; iii) determine the most appropriate outcome measures.

In the task, two neutral visual stimuli were presented: one  safe cue presented alone; one  threat cue paired with a threat stimulus (aversive noise) to enable conditioning of physiological startle responses (skin conductance response, SCR, and heart rate). Outcomes were the unconditioned physiological startle responses to the initial threat, and retention of conditioned responses in the absence of the threat stimulus.

We present the protocol development and optimisation of data processing methods based on empirical data. We found that the task was effective in producing significantly higher physiological startle SCR in reinforced  threat trials compared to  safe trials (P<.001). Different data extraction methods were compared and optimised, and the optimal sampling window was derived empirically. SCR amplitude was the most effective physiological outcome measure when compared to SCR area and change in heart rate, with the best profile on data processing, the least variance, successful conditioned response retention (P=.01) and reliability assessment in test-retest analysis (rho=.86). The definition of this novel outcome will allow us to study this response in a DMD population.


title: Media Exposure and the Social Determinants of Health Insurance Coverage in Ethiopia 2011 - 2016

abstract:
BackgroundIn a push for universal health coverage, Ethiopia introduced two insurance schemes in 2010. Yet coverage rates remain very low. To encourage greater adoption, policymakers require a better understanding of who chooses to enroll and which promotional efforts are most effective in encouraging enrollment.

ObjectiveUsing nationally representative Demographic and Health Surveys, this research assessed the social determinants of health insurance coverage, including media exposure, in Ethiopia from 2011-2016.

MethodsThis research analyzed health insurance coverage and other sociodemographic and media exposure variables using multivariable logistic regression model.

ResultsHealth insurance coverage increased 3.30 times from 1.48% in 2011 to 4.89% in 2016. In both years, coverage was associated with higher education, older age, higher wealth levels, and exposure to newspaper and television. Compared to those with no exposure to newspaper, those with newspaper exposure at least once a week were 1.80 times (2011) and 1.86 times (2016) more likely to be insured. Similar results were obtained for television exposure.

ConclusionInitiatives that target the poor and less educated will be necessary if Ethiopia is to achieve universal health coverage. This research suggests that, to date, newspaper and television mediums have been effective promotion mechanisms for growing enrollment.


title: Tobacco 21: Retailer Perceptions, Experiences, and Challenges Before and After a New Minimum Legal Sales Age Law in Maryland

abstract:
ObjectivesBy raising the legal age of sale from 18 to 21 years old, Tobacco 21 laws (T21) are reshaping the tobacco landscape in the United States. In 2019, Maryland became the 13th state to adopt T21. This study is among the first to examine the perception, awareness, and ease of compliance of T21 among tobacco retailers through a two-wave survey conducted pre-T21 and post-T21.

DesignSurveys were conducted among the states more than 6,000 registered retailers prior to the states T21 law going into effect and eight months later after T21 had been enacted. The pre-T21 and post-T21 survey instruments measured retailer awareness, support, and perceived ability to comply with T21, current tobacco practices, revenue from tobacco products, and challenges faced in compliance. 414 retailers completed the pre-T21 survey and 360 completed the post-T21 survey. The final survey data was weighted to reflect the geographic distributions of licensed tobacco retailers in Maryland.

ResultsThere was no significant difference in retailer awareness, support and challenges comparing pre and post T21. One notable caveat is lack of consumer knowledge about T21, resulting in retailers being responsible for educating customers.

ConclusionsThe evaluation of T21 and impact to retailers is a valuable tool in determining the laws success and barriers to implementation. Results support the idea that T21 laws have had a minor impact on how retailers conduct their business. As a result of the communication and materials provided by the state, retailers largely understand the law and how to adhere to guidelines.


title: Rehabilitation in Survivors of COVID-19 (RE2SCUE): a nonrandomized, controlled, and open protocol

abstract:
ObjectiveThis study aimed to evaluate the effects of physical rehabilitation for adults with sequelae after COVID-19.

MethodsThis clinical, nonrandomized, controlled, and open study will examine 82 participants who have met the inclusion criteria and who will be divided into treatment and control groups according to participant preference. The intervention group will receive face-to-face care; the control group will receive remote educational guidance for 8 weeks, with pre-post evaluations. The primary outcomes are dyspnea, fatigue, and exercise capacity; the secondary outcomes are lung function, heart rate variability, handgrip strength, knee extensor strength and electrical activity, physical activity, functional limitation, cognitive function, depression and anxiety, and biochemical measures of hypoxia, inflammation, oxidative stress, blood glucose, and lactate blood tests. The survey will follow the Standard Protocol Items for Randomized Trials guidelines, and the results will be reported according to the Consolidated Standards of Reporting Trials guidelines. Effects will be assessed based on the intent-to-treat data collected. Analysis of covariance will be used for the initial and final evaluations, with a significance level of 5%.

Results and ConclusionsThe results will show the effectiveness of rehabilitation in adults with post-COVID-19 sequelae.

ImpactFatigue, dyspnea, cough, and muscle and joint pain are common sequelae of post-COVID-19 syndrome. Physical rehabilitation is one modality for treating these sequelae. This protocol can provide a treatment model for patients with post-COVID-19 sequelae.

category: rehabilitation medicine and physical therapy


title: Effects of polygenic risk for suicide attempt and risky behavior on brain structure in young people with familial risk of bipolar disorder

abstract:
AimsBipolar Disorder (BD) is associated with a 20-30 fold increased suicide risk compared to the general population. First-degree relatives of BD patients show inflated rates of psychopathology including suicidal behaviors. As reliable biomarkers of suicide attempts (SA) are lacking, we examined associations between suicide-related polygenic risk scores (PRS) - a quantitative index of genomic risk - and variability in brain structures implicated in SA.

MethodsParticipants (n=206; aged 12-30 years) were unrelated individuals of European ancestry and comprised three groups: 41 BD cases, 96 BD relatives ( high-risk), and 69 controls. Genotyping employed PsychArray, followed by imputation. Three PRS were computed using genome-wide association data for SA in BD (SA-in-BD), SA in Major Depressive Disorder (SA-in-MDD) [Mullins et al., 2019], and risky behavior [Karlsson Linner et al., 2019]. Structural MRI processing employed FreeSurfer v5.3.0. General linear models were constructed using 32 regions-of-interest identified from suicide neuroimaging literature, with false-discovery-rate correction.

ResultsSA-in-MDD and SA-in-BD PRS negatively predicted parahippocampal thickness, with the latter association modified by group membership. SA-in-BD and Risky Behavior PRS inversely predicted rostral and caudal anterior cingulate structure, respectively, with the latter effect driven by the  high-risk group. SA-in-MDD and SA-in-BD PRS positively predicted cuneus structure, irrespective of group.

ConclusionsThis study demonstrated associations between PRS for suicide-related phenotypes and structural variability in brain regions implicated in SA. Future exploration of extended PRS, in conjunction with a range of biological, phenotypic, environmental and experiential data in high-risk populations, may inform predictive models for suicidal behaviors.


title: Safety and immunopotency of an adenovirus-vectored tuberculosis vaccine delivered via inhaled aerosol to healthy humans: a dose and route comparison phase 1b study

abstract:
BackgroundAdenoviral (Ad)-vectored vaccines are typically administered via intramuscular injection to humans, but this route of delivery is unable to induce respiratory mucosal immunity which requires respiratory mucosal route of vaccination. However, inhaled aerosol delivery of Ad-vectored vaccines has remained poorly characterized and its ability to induce respiratory mucosal immunity in humans is still unknown. The goal of our study was to evaluate and compare the safety and immunogenicity of a human serotype 5 Ad-based tuberculosis (TB) vaccine (AdHu5Ag85A) delivered to healthy humans via inhaled aerosol or intramuscular injection.

MethodsIn this open-labeled phase 1b trial, 31 healthy adults between 18 and 55 years of age with a history of BCG vaccination were enrolled at McMaster University Medical Centre, Hamilton, Ontario, Canada. AdHu5Ag85A was administered by a single-dose aerosol using the Aeroneb(R) Solo Vibrating Mesh Nebulizer or by intramuscular (IM) injection; 11 in the low dose (LD, 1x106 PFU) aerosol group, 11 in the high dose (HD, 2x106 PFU) aerosol group and 9 in the IM (1x108 PFU) group. The primary outcome was safety of a single administration of vaccine delivered to the respiratory tract by aerosol or by IM injection. The vaccine-related local and systemic adverse events were collected from participants from a self-completed diary for 14 days after vaccination and at scheduled follow-up visits. Routine laboratory biochemical and haematological tests were measured at 2, 4 and 12 weeks after vaccination and lung function was measured at 2, 4, 8 and 12 weeks after vaccination. The secondary outcome was comparison of immunogenicity among the different routes and aerosol dose groups. Immunogenicity to aerosol or IM vaccination was measured both in the peripheral blood and bronchoalveolar lavage samples by Luminex, and cell surface and intracellular cytokine immunostaining. Anti-AdHu5 antibodies and neutralization titers were determined before and after vaccination using ELISA and bioassay, respectively. This trial is registered with ClinicalTrial.gov, NCT02337270.

ResultsThe aerosol droplets generated by Aeroneb(R) Solo Nebulizer were mostly <5.39{micro}m in size, suitable for efficient Ad-vectored vaccine deposition to major human airways. Both LD and HD of AdHu5Ag85A administered by aerosol inhalation and the intramuscular injection were safe and well-tolerated. Respiratory adverse events were infrequent, mild, transient and similar among groups. IM injection was associated with a mild local injection site reaction in two participants. Systemic adverse events were also infrequent, mild, transient and similar among all groups. There were no grade 3 or 4 adverse events reported nor any serious adverse events. Both aerosol doses, particularly LD, but not IM, vaccination markedly induced Ag85A-specific airway tissue-resident memory CD4 and CD8 T cells of polyfunctionality. While as expected, IM vaccination induced Ag85A-specific T cell responses in the blood, the LD aerosol vaccination also elicited such T cells in the blood. Furthermore, the LD aerosol vaccination induced persisting transcriptional changes in alveolar macrophages indicative of trained innate immunity.

InterpretationInhaled aerosol delivery of Ad-vectored vaccine is a safe, economical and superior way to elicit respiratory mucosal immunity. The results of this study encourage further development of aerosol vaccine strategies against not only TB but also other respiratory pathogens including COVID-19.

FundingThe Canadian Institutes for Health Research and the Natural Sciences and Engineering Research Council of Canada.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed for published research articles without language or date restrictions by using search terms "adenovirus", "aerosol" and "clinical trial" or "virus", "vaccine", "aerosol", and "clinical trial". Our search results indicate that adenoviral-vectored vaccine has rarely been delivered via inhaled aerosol into the respiratory tract of healthy humans. Adenoviral-vectored TB or HIV vaccine was delivered via inhaled aerosol to non-human primates, providing support for its further development for human application. An aerosolized adenoviral vector expressing CFTR was tested as a gene replacement therapeutic in cystic fibrosis patients. Recently, although an adenoviral-vectored COVID-19 vaccine was delivered via aerosol to humans, there were no evidence presented that it induced local mucosal immunity. Given the increased recognition of its value, inhaled aerosol has been explored in humans with non-adenoviral, viral vaccines against respiratory infections of global importance including measles and TB. However, since different aerosol technologies were used in these studies and aerosol characteristics including delivery efficiency vary according to the viral platform, aerosol delivery technology and its efficiency in inducing respiratory mucosal immunity remain to be established for administering adenoviral-vectored vaccine to healthy humans.

Added value of this studyThis represents the first study to demonstrate the characteristics of a single-dose aerosolized human serotype 5 adenoviral-vectored vaccine, and its safety and immunogenicity in BCG-vaccinated healthy humans. It is also the first to show the superiority of inhaled aerosol immunization with this type of vaccine platform, over intramuscular (IM) route of immunization, in inducing respiratory mucosal immunity. Robust adaptive immune memory responses were induced in the respiratory tract with an aerosol vaccine dose up to 100 times smaller than the dose for IM immunization. Besides local mucosal immunity induced by aerosol immunization, it also induces levels of systemic immunity comparable to those by IM immunization. Also for the first time, we show that contrast to IM immunization, aerosol immunization does not increase either local or systemic anti-adenoviral neutralizing antibodies.

Implications of all the available evidenceCollectively our findings show the technical feasibility, safety and potency of needle/pain-free delivery of a recombinant adenoviral-vectored vaccine to the respiratory tract of healthy adults. This vaccine strategy differs from parenteral route of immunization in its potency to elicit much desired respiratory mucosal immunity consisting of trained macrophages and tissue-resident memory T cells. The study provides the proof of concept to endorse inhaled aerosol vaccine strategies against pulmonary TB. Of further importance, as a number of currently authorized COVID-19 vaccines are also adenoviral-vectored, our study offers important technological details and scientific rationale for the development of inhalable next-generation COVID-19 vaccines aiming to induce all-around protective respiratory mucosal immunity in humans.


title: Iron related biomarkers predict disease severity in a cohort of Portuguese adult patients during COVID-19 acute infection

abstract:
BACKGROUNDGrowing evidence indicates a link between iron metabolism and COVID-19 clinical progression, supporting the use of iron and inflammatory parameters as relevant biomarkers to predict patients outcomes.

METHODSWe evaluated iron metabolism and immune response in 303 patients admitted to the main hospital of the northern region of Portugal with variable clinical pictures, from September to November 2020. Of these, 127 tested positive for SARS-CoV-2 and 176 tested negative. Iron-related laboratory parameters and cytokines were determined in blood samples collected soon after admission and, in a subgroup of patients, throughout hospitalization. Demographic data, comorbidities and clinical outcomes were recorded. Patients were assigned into 5 groups according to disease severity.

RESULTSSerum iron and transferrin levels at admission were lower in COVID-19-positive than in COVID-19-negative patients. Conversely, the levels of interleukin(IL)-6 and monocyte chemoattractant protein 1 (MCP1) were increased in COVID-19-positive patients. The lowest serum iron and transferrin levels at diagnosis were associated with the worst outcomes. Iron levels negatively correlated with IL-6 and higher levels of this cytokine were associated with a worse prognosis. Serum ferritin levels at diagnosis were higher in COVID-19-positive than in COVID-19-negative patients but did not correlate with disease severity. Longitudinal determinations of iron and ferritin made in a subgroup of patients (n=23) revealed highly variable results.

CONCLUSIONSSerum iron is the simplest laboratory test to be implemented as a predictor of disease progression in hospitalized acute COVID-19-positive patients. Variation of ferritin with time should be revisited in larger cohorts.

Key pointsCOVID-19-positive patients have lower serum iron and higher ferritin than COVID-19-negative patients in variable clinical contexts. Lowest serum iron and highest IL-6 levels at hospital admission associate with the poorest outcomes. Association of serum ferritin with disease progression is debatable.


title: Deep Learning-based Prediction of Early Cerebrovascular Events after Transcatheter Aortic Valve Replacement

abstract:
BackgroundCerebrovascular events (CVE) are one of the most feared complications of transcatheter aortic valve replacement (TAVR). CVE appear difficult to predict due to their multifactorial origin incompletely explained by clinical predictors. We aimed to build a deep learning-based predictive tool for TAVR-related CVE.

MethodsIntegrated clinical and imaging characteristics from consecutive patients enrolled into a prospective TAVR registry were analysed. CVE comprised any strokes and transient ischemic attacks. Predictive variables were selected by recursive feature reduction to train an autoencoder predictive model. Area under the curve (AUC) represented the models performance to predict 30-day CVE.

ResultsAmong 2,279 patients included between 2007 and 2019, both clinical and imaging data were available in 1,492 patients. Median age was 83 years and STS score was 4.6%. Acute (<24 hours) and subacute (day 2-30) CVE occurred in 19 (1.3%) and 36 (2.4%) patients, respectively. The occurrence of CVE was associated with an increased risk of death (HR [95%CI]: 2.62 [1.82-3.78]). The constructed predictive model uses less than 107 clinical and imaging variables and has an AUC of 0.79 (0.65-0.93).

ConclusionsTAVR-related CVE can be estimated using a deep learning-based predictive algorithm. The model was implemented online for broad usage. (https://www.welcome.alviss.ai/#/cvecalculator).

category: cardiovascular medicine