title: The impact of the COVID-19 pandemic on diagnoses of common mental health disorders in adults in Catalonia, Spain

abstract:
ObjectivesTo investigate how incidence trends of anxiety and depressive disorders have been affected by the COVID-19 pandemic.

DesignPopulation-based cohort study.

SettingObservational cohort study from 2018 to 2021 using the Information System for Research in Primary Care (SIDIAP) database in Catalonia, Spain.

Participants4,255,847 individuals aged 18 or older in SIDIAP on 1 March, 2018 with no prior history of anxiety and depressive disorders.

Primary and secondary outcomes measuresIncidence of anxiety and depressive disorders prior to COVID-19 (March, 2018 to February, 2020), during the COVID-19 lockdown (March to June, 2020) and post-lockdown periods (from July, 2020 to March, 2021) were calculated. Forecasted rates over COVID-19 periods were estimated using negative binomial regression models based on previous data. The percentage reduction was estimated by comparing forecasted versus observed events, overall and by age, sex and socioeconomic status.

ResultsThe incidence rates per 100,000 person-months of anxiety and depressive disorders were 171.0 (95%CI: 170.2-171.8) and 46.6 (46.2-47.0), respectively, during the pre-lockdown period. We observed an increase of 39.7% (95%PI: 26.5 to 53.3) in incident anxiety diagnoses compared to the expected in March, 2020, followed by a reduction of 16.9% (8.6 to 24.5) during the post-lockdown periods. A reduction of incident depressive disorders occurred during the lockdown and post-lockdown periods (46.6% [38.9 to 53.1] and 23.2% [12.0 to 32.7], respectively). Reductions were higher among adults aged 18 to 34 and individuals living in most deprived areas.

ConclusionsThe COVID-19 pandemic in Catalonia was associated with an initial increase in anxiety disorders diagnosed in primary care, but a reduction in cases as the pandemic continued. Diagnoses of depressive disorders were lower than expected throughout the pandemic.

Summary boxO_ST_ABSWhat is already known on this topicC_ST_ABS- While previous self-reported studies have provided evidence of increased mental health burden during the initial phase of the COVID-19 pandemic, a number of studies observed that fewer diagnoses were made in primary care settings than would have been expected during the initial stages of the pandemic.
- Population data that examine the impact of COVID-19 on temporal trends of incident cases of common mental health disorders are lacking in Catalonia, Spain.

What this study adds- This study has quantified the impact of the COVID-19 pandemic on trends of incidence of anxiety and depressive disorders among adults living in Catalonia.
- Reductions in incident cases of anxiety and depressive disorders were higher for young adults and people living in most deprived areas.
- Incident diagnoses of anxiety and depressive disorders have not been fully recovered to what would have been expected.


title: INTERNATIONAL PREVALENCE OF CONSULTATION WITH A NATUROPATHIC PRACTITIONER: A SYSTEMATIC REVIEW AND META-ANALYSIS

abstract:
AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSObjectivesC_ST_ABSNaturopathy is a traditional medicine system informed by codified philosophies and principles, and an emphasis on non-pharmacologic therapeutic interventions. While naturopathy is practiced by approximately 75 000 to 100 000 naturopathic practitioners in at least 98 countries, little is known about the international prevalence of history of consultation with a naturopathic practitioner. This study reports a systematic review and meta-analysis of studies describing the global prevalence of history of consultation with a naturopathic practitioner by the general population.

SettingThe included literature was identified through a systematic search of eight databases between September and October 2019, as well as the grey literature.

ParticipantsStudies were included if they reported the prevalence rate of consultations with a naturopathic practitioner by the general population

InterventionsSurvey items needed to report consultations with a naturopathic practitioner as defined in the country where data was collected, and not combine naturopathic consultations with other health services or only report consulations for illness populations.

Primary and secondary outcome measuresPrimary measures used for the analysis was consultations in the previous 12-months. Other prevalence timeframes were reported as secondary measures.

MethodsMeta-analysis of prevalence data was conducted using random effects models based on individual countries and World Health Organisation (WHO) world regions.

ResultsThe literature search identified eight manuscripts summarizing 13 studies reporting prevalence for inclusion in the review. All included studies had a low risk of bias. Meta-analysis of the included studies by world region found the 12-month prevalence of history of naturopathy consultations ranged from 1% in the Region of the Americas to 6% in the European and Western Pacific Regions.

ConclusionsThere are up to 6-fold differences in the prevalence of naturopathy consults over 12-months between and within world regions, which may be driven by a range of policy, legislative and social factors.

SO_SCPLOWTRENGTHSC_SCPLOWO_SCPCAP C_SCPCAPO_SCPLOWANDC_SCPLOW LO_SCPLOWIMITATIONSC_SCPLOWO_SCPCAP C_SCPCAPO_SCPLOWOFC_SCPLOWO_SCPCAP C_SCPCAPO_SCPLOWTHISC_SCPLOWO_SCPCAP C_SCPCAPO_SCPLOWSTUDYC_SCPLOWO_LINaturopathy is one of the most commonly used traditional and complementary medicines in the Western world and this is the first systematic review and meta-analysis reporting the prevalence of consutations with a naturopathic practitioner.
C_LIO_LIThis study includes only includes data published after 2010 to ensure the results are contemporary, however this may have excluded some studies in countries with older data.
C_LIO_LIThe results are limited by the poor availability of data reporting consultations with a naturopathic practitioner, including in countries where a large number of naturopathic practitioners are known to provide care.
C_LI

category: public and global health


title: Assessing unused residual Pfizer-BioNTech Covid-19 vaccine: a community observational study

abstract:
Worldwide morbidity and mortality associated with Covid-19 are severe and ongoing. The Pfizer-BioNTech vaccine is said to be up to 95% effective against severe disease or death. We were able to demonstrate that an additional 9.8% of COVID-19 vaccine doses could theoretically be given if the residual vaccine within the reconstituted Pfizer vials after six doses are extracted were used. This could be achieved by aseptically combining this excess vaccine from multiple vials to achieve full 0.3ml doses.

MethodsAn observational study was conducted in April, 2021, at a mass vaccine site run by a community volunteer organization on Bainbridge Island, Washington. We measured the amount of Pfizer-BioNTech COVID-19 vaccine that was left in 172 vials after six doses had been withdrawn per Centers for Disease Control (CDC) protocol.

ResultsA total of 30.68 ml of leftover vaccine was measured and discarded as medical waste. 1,036 doses were given from these vials. An extra 102 doses theoretically could have been given using the residual vaccine in the vials. This would have resulted in 9.8% additional doses of COVID-19 vaccine without requiring new vials.

ConclusionThe ability to combine solution from reconstituted Pfizer vaccine vials to minimize waste and obtain additional doses of vaccine could result in an increase in the number of individuals that could be vaccinated worldwide without additional cost. Further studies to validate our findings are warranted. Clinical trials to study the feasibility, safety and efficacy of protocols using this excess vaccine should be considered.

category: infectious diseases


title: Durability and Cross-Reactivity of Immune Responses Induced by an AS03 Adjuvanted Plant-Based Recombinant Virus-Like Particle Vaccine for COVID-19

abstract: As the SARS-COV-2 pandemic evolves, what is expected of vaccines extends beyond efficacy and includes evaluations of both durability and cross-reactivity to emerging variants. To complement an on-going Phase 3 efficacy study, this report expands on previously reported immunogenicity results from a Phase 1 trial of an AS03-adjuvanted, plant-based virus-like particle (VLP) displaying the spike glycoprotein of the Wuhan strain of SARS-CoV-2 virus (NCT04450004). Durability of the humoral and cellular responses against the ancestral strain was evaluated 6 months post-second dose (Day 201) at which time [~]94% of vaccinated individuals remained seropositive. Interferon gamma (IFN-{gamma}) and interleukin 4 (IL-4) responses remained detectable in [~]94% and [~]92% of vaccinated individuals respectively. Cross-reactivity of neutralizing antibodies to Alpha (B.1.17), Beta (B.1.351), and Gamma (P.1) variants of concern (VOC) were also measured. Twenty-one days after the second vaccination, detectable neutralizing antibodies were observed to the Alpha variant by both pseudovirion and wild-type assays for all vaccinated individuals, while 94.7% of individuals had detectable antibodies to the Beta variant in both assays. Neutralizing antibodies to the Gamma variant were detected in 100% and 94.7% of individuals using the pseudovirion and live virus neutralization assays, respectively. In all cases, the vaccine-induced neutralizing GMTs to the VOC 3 weeks post-vaccination were greater than the Wuhan-specific neutralization titers seen in individuals recovered from COVID-19.


title: INDI - Integrated Nanobody Database for Immunoinformatics

abstract: Nanobodies, a subclass of antibodies found in camelids, are a versatile molecular binding scaffold composed of a single polypeptide chain. The small size of nanobodies bestows multiple therapeutic advantages (stability, tumor penetration) with the first therapeutic approval in 2018 cementing the clinical viability of this format. Structured data and sequence information of nanobodies will enable the accelerated clinical development of nanobody-based therapeutics. Though the nanobody sequence and structure data are deposited in the public domain at an accelerating pace, the heterogeneity of sources and lack of standardization hampers reliable harvesting of nanobody information. We address this issue by creating the Integrated Database of Nanobodies for Immunoinformatics (INDI, http://research.naturalantibody.com/nanobodies). INDI collates nanobodies from all the major public outlets of biological sequences: patents, GenBank, next-generation sequencing repositories, structures and scientific publications. We equip INDI with powerful nanobody-specific sequence and text search facilitating access to more than 11 million nanobody sequences. INDI should facilitate development of novel nanobody-specific computational protocols helping to deliver on the therapeutic promise of this drug format.

category: allergy and immunology


title: Analysis of Whole Genome Sequencing in a Cohort of Individuals with PHACE Syndrome Suggests Dysregulation of RAS/PI3K Signaling

abstract: The acronym PHACE stands for the co-occurrence of posterior brain fossa malformations, hemangiomas, arterial anomalies, cardiac defects, and eye abnormalities. The majority of patients have a segmental hemangioma and at least one developmental structural anomaly. The etiology and pathogenesis are unknown. Here we discuss the candidate causative genes identified in a de novo analysis of whole genome sequencing of germline samples from 98 unrelated trios in which the probands had PHACE, all sequenced as part of the Gabriella Miller Kids First Pediatric Research Program. A g:Profiler pathway analysis of the genes with rare, de novo variants suggested dysregulation of the RAS/MAPK and PI3K/AKT pathways that regulate cell growth, migration, and angiogenesis. These findings, along with the developmental anomalies and the vascular birthmark, support including PHACE within the RASopathy family of syndromes.

category: cardiovascular medicine


title: COVID-19 Outcomes Among Users of CD20 Inhibitors for Immune-Mediated Diseases: A Comparative Cohort Study

abstract:
ObjectivePatients with immune-mediated diseases treated with CD20 inhibitors may have worse COVID-19 outcomes due to impaired humoral immunity, but differences versus the general population are unknown.

MethodsWe identified patients with immune-mediated diseases who received CD20 inhibitors within one year prior to the index date of PCR-confirmed COVID-19 between January 31, 2020, and January 31, 2021. Comparators with COVID-19 were matched up to 5:1 by age, sex, and PCR date. Hazard ratios (HRs) and 95% confidence intervals (CIs) for hospitalization, mechanical ventilation, and death in CD20 inhibitor users versus comparators were estimated using Cox regression.

ResultsWe identified 114 cases with COVID-19 who had received CD20 inhibitors for immune-mediated diseases (mean age 55 years, 70% female) and 559 matched comparators with COVID-19 (mean age 54 years, 70% female). CD20 inhibitor-treated cases had higher mortality (aHR 2.16; 95% CI: 1.03 to 4.54) than matched comparators. Risks of hospitalization (aHR 0.88; 95% CI: 0.62 to 1.26) and mechanical ventilation (aHR 0.82; 95% CI: 0.36 to 1.87) were similar. Similar trends were seen in analyses according to type of indication (e.g., rheumatic or neurologic disease) and duration of CD20 inhibitor use (<1 or [≥]1 year), and after excluding patients with interstitial lung disease, cancer, and those on glucocorticoids prior to COVID-19 diagnosis.

ConclusionsPatients who received CD20 inhibitors for immune-mediated diseases prior to COVID-19 had higher mortality following COVID-19 than matched comparators, highlighting the urgent need to mitigate excess risks in CD20 inhibitor users during the ongoing pandemic.

Key MessagesO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIPatients with immune-mediated diseases treated with CD20 inhibitors may have worse COVID-19 outcomes than those treated with other immunomodulatory medications, but differences compared to the general population are unknown.
C_LI

What does this study add?O_LICD20 inhibitor-treated cases had over two-fold higher risk of mortality than matched general population comparators, although risks of hospitalization and mechanical ventilation were similar.
C_LI

How might this impact on clinical practice or future developments?O_LIThere is an urgent need for risk mitigation strategies, such as SARS-CoV-2 monoclonal antibodies or booster vaccinations, for patients with immune-mediated diseases treated with CD20 inhibitors during the ongoing COVID-19 pandemic.
C_LI

category: rheumatology


title: Rapid Lifestyle Prototyping: Assessment of Infrared Spectroscopic Blood Responses for Short-term Lifestyle Interventions

abstract:
BackgroundAt the present time, optimization of dietary and fitness practices are inadequately addressed in the clinical setting, and poorly documented through research studies investigating response to surrogate disease markers. Identifying and quantifying the personal response to lifestyle interventions requires a new tool and a new measurement metric.

MethodsIn this prospective observational study, COR.RELATE study, we investigated the effect of four lifestyle interventions, each spanning 21 days and consisting of seven validated practices, in a healthy population. We used a novel at-home near-infrared spectrometer (wavelength 1600-2450 nm), COR console, to measure the spectral blood changes in a cohort of 178 healthy males and females who participated in four 21-day cycles of lifestyle programs. In the first round, study participants also completed dried blood spot cards, provided by omega quant, at the start and end of their program.

ResultsWe analyzed 1,870 infrared spectroscopy samples from 178 participants (131 males and 47 females) who participated in the first four programs of COR.RELATE. We found on average 79.75% of the participants are responsive to one or more of the COR programs. We describe an algorithmic approach, ranking personal responses to different nutrition and fitness interventions.

ConclusionThe COR console and data analytics enables the use of a novel near-infrared based metric--which we call the COR Blood Response Pattern (BRP)--to measure individual response to lifestyle change, and has the sensitivity to discern, classify, and rank the success of rapid lifestyle interventions in terms of the correlated spectroscopic response they produce. Rapid Lifestyle Prototyping is a new concept in consumer life optimization and improvement - the ability to know in no more than 21 days whether a particular single, or set of, lifestyle practices is going to evoke a strong response for an individual and therefore if it is worth continuing that practice in their quest for deep optimization and life improvement.

category: nutrition


title: Defective X-gating caused by de novo gain-of-function mutations in KCNK3 underlies a developmental disorder with sleep apnea

abstract: Sleep apnea is a common disorder that represents a global public health burden. KCNK3 encodes TASK-1, a K+ channel implicated in the control of breathing, but its link with sleep apnea remains poorly understood. Here we describe a novel developmental disorder with sleep apnea caused by rare de novo gain-of-function mutations in KCNK3. The mutations cluster around the  X-gate, a gating motif which controls channel opening, and produce overactive channels that no longer respond to inhibition by G-protein coupled receptor pathways, but which can be inhibited by several clinically relevant drugs. These findings demonstrate a clear role for TASK-1 in sleep apnea and identify possible therapeutic strategies.

category: genetic and genomic medicine


title: Metabolomic signatures of lipid-modifying therapies using drug target Mendelian randomization

abstract:
BackgroundLarge-scale molecular profiling and genotyping provide a unique opportunity to systematically compare the genetically predicted effects of therapeutic targets on the human metabolome.

MethodsWe firstly constructed genetic risk scores for 8 drug targets on the basis that they primarily modify low-density lipoprotein (LDL) cholesterol (HMGCR, PCKS9 & NPC1L1), high-density lipoprotein (HDL) cholesterol (CETP), or triglycerides (APOC3, ANGPTL3, ANGPTL4 & LPL). We then used Mendelian randomization to evaluate the effect of each score on coronary artery disease (CAD) risk, and to systematically estimate their effects on 249 metabolic traits derived using blood samples from an unprecedented sample size of up to 115,082 UK Biobank participants.

ResultsThere was strong evidence of an effect of drug-based genetic scores on CAD risk with the exception of ANGPTL3. Genetically predicted effects on the blood metabolome were generally consistent amongst drug targets which were intended to modify the same lipoprotein lipid trait. For example, the linear fit for the MR estimates on all 249 metabolic traits for genetically-predicted inhibition of LDL cholesterol lowering targets HMGCR and PCSK9 was r2=0.91. In contrast, comparisons between drug classes that were designed to modify discrete lipoprotein traits typically had very different effects on metabolic signatures (e.g. HMGCR vs all 4 triglyceride targets had r2<0.02), despite largely consistent effects on risk of CAD. Furthermore, we highlight this discrepancy for specific metabolic traits, for example finding that LDL cholesterol lowering therapies typically had a weak effect on glycoprotein acetyls, a marker of inflammation (e.g. PCSK9: Beta=0.01, 95 CI%=-0.06 to 0.08, P=0.78). In contrast, all of the triglyceride modifying therapies assessed provided evidence of a strong effect on lowering levels of this inflammatory biomarker (e.g. LPL: Beta=-0.43, 95 CI%=-0.37 to -0.48, P=9x10-50).

ConclusionsMultiple lipid-modifying drug targets have therapeutically beneficial effects on CAD risk. Our findings indicate that genetically predicted perturbations of these drug targets on the blood metabolome can drastically differ, with potential implications for biomarkers in clinical development and measuring treatment response.


title: Safety and Immunogenicity of Inactivated SARS-CoV-2 Vaccine in High-Risk Occupational Population: a randomized, parallel, controlled clinical trial

abstract: Vaccination is urgently needed to prevent the global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we conducted a randomized, parallel, controlled clinical trial for assessment of the immunogenicity and safety of an inactivated SARS-CoV-2 vaccine, aiming to determine an appropriate vaccination interval for high-risk occupational population. Participants were randomly assigned to receive two doses of inactivated SARS-CoV-2 vaccine (4 {micro}g per dose) at an interval of either 14 days, 21 days or 28 days. The primary immunogenicity endpoints were neutralization antibody seroconversion and geometric mean titer (GMT) at 28 days after the second dose. Our results showed that the seroconversion rates (GMT [≥] 16) were all 100% in the three groups and the 0-21 and 0-28 groups elicited significantly higher SARS-CoV-2 neutralizing antibody level. All reported adverse reactions were mild. (Chinese Clinical Trial Registry: ChiCTR2100041705, ChiCTR2100041706)


title: Modeling spatiotemporal Aedes aegypti risk in French Guiana using meteorological and remote sensing data

abstract: Although the development of vaccines for the prevention of arboviral diseases has been a priority in recent years, prevention strategies continue to depend on vector control. Risk maps at scales appropriate for these strategies can provide valuable information to assess entomological risk levels and guide actions. We used a spatio-temporal modeling approach to predict, at the local scale, the risk of homes potentially harboring Aedes aegypti larvae. The model used integrated larvae risk data collected in the field from September 2011 to February 2013, environmental data obtained from very high spatial resolution Pleiades imagery, and daily meteorological data, collected in the city of Matoury in French Guiana. Various environmental and meteorological conditions were identified as risk or protective factors for the presence of immature stages of Aedes aegypti in homes on a given date and used to produce dynamic maps with high spatial and temporal resolution. Aedes vector risk was modeled between 50 and 200 m, around houses, on a time scale of 3 to 5 days. The resulting model was extrapolated to other municipalities with the same characteristics of urbanization during the 2019-2020 dengue epidemic in French Guiana. This work represents a major opportunity to monitor the evolution of vector risk and constitutes information that could be particularly useful for public health authorities in charge of vector control.

category: epidemiology


title: Internet Use impact on Physical Health during COVID-19 pandemic in Bangladesh: A Web-based Cross-sectional study

abstract:
BackgroundBangladesh ranked fifth largest internet user in Asia. Past studies on internet use have focused on its impact on mental health, with little known about its impact on the physical health of individuals during COVID-19 pandemic. Hence, this study examines the impact of Internet use frequency on physical health during the Covid-19 lockdown in Bangladesh.

MethodsA web-based cross-sectional study on 3242 individuals aged 18 and above was conducted from 2nd August - 1st October 1, 2020, during the lockdown in Bangladesh. The survey covers demographics, Internet use frequency and physical health questions. Multiple linear regression analyses were used to examine the impact of internet use frequency on physical health.

ResultsThe result indicated that 72.5%, 69.9%, 65.1% and 55.3% reported headache, back pain, numbness of the fingers and neck pain, respectively. The multivariable analyses showed increased physical health impact among regular (coefficient {beta} =0.52, 95% confidence interval [CI]: 0.18-0.85, P=0.003), frequent ({beta} = 1.21, 95%CI: 0.88-1.54, P < .001) and intense ({beta} = 2.24, 95%CI: 1.91-2.57, P < .001) internet users. Other factors associated with physical health scores were gender, income (in Taka), occupation, regions, and working status.

ConclusionFrequent, intensive, and extensive use of the internet were strong predictors of increased physical health problems, and the study suggests the need for raising awareness of physical health problems triggered by high internet users among the high socioeconomic group in Bangladesh.


title: Impact of a National Immunisation Program on herpes zoster incidence in Australia

abstract:
ObjectivesTo evaluate the impact of the National Herpes Zoster (zoster) Immunisation Program in Australia on zoster incidence.

MethodsEcological analysis of zoster incidence related to timing of implementation of the national program in vaccine-targeted (70-79 years) and non-targeted age groups (60-69 and 80-89 years) during January 2013-December 2018 was estimated using interrupted time-series analyses.

ResultsPrior to program commencement (Jan 2013 to Oct 2016) in patients aged 60-69, 70-79 and 80-89 years, incidence was mostly stable averaging respectively 7.2, 9.6 and 10.8 per 1000 person-years. In the two years following program commencement, incidence fell steadily in those aged 70-79 years, with an estimated decrease of 2.25 (95% CI: 1.34, 3.17) per 1000 person-years per year, with women having a greater decrease than men (2.83 versus 1.68, p-interaction<0.01). In the two non-vaccine-program-targeted age groups there was no evidence of reduction in zoster incidence: 60-69 years, 0.46 (95% CI: -0.46, 1.38) and 80-89 years, 0.11 (95% CI: -1.64, 1.87).

ConclusionsTwo years after implementation, an estimated 7000 zoster cases were prevented through the national program. With known waning vaccine efficacy, continued surveillance is needed to ensure these early reductions in incidence are sustained.


title: Investigating heterogeneous genetic effects contributing to smoking behaviors

abstract:
The genetic architecture of numerous smoking behaviors is highly polygenic, but these genetic effects are heterogeneous and depend on moderating factors. Here, we used common SNPs from the UK Biobank to investigate heterogeneous genetic effects for smoking heaviness using cigarettes per day (CPD) records, smoking initiation (SI), and smoking cessation (SC). We assessed heterogeneous effects across levels of sex, age of smoking initiation, major depressive disorder (MDD) DSM-V-like diagnosis, generalized anxiety disorder (GAD) DSM-V-like diagnosis, and whether an individual has seen a psychiatrist for nerves, anxiety, tension, or depression. We observed suggestive evidence of heterogeneous genetic effects for CPD and SC, moderated by MDD and GAD, respectively [[Formula] (SE = 0.15) between MDD cases and controls, and [Formula] (SE = 0.28) between GAD cases and controls, p < 0.05]. We detected 5 SNPs with genome-wide significant evidence of heterogeneous effects moderated by either MDD or GAD (p-value < 5x10-8) for CPD and SC. We also observed strong evidence for heterogeneous genetic effects for SI between sexes (between-sex [Formula], SE = 0.02). While we detected no individual SNPs that were moderated by sex at genome-wide significance (all p-value > 5x10-8), we observed evidence of novel genome-wide significant SI-SNP associations using sex-stratified GWAS; six loci were discovered in either men or women separately that were not identified in a previous smoking meta-analysis that had a 6-fold larger, sex-combined sample. Furthermore, using several independent testing samples, there was suggestive evidence that the prediction ability of a polygenic risk score (PRS) for smoking initiation improved through the utilization of sex-specific SNP effects. This work suggests that a more nuanced approach to GWAS analyses is warranted, as potential heterogeneous effects can complicate variant discovery and polygenic risk score accuracy.

Author SummarySmoking imposes a heavy health burden and is highly polygenic in architecture. Consistent with most complex traits, many causal loci have yet to be identified, even when using the largest available samples. One possible reason for the difficulty in inferring genetic variants associated with such complex traits is that common genetic variants possess context-dependent (or heterogeneous) effects. Utilizing the UK Biobank, we find evidence for heterogeneous SNP effects on smoking initiation, heaviness, and cessation among psychiatric disorder cases and controls and between sexes. Failure to model such heterogeneity (when accounting for sample size) resulted in lower independent sample predictive ability. This work encourages a more nuanced approach to GWAS and polygenic risk prediction. The assumption that all genetic effects are homogeneous limits our understanding of complex traits when heterogeneous effects are present.


title: Immunogenicity of BNT162b2 vaccine Against the Alpha and Delta Variants in Immunocompromised Patients

abstract:
BackgroundThe emergence of strains of SARS-CoV-2 exhibiting increase viral fitness and immune escape potential, such as the Delta variant (B.1.617.2), raises concerns in immunocompromised patients. To what extent Delta evades vaccine-induced immunity in immunocompromised individuals with systemic inflammatory diseases remains unclear.

MethodsWe conducted a prospective study in patients with systemic inflammatory diseases (cases) and controls receiving two doses of BNT162b2. Primary end points were anti-spike antibodies levels and cross-neutralization of Alpha and Delta variants after BNT162b2 vaccine. Secondary end points were T-cell responses, breakthrough infections and safety.

ResultsSixty-four cases and 21 controls not previously infected with SARS-CoV-2 were analyzed. Kinetics of anti-spike IgG and IgA after BNT162b2 vaccine showed lower and delayed induction in cases, more pronounced with rituximab. Administration of two doses of BNT162b2 generated a neutralizing response against Alpha and Delta in 100% of controls, while sera from only one of rituximab-treated patients neutralized Alpha (5%) and none Delta. Other therapeutic regimens induced a partial neutralizing activity against Alpha, even lower against Delta. All controls and cases except those treated with methotrexate mounted a SARS-CoV-2 specific T-cell response. Methotrexate abrogated T-cell responses after one dose and dramatically impaired T-cell responses after 2 doses of BNT162b2.

ConclusionsRituximab and methotrexate differentially impact the immunogenicity of BNT162b2, by impairing B-cell and T-cell responses, respectively. Delta fully escapes the humoral response of individuals treated with rituximab. These findings support efforts to improve BNT162b2 immunogenicity in immunocompromised individuals (Funded by the Fonds IMMUNOV; ClinicalTrials.gov number, NCT04870411).


title: Anti-CD38 therapy impairs SARS-CoV-2 vaccine response in multiple myeloma patients

abstract: Multiple myeloma (MM) patients are at risk of fatal outcome after SARS-CoV-2 infection. Preliminary data suggest that MM patients have an impaired response to vaccination. This prospective study analyzed the humoral and cellular immune responses to two doses of BNT162b2 in 72 MM patients, including 48 receiving anti-CD38 immunotherapy. Results evidenced that MM patients display lower levels of SARS-CoV-2 specific IgG and IgA antibodies and decreased neutralization of alpha and delta variants when compared to healthy controls. They also showed decreased numbers of circulating IFN{gamma}-producing Spike SARS-CoV-2 specific T lymphocytes. This defective immune response was particularly marked in patients receiving anti-CD38 immunotherapy. Furthermore, a retrospective investigation of MM patients among COVID-19-related death in the Paris area suggested a limited efficacy of BNT162b2 in patients treated with anti-CD38. Overall, these results show a decreased immunogenicity of BNT162b2 in MM patients and stress the need for novel strategies to improve SARS-CoV-2 prophylaxis in immunocompromised individuals.


title: Speeding and Traffic-Related Injuries and Fatalities during the 2020 COVID-19 Pandemic: The Cases of Seattle and New York City

abstract: Despite fewer cars on roads during the COVID-19 pandemic, deaths associated with motor vehicle collisions in New York City and Seattle remained largely unchanged in 2020. Using police data on weekly counts of collisions, we compared trends in 2020 with those of 2019, while controlling for the reduction of traffic volumes and seasonal weather conditions. Results of difference-in-differences estimation suggest that during the early months of the pandemic, or March-May, the incidence rates of severe or fatal injury crashes related to speeding increased by nearly 8 times in Seattle and more than 4 times in New York City. In the rest of 2020, they were still significantly higher than what would be expected in the absence of the pandemic. This research suggests that in similar situations that depress travel demand (e.g., another pandemic), policymakers should formulate plans to reduce speeding which may prevent an upswing in severe injuries and fatalities.

category: emergency medicine


title: Time-analysis of COVID-19 dispersion among health care workers and the general population

abstract:
IntroductionHeath care workers with direct (HCW-D) or indirect (HCW-A) patient contact represent 4.2% to 17.8% of COVID-19 cases. We evaluate the temporal COVID-19 infection behavior among HCW-D, HCW-A, and non-HCW.

MethodsFrom February 2020 to April 2021, trained nurses recorded age, gender, occupation, and symptoms in a COVID-19 testing outpatient health center. We allocated data into weekly time fractals and calculated the proportion of COVID-19 positive among HCW vs. non-HCW and incorporated an ARFIMA model (traditionally used in weather forecast) to predict future cases of COVID-19.

ResultsAmong 8,998 COVID-19 RT-PCR tests, 3,462 (42%) patients were HCW-D, and 933 (11%) were HCW-A. Overall, 1,914 (21.3%) returned positive, representing 27%, 25% and 19% of HCW-D, HCW-A and non-HCW, respectively. HCW-D or HCW-A were significantly more likely to test positive for COVID-19 than non-HCW (OR=1.5, p<0.0001). The percentage of positive to negative test results remained steady over time. In the positive cases, the percentage of HCW to non-HCW declined significantly over time (Mann-Kendal trend test: tau=-0.58, p<0.0001). Our ARFIMA model showed a long-memory infection pattern in the occurrence of new COVID-19 cases lasting for months. Average error was 1.9 cases per week comparing predicted to actual values three months later (May-July 2021).

ConclusionHCW have a sustained 50% higher risk of COVID-19 positivity in the pandemic. Time-series analysis showed a long-memory infection pattern with virus spread mainly among HCWs before the general population. The tool http://wdchealth.covid-map.com/shiny/covid-map/ will be updated according to population previous infection and vaccination impact.


title: Limited genomic reconstruction of SARS-CoV-2 transmission history within local epidemiological clusters

abstract: A detailed understanding of how and when SARS-CoV-2 transmission occurs is crucial for designing effective prevention measures. Other than contact tracing, genome sequencing provides information to help infer who infected whom. However, the effectiveness of the genomic approach in this context depends on both (high enough) mutation and (low enough) transmission rates. Today, the level of resolution that we can obtain when describing SARS-CoV-2 outbreaks using just genomic information alone remains unclear. In order to answer this question, we sequenced 49 SARS-CoV-2 patient samples from ten local clusters for which partial epidemiological information was available, and inferred transmission history using genomic variants. Importantly, we obtained high-quality genomic data, sequencing each sample twice and using unique barcodes to exclude cross-sample contamination. Phylogenetic and cluster analyses showed that consensus genomes were generally sufficient to discriminate among independent transmission clusters. However, levels of intrahost variation were low, which prevented in most cases the unambiguous identification of direct transmission events. After filtering out recurrent variants across clusters, the genomic data were generally compatible with the epidemiological information but did not support specific transmission events over possible alternatives. We estimated the effective transmission bottleneck size to be 1-2 viral particles for sample pairs whose donor-recipient relationship was likely. Our analyses suggest that intrahost genomic variation in SARS-CoV-2 might be generally limited and that homoplasy and recurrent errors complicate identifying shared intrahost variants. Reliable reconstruction of direct SARS-CoV-2 transmission based solely on genomic data seems hindered by a slow mutation rate, potential convergent events, and technical artifacts. Detailed contact tracing seems essential in most cases to study SARS-CoV-2 transmission at high resolution.


title: Vaccine safety surveillance using routinely collected healthcare data - An empirical evaluation of epidemiological designs

abstract:
BackgroundRoutinely collected healthcare data such as administrative claims and electronic health records (EHR) can complement clinical trials and spontaneous reports when ensuring the safety of vaccines, but uncertainty remains about what epidemiological design to use.

MethodsUsing 3 claims and 1 EHR database, we evaluate several variants of the case-control, comparative cohort, historical comparator, and self-controlled designs against historical vaccinations with real negative control outcomes (outcomes with no evidence to suggest that they could be caused by the vaccines) and simulated positive controls.

ResultsMost methods show large type 1 error, often identifying false positive signals. The cohort method appears either positively or negatively biased, depending on the choice of comparator index date. Empirical calibration using effect-size estimates for negative control outcomes can restore type 1 error to close to nominal, often at the cost of increasing type 2 error. After calibration, the self-controlled case series (SCCS) design shows the shortest time to detection for small true effect sizes, while the historical comparator performs well for strong effects.

ConclusionsWhen applying any method for vaccine safety surveillance we recommend considering the potential for systematic error, especially due to confounding, which for many designs appears to be substantial. Adjusting for age and sex alone is likely not sufficient to address the differences between vaccinated and unvaccinated, and for the cohort method the choice of index date plays an important role in the comparability of the groups Inclusion of negative control outcomes allows both quantification of the systematic error and, if so desired, subsequent empirical calibration to restore type 1 error to its nominal value. In order to detect weaker signals, one may have to accept a higher type 1 error.

HighlightsO_LIMost methods used in vaccine safety surveillance show large type 1 error, which could lead to many false safety signals.
C_LIO_LIEmpirical calibration using effect-size estimates for negative control outcomes can restore type 1 error to close to nominal, often at the cost of marginal increases in type 2 error.
C_LIO_LIAfter calibration, the self-controlled case series (SCCS) design shows the shortest time to detection for small true effect sizes, while the historical comparator appears best for large true effect sizes.
C_LIO_LIImplementing negative control outcomes in a safety surveillance system is recommended to identify vulnerability to systematic error.
C_LI


title: High vaccine effectiveness against COVID-19 infection and severe disease among residents and staff of long-term care facilities in Norway, November - June 2021

abstract: COVID-19 has caused high morbidity and mortality in long-term care facilities (LTCFs) worldwide. We estimated vaccine effectiveness (VE) among residents and health care workers (HCWs) in LTCFs using Cox regressions. The VE against SARS-CoV-2 infection was 81.5 (95%CI: 75.3 - 86.1 82.7%) and 81.4% (95%CI: 74.5-86.4%) [≥] 7 days after 2nd vaccine dose among residents and staff respectively. The VE against COVID-19 associated death was 93.1% among residents, no hospitalisations occurred among HCW [≥]7 days after 2nd dose.


title: Integrated Single Cell and Spatial Transcriptomics Reveal Autoreactive Differentiated B Cells in Joints of Early Rheumatoid Arthritis

abstract:
Rheumatoid Arthritis (RA) is a prevalent autoimmune disease characterized by inflammation of peripheral joints. Patients can be subdivided by the presence or absence of Rheumatoid Factor and anti-citrullinated protein antibodies (ACPA) in their circulation. Inflammation of the joint tissue is associated with infiltration of leukocytes from the blood, which can result in generation of lymphoid structures composed of B and T cells. Previous studies have shown that both memory B cells and antibody-secreting plasma cells populate the rheumatic joint tissue when captured from established and often long-standing disease. However, it has remained unclear, whether these cells are autoreactive and whether the associated lymphoid structures are present at the site of inflammation already at the time of diagnosis. Here, we used an integrated single cell and spatial transcriptomic approach to study B and plasma cells in synovial tissue of ACPA- and ACPA+ RA patients at this early time point. We found evidence for T cell help to B cells and presence of memory B and plasma cell pools in ACPA- as well as in ACPA+ RA. Our results demonstrated common supportive microenvironments in both patient subgroups, clonal relationships between the memory B and plasma cell pools and autoreactivity within the plasma cell compartment. These findings challenge our understanding of the dynamics of local adaptive immune responses in the RA joint of ACPA- and ACPA+ patients at the time of diagnosis, with direct implications for B and T cell targeting therapies for both patient subgroups.

One Sentence SummaryA B cell maturation and plasma cell maintenance niche is evident at onset of Rheumatoid arthritis in both ACPA- and ACPA+ patients.


title: Observational study of HPV genitalia and oral infection in an unvaccinated population of men who have sex with men infected with HIV in Northwest Spain

abstract:
BackgroundHuman papillomavirus (HPV) infection is the most common sexual transmitted disease (STD) and a risk factor for penile, oral and anal cancer. Human immunodeficiency virus (HIV) coinfection increases the risk of cancer. While HPV anal infection is well studied in men-who-have-sex-with-men (MSM), HPV genitalia and oral infection is less known.

MethodsThis prevalence study of HPV infection in genitalia and oral cavity in HIV-MSM patients included 107 HPV non-vaccinated subjects. HPV-DNA was detected with Anyplex II HPV28 method. Participants completed a questionnaire on lifestyle and sexual behavior.

ResultsMedian age was 43 years (range 35-54 years); 97 patients were on antiretroviral treatment (ART); 81 (75.7%) had undetectable HIV-RNA; median CD4-lymphocyte count was 746 cell/mm3; 70 (65.4%) participants had a previous STD. HPV was detected in genitalia in 37 (34.6%) subjects; 26 (24.3%) in oral cavity and 12 (11.2%) in both locations. High-risk HPV genotypes were detected in 24 (22.4%) patients in genitalia and 15 (14%) in oral cavity.

ConclusionsHPV infection is common in unvaccinated HIV-MSM patients. Detectable HIV-RNA was associated with higher HPV prevalence in genitalia. High oncogenic risk HPV genotypes were more common in genitalia than in mouth.

Summary textHPV infection is common in HIV infected subjects and it is a risk factor for many types of cancer. Although anal conduct is the most studied location, HPV can also infect genitalia and oral cavity. However, the frequency and distribution of HPV strains is different in both locations.

category: hiv aids


title: Reducing false reassurance following negative results from asymptomatic coronavirus (Covid-19) testing: an online experiment

abstract:
ObjectivesIndividuals who receive a negative lateral flow coronavirus (Covid-19) test result may misunderstand it as meaning  no risk of infectiousness, giving false reassurance. This experiment tested the impact of adding information to negative test result messages about (a) residual risk and (b) need to continue protective behaviours.

Design4 (residual risk) x 2 (post-test result behaviours) between-subjects design.

SettingOnline.

Participants1200 adults from a representative UK sample recruited via Prolific (12-15 March 2021).

InterventionsParticipants were randomly allocated to one of eight messages. Residual risk messages were: 1)  Your coronavirus test result is negative (control); 2) Message 1 plus  Its likely you were not infectious when the test was done (Current NHS Test & Trace); 3) Message 2 plus  But there is still a chance you may be infectious (Elaborated NHS T&T); 4) Message 3 plus infographic depicting residual risk (Elaborated NHS T&T + infographic). Each message contained either no additional information or information about behaviour, i.e. the need to continue following guidelines and protective behaviours.

Outcome measures(i) proportion understanding residual risk of infectiousness and (ii) likelihood of engaging in protective behaviours (score range 0-7).

ResultsThe control message decreased understanding relative to the current NHS T&T message: 54% vs 71% (AOR=0.37 95% CI [0.22, 0.61], p<.001). Understanding increased with the elaborated NHS T&T (89%; AOR=3.27 95% CI [1.78, 6.02], p<.001) and elaborated NHS T&T + infographic (91%; AOR=4.03 95% CI [2.14, 7.58], p<.001) compared to current NHS T&T message. Likelihood of engaging in protective behaviours was unaffected by information (F(1,1192)=0.43, p=.513), being high (M=6.4, SD=0.9) across the sample.

ConclusionsThe addition of a single sentence ( But there is still a chance you may be infectious) to current NHS Test & Trace wording increased understanding of the residual risk of infection.

Trial registrationOpen Science Framework: https://osf.io/byfz3/


title: Lead-OR: A Multimodal Platform for Deep Brain Stimulation Surgery

abstract: Deep Brain Stimulation (DBS) electrode implant trajectories are stereotactically defined using preoperative neuroimaging. To validate the correct trajectory, microelectrode recordings (MER) can be used to match the neuroanatomy with expected neurophysiological activity patterns, commonly using up to five trajectories in parallel. However, understanding their location in relationship to basal ganglia anatomy can be challenging. Here we present a tool that integrates resources from stereotactic planning, neuroimaging, MER and high-resolution atlas data to create a real-time visualization of the implant trajectory. We show a general correspondence between features derived from neuroimaging and electrophysiological recordings and present example use cases that demonstrate the functionality of the tool. The software toolbox is made openly available, extendable and holds translational potential in the field of stereotactic neurosurgery.

category: neurology


title: Mixed ancestry analysis of whole-genome sequencing reveals common, rare, and structural variants associated with posterior urethral valves

abstract: Posterior urethral valves (PUV) are the commonest cause of end-stage renal disease in children, but the genetic architecture of this rare disorder remains largely unknown. We analyzed whole-genome sequencing (WGS) data from 132 unrelated PUV cases and 23,727 controls of mixed ancestry and identified statistically significant associations with common variants at 12q24.21 (P=7.8x10-12; OR 0.4) and rare variants at 6p21.1 (P=2x10-8; OR 7.2), that were replicated in an independent European cohort. Bayesian fine mapping and functional annotation mapped these loci to the transcription factor TBX5 and planar cell polarity gene PTK7, respectively, with the encoded proteins detected in the normal human developing urinary tract. These findings represent the first known genetic associations of PUV, providing novel insights into the underlying biology of this poorly understood disorder and demonstrate that a mixed ancestry WGS approach can increase power for disease locus discovery and facilitate fine-mapping of causal variants.


title: Mixed ancestry analysis of whole-genome sequencing identifies TBX5 and PTK7 as susceptibility genes for posterior urethral valves


title: Impacts of Regional Lockdown Policies on COVID-19 Transmission in India in 2020

abstract:
ObjectiveTo assess the impact of non-pharmaceutical interventions (NPIs) on the first wave of COVID transmission and fatalities in India.

MethodsWe collected data on NPIs, using government notifications and news reports, in six major Indian states from March to August 2020, and we matched these with district-level data on COVID related deaths and Google Mobility reports. We used a district fixed effect regression approach to measure the extent to which district-level lockdowns and mobility restrictions helped reduce deaths in 2020.

ResultsIn most states, COVID deaths grew most rapidly only after the initial lockdown was lifted. District-level NPIs were associated with a statistically significantly lower COVID death count in three out of five sample states (district analysis was not possible in Delhi) and in the aggregate. Interventions that were most associated with slowing fatalities were temple closures, retail closures, and curfews.

DiscussionOutside of Maharashtra (the first state struck) the first fatality wave appears to have been delayed by the national lockdown. Indias NPIs, however incomplete, were successful in delaying or limiting COVID-19 deaths. Even with incomplete compliance, limiting mass gatherings in face of incipient viral waves may save lives.

category: health policy


title: Diagnosing COVID-19 in human serum using Raman spectroscopy: a preliminary study

abstract: This preliminary study proposed the diagnosis of COVID-19 by means of Raman spectroscopy. Samples of blood serum from 10 patients positive and 10 patients negative for COVID-19 by RT-PCR RNA and ELISA tests were analyzed. Raman spectra were obtained with a dispersive Raman spectrometer (830 nm, 350 mW) in triplicate, being submitted to exploratory analysis with principal component analysis (PCA) to identify the spectral differences and discriminant analysis with PCA (PCA-DA) and partial least squares (PLS-DA) for classification of the blood serum spectra into Control and COVID-19. The spectra of both groups positive and negative for COVID-19 showed peaks referred to the basal constitution of the serum (mainly albumin). The difference spectra showed decrease in the peaks referred to proteins and amino acids for the group positive. PCA variables showed more detailed spectral differences related to the biochemical alterations due to the COVID-19 such as increase in lipids, nitrogen compounds (urea and amines/amides) and nucleic acids, and decrease of proteins and amino acids (tryptophan) in the COVID-19 group. The discriminant analysis applied to the principal component loadings (PC 2, PC 4, PC 5 and PC 6) could classify spectra with 87% sensitivity and 100% specificity compared to 95% sensitivity and 100% specificity indicated in the RT-PCR kit leaflet, demonstrating the possibilities of a rapid, label-free and costless technique for diagnosing COVID-19 infection.


title: Antibody response in individuals affected with Sars-Cov-2 infection: temporal trends and qualitative and quantitative differences in symptomatic and asymptomatic subjects. A Cross Sectional Analysis. Ab-Covid Study

abstract:
ObjectivesTo describe clinical characteristics and treatment used in subjects who had Sars-Cov-2 infection during the first pandemic and to assess the correlation between serological titers and clinical characteristics; to evaluate the persistence of antibody titer.

DesignCross-sectional study; 12 months follow-up.

SettingResidents in Azienda USL Umbria 2.

ParticipantsConsecutive subjects aged 15 to 75 who were discharged with the diagnosis of Sars-Cov-2 from the hospitals of the AUSL Umbria 2, or resulted positive to a PCR test for Sars-Cov-2 infection with or without symptoms. SARS-CoV-2 serologic testing for antibodies targeting the Nucleocapside and Spike proteins were determined.

ResultsOf 184 eligible subjects, 149 were available for evaluation: 17 were classified as Oligo/asymptomatic, 107 as Symptomatic, 25 as Hospital admitted. While fever resulted common to all the groups, headache or musculoskeletal pain was common to symptomatic participants whereas cough and dyspnea was present in all the hospital admitted. Participants with significant signs and symptoms were more likely to use antibiotics, hydroxychloroquine, heparin and steroids. Compared to Oligo/asymptomatic participants, Symptomatic and Hospital admitted participants had higher levels of anti-S titers at every follow-up (median titer at 12 month follow-up: 29 vs 94 vs 116 respectively; P < 0.001). At 12 months follow-up, anti-S titers persisted above the threshold for at least 12 months in all Hospital admitted participants, in 90% of the Symptomatic participants and 83% in the oligo/asymptomatic participants; in 30% of participants the titer raised significantly probably due to reinfection. Anti-N antibody titer tended to decrease over time and in 62% of the entire cohort resulted negative. None of the participants reported clinical reinfection with Sars-Cov-2 virus.

ConclusionAnti-S and anti-N antibody titers correlates well with disease severity. Anti-S antibodies persist for at least one year and most probably provide protection from reinfection.

O_TEXTBOXStrengths and limitations of this study

O_LIThe key strength of this study is the evaluation of anti-Sars-Cov-2 serology using two types of serological assays and the follow-up that endured for at least 12 months
C_LIO_LIIn addition to serological evaluation participants were also followed-up clinically
C_LIO_LIThe study does not have a baseline serologic testing since it was conceived in late April when most of the participants were discharged from hospital or had their symptoms resolved
C_LIO_LIThe study lacks clinical and serological information regarding those who died during the pandemic event, hence we are unable to conclude whether quantitative serologic testing could predict survival
C_LI

C_TEXTBOX


title: Evaluation of the Liberty16 mobile real time PCR device for use with the SalivaDirect assay for SARS-CoV-2 testing

abstract: The COVID-19 pandemic has highlighted the need and benefits for all communities to be permitted timely access to on-demand screening for infectious respiratory diseases. This can be achieved with simplified testing approaches and affordable access to core resources. While RT-qPCR-based tests remain the gold standard for SARS-CoV-2 detection due to their high sensitivity, implementation of testing requires high upfront costs to obtain the necessary instrumentation. This is particularly restrictive in low-resource settings. The Ubiquitome Liberty16 system was developed as an inexpensive, portable, battery-operated single-channel RT-qPCR device with an associated iPhone app to simplify assay set-up and data reporting. When coupled with the SalivaDirect protocol for testing saliva samples for SARS-CoV-2, the Liberty16 device yielded a limit of detection (LOD) of 12 SARS-CoV-2 RNA copies/{micro}L, comparable to the upper end of the LOD range for the standard SalivaDirect protocol when performed on larger RT-qPCR instruments. While further optimization may deliver even greater sensitivity and assay speed, findings from this study indicate that small portable devices such as the Liberty16 can deliver reliable results and provide the opportunity to further increase access to gold standard SARS-CoV-2 testing.


title: A multidimensional cross-sectional analysis of COVID-19 seroprevalence among a police officer cohort: The PoliCOV-19 study

abstract:
OBJECTIVETo determine the seroprevalence of SARS-CoV-2 antibodies in employees of the Cantonal Police Bern, Switzerland; to investigate individual and work-related factors associated with seropositivity; and to assess the neutralizing capacity of the antibodies of seropositive study participants.

DESIGNCross-sectional analysis of a cohort study.

SETTINGWearing face masks was made mandatory for employees of the police during working hours at the rise of the second wave of the pandemic in mid-October 2020. Protests and police fieldwork provided a high exposure environment for SARS-CoV-2 infections. The investigation was performed prior to initiation of a vaccine programme. Study participants were invited for serological testing of SARS-CoV-2 and to complete questionnaires on sociodemographic, work and health-related questions.

PARTICIPANTS978 police personnel working in four different geographic districts, representing 35% of the entire staff, participated from February to March 2021.

MAIN OUTCOME MEASURESSeroprevalence of anti-SARS-CoV-2 antibodies in February to March 2021, geographic and work-related risk factors for seropositivity, and serum neutralization titres towards the wild-type SARS-CoV-2 spike protein (expressing D614G) and the alpha and beta variants.

RESULTSSeroprevalence was 12.9% (126 of 978 employees). It varied by geographic region within the canton; ranged from 9% to 13% in three regions, including the city; and was 22% in Bernese Seeland/Jura. Working in the latter region was associated with higher odds for seropositivity (odds ratio 2.38, 95% confidence interval 1.28 to 4.44, P=0.006). Job roles with mainly office activity were associated with a lower risk of seropositivity (0.33, 0.14 to 0.77, P=0.010). Most seropositive employees (67.5%) reported having had coronavirus disease 2019 (COVID-19) 3 months or longer prior to serological testing, and the proportion of agreement between positive nasopharyngeal test results and seroconversion was 95% to 97%. Among reported symptoms, new loss of smell or taste was the best discriminator for seropositivity (odds ratio 52.4, 30.9 to 89.0, P<0.001). Compliance with mask wearing during working hours was 100%, and 45% of all seropositive versus 5% of all seronegative participants (P<0.001) reported having had contact with a proven COVID-19 case living in the same household. The level of serum antibody titres correlated well with neutralization capacity. Antibodies derived from natural SARS-CoV-2 infection effectively neutralized the SARS-CoV-2 spike protein (expressing D614G), but were less effective against the alpha and beta variants. A regression model demonstrated that anti-spike antibodies had higher odds for neutralization than did anti-nucleocapsid protein antibodies.

CONCLUSIONSSeroprevalence in the pre-vaccinated police cohort was similar to that reported in the general population living in the same region. The high compliance with mask wearing and the low proportion of seroconversion after contact with a presumed or proven COVID-19 case during working hours imply that personal protective equipment is effective and that household contacts are the leading transmission venues. The level of serum antibody titres, in particular that of anti-spike antibodies, correlated well with neutralization capacity. Low antibody titres were not effective against the alpha and beta variants.

SUMMARY BOXESO_ST_ABSWHAT IS ALREADY KNOWN ON THIS TOPICC_ST_ABSO_LIThe seroprevalence of anti-SARS-CoV-2 antibodies in the general population shows variations, depending on the geographic location of investigated study participants.
C_LIO_LISocial distancing by avoiding crowds and maintaining a distance of 6 feet from others when in public are recommended. These recommendations are not realistic for security personnel and employees of a police department.
C_LIO_LIPreventive strategies for individuals in a health care setting are warranted and effective to reduce potential exposures. The effect of preventive strategies on individuals working for the police force has not been investigated.
C_LI

WHAT THIS STUDY ADDSO_LIThe study suggests that the overall seroprevalence of anti-SARS-CoV-2 antibodies among police officers is not higher than that in the general population, despite presumed higher exposure (e.g., public protests).
C_LIO_LICompliance with use of personal protective equipment among police officers was very high. The study results suggested that household contacts, rather than exposure during working hours, is the main source for viral transmission.
C_LIO_LIAnti-SARS-CoV-2 antibodies derived from natural infection demonstrated good neutralization capacity towards strains that epidemiologically likely caused the infection, but moderate to poor neutralization capacity towards the alpha and beta variant.
C_LI


title: Genomic analysis of SARS-CoV-2 variants of concern identified from the ChAdOx1 nCoV-19 immunized patients from Southwest part of Bangladesh

abstract:
IntroductionBangladesh introduced ChAdOx1 nCoV-19 since February, 2021 and in six months, only a small population (3.5%) received their first dose of vaccination like other low-income countries. The remaining populations are struggling with increased rate of infection due to beta and delta variants. Although this uncontrolled COVID-19 pandemic did not leave even the immunized group because of immune escaping capacity of those new variants.

MethodsA total of 4718 nasopharygeal samples were collected from 1st March until 15th April, 2021, of which, 834 (18%) were SARS-CoV-2 positive. Randomly generated 135 positive cases were selected for telephone interview and 108 were available and provided consent. The prevalence of SARS-CoV-2 variants and disease severity among both immunized and unimmunized group was measured. A total of 63 spike protein sequence and 14 whole genome sequences were performed from both groups and phylogenetic reconstruction and mutation analysis were compared.

ResultsA total of 40 respondents (37%, N=108) received single-dose and 2 (2%) received both doses of ChAdOx1 nCoV-19 vaccine which significantly reduce dry cough, loss of appetite and difficulties in breathing compared to none. There was no significant difference in hospitalization, duration of hospitalization or reduction of other symptoms like running nose, muscle pain, shortness of breathing or generalized weakness between immunized and unimmunized group. Spike protein sequence assumed 21 (87.5%) B.1.351, one B.1.526 and two 20B variants in immunized group compared to 27 (69%) B.1.351, 5 (13%) B.1.1.7, 4 (10%) 20B, 2 B.1.526 and one B.1.427 variant in unimmunized group. Those variants were further confirmed by 14 whole genome sequence analysis. Complete genome analysis included seven B.1.351 Beta V2, three B.1.1.7 Alpha V1, one B.1.526 Eta and rest three 20B variant.

ConclusionSingle dose of ChAdOx1 couldnt prevent the new infection or disease severity by the COVID-19 variants of concern, B.1.351, in Bangladesh.


title: Time-to-event comparative effectiveness of NOACs vs VKAs in newly diagnosed non-valvular atrial fibrillation patients.

abstract:
AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSObjectiveC_ST_ABSTo investigate the difference in the time-to-event probabilities of ischaemic events, major bleeding and death of NOAC vs VKAs in newly diagnosed non-valvular atrial fibrillation patients.

DesignRetrospective observational cohort study.

SettingUKs Clinical Practice Research Data linked to the Hospital Episode Statistics inpatient and outpatient data, mortality data and the Patient Level Index of Multiple Deprivation.

ParticipantsPatients over 18 years of age, with an initial diagnosis of atrial fibrillation between 1st-Mar-2011 and 31-July-2017, without a record for a valve condition, prosthesis or procedure previous to initial diagnosis, and without a record of oral anticoagulant treatment in the previous year.

InterventionOral anticoagulant treatment with either vitamin K antagonists (VKAs) or the newer target-specific oral anticoagulants (NOACs).

Main Outcome MeasuresIschaemic event, major bleeding event and death from 15 days from initial prescription up to two years follow-up.

Statistical AnalysisTreatment effect was defined as the difference in time-to-event probability between NOAC and VKA treatment groups. Treatment and outcomes were modelled using an ensemble of parametric and non-parametric models, and the average and conditional average treatment effects were estimated using one-step Targeted Maximum Likelihood Estimation (TMLE). Heterogeneity of treatment effect was examined using variable importance methods in Bayesian Additive Regression Trees (BART).

ResultsThe average treatment effect of NOAC vs VKA was consistently close to zero across all times, with a temporal average of 0.00[95%0.00, 0.00] for ischaemic event, 0.00%[95% -0.01, 0.01] for major bleeding and 0.00[95% -0.01, 0.01] for death. Only history of major bleeding was found to influence the distribution of treatment effect for major bleeding, but its impact on the associated conditional average treatment effect was not significant.

ConclusionsThis study found no statistically significant difference between NOAC and VKA users up to two years of medication use for the prevention of ischaemic events, major bleeding or death.


title: When does contacting more people lessen the transmission of infectious diseases?

abstract: A primary concern in epidemics is to minimize the probability of contagion, often resorting to reducing the number of contacted people. However, the success of that strategy depends on the shape of the dose-response curve, which relates the response of the exposed person to the pathogen dose received from surrounding infected people. If the reduction is achieved by spending more time with each contacted person, the pathogen charge received from each infected individual will be larger. The extended time spent close to each person may worsen the expected response if the dose-response curve is concave for small doses. This is the case when the expected response is negligible below a certain dose threshold and rises sharply above it. This paper proposes a mathematical model to calculate the expected response and uses it to identify the conditions when it would be advisable to reduce the contact time with each individual even at the cost of increasing the number of contacted people.


title: Progress of the Delta variant and erosion of vaccine effectiveness, a warning from Utah

abstract: Since the emergence of SARS-CoV-2, vaccines have been heralded as the best way to curtail the pandemic. Clinical trials have shown SARS-CoV-2 vaccines to be highly efficacious against both disease and infection. However, those currently in use were primarily tested against early lineages. Data on vaccine effectiveness (VE) against variants of concern (VOC), including the Delta variant (B.1.617.2), remain limited. To examine the effectiveness of vaccination in Utah we compared the proportion of cases reporting vaccination to that expected at different VEs, then estimated the combined daily vaccine effectiveness using a field evaluation approach. Delta has rapidly outcompeted all other variants and, as of June 20th, represents 70% of all SARS-CoV-2 viruses sequenced in Utah. If we attribute the entire change in VE to the Delta variant, the estimated vaccine effectiveness against Delta would be 82% (95% CI: 78%, 85%). We show a modest reduction in vaccine effectiveness against COVID-19 in Utah corresponding to the expansion of the Delta lineage in the state. This reduction in the effectiveness of available vaccines correlated with the arrival of novel VOCs, rather than waning immunity, is highly concerning.


title: Clinical efficacy and increased donor strain engraftment after antibiotic pretreatment in a randomized trial of ulcerative colitis patients receiving fecal microbiota transplant

abstract: Fecal microbiota transplant is a promising therapy for ulcerative colitis. Parameters maximizing effectiveness and tolerability are not yet clear, and it is not known how import the transmission of donor microbes to patients is. Here (clinicaltrails.gov: NCT03006809) we have tested the effects of antibiotic pretreatment and compared two modes of maintenance dose delivery, capsules versus enema, in a randomized, pilot, open-label, 2x2 factorial design with 22 patients analyzed with mild to moderate UC. Clinically, the treatment was well-tolerated with favorable safety profile. Of patients who received antibiotic pretreatment, 6 of 11 experienced remission after six weeks of treatment, versus 2 of 11 non-pretreated patients (odds ratio: 1.69, 95% confidence interval: -0.25 to 3.62). No significant differences were found between maintenance dosing via capsules versus enema. In exploratory analyses, microbiome turnover at both the species and strain levels was extensive and significantly more pronounced in the pretreated patients. Associations were also revealed between taxonomic turnover and changes in the composition of primary and secondary bile acids. Together these findings suggest that antibiotic pretreatment contributes to microbiome engraftment and possibly clinical effectiveness, and validate longitudinal strain tracking as a powerful way to monitor the dynamics and impact of microbiota transfer.

category: gastroenterology


title: Strain-resolved analysis in a randomized trial of antibiotic pretreatment and maintenance dose delivery mode with fecal microbiota transplant for ulcerative colitis


title: Rapid-CNS2: Rapid comprehensive adaptive nanopore-sequencing of CNS tumors, a proof of concept study

abstract:
BackgroundThe 2021 WHO classification of central nervous system tumors includes multiple molecular markers and patterns that are recommended for routine diagnostic use in addition to histology. Sequencing infrastructures for complete molecular profiling require considerable investment, while batching samples for sequencing and methylation profiling can delay turnaround time. We introduce RAPID-CNS2, a nanopore adaptive sequencing pipeline that enables comprehensive mutational, methylation and copy number profiling of CNS tumours with a single, cost-effective sequencing assay. It can be run for single samples and offers highly flexible target selection that can be personalized per case with no additional library preparation.

MethodsUtilizing ReadFish, a toolkit enabling targeted nanopore sequencing without the need for library enrichment, we sequenced DNA from 22 diffuse glioma samples on a MinION device. Target regions comprised our Heidelberg brain tumor NGS panel and pre-selected CpG sites for methylation classification using an adapted random forest classifier. Pathognomonic alterations, copy number profiles, and methylation classes were called using a custom bioinformatics pipeline. The resulting data were compared to their corresponding standard NGS panel sequencing and EPIC methylation array results.

ResultsComplete concordance with the EPIC array was found for copy number profiles. The vast majority (94%) of pathognomonic mutations were congruent with standard NGS panel-seq data. MGMT promoter status was correctly identified in all samples. Methylation families from the random forest classifier were detected with 96% congruence. Among the alterations decisive for rendering a WHO 2021 classification-compatible integrated diagnosis, 97% of the alterations were consistent over the entire cohort (completely congruent in 19/22 cases and sufficient for unequivocal diagnosis in all 22 samples).

ConclusionsRAPID-CNS2 provides a swift and highly flexible alternative to conventional NGS and array-based methods for SNV/InDel analysis, detection of copy number alterations, target gene methylation analysis (e.g. MGMT) and methylation-based classification. The turnaround time of [~]5 days for this proof-of-concept study can be further shortened to < 24h by optimizing target sizes and enabling real-time computational analysis. Expected advances in nanopore sequencing and analysis hardware make the prospect of integrative molecular diagnosis in an intra-operative setting a feasible prospect in future. This low-capital approach would be cost-efficient for low throughput settings or in locations with less sophisticated laboratory infrastructure, and invaluable in cases requiring immediate diagnoses.

category: pathology


title: Data Visualization for Epidemiological and Demographic Data for Malaria Surveillance in the Brazilian Amazon, 2007-2019

abstract: Malaria represents one of the main public health problems worldwide and continues to be a great challenge to Brazil which concentrates about 34.4% of the disease cases registered in the American continent. Approximately 99% of Malaria cases occur in Amazonia. In 2017, 194,000 cases were recorded. This increase in the number of cases may be a warning of a possible decline in the effectiveness of control and surveillance programs in the region. The objective of this study is to propose the design of interactive visualizations of data related to Malaria Surveillance in the Brazilian Amazon, between the years of 2007-2019. Data came from SIVEPMalaria. We used data visualization techniques to explore epidemiological and demographic aspects of Malaria Surveillance. We hope tools of this kind can reduce the burden of data extraction and analysis on health staff and local policy makers.


title: Lesion Normalization and Supervised Learning in Post-Traumatic Seizure Classification with Diffusion MRI

abstract: Traumatic brain injury (TBI) is a serious condition, potentially causing seizures and other lifelong disabilities. Patients who experience at least one seizure one week after TBI (late seizure) are at high risk for lifelong complications of TBI, such as post-traumatic epilepsy (PTE). Identifying which TBI patients are at risk of developing seizures remains a challenge. Although magnetic resonance imaging (MRI) methods that probe structural and functional alterations after TBI are promising for biomarker detection, physical deformations following moderate-severe TBI present problems for standard processing of neuroimaging data, complicating the search for biomarkers. In this work, we consider a prediction task to identify which TBI patients will develop late seizures, using fractional anisotropy (FA) features from white matter tracts in diffusion-weighted MRI (dMRI). To understand how best to account for brain lesions and deformations, four preprocessing strategies are applied to dMRI, including the novel application of a lesion normalization technique to dMRI. The pipeline involving the lesion normalization technique provides the best prediction performance, with a mean accuracy of 0.819 and a mean area under the curve of 0.785. Finally, following statistical analyses of selected features, we recommend the dMRI alterations of a certain white matter tract as a potential biomarker.

category: radiology and imaging


title: Use of health care services during the Covid-19 pandemic in Ethiopia: Evidence from a health facility survey

abstract:
IntroductionIn recent years Ethiopia has made enormous strides in enhancing access to health care, especially, maternal and child health care (MCH). With the onset and spread of Covid-19, the attention of the health care system has pivoted to handling the disease, potentially at the cost of other health care needs. This paper explores whether this shift has come at the cost of non-Covid related health care, especially the use of MCH services.

MethodsGraphs, descriptive statistics and paired t-tests of significance are used to compare levels of inpatient and outpatient health care service utilization before and after the onset and spread of the virus. The analysis is based on a survey of 59 health centers and 29 public hospitals located in urban Ethiopia - the most acutely affected region of the country. Data on the use of health care services for a period of 24 months was gathered from the health management information systems (HMIS) of these facilities.

ResultsThere is a sharp reduction in the use of both inpatient (20-27%) and outpatient (27-34%) care, particularly in Addis Ababa, which has been most acutely affected by the virus. However, the decline does not come at the cost of MCH services. The use of several MCH components (skilled birth attendant deliveries, immunization, post-natal care) remains unaffected throughout the period while others (family planning services, ante-natal care) experience a decline (8-17%) in the immediate aftermath but recover soon after.

ConclusionConcerns about the crowding out of MCH services due to the focus on Covid 19 are unfounded. Pro-active measures taken by the government and health care facilities to ring-fence the use of essential health care services have mitigated service disruptions. The results underline the resilience and agility displayed by one of the worlds most resource-constrained health care systems.

O_TEXTBOXSummary BoxO_ST_ABSWhat is already known?C_ST_ABSO_LISimulation studies suggest sharp increases in unwanted pregnancies, and in maternal and child mortality due to Covid related disruptions in the provision of mother and child health care services.
C_LIO_LIEvidence on whether such service disruptions have indeed occurred is limited.
C_LI

What are the new findings?O_LIBased on retrospective health facility data collected from parts of Ethiopia that have been most acutely affected by Covid, we find that for most MCH services, disruption is temporary and rebounds to pre-covid levels within two months.
C_LI

What do the new findings imply?O_LIConcerns about the crowding out of MCH services due to the focus on Covid seem to be unfounded.
C_LIO_LIPro-active measures taken by the government and health care facilities to adapt and to ring-fence the use of essential health care services have mitigated service disruptions.
C_LIO_LIDespite resource-constraints it is possible to protect the provision of essential health care services and thereby hard-won gains in maternal and child health outcomes
C_LI

C_TEXTBOX


title: Antibody mediated neutralization of authentic SARS-CoV-2 B.1.617 variants harboring L452R and T478K/E484Q

abstract:
The capacity of convalescent and vaccine-elicited sera and monoclonal antibodies (mAb) to neutralize SARS-CoV-2 variants is currently of high relevance to assess the protection against infections.

We performed a cell culture-based neutralization assay focusing on authentic SARS-CoV-2 variants B.1.617.1 (Kappa), B.1.617.2 (Delta), B.1.427/B.1.429 (Epsilon), all harboring the spike substitution L452R.

We found that authentic SARS-CoV-2 variants harboring L452R had reduced susceptibility to convalescent and vaccine-elicited sera and mAbs. Compared to B.1, Kappa and Delta showed a reduced neutralization by convalescent sera by a factor of 8.00 and 5.33, respectively, which constitutes a 2-fold greater reduction when compared to Epsilon. BNT2b2 and mRNA1273 vaccine-elicited sera were less effective against Kappa, Delta, and Epsilon compared to B.1. No difference was observed between Kappa and Delta towards vaccine-elicited sera, whereas convalescent sera were 1.5-fold less effective against Delta, respectively. Both B.1.617 variants Kappa (+E484Q) and Delta (+T478K) were less susceptible to either casirivimab or imdevimab.

In conclusion, in contrast to the parallel circulating Kappa variant, the neutralization efficiency of convalescent and vaccine-elicited sera against Delta was moderately reduced. Delta was resistant to imdevimab, which however, might be circumvented by a combination therapy with casirivimab together.


title: RELATIONSHIP BETWEEN HELMINTHASIS AND GASTRIC CANCER: A SYSTEMATIC REVIEW

abstract:
Introductionhelminths are parasitic worms able to produce diverse clinical manifestations in humans, mainly in the gut. Gastric cancer its a high incidence entity in Colombia, being the highland regions where its incidence is the highest in comparison with the lower incidence coastal region. From the above it is intended to determine the relationship between helminthiasis and the development of gastric cancer.

MethodologyA systematic review was performed in four databases for studies evaluating the relationship between helminthiasis and the development of gastric cancer.

ResultsWe included 16 articles from 929 records, with 11 articles reporting a positive relationship and 5 articles with negative relationship.

ConclusionsParasitic infections of the gastrointestinal tract by helminths promote TH-2 type immune responses and decrease TH-1 type that are involved in the progression of precancerous lesions associated with Helicobacter pylori infection.

category: oncology


title: Associations between different tau-PET patterns and longitudinal atrophy in the Alzheimer's disease continuum

abstract:
INTRODUCTIONDifferent subtypes/patterns have been defined using tau-PET and structural-MRI in Alzheimers disease (AD), but the relationship between tau pathology and atrophy remains unclear. Our goals were twofold: (a) investigate the association between baseline tau-PET patterns and longitudinal atrophy in the AD continuum; (b) characterize heterogeneity as a continuous phenomenon over the conventional notion using discrete subgroups.

METHODSIn 366 individuals (amyloid-beta-positive: cognitively normal, prodromal AD, AD dementia; amyloid-beta-negative healthy), we examined the association between tau-PET patterns (operationalized as a continuous phenomenon and a discrete phenomenon) and longitudinal sMRI.

RESULTSWe observed a differential association between tau-PET patterns and longitudinal atrophy. Heterogeneity, measured continuously, may offer an alternative characterization, sharing correspondence with the conventional subgrouping.

DISCUSSIONSite and the rate of atrophy are modulated differentially by tau-PET patterns in the AD continuum. We postulate that heterogeneity be treated as a continuous phenomenon for greater sensitivity over the current/conventional discrete subgrouping.


title: Predictive Structured-Unstructured Interactions in EHR Models: A Case Study of Suicide Prediction

abstract: Clinical risk prediction models powered by electronic health records (EHRs) are becoming increasingly widespread in clinical practice. With suicide-related mortality rates rising in recent years, it is becoming increasingly urgent to understand, predict, and prevent suicidal behavior. Here, we compare the predictive value of structured and unstructured EHR data for predicting suicide risk. We find that Naive Bayes Classifier (NBC) and Random Forest (RF) models trained on structured EHR data perform better than those based on unstructured EHR data. An NBC model trained on both structured and unstructured data yields similar performance (AUC = 0.743) to an NBC model trained on structured data alone (0.742, p = 0.668), while an RF model trained on both data types yields significantly better results (AUC = 0.903) than an RF model trained on structured data alone (0.887, p<0.001), likely due to the RF models ability to capture interactions between the two data types. To investigate these interactions, we propose and implement a general framework for identifying specific structured-unstructured feature pairs whose interactions differ between case and non-case cohorts, and thus have the potential to improve predictive performance and increase understanding of clinical risk. We find that such feature pairs tend to capture heterogeneous pairs of general concepts, rather than homogeneous pairs of specific concepts. These findings and this framework can be used to improve current and future EHR-based clinical modeling efforts.

category: health informatics


title: Infected surfaces as a source of transmissible material in healthcare settings dealing with COVID 19 patients

abstract: The disease COVID-19 has turned out to be a tremendous slayer and has had some of the most devastating impacts on human beings ever seen in history. To overcome this major public health crisis, an understanding of the transmission of the virus underlying this disease is of paramount importance. Evidence suggests that the most common route of transmission for the SARS-CoV-2 virus is likely via direct contact in person-to-person encounter with aerosol droplets. However, the possibility of transmission via contact with fomites from surfaces is a possible route of infection as well. Environmental contamination in rooms with COVID-19 patient has been widely observed due to viral shedding from both asymptomatic and symptomatic patients. Also, in hospitals, SARS-CoV-2 is known to survive on various surfaces for extended periods of time. Because repetitive contact cycles can spread the virus from one surface to the other in healthcare settings, here we evaluated contamination on different types of surfaces commonly found in healthcare settings. Also, based on various datasets, we analyzed the importance of various surfaces in transmission modalities. Based on the findings of this study, decontamination of surfaces that frequently are in touch contact throughout all segments of the healthcare system should constitute an important part of the infection control and prevention of COVID-19. We also recommend the selection of a non-reactive disinfectant for hospital monitors, devices, ventilators and computers so that active surface disinfection can be effected without damage to the devices.

category: health systems and quality improvement


title: Immune Correlates Analysis of the mRNA-1273 COVID-19 Vaccine Efficacy Trial

abstract:
BackgroundIn the Coronavirus Efficacy (COVE) trial, estimated mRNA-1273 vaccine efficacy against coronavirus disease-19 (COVID-19) was 94%. SARS-CoV-2 antibody measurements were assessed as correlates of COVID-19 risk and as correlates of protection.

MethodsThrough case-cohort sampling, participants were selected for measurement of four serum antibody markers at Day 1 (first dose), Day 29 (second dose), and Day 57: IgG binding antibodies (bAbs) to Spike, bAbs to Spike receptor-binding domain (RBD), and 50% and 80% inhibitory dilution pseudovirus neutralizing antibody titers calibrated to the WHO International Standard (cID50 and cID80). Participants with no evidence of previous SARS-CoV-2 infection were included. Cox regression assessed in vaccine recipients the association of each Day 29 or 57 serologic marker with COVID-19 through 126 or 100 days of follow-up, respectively, adjusting for risk factors.

ResultsDay 57 Spike IgG, RBD IgG, cID50, and cID80 neutralization levels were each inversely correlated with risk of COVID-19: hazard ratios 0.66 (95% CI 0.50, 0.88; p=0.005); 0.57 (0.40, 0.82; p=0.002); 0.42 (0.27, 0.65; p<0.001); 0.35 (0.20, 0.61; p<0.001) per 10-fold increase in marker level, respectively, multiplicity adjusted P-values 0.003-0.010. Results were similar for Day 29 markers (multiplicity adjusted P-values <0.001-0.003). For vaccine recipients with Day 57 reciprocal cID50 neutralization titers that were undetectable (<2.42), 100, or 1000, respectively, cumulative incidence of COVID-19 through 100 days post Day 57 was 0.030 (0.010, 0.093), 0.0056 (0.0039, 0.0080), and 0.0023 (0.0013, 0.0036). For vaccine recipients at these titer levels, respectively, vaccine efficacy was 50.8% (-51.2, 83.0%), 90.7% (86.7, 93.6%), and 96.1% (94.0, 97.8%). Causal mediation analysis estimated that the proportion of vaccine efficacy mediated through Day 29 cID50 titer was 68.5% (58.5, 78.4%).

ConclusionsBinding and neutralizing antibodies correlated with COVID-19 risk and vaccine efficacy and likely have utility in predicting mRNA-1273 vaccine efficacy against COVID-19.

Trial registration numberCOVE ClinicalTrials.gov number, NCT04470427

category: infectious diseases


title: Ignoring spatial heterogeneity in drivers of SARS-CoV-2 transmission in the US will impede sustained elimination

abstract: To dissect the transmission dynamics of SARS-CoV-2 in the United States, we integrate parallel streams of high-resolution data on contact, mobility, seasonality, vaccination and seroprevalence within a metapopulation network. We find the COVID-19 pandemic in the US is characterized by a geographically localized mosaic of transmission along an urban-rural gradient, with many outbreaks sustained by between-county transmission. We detect a dynamic tension between the spatial scale of public health interventions and population susceptibility as pre-pandemic contact is resumed. Further, we identify regions rendered particularly at risk from invasion by variants of concern due to spatial connectivity. These findings emphasize the public health importance of accounting for the hierarchy of spatial scales in transmission and the heterogeneous impacts of mobility on the landscape of contagion risk.


title: Suppression of influenza virus infection by rhinovirus interference at the population, individual and cellular levels

abstract:
BackgroundInvestigations of the natural viral interference effect between rhinovirus (RV) and influenza virus (IV) were conducted in temperate regions. We conducted an epidemiological study in Hong Kong, a major epicentre of influenza virus in the sub-tropical region. RV is the most prevalent respiratory virus year-round and causes asymptomatic to mild symptoms while IV infection exerts a great burden of public health. We aimed to examine the correlation of RV prevalence against IV activity.

MethodsNasopharyngeal aspirates (NPA) collected from patients hospitalized in the regional hospitals from 2015 to 2019 were examined for the presence of respiratory viruses. The correlation of the monthly prevalence between all pairs of virus infection, the co-infection rate and the temporal interference of RV and IV were tested. The viral interference was validated in vitro by conducting sequential RV and IV infection in the well-differentiated primary human airway epithelial cells.

FindingsA total of 112,926 NPA were evaluated, and the Enterovirus/RV was the most prevalent respiratory virus detected. The negative correlation between EV/RV and IVs prevalence was independent of age and meteorological factors. Co-infection of EV/RV and IV was significantly less when compared with other virus pairs. Prior exposure to RV inhibited the replication of influenza A, B and oseltamivir-resistance stain in vitro and the inhibition is replication dependent.

InterpretationEpidemiological surveillance and the sequential infection in vitro suggested viral interference between EV/RV and IV operated at the population, individual and cellular levels.

FundingThis study was supported by the General Research Fund (Ref: 24107017 and 14103119 to RWYC), Health and Medical Research Fund (Ref: COVID190112 to RWYC) and the Chinese University Direct Grant for Research (Ref: 2019.073 to RWYC).


title: Using Novel, Agent-Based Periodic Mobility Model with Super Spreaders to Analyze Vaccination Strategies for COVID-19

abstract: The authors have withdrawn this manuscript because there have been a number of mutations of COVID-19, since the manuscript was posted, as well as changes in virus behavior, such as increased transmissibility. As a result, both the vaccination strategies and parameters used during the simulation are less applicable to the current situation, and thus the results from the simulations may be incorrect for the current situation. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.


title: The Epithelial and Stromal Immune Microenvironment in Gastric Cancer: A Comprehensive Analysis Reveals Prognostic Factors with Digital Cytometry

abstract:
BackgroundGastric cancer (GC) is the third leading cause of cancer-related deaths worldwide. Tumor heterogeneity continues to confound researchers understanding of tumor growth and the development of an effective therapy. Digital cytometry allows interpretation of heterogeneous bulk tissue transcriptomes at the cellular level.

MethodsWe built a novel signature matrix to dissect epithelium and stroma signals using a scRNA-seq data set for GC. We applied cell mixture deconvolution to estimate diverse epithelial, stromal, and immune cell proportions from bulk transcriptome data in four independent GC cohorts. Robust computational methods were applied to identify strong prognostic factors for GC.

ResultsWe identified an EMEC population whose proportions were significantly higher in patients with stage I cancer than other stages, and it was predominantly present in tumor samples but not typically found in normal samples. We found that the ratio of EMECs to stromal cells and the ratio of adaptive T cells to monocytes were the most significant prognostic factors within the non-immune and immune factors, respectively. The STEM score, which unifies these two prognostic factors was an independent prognostic factor of overall survival (HR=0.92, 95% CI=0.89-0.94, p = 2.05 x 10-9). The entire GC cohort was stratified into three risk groups (high-, moderate-, and low-risk) which yielded incremental survival times (p < 0.0001). For stage III disease, patients in the moderate- and low-risk groups experienced better survival benefits from radiation therapy ((HR=0.16, 95% CI=0.06-0.4, p < 0.0001), whereas those in the high-risk group did not (HR=0.49, 95% CI=0.14-1.72, p = 0.25).

ConclusionsWe conclude that the STEM score is a promising prognostic factor for gastric cancer.


title: Predictive Analysis of COVID-19 Spread in Sri Lanka using an Adaptive Compartmental Model: Susceptible-Exposed-Infected-Recovered-Dead (SEIRD) Model

abstract:
The role of modelling in predicting the spread of an epidemic is important for health planning and policies. This study aimed to apply a dynamic Susceptible-Exposed-Infected-Recovered-Deaths (SEIRD) model and simulated it under a range of epidemic conditions using python programme language. The predictions were based on different scenarios from without any preventive measures to several different preventive measures under R0 of 4. The model shows that more weight to personal protection can halt the spread of transmission followed by the closure of public places and interprovincial movement restriction. Results after simulating various scenarios indicate that disregarding personal protective measures can have devastating effects on the Sri Lankan population. The importance of strict adherence, maintain and monitoring of self-preventive measures lead to minimizing the death toll from COVID-19.

What we already knowO_LICompartmental models can be used to project scenarios with various disease control measures individually or as a useful combination for evidence-based policy formulation.
C_LIO_LIEpidemiologists have been using mass action, compartmental models, over a hundred years which are famous for simplicity in both analysis and outcome assessment.
C_LIO_LIMathematical modelling plays a vital role in the highest level of policymaking in the fields of health economics, emergency planning, monitoring of surveillance data and, risk assessment and control.
C_LI

What this article addsO_LIThis paper aimed to describe a dynamic Susceptible-Exposed-Infected-Recovered-Deaths (SEIRD) model and simulate it under a range of epidemiological conditions to give an insight into COVID-19 spread in Sri Lanka.
C_LIO_LIThe SEIRD model produces a time frame for preparedness and resource allocation of a country without exceeding the surge capacity which may lead to a disastrous situation which allows authorities to plan potential mortuary capacity and understand the burden on crematoria and burial services.
C_LIO_LINew policy discussions need to occur whenever the best available options such as different preventive strategies and knowledge about the epidemiology changes.
C_LIO_LIThe proposed model can serve as a tool for health authorities for planning and policymaking to control the pandemic by implementing appropriate policy decisions on time to prevent a disastrous situation.
C_LI

category: public and global health


title: Automated differentiation of malignant and benign primary solid liver lesions on MRI: an externally validated radiomics model

abstract:
Background & AimsDistinguishing malignant from benign primary solid liver lesions is highly important for treatment planning. However, diagnosis on radiological imaging is challenging. In this study, we developed a radiomics model based on magnetic resonance imaging (MRI) to distinguish the most common malignant and benign primary solid liver lesions, and externally validated the model in two centers.

Approach & ResultsDatasets were retrospectively collected from three tertiary referral centers (A, B and C) including data from affiliated hospitals sent for revision. Patients with malignant (hepatocellular carcinoma and intrahepatic cholangiocarcinoma) and benign (hepatocellular adenoma and focal nodular hyperplasia) lesions were included. For each patient, only a T2-weighted MRI was included. A radiomics model was developed on dataset A using a combination of machine learning approaches, and internally evaluated on dataset A through cross-validation. Next, the model was externally validated on datasets B and C, and compared to scoring by two experienced abdominal radiologists on dataset C. In the resulting dataset, in total, 486 patients were included (A: 187, B: 98 and C: 201). Despite substantial MRI acquisition heterogeneity, the radiomics model developed on dataset A had a mean area under the receiver operating characteristic curve (AUC) of 0.78 in the internal validation on dataset A, and a similar AUC in the external validations (B: 0.74, C: 0.76). In dataset C, the two radiologists showed moderate agreement (Cohens {kappa}: 0.61) and achieved AUCs of 0.86 and 0.82, respectively.

ConclusionsOur radiomics model using T2-weighted MRI only can non-invasively distinguish malignant from benign primary solid liver lesions. External validation indicated that our model is generalizable despite substantial differences in the acquisition protocols.