title: Safety and immunogenicity of a heterologous boost with a recombinant vaccine, NVSI-06-07, in the inactivated vaccine recipients from UAE: a phase 2 randomised, double-blinded, controlled clinical trial

abstract:
BackgroundThe increased coronavirus disease 2019 (COVID-19) breakthrough cases pose the need of booster vaccinations. In this study, we reported the safety and immunogenicity of a heterologous boost with a recombinant COVID-19 vaccine (CHO cells), named NVSI-06-07, as a third dose in participants who have previously received two doses of the inactivated vaccine (BBIBP-CorV) at pre-specified time intervals. Using homologous boost with BBIBP-CorV as control, the safety and immunogenicity of the heterologous boost with NVSI-06-07 against various SARS-CoV-2 strains, including Omicron, were characterized.

MethodsThis study is a single-center, randomised, double-blinded, controlled phase 2 trial for heterologous boost of NVSI-06-07 in BBIBP-CorV recipients from the United Arab Emirates (UAE). Healthy adults (aged [≥]18 years) were enrolled and grouped by the specified prior vaccination interval of BBIBP-CorV, i.e., 1-3 months, 4-6 months or [≥]6 months, respectively, with 600 individuals per group. For each group, participants were randomly assigned at 1:1 ratio to receive either a heterologous boost of NVSI-06-07 or a homologous booster dose of BBIBP-CorV. The primary outcome was to comparatively assess the immunogenicity between heterologous and homologous boosts at 14 and 28 days post-boosting immunization, by evaluation of the geometric mean titers (GMTs) of IgG and neutralizing antibodies as well as the corresponding seroconversion rate ([≥]4-fold rise in antibody titers). The secondary outcomes were the safety profile of the boosting strategies within 30 days post vaccination. The exploratory outcome was the immune efficacy against Omicron and other variants of concern (VOCs) of SARS-CoV-2. This trial is registered with ClinicalTrials.gov, NCT05033847.

FindingsA total of 1800 individuals who have received two doses of BBIBP-CorV were enrolled, of which 899 participants received a heterologous boost of NVSI-06-07 and 901 received a homologous boost for comparison. No vaccine-related serious adverse event (SAE) and no adverse events of special interest (AESI) were reported. 184 (20{middle dot}47%) participants in the heterologous boost groups and 177 (19{middle dot}64%) in the homologous boost groups reported at least one adverse reaction within 30 days. Most of the local and systemic adverse reactions reported were grades 1 (mild) or 2 (moderate), and there was no significant difference in the overall safety between heterologous and homologous boosts. Immunogenicity assays showed that the seroconversion rates in neutralizing antibodies against prototype SARS-CoV-2 elicited by heterologous boost were 89{middle dot}96% - 97{middle dot}52% on day 28 post-boosting vaccination, which was much higher than what was induced by homologous boost (36{middle dot}80% - 81{middle dot}75%). Similarly, in heterologous NVSI-06-07 booster groups, the neutralizing geometric mean titers (GMTs) against the prototype strain increased by 21{middle dot}01 - 63{middle dot}85 folds from baseline to 28 days post-boosting vaccination, whereas only 4{middle dot}20 - 16{middle dot}78 folds of increases were observed in homologous BBIBP-CorV booster group. For Omicron variant, the neutralizing antibody GMT elicited by the homologous boost of BBIBP-CorV was 37{middle dot}91 (95%CI, 30{middle dot}35-47{middle dot}35), however, a significantly higher level of neutralizing antibodies with GMT 292{middle dot}53 (95%CI, 222{middle dot}81-384{middle dot}07) was induced by the heterologous boost of NVSI-06-07, suggesting that it may serve as an effective boosting strategy combating the pandemic of Omicron. The similar results were obtained for other VOCs, including Alpha, Beta and Delta, in which the neutralizing response elicited by the heterologous boost was also significantly greater than that of the homologous boost. In the participants primed with BBIBP-CorV over 6 months, the largest increase in the neutralizing GMTs was obtained both in the heterologous and homologous boost groups, and thus the booster vaccination with over 6 months intervals was optimal.

InterpretationOur findings indicated that the heterologous boost with NVSI-06-07 was safe, well-tolerated and immunogenic in adults primed with a full regimen of BBIBP-CorV. Compared to homologous boost with a third dose of BBIBP-CorV, incremental increases in immune responses were achieved by the heterologous boost with NVSI-06-07 against SARS-CoV-2 prototype strain, Omicron variant, and other VOCs. The heterologous BBIBP-CorV/NVSI-06-07 prime-boosting vaccination may be valuable in preventing the pandemic of Omicron. The optimal booster strategy was the heterologous boost with NVSI-06-07 over 6 months after a priming with two doses of BBIBP-CorV.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed for clinical trials or prospective/cohort studies involving heterologous booster vaccination in non-immunocompromised population published up to Dec 25, 2021, using the term "(COVID) AND (vaccin*) AND (clinical trial OR cohort OR prospective) AND (heterologous) AND (booster OR prime-boost OR third dose)" with no language restrictions. Nine studies of heterologous prime-boost vaccinations with adenovirus-vector vaccines (ChAdOx1 nCov-19, Oxford-AstraZeneca, Ad26.COV2.S, Janssen) and mRNA vaccines (BNT162b2, Pfizer-BioNtech; mRNA1273, Moderna) were identified. The adenovirus-vector and mRNA heterologous prime-boost vaccination was found to be well tolerated and immunogenic. In individuals primed with adenovirus-vector vaccine, mRNA booster vaccination led to greater immune response than homologous boost. However, varied results were obtained on whether heterologous boost was immunogenically superior to the homologous mRNA prime-boost vaccination. Besides that, A preprint trial in population previously immunized with inactivated vaccines (CoronaVac, Sinovac Biotech) showed that the heterologous boost with adenovirus-vector vaccine (Convidecia, CanSino Biologicals) was safe and induced higher level of live-virus neutralizing antibodies than by the homogeneous boost. A pilot study reported that boosting with BNT162b2 in individuals primed with two doses of inactivated vaccines (BBIBP-CorV) was significantly more immunogenic than homologous vaccination with two-dose of BNT162b2. In addition, a preprint paper demonstrated that heterologous boost of ZF2001, a recombinant protein subunit vaccine, after CoronaVac or BBIBP-CorV vaccination potently improved the immunogenicity. But only a small size of samples was tested in this study and the live-virus neutralization was not detected. Till now, it is still lacking a formal clinical trial to evaluate the immunogenicity and safety of the heterologous prime-boost vaccination with an inactivated vaccine followed by a recombinant protein subunit-based vaccine.

Added value of this studyTo our knowledge, this is the first reported result of a large-scale randomised, controlled clinical trial of heterologous prime-boost vaccination with an inactivated vaccine followed by a recombinant protein subunit vaccine. This trial demonstrated that the heterologous prime-booster vaccination with BBIBP-CorV/NVSI-06-07 is safe and immunogenic. Its immunoreactivity is similar to that of homologous vaccination with BBIBP-CorV. Compared to homologous boost, heterologous boost with NVSI-06-07 in BBIBP-CorV recipients elicited significantly higher immunogenicity not only against the SARS-CoV-2 prototype strain but also against Omicron and other variants of concern (VOCs).

Implications of all the available evidenceBooster vaccination is considered an effective strategy to improve the protection efficacy of COVID-19 vaccines and control the epidemic waves of SARS-CoV-2. Data from our trial suggested that the booster vaccination of NVSI-06-07 in BBIBP-CorV recipients significantly improved the immune responses against various SARS-CoV-2 strains, including Omicron. Due to no Omicron-specific vaccine available currently, the BBIBP-CorV/NVSI-06-07 heterologous prime-boost might serve as an effective strategy combating Omicron variant. Besides that, BBIBP-CorV has been widely inoculated in population, and thus further boosting vaccination with NVSI-06-07 is valuable in preventing the COVID-19 pandemic. But further studies are needed to assess the long-term protection of BBIBP-CorV/NVSI-06-07 prime-booster vaccination.


title: Immunological Cross-Reactivity to Dengue Virus among Persons with Neuroinvasive West Nile Virus Infection

abstract: Antibody dependent enhancement has been well described between Zika and dengue viruses, but is poorly characterized between West Nile and dengue viruses. We demonstrate that neuroinvasive West Nile virus infection leads to the development of non-neutralizing, cross-reactive IgG antibodies to dengue and Zika viruses capable of causing antibody dependent enhancement in vitro of dengue virus and leads to the formation of flavivirus cross-reactive memory B cells in some patients.

category: infectious diseases


title: BARRIERS TO THE USE OF METHYLPHENIDATE IN PAEDIATRIC NEURO-ONCOLOGY SERVICES

abstract:
BackgroundThe increasing effectiveness of childhood cancer treatment has resulted in a greater number of children surviving previously incurable central nervous system tumours. This growing population of survivors report significant treatment-related difficulties, including attentional impairment associated with poor long-term intellectual development, academic attainment, and health-related quality of life. Clinical findings show benefit to attention and executive functions following methylphenidate administration. The current project explored barriers associated with use of methylphenidate in paediatric neuro-oncology services in the UK.

MethodQualitative data was gathered by semi-structured questionnaire sent to clinical psychologists/neuropsychologists in 19 of the 21 NHS primary treatment oncology centres in the UK in May 2018. Thematic analytic methods were used to explore the data.

Results11 responses were received from primary treatment centres. Knowledge of the evidence base for methylphenidate in paediatric brain injury was limited. This was primarily attributable to the inadequate resource of psychology into many primary treatment centres, limiting provision to service to a restricted proportion of the patient group. Psychologists reported an interest in exploring the utility of methylphenidate in their patient group. Respondents highlighted the need for provision of accessible research summaries and treatment protocols addressing the potential use of psychostimulants, stating that these would support their team to consider expanding the interventions offered.

ConclusionsThe development of shared resources for clinicians will be important in supporting the application of research findings to clinical practice. We anticipate national collaboration will support the advancement of intervention for the growing clinical population of long-term survivors.

category: oncology


title: Frequent Quantitation of Circulating Tumor Cells Predictive of Real-Time Therapy Response

abstract: Precision medicine is playing an increasingly important role in cancer management and treatment. Specifically in the field of oncology, circulating tumor cells (CTCs) hold significant promise in enabling non-invasive prognostication and near real-time monitoring to individualize treatments. In this study, we present strong associations between CTC subtype counts with treatment response and tumor staging in lung, nasopharyngeal and breast cancers. Longitudinal analysis of CTC count changes over short-time windows further reveals the ability to predict treatment response close to real-time. Our findings demonstrate the suitability of CTCs as a definitive blood-based metric for continuous treatment monitoring. Robust processing of high-throughput image data, explainable classification of CTC subtypes and accurate quantification were achieved using an in-house image analysis system  CTC-Quant, which showed excellent agreement with expert opinion upon extensive validation.


title: Discordant SARS-CoV-2 PCR and Rapid Antigen Test Results When Infectious: A December 2021 Occupational Case Series

abstract: The performance of Covid-19 diagnostic tests must continue to be reassessed with new variants of concern. The objective of this study was to describe the discordance in saliva SARS-CoV-2 PCR and nasal rapid antigen test results during the early infectious period. We identified a high-risk occupational case cohort of 30 individuals with daily testing during an Omicron outbreak in December 2021. Based on viral load and transmissions confirmed through epidemiological investigation, most Omicron cases were infectious for several days before being detectable by rapid antigen tests.


title: The French domestic "sanitary pass" did not solve Covid-19 vaccination inequities in France

abstract:
ContextTo encourage Covid-19 vaccination, France introduced during the Summer 2021 a "Sanitary Pass," which morphed into a "Vaccine Passe" in early 2022. While the Sanity Pass led to an increase in Covid-19 vaccination rates, spatial heterogeneities in vaccination rates remained. To identify potential determinants of these heterogeneities and evaluate the French Sanitary and Vaccine Pass efficacies in reducing them, we used a data-driven approach on exhaustive nationwide data, gathering 141 socio-economic, political and geographic indicators.

MethodsWe considered the association between being a district above the median value of the first-dose vaccination rates and being above the median value of each indicator at different time points: just before the sanitary pass announcement (week 2021-W27), just before the sanitary pass came into force (week 2021-W31) and one month after (week 2021-W35), and the equivalent dates for the vaccine pass (weeks 2021-W49, 2022-W03, 2022-W07). We then considered the change over time of vaccination rates according to deciles of the three of the most associated indicators.

ResultsThe indicators most associated with vaccination rates were the share of local income coming from unemployment benefits, the proportion of overcrowded households, the proportion of immigrants in the district, and vote for an "anti-establishment" candidate at the 2017 Presidential election. Vaccination rate also were also contrasted along a North-West - South East axis, with lower vaccination coverage in the South-East of France.

ConclusionOur analysis reveals that, both before and after the introduction of the French sanitary and vaccination passes, factors with the largest impact are related to poverty, immigration, and trust in the government.

category: public and global health


title: The French Covid-19 vaccination policy did not solve vaccination inequities: a nationwide longitudinal study on 64.5 million individuals


title: An integrated genome and phenome-wide association study approach to understanding Alzheimer's disease predisposition

abstract:
BackgroundGenome-wide association studies (GWAS) have identified common, heritable alleles that increase late-onset Alzheimers disease (LOAD) risk. We recently published an analytic approach to integrate GWAS and phenome-wide association study (PheWAS) data, enabling identification of candidate traits and trait-associated variants impacting disease risk, and apply it here to LOAD.

MethodsPheWAS was performed for 23 known LOAD-associated single nucleotide polymorphisms (SNPs) and 4:1 matched control SNPs using UK Biobank data. Traits enriched for association with LOAD SNPs were ascertained and used to identify trait-associated candidate SNPs to be tested for association with LOAD risk (17,008 cases; 37,154 controls).

ResultsLOAD-associated SNPs were significantly enriched for associations with 6/778 queried traits, including three platelet traits. The strongest enrichment was for platelet distribution width (PDW) (P=1.2x10-5), but no consistent direction of effect was observed between increased PDW and LOAD susceptibility across variants or in Mendelian randomization analysis. Of 384 PDW-associated SNPs identified by prior GWAS, 36 were nominally associated with LOAD risk and 5 survived false-discovery rate correction for multiple testing. Associations confirmed known LOAD risk loci near PICALM, CD2AP, SPI1, and NDUFAF6, and identified a novel risk locus in the epidermal growth factor receptor (EGFR) gene.

ConclusionsThrough integration of GWAS and PheWAS data, we identify substantial pleiotropy between genetic determinants of LOAD and of platelet morphology, and for the first time implicate EGFR - a mediator of {beta}-amyloid toxicity - in Alzheimers disease susceptibility.

category: genetic and genomic medicine


title: Safety and immunogenicity of anti-SARS CoV-2 conjugate vaccine SOBERANA 02 in a two-dose or three-dose heterologous scheme in adults: Phase IIb Clinical Trial

abstract:
BackgroundWe report results of immunogenicity, safety and reactogenicity of SOBERANA 02 in a two-dose or three-dose heterologous scheme in adults in a phase IIb clinical trial.

MethodThis phase IIb trial was designed as parallel, multicentre, adaptive, double blind, randomized and placebo-controlled. Subjects (N=810) aged 19-80 years were randomized to receive two doses of the recombinant SARS CoV-2 receptor binding domain (RBD) conjugated to tetanus toxoid (SOBERANA 02) and a third dose of dimeric RBD (SOBERANA Plus) 28 days apart; two production batches of active ingredient of SOBERANA 02 were evaluated. Primary outcome was the percentage of seroconverted subjects with [≥]4-fold the anti-RBD IgG concentration. Secondary outcomes were safety, reactogenicity and neutralizing antibodies.

ResultsSeroconversion rate in vaccinees was respectively 76.3 and 96.8% after two or three doses, compared with 7.3% in placebo group. Anti-RBD IgG increased significantly after first and second dose of SOBERANA 02 respect to placebo group; and the third dose with SOBERANA Plus boosts the response compared to the second dose. Neutralizing IgG antibodies were detected against D614G and VOCs , {beta} and {delta}. Specific and functional antibodies were detected at least until 7-8 months after the third dose. The frequency of serious adverse events (AEs) associated with vaccination was very low (0.1%); with only one serious AE consistent with vaccination. Local pain was the most frequent AE.

ConclusionsTwo doses of SOBERANA 02 were well tolerated, safe an immunogenic in adults aged 19-80 years old. The heterologous combination with a third dose of SOBERANA Plus increased neutralizing antibodies, detectable 7-8 months after finishing the vaccination schedule.

Trial registryhttps://rpcec.sld.cu/trials/RPCEC00000347


title: Daily Lactobacillus Probiotic versus Placebo in COVID-19-Exposed Household Contacts (PROTECT-EHC): A Randomized Clinical Trial

abstract:
STRUCTURED ABSTRACTO_ST_ABSImportanceC_ST_ABSThe COVID-19 pandemic continues to pose unprecedented challenges to worldwide health. While vaccines are effective, supplemental strategies to mitigate the spread and severity of COVID-19 are urgently needed. Emerging evidence suggests susceptibility to infections, including respiratory tract infections, may be reduced by probiotic interventions; therefore, probiotics may be a low-risk, widely implementable modality to mitigate risk of COVID-19 disease, particularly in areas with low vaccine availability and/or uptake.

ObjectiveTo determine whether daily probiotic Lactobacillus rhamnosus GG (LGG) is effective in preventing development of symptoms of illness within 28 days of COVID-19 exposure.

DesignThis randomized, double-blind, placebo-controlled trial across the United States (PROTECT-EHC) enrolled in 2020-2021. Participants were followed for 60 days.

SettingDescribe the study setting to assist readers to determine the applicability of the report to other circumstances, for example, multicenter, population-based, primary care or referral center(s), etc.

ParticipantsParticipants included individuals [≥] 1 year of age with a household contact with a recent ([≤] 7 days) diagnosis of COVID-19. 182 participants were enrolled and randomized during the study period.

InterventionParticipants were randomized to receive daily oral LGG or microcrystalline cellulose placebo for 28 days.

Main Outcomes and MeasuresThe primary outcome was development of symptoms within 28 days of exposure to a COVID-19-infected household contact. Stool was collected to evaluate for changes in microbiome structure.

Results182 participants were enrolled and randomized during the study period. Intention-to-treat analysis showed that participants randomized to LGG were less likely to develop symptoms versus those randomized to placebo (26.4% vs. 42.9%, p=0.02). Further, LGG was associated with a statistically significant reduction in COVID-19 diagnosis (log rank p=0.049) via time-to-event analysis. Overall incidence of COVID-19 diagnosis did not significantly differ between LGG and placebo groups (8.8% vs. 15.4%, p=0.17). LGG was well-tolerated with no increased side effects versus placebo. Placebo recipients were more likely to stop the study product, temporarily or permanently, due to symptoms attributed to the study product (5.5% vs. 0%, p = 0.02).

Conclusions and RelevanceOur study suggests that LGG is well-tolerated and is associated with prolonged time to development of COVID-19 infection, reduced incidence of symptoms, and changes to gut microbiome structure when used as post-exposure prophylaxis within 7 days after exposure. This preliminary work may inform the approach to prevention of COVID-19, particularly in underdeveloped nations where Lactobacillus probiotics have already been utilized to reduce non-COVID sepsis and infectious-morbidity. This study was limited by its remote format, which necessitated a primary endpoint of self-reported symptoms rather than laboratory-confirmed infection; further laboratory-based studies are needed to further define the efficacy of LGG in preventing COVID-19 infection, especially in larger populations and including comparison of pre-exposure vs. post-exposure prophylaxis.

Trial registrationClinicalTrials.gov, NCT04399252, https://clinicaltrials.gov/ct2/show/NCT04399252

KEY POINTSO_ST_ABSQuestionC_ST_ABSIs daily probiotic Lactobacillus rhamnosus GG (LGG) effective in preventing development of symptoms of illness compatible with COVID-19 within 28 days of COVID-19 exposure compared to placebo?

FindingsIn this randomized clinical trial that included 182 participants, the proportion who developed symptoms was 26.4% with LGG versus 42.9% with placebo, a significant difference.

MeaningLGG probiotic may protect against the development of symptoms when used as post-exposure prophylaxis within 7 days after COVID-19 exposure.


title: An electrocardiography score predicts heart failure hospitalization or death beyond that of cardiovascular magnetic resonance imaging

abstract:
BackgroundThe electrocardiogram (ECG) and cardiovascular magnetic resonance imaging (CMR) both provide powerful prognostic information. The aim was to determine the relative prognostic value of ECG and CMR, respectively.

MethodsConsecutive patients (n=783) undergoing CMR and resting 12-lead ECG with a QRS duration <120 ms were included. CMR measures included feature tracking global longitudinal strain (GLS), extracellular volume fraction (ECV), left ventricular mass and volumes, and ischemic and non-ischemic scar size. Prognosis scores for one-year event-free survival were derived using continuous ECG or CMR measures, and multinomial logistic regression, and compared with regards to the combined outcome of survival free from hospitalization for heart failure or death.

ResultsPatients (median [interquartile range] age 55 [43-64] years, 44% female) had 155 events during 5.7 [4.4-6.6] years. The ECG prognosis score included 1) the frontal plane QRS-T angle, and 2) the heart rate corrected QT duration (QTc) (log-rank 55, p<0.001). The CMR prognosis score included 1) GLS, and 2) ECV (log-rank 85, p<0.001). The combination of positive scores for both ECG and CMR yielded the highest prognostic value (log-rank 105, p<0.001). Multivariable analysis showed an association with outcomes for both the ECG prognosis score (log-rank 8.4, hazard ratio [95% confidence interval] 1.29 [1.09-1.54], p=0.004) and the CMR prognosis score (log-rank 47, hazard ratio 1.90 [1.58-2.28], p<0.001).

ConclusionsAn ECG prognosis score predicted outcomes independently of, and beyond CMR. Combining the results of ECG and CMR using both prognosis scores improved the overall prognostic performance.

category: cardiovascular medicine


title: Preliminary modeling estimates of the relative transmissibility and immune escape of the Omicron SARS-CoV-2 variant of concern in South Africa

abstract: We develop a stochastic, multi-strain, compartmental epidemic model to estimate the relative transmissibility and immune escape of the Omicron variant of concern (VOC) in South Africa. The model integrates population, non-pharmaceutical interventions, vaccines, and epidemiological data and it is calibrated in the period May 1st, 2021 - November 23rd, 2021. We explore a parameter space of relative transmissibility with respect to the Delta variant and immune escape for Omicron by assuming an initial seeding, from unknown origin, in the first week of October 2021. We identify a region of the parameter space where combinations of relative transmissibility and immune escape are compatible with the growth of the epidemic wave. We also find that changes in the generation time associated with Omicron infections strongly affect the results concerning its relative transmissibility. The presented results are informed by current knowledge of Omicron and subject to changes.

category: epidemiology


title: Bayesian Estimation of real-time Epidemic Growth Rates using Gaussian Processes: local dynamics of SARS-CoV-2 in England

abstract: Quantitative assessments of the recent state of an epidemic and short-term projections into the near future are key public health tools that have substantial policy impacts, helping to determine if existing control measures are sufficient or need to be strengthened. Key to these quantitative assessments is the ability to rapidly and robustly measure the speed with which the epidemic is growing or decaying. Frequently, epidemiological trends are addressed in terms of the (time-varying) reproductive number R. Here, we take a more parsimonious approach and calculate the exponential growth rate, r, using a Bayesian hierarchical model to fit a Gaussian process to the epidemiological data. We show how the method can be employed when only case data from positive tests are available, and the improvement gained by including the total number of tests as a measure of heterogeneous testing effort. Although the methods are generic, we apply them to SARS-CoV-2 cases and testing in England, making use of the available high-resolution spatio-temporal data to determine long-term patterns of national growth, highlight regional growth and spatial heterogeneity.


title: Test to release from isolation after testing positive for SARS-CoV-2

abstract:
O_LIThe rapid spread and high transmissibility of the Omicron variant of SARS-CoV-2 is likely to lead to a significant number of key workers testing positive simultaneously.
C_LIO_LIUnder a policy of self-isolation after testing positive, this may lead to extreme staffing shortfalls at the same time as e.g. hospital admissions are peaking.
C_LIO_LIUsing a model of individual infectiousness and testing with lateral flow tests (LFT), we evaluate test-to-release policies against conventional fixed-duration isolation policies in terms of excess days of infectiousness, days saved, and tests used.
C_LIO_LIWe find that the number of infectious days in the community can be reduced to almost zero by requiring at least 2 consecutive days of negative tests, regardless of the number of days wait until testing again after initially testing positive.
C_LIO_LIOn average, a policy of fewer days wait until initiating testing (e.g 3 or 5 days) results in more days saved vs. a 10-day isolation period, but also requires a greater number of tests.
C_LIO_LIDue to a lack of specific data on viral load progression, infectivity, and likelihood of testing positive by LFT over the course of an Omicron infection, we assume the same parameters as for pre-Omicron variants and explore the impact of a possible shorter proliferation phase.
C_LI


title: Full title: COVID-19 disease progression according to initial symptoms. A telemedicine cohort study.

abstract:
ObjectiveCOVID-19 progression to severe or critical illness may be related to initial clinical presentation. Main objective was to identify initial symptoms related to highest risk of disease progression, in mild or moderate suspected or confirmed COVID-19 patients or in asymptomatic subjects in contact with a recently diagnosed patient.

Design and methodsHistoric cohort study of Mexican patients with suspected or confirmed mild or moderate COVID-19 or asymptomatic subjects in recent contact with positive patients. They sought medical attention in "Centro Medico ABC" or claimed for remote attention, and daily telemedicine follow up until recovery or illness progression, from April 17th to October 08th 2020. Data excerpted for analysis were sex, age, body mass index, comorbidities, and signs, and symptoms presented in first day of disease manifestations and during follow up. We used logistic regression to identify initial symptoms associated with progression disease and through a conjunctive consolidation analysis a symptom index was created.

Results120 of 1635 patients (7.2%) had clinical progression disease. By logistic regression we found as initial symptoms related to progression: fever OR 3 (1.89-4.77, p<0.001), cough OR 2.34 (1.56-3.52, p<0.001), myalgias or arthralgias OR 1.69 (1.09-2.63, p=0.018), and fatigue OR 1.65 (1.08-2.53, p=0.019). Conjunctive consolidation was processed with the previous symptoms, and a 3 groups score resulted C-19PAIS Index: 1) Fever with cough or fever with fatigue, with a probability of progression disease of 29% (31/106 patients), 2) Fever or cough or fatigue or cough with fatigue, 10.7% (66/615 patients) and 3) No fever, no cough, no fatigue, 2% (23/914).

ConclusionsInitial symptoms predict clinical progression in COVID-19 patients.

category: primary care research


title: Infrequent intranasal oxytocin followed by positive social interaction improves symptoms in autistic children: a randomized clinical trial

abstract: There are currently no approved drug interventions for social behavior dysfunction in autism spectrum disorder (ASD). Previous trials investigating effects of daily intranasal oxytocin treatment have reported inconsistent results and have not combined it with positive social interaction. However, In two preclinical studies we established that treatment every-other-day rather than daily is more efficacious in maintaining neural and behavioral effects by reducing receptor desensitization. We aimed to establish whether a 6-week intranasal oxytocin compared with placebo treatment, followed by a period of positive social interaction, would produce reliable symptom improvements in children with ASD. A pilot double-blind, randomized, crossover design trial was completed including 41 children with ASD aged 3-8 years. Primary outcomes were the Autism Diagnostic Observation Schedule-2 (ADOS-2) and social responsivity scale-2 (SRS-2). Secondary measures included cognitive, autism and caregiver-related questionnaires and social attention assessed using eye-tracking. Significant improvements were found for oxytocin relative to placebo in primary outcome measures (total ADOS-2 and SRS-2 scores, ps < 0.001) and in behavioral adaptability and repetitive behavior secondary measures. Altered SRS-2 scores were associated with increased saliva oxytocin concentrations. Additionally, oxytocin significantly increased time spent viewing dynamic social compared to geometric stimuli and the eyes of angry, happy and neutral expression faces. There were no adverse side-effects of oxytocin treatment. Overall, results demonstrate that a 6-week intranasal oxytocin treatment administered every other day and followed by positive social interactions can improve clinical, eye-tracking and questionnaire-based assessments of symptoms in young autistic children.

category: psychiatry and clinical psychology


title: Infrequent intranasal oxytocin followed by positive social interaction improves symptoms in autistic children: a pilot randomized clinical trial


title: Effect of vitamin D on infection and inflammation in patients with cystic fibrosis: a systematic review and meta-analysis

abstract:
BackgroundCystic fibrosis (CF) is a genetic disorder in which the respiratory system gets clogged with mucus leads to progressive lung damage. There is no known cure for CF but several treatments to manage symptoms and reduce complications. Vitamin D deficiency is common in CF associated with increased infection and inflammation. This systematic review and meta-analysis will evaluate the effectiveness of vitamin D treatment in reducing respiratory tract infection and inflammation in patients with CF.

MethodsRandomized and quasi-randomised studies in CF patients with control groups will be identified. The antibacterial activity of vitamin D supplementation will help in reducing respiratory tract infection and inflammation in CF. Overall effects of vitamin D in terms of infection and inflammatory markers such as C-reactive protein, inflammatory cytokine interleukin (IL)-6, IL-8, IL-17, IL-23, antimicrobial peptide (LL-37), lung function defined by forced expiratory volume in 1 second (FEV1) %, other assessed respiratory parameters will be calculated using random-effect models. Study quality will be assessed using RoB 2 - A revised Cochrane Risk of Bias tool for randomised trials. The overall quality of evidence for each outcome will be summarised according to the Grading of Recommendations Assessment, Development, and Evaluations (GRADE) framework.


title: Assessing the relationship between measures of healthcare access and functional limitations among individuals with Chronic Obstructive Pulmonary Disease (COPD)

abstract:
ObjectivesFunctional limitation from COPD manifests more from physical rather than respiratory impairment. To what extent health access affects the functional limitation among individuals with COPD is yet to be known. This study aims to assess the relationship between healthcare access and functional limitations among individuals with COPD.

Study DesignRetrospective analysis of a cross-sectional population-based survey

MethodsThis study pooled 11-year (2008 - 2018) data from the Integrated Public Use Microdata Series - National Health Interview Survey (IPUMS-NHIS). We restricted the data to respondents with self-reported COPD, aged 40 years and older. The independent variables were sociodemographic and behavioral characteristics. The exploratory variables were measures of healthcare access - healthcare coverage, delayed appointment, affordable care, and a usual place for care. The outcome variable was the presence or absence of functional limitations.

ResultsThe age, race, educational attainment, marital status, smoking status, and poverty-income ratio had a significant association with functional limitation (p<0.001) We found statistically significant associations between functional limitation and healthcare coverage, delayed appointment, affordable care, and a usual place for care. Poverty modified the relationship between functional limitations and the four measures of healthcare access, with the odds of functional limitation increased among the poor with no healthcare coverage, delayed appointment, unaffordable care, and no usual place for care.

ConclusionsA strong relationship exists between the quartet of healthcare coverage, delayed appointment, affordable care, and usual place for care and self-reported functional limitation among individuals with COPD. Poverty was an effect modifier, with the odds of functional limitation worse among the poor.

category: respiratory medicine


title: Does choice of athletic footwear affect musculoskeletal injury risk in US Coast Guard recruits? A retrospective cohort study.

abstract:
ContextMusculoskeletal injuries (MSKIs) are ubiquitous during initial entry military training, with overuse injuries in the lower extremities the most frequent. A common mechanism for overuse injuries is running, an activity that is an integral part of United States Coast Guard (USCG) training and a requirement for graduation.

ObjectiveAssess the effects of athletic footwear choice on lower quarter MSKI risk in USCG recruits.

DesignDescriptive Epidemiological Study

SettingUSCG Training Center, Cape May, NJ

ParticipantsA retrospective cohort study was performed in which 1229 recruits (1038 males, 191 females) were allowed to self-select athletic footwear during training. A group of 2876 recruits (2260 males, 616 females) who trained under a policy that required obligatory wear of prescribed athletic shoes served as a control.

Main Outcome MeasuresDemographic data and physical performance were derived from administrative records. Injury data were abstracted from a medical tracking database. Multivariable logistic regression was used to assess group, age, sex, height, body mass, and run times on MSKI outcomes.

ResultsAnkle-foot, leg, knee and lumbopelvic-hip complex diagnoses were ubiquitous in both groups (experimental: 20.37 to 29.34 per 1000 recruits; control: 18.08 to 25.59 per 1000 recruits). Group was not a significant factor for any of the injuries assessed. Sex was a significant factor in all injury types, with female recruits demonstrating [~]2.00 greater odds of experiencing running-related injuries (RRIs), overuse injuries, or any MSKI in general. When considering ankle-foot or bone stress injuries, the risk in female recruits was 3.73 to 4.11 greater odds than their male counterparts. Run time was a significant predictor in RRI, all overuse injuries, and for any MSKI in general.

ConclusionWhile footwear choice did not influence MSKI risk in USCG recruits, female sex was a primary, nonmodifiable intrinsic risk factor.

Key PointsO_LISelf-selection of athletic footwear was not a significant factor for MSKI in USCG recruits, despite widespread reports of discomfort and perceived deleterious effects of wear.
C_LIO_LIMSKI continues to be a major source of morbidity in the recruit training population, with female sex found to be a robust and significant factor regardless of footwear choice.
C_LIO_LIWhile there is no indication that prescribed athletic footwear is associated with MSKI, policymakers should factor in individual preference when considering the mandate for wear.
C_LI

category: sports medicine


title: Efficacy and Safety of Viable Selective Germline Genome  Edited Pigs Skin Xenotransplants in Patients with Thermal Burns

abstract:
BackgroundRapid closure of open wound, either temporarily or perpetually, is recognized as the standard of care in patients with thermal burns. Human cadaveric allograft and simple genetically modified porcine xenografts are not able to provide enough durable time for extensively burned patients. A selective germline genome edited pig (SGGEP) skin xenograft, Xeno X skin, would be a valuable candidate to the clinical options.

MethodsIn an ongoing investigator-initiated clinical trial in patients with thermal burns, the efficacy and safety of cryopreserved Xeno X skin grafts of SGGEP for burned patients were evaluated. Each patient received surgical grafting with a skin xenotransplant and wild type pig extracellular matrix (wpECM) in a side-by-side manner for in-situ comparison.

The primary outcome measures of xeno-skin grafts included Xeno X skin safety and tolerability, as well as the quality and duration of temporary barrier function yielded by Xeno X skin grafts (as determined by Baux score). Seven parameters included in the analysis were vascularization, pigmentation, thickness, relief, pliability, surface area and the overall opinion, with each calculated on an independent 0-10 scale.

ResultsA total of 16 burned patients completed the trial. All the patients tolerated Xeno X skin grafts well and no advent events were observed. In all cases, Xeno X skin grafts were vascularized and fully adherent, they also exhibited better overall outcomes than those of wpECM. Xeno X skin grafts survived for at least 25 days without a need of any immunosuppressive drug, well consistent with our earlier preclinical studies in non-human primates.

ConclusionXeno X skin grafts of SGGEP did not incur any signs of local and systemic safety issues, and in the meanwhile provided a high quality and long duration of temporary barrier function for burned patients. This is a major milestone in the xenotransplant field, indicating that genome-edited organ xenotransplant has become a clinical reality.

category: transplantation


title: Seroresponse to third doses of SARS-CoV-2 vaccine among patients receiving maintenance dialysis

abstract: Given the increased morbidity and mortality from COVID-19 among patients undergoing maintenance dialysis, we examined the seroresponse to an additional dose of SARS-CoV-2 mRNA vaccine, using a hypothesized protective anti-spike protein IgG antibody threshold of 7 based on prior work. Among 395 patients, 384 (97%) had seroresponse [≥]7 following administration of the third dose. Among those with suboptimal (peak <7) and minimal (peak <1) seroresponse to an initial mRNA vaccine regimen, the rate of seroresponse [≥]7 following a third dose was 97% (36 of 37) and 64% (14 of 22), respectively. Given ongoing high rates of COVID-19 and rapidly waning immunity after an initial vaccine series, we recommend a third mRNA vaccine dose be standard for all patients receiving maintenance dialysis.

category: nephrology


title: Multiple and quantitative measurements using computed tomography images reveal the factors associated with chronic subdural hematoma recurrence

abstract:
ObjectiveThe aim of this retrospective single-center study was to quantitatively assess chronic subdural hematomas (CSDHs), reveal the correlations between multiple and quantitative values calculated from computed tomography images, and determine the risk factors for CSDH recurrence.

MethodsWe enrolled 225 patients who underwent 304 burr-hole surgeries between April 2005 and October 2021 at Otemae Hospital. Patients medical records and quantitative values including preoperative CSDH volume (ml), thickness (mm), computed tomography values (CTV), postoperative CSDH volume (ml), and air volume (ml) were evaluated. The locations of CSDH thickness and burr holes were also assessed quantitatively using Montreal Neurological Institute coordinates. Univariate and multivariate regression analyses and receiver operating characteristic (ROC) analyses were performed.

ResultsThirty-seven patients (12%) showed CSDH recurrence requiring reoperation. Preoperative CSDH volume was positively correlated with age, preoperative CSDH thickness, CTV, postoperative CSDH volume, and air volume. Univariate Cox proportional hazards regression analysis showed that age, preoperative CSDH volume, Glasgow Coma Scale score (3-14), postoperative hemiplegia, and gait disturbance were risk factors for recurrence requiring reoperation, and a higher CTV (hazard ratio 0.95, 95% confidence interval 0.91-0.99) was associated with a lower risk of recurrence requiring reoperation. Only preoperative CSDH volume was a significant risk factor for recurrence requiring reoperation in multivariate regression analyses. The postoperative air volume and locations of CSDH thickness and burr hole had no influence on recurrence requiring reoperation. ROC curve analysis revealed that the optimal preoperative CSDH volume cut-off value as a predictor was 155 ml, the thickness was approximately 36.3 mm calculated from a regression line.

ConclusionsA larger and more hypodense CSDH has a high risk of recurrence requiring reoperation. Residual air volume after surgery and locations of CSDH and burr hole had no influence on recurrence requiring reoperation.

category: neurology


title: A Nonrandomized Phase 2 Trial of EG-Mirotin, a Novel, First-in-class, Subcutaneously Delivered Peptide Drug for Non-Proliferative Diabetic Retinopathy

abstract:
BackgroundEG-Mirotin, which includes an active ingredient; EGT022, targeting Non-Proliferative Diabetic Retinopathy (NPDR), the early stage of retinopathy. EG-Mirotin is a drug that is used before capillary damage progresses to an irreversible stage. Safety and efficacy of EG-Mirotin were investigated in subjects with Type 1 or 2 diabetes and NPDR with the degree from moderate to severe.

MethodsSubjects (n=10, 20 eyes) satisfying the selection criteria through the screening test were administered EG-Mirotin once a day (3 mg in 1.5 ml of sterile saline) for 5 days, 5 times in total, and were evaluated of the Ischemic index changes and safety. End-of-study (EOS) is performed approximately 8 weeks {+/-} 1 (57 days {+/-} 7) from the first dose.

ResultsA total of 4 Treatment Emergent Adverse Events (TEAE) were observed in 2 subjects out of 10 (20.00%) who received the investigational drug. Among them, no subjects were reported experiencing a TEAE related to the investigational drug. All injections were well tolerated (3 mg in 1.5 ml of sterile saline) with no dose-limiting adverse events, deaths, serious adverse events. The overall average percent change in ischemic index at each evaluation point compared to baseline was statistically significant (Greenhouse-Geisser F=9.456, p=0.004 for the main effect of time), and a larger change was observed when the baseline ischemic index value was high (Greenhouse-Geisser F=10.946, p=0.002 for the time*group interaction).

ConclusionsEG-Mirotin was well tolerated and found to reverse the ischemia and leakage of capillaries in the retina caused by diabetes.

category: ophthalmology


title: Causal effects of motor control on gait kinematics after orthopedic surgery in cerebral palsy: a machine-learning approach

abstract:
BackgroundAltered motor control is common in cerebral palsy (CP). Understanding how altered motor control effects movement and treatment outcomes is important, but challenging due to complex interactions between impairments. While regression can be used to examine associations between impairments and gait, causal modeling provides a mathematical framework to specify assumed causal relationships, identify covariates that may introduce bias, and test model plausibility. The goal of this research was to quantify the causal effects of altered motor control and other impairments on gait, before and after single-event multi-level orthopedic surgery (SEMLS).

MethodsWe evaluated the impact of SEMLS on change in Gait Deviation Index ({Delta}GDI) between gait analyses. We constructed our causal model with a Directed Acyclic Graph that included the assumed causal relationships between SEMLS, {Delta}GDI, baseline GDI (GDIpre), baseline neurologic and orthopedic impairments (Imppre), age, and surgical history. We identified the adjustment set to evaluate the causal effect of SEMLS on {Delta}GDI and the impact of Imppre on {Delta}GDI and GDIpre. We used Bayesian Additive Regression Trees (BART) and accumulated local effects to assess relative effects.

ResultsWe prospectively recruited a cohort of children with bilateral CP undergoing SEMLS (N=54, 35 males, age: 10.5{+/-}3.1 years) and identified a control cohort with bilateral CP who did not undergo SEMLS (N=55, 30 males, age: 10.0{+/-}3.4 years). There was a small positive causal effect of SEMLS on {Delta}GDI (1.68 GDI points). Altered motor control (i.e., dynamic and static motor control) and strength had strong effects on GDIpre, but minimal effects on {Delta}GDI. Spasticity and orthopedic impairments had minimal effects on GDIpre or {Delta}GDI.

ConclusionsAltered motor control and other baseline impairments did have a strong effect on GDIpre, indicating that these impairments do have a causal effect on a childs gait pattern but minimal effect on expected changes in GDI after SEMLS. Heterogeneity in outcomes suggests there are other factors contributing to changes in gait. Identifying these factors and employing causal methods to examine the complex relationships between impairments and movement will be required to advance our understanding and care of children with CP.

category: orthopedics


title: Genome-wide association study of nociceptive musculoskeletal pain treatment response in UK Biobank

abstract: Drug treatment for nociceptive musculoskeletal pain (NMP) follows a three-step analgesic ladder proposed by the World Health Organization (WHO), starting from non-steroidal anti-inflammatory drugs (NSAIDs), followed by weak or strong opioids until the pain is under control. However, effective pain treatment is challenged by inter-individual differences, and unsatisfied pain treatment response (PTR) rates ranging from 34 to 79% in those suffering from NMP. To investigate the underlying genetic component of PTR, we performed a genome-wide association study (GWAS) in [~] 23,000 participants with NMP from the UK Biobank. In our primary analysis, we compared NSAID vs. opioid users as a reflection of (non)response to NSAIDs, adjusting for age, sex, BMI, population substructure, and study-specific covariates. One genome-wide significant hit was identified in an intergenic region on chromosome 4, rs549224715 (P = 3.88x10-8), and seven signals pass the suggestively significant threshold (P < 1x10-6). All identified loci were in non-coding regions, but most variants showed potential regulatory functions. SNPs in LD (r2 > 0.6) with the lead SNPs passing the nominal significant threshold (P < 0.05) were mapped to 28 target genes in FUMA. Eight of these 28 genes are involved in processes linked to neuropathic pain and musculoskeletal development. Pathway and network analyses with Ingenuity resulted in the identification of immunity-related processes and a (putative) central role of EGFR. Genetic correlation analysis including 596 traits resulted in the identification of 67 nominally significant (P < 0.05) genetic correlations, and these traits were significantly enriched for chronic pain and socioeconomic status traits (P = 3.35 x 10-12). Additionally, we conducted a subtype GWAS for inflammatory NMP and a secondary GWAS for participants with NMP disease history, but no significant hits or overlap with the primary analysis were observed. Overall, we identified one genome-wide significant association in this first GWAS focusing on pain treatment using the analgesic ladder as phenotype. However, we realize that this study lacked power and should be viewed as a first step to elucidate the genetic background of NMP treatment.


title: Should rapid antigen tests be government funded in Australia? An economic evaluation

abstract:
IntroductionEasy and equitable access to testing is a cornerstone of the public health response to COVID-19. Currently in Australia, testing using Polymerase Chain Reaction (PCR) tests for COVID-19 is free-to-the-user, but the public purchase their own Rapid Antigen Tests (RATs). We conduct an economic analysis of government-funded RATs in Australia.

MethodsAn interactive decision tree model was developed to compare one policy in which government-funded RATs are free-to-the-user, and one in which individuals purchase their own RATs. The decision tree represents RAT and PCR testing pathways for a cohort of individuals without COVID-19-like symptoms, to estimate the likelihood of COVID-19 positive individuals isolating prior to developing symptoms and the associated costs of testing, from a government perspective. Key input parameter values are uncertain, so a range of scenario analyses are presented.

ResultsAssuming 10% prevalence of COVID-19 in a cohort of 10,000 individuals who would use government-funded RATs, and assuming 20% of the cohort would purchase RATs if not government-funded, the model estimates an additional 696 individuals would isolate early at a cost to the government of around $52,000. From these values, for every additional $112 associated with government funding of RATs, an additional individual with COVID-19 and no symptoms is expected to isolate. Scenario analyses indicate that the incremental cost to the government per additional COVID-19 positive individual isolating with no symptoms would, at most, be a few hundred dollars.

ConclusionsBased on the presented decision tree model, even only minor reductions in COVID-19 transmission rates due to early isolation would justify the additional costs associated with a policy of government-funded RATs.

category: health economics


title: Burden of SARS-CoV-2 and protection from symptomatic second infection in children

abstract:
ImportanceThe impact of the SARS-CoV-2 pandemic on children remains unclear. Better understanding of the burden of COVID-19 among children and their protection against re-infection is crucial as they will be among the last groups vaccinated.

ObjectiveTo characterize the burden of COVID-19 and assess how protection from symptomatic re-infection among children may vary by age.

DesignA prospective, community-based pediatric cohort study conducted from March 1, 2020 through October 15, 2021.

SettingThe Nicaraguan Pediatric Influenza Cohort is a community-based cohort in District 2 of Managua, Nicaragua.

ParticipantsA total of 1964 children aged 0-14 years participated in the cohort. Non-immunocompromised children were enrolled by random selection from a previous pediatric influenza cohort. Additional newborn infants aged [≤]4 weeks were randomly selected and enrolled monthly, via home visits.

ExposuresPrior COVID-19 infection as confirmed by positive anti SARS-CoV-2 antibodies (receptor binding domain [RBD] and spike protein) or real time RT-PCR confirmed COVID-19 infection [≥]60 days prior to current COVID-19.

Main Outcomes and MeasuresSymptomatic COVID-19 cases confirmed by real time RT-PCR and hospitalization within 28 days of symptom onset of confirmed COVID-19 case.

ResultsOverall, 49.8% of children tested were seropositive over the course of the study. There were also 207 PCR-confirmed COVID-19 cases, 12 (6.4%) of which were severe enough to require hospitalization. Incidence of COVID-19 was highest among children aged <2 years--16.1 per 100 person-years (95% Confidence Interval [CI]: 12.5, 20.5)--approximately three times that of children in any other age group assessed. Additionally, 41 (19.8%) symptomatic SARS-CoV-2 episodes were re-infections, with younger children slightly more protected against symptomatic reinfection. Among children aged 6-59 months, protection was 61% (Rate Ratio [RR]:0.39, 95% CI:0.2,0.8), while protection among children aged 5-9 and 10-14 years was 64% (RR:0.36,0.2,0.7), and 49% (RR:0.51,0.3-0.9), respectively.

Conclusions and RelevanceIn this prospective community-based pediatric cohort rates of symptomatic and severe COVID-19 were highest among the youngest participants, with rates stabilizing around age 5. Reinfections represent a large proportion of PCR-positive cases, with children <10 years displaying greater protection from symptomatic reinfection. A vaccine for children <5 years is urgently needed.

Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the burden of COVID-19 among young children and how does protection from re-infection vary with age?

FindingsIn this study of 1964 children aged 0-14 years children <5 years had the highest rates of symptomatic and severe COVID-19 while also displaying greater protection against re-infection compared to children [≥]10 years.

MeaningGiven their greater risk of infection and severe disease compared to older children, effective vaccines against COVID-19 are urgently needed for children under 5.


title: Household composition, smoking cessation and relapse: results from a prospective longitudinal Australian cohort

abstract:
AimsTo examine the association between household members and their tobacco smoking behaviour on patterns of smoking cessation and relapse.

Design and participantsData was sourced from 19 waves (years 2001 to 2019) of the nationally representative Household Income and Labour Dynamics in Australia (HILDA) survey, with all household members 15 years or older completing the survey annually. The final sample included, on average, 3,056 ex-smokers and 2,612 smokers per wave.

MeasurementsSelf-reported annual smoking status was used to construct measures of smoking cessation and relapse. Information on household structure and relationships was then used to develop variables describing the presence of household members and their smoking status by relationship to the individual (i.e., child, parent, spouse, sibling, or other). Multivariate regression analyses were then used to predict the likelihood of smoking cessation and relapse controlling for the presence of other household members and their smoking status, sociodemographic characteristics, number of cigarettes smoked per day, previous quit attempts, and years abstained from smoking.

FindingsIndividuals that lived with non-smokers were more likely to quit [OR1.22 (95%CI 1.11;1.34)] relative to those living alone. However, this favourable association was negated if living with another smoker, which was associated with a reduced likelihood of smoking cessation [OR0.77 (95%CI 0.72;0.83)] and a higher likelihood of relapse [1.37 (95%CI 1.22;1.53)]. In particular, living with a spouse or parent that smoked reduced the likelihood of smoking cessation [OR0.71 (95%CI 0.65;0.78) and OR0.71 (95%CI 0.59;0.84), respectively] and increased the likelihood of relapse [OR1.47 (95%CI 1.28;1.69) and OR1.39 (95%CI 1.00;1.94) respectively] relative to living with their non-smoking counterparts.

ConclusionsHousehold composition and intrahousehold smoking behaviour should be considered when delivering, or estimating the benefits of, smoking cessation interventions. Interventions which encourage smoking cessation at the household level may assist individuals to quit and abstain from smoking.

category: addiction medicine


title: Immune responses to inactivated and vector-based vaccines in individuals previously infected with SARS-CoV-2

abstract: Immunity wanes in individuals previously infected with SARS-CoV-2, and vaccinating those individuals may help reduce reinfection. Herein, reactogenicity and immunogenicity following vaccination with inactivated (CoronaVac) and vector-based (ChAdOx1-S, AZD1222) vaccines were examined in previously infected individuals. Immune response was also compared between short and long intervals between first date of detection and vaccination. Adverse events were mild but were higher with AZD1222 than with CoronaVac. Baseline IgG-specific antibodies and neutralizing activity were significantly higher with shorter than longer intervals. With a single-dose vaccine, IgG and IgA-specific binding antibodies, neutralizing activity, and total interferon-gamma response peaked at 14 days. Immune response was significantly higher in recovered individuals than in infection-naive individuals. Antibody response was greater with longer than shorter intervals. AZD1222 induced higher antibody and T cell responses than those of CoronaVac. Thus, to achieve immunity, individuals with prior SARS-CoV-2 exposure may require only a single dose of AZD1222 or two doses of CoronaVac to achieve the immune response. These findings supported vaccine strategies in previously infected individuals.

category: allergy and immunology


title: I do not know anybody who said, oh great, lets get measles: a qualitative study of responses to childhood vaccinations (MMRV) among Orthodox Jews in Jerusalem following the 2018-19 measles outbreaks

abstract:
Measles outbreaks have emerged among religious minorities in the global north, which cross regional and national boundaries and raise implications for measles elimination targets. Yet, studies are ambiguous about the reasons that underlie non-vaccination in religious populations, and whether and how religious "beliefs" influence vaccine decision-making among populations with suboptimal vaccination coverage. In 2018-19, Israel experienced the largest measles outbreaks in a quarter century - the burden of which disproportionately affected Orthodox Jewish neighbourhoods in Jerusalem. The objective of this study was to explore how Orthodox Jewish households in Jerusalem responded to the measles outbreaks in their neighbourhoods and how they viewed childhood vaccination (MMRV) during a public health emergency.

Research methods primarily consisted of 25 in-depth semi-structured interviews conducted with 23 household heads, and 2 public health professionals involved in planning and implementation of vaccination services. Thematic analysis generated five key themes, i) where the issue of sub-optimal vaccination uptake was perceived to be located; ii) how responsive people and services were to the measles outbreaks; iii) the sources of information used in vaccine decisions by religious parents; vi) whether vaccination was deemed a religious issue; and v) how vaccination influenced social relations within religious neighbourhoods.

Results demonstrate parental investment in protecting child health, with decisions around vaccination reflecting vaccine efficacy and safety, and the risk of measles transmission. Household heads across all Orthodox Jewish backgrounds were not apathetic towards measles transmission. No religious "beliefs" were identified for non-vaccination among the household heads in this cohort. Rather than relegating suboptimal vaccination uptake among religious minorities and populations as an issue of religious "beliefs," quality social science research should examine - and clearly convey - how religion influences vaccine decision-making. Such clarity can help to avoid stigmatizing religious minorities and populations, and to plan for appropriate vaccination programmes and promotion campaigns.


title: Reported Cases of Multisystem Inflammatory Syndrome in Children Aged 12 to 20 Years in the United States Who Received COVID-19 Vaccine, December 2020 through August 2021

abstract:
BackgroundMultisystem inflammatory syndrome in children (MIS-C) is a hyperinflammatory condition associated with antecedent SARS-CoV-2 infection. In the United States, reporting of MIS-C after vaccination is required under COVID-19 vaccine emergency use authorizations. This case series describes persons aged 12-20 years with MIS-C following COVID-19 vaccination reported to passive surveillance systems or through clinician outreach to CDC.

MethodsWe investigated potential cases of MIS-C after COVID-19 vaccination reported to CDCs health department-based national MIS-C surveillance, the Vaccine Adverse Event Reporting System (VAERS, co-administered by CDC and the U.S. FDA), and CDCs Clinical Immunization Safety Assessment Project (CISA) from December 14, 2020, to August 31, 2021. We describe cases meeting the CDC MIS-C case definition. Any positive SARS-CoV-2 serology test satisfied the case criteria although anti-nucleocapsid antibody indicates SARS-CoV-2 infection, while anti-spike protein antibody indicates either infection or COVID-19 vaccination.

FindingsWe identified 21 persons with MIS-C after COVID-19 vaccination. Of these 21 persons, median age was 16 years (range, 12-20 years); 13 (62%) were male. All were hospitalized; 12 (57%) had intensive care unit admission, and all were discharged home. Fifteen (71%) of the 21 had laboratory evidence of past or recent SARS-CoV-2 infection, and six (29%) did not. Through August 2021, 21,335,331 persons aged 12-20 years had received [≥]1 dose of COVID-19 vaccine, making the overall reporting rate for MIS-C following vaccination 1{middle dot}0 case per million persons receiving [≥]1 vaccine dose in this age group. The reporting rate for those without evidence of SARS-CoV-2 infection was 0{middle dot}3 cases per million vaccinated persons.

InterpretationIn our case series, we describe a small number of persons with MIS-C who had received [≥]1 COVID-19 vaccine dose before illness onset. Continued reporting of potential cases and surveillance for MIS-C illnesses after COVID-19 vaccination is warranted.

FundingThis work was supported by the Centers for Disease Control and Prevention Clinical Immunization Safety Assessment (CISA] Project contracts 200-2012-50430-0005 to Vanderbilt University Medical Center and 200-2012-53661 to Cincinnati Childrens Hospital Medical Center.

Research in context panelO_ST_ABSEvidence before this studyC_ST_ABSMultisystem inflammatory syndrome in children (MIS-C), also known as paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS), is an uncommon, but serious, complication described after SARS-CoV-2 infection that is characterized by a generalized hyperinflammatory response. A review of the literature using PubMed identified reports of six persons aged 12-20 years who developed MIS-C following COVID-19 vaccination. Search terms used to identify these reports were: "multisystem inflammatory syndrome in children", "MIS-C", "MISC", "multisystem inflammatory syndrome in adults", "MIS-A", "MISA", "paediatric inflammatory multisystem syndrome", and "PIMS-TS" each with any COVID-19 vaccine type. There were no exclusion criteria (i.e., all ages and languages).

Added value of this studyWe conducted integrated surveillance for MIS-C after COVID-19 vaccination using two passive surveillance systems, CDCs MIS-C national surveillance and the Vaccine Adverse Event Reporting System (VAERS), and clinician or health department outreach to CDC, including through Clinical Immunization Safety Assessment (CISA) Project consultations. We investigated reports of potential MIS-C occurring from December 14, 2020, to August 31, 2021, in persons aged 12-20 years any time after receipt of COVID-19 vaccine to identify those that met the CDC MIS-C case definition. Any positive serology test was accepted as meeting the CDC MIS-C case definition, although anti- nucleocapsid antibody is indicative of SARS-CoV-2 infection, while anti-spike protein antibody may be induced either by SARS-CoV-2 infection or by COVID-19 vaccination. We investigated 47 reports and identified 21 persons with MIS-C after receipt of COVID-19 vaccine. Of the 21 persons with MIS-C, median age was 16 years (range 12-20 years), and 13 (62%) were male. Fifteen (71%) had laboratory evidence of past or recent SARS-CoV-2 infection (positive SARS-CoV-2 nucleic acid amplification test [NAAT], viral antigen, or serology test before or during MIS-C illness evaluation), and 5 (33%) of those 15 had illness onset after their second vaccine dose. Six (29%) of 21 persons had no laboratory evidence of past or recent SARS-CoV-2 infection, and five of those six (83%) had onset of MIS-C after the second vaccine dose.

Implications of all the available evidenceDuring the first nine months of the COVID-19 vaccination program in the United States, >21 million persons aged 12 to 20 years received [≥]1 dose of COVID-19 vaccine as of August 31, 2021. This case series describes MIS-C in 21 persons following vaccine receipt during this time period; the majority of persons reported also had evidence of SARS-CoV-2 infection. The surveillance has limitations, but our findings suggest that MIS-C as identified in this report following COVID-19 vaccination is rare. In evaluating persons with a clinical presentation consistent with MIS-C after COVID-19 vaccination it is important to consider alternative diagnoses, and anti-nucleocapsid antibody testing may be helpful. Continued surveillance for MIS-C illness after COVID-19 vaccination is warranted, especially as pediatric COVID-19 vaccination expands. Providers are encouraged to report potential MIS-C cases after COVID-19 vaccination to VAERS.


title: COVID-19 vaccination status is associated with physical activity in German-speaking countries: the COR-PHYS-Q cohort study

abstract:
BackgroundTo examine the association between COVID-19 vaccination status and physical activity (PA), sporting behavior, as well as barriers to PA in adults in Switzerland, Germany, and Austria.

MethodsA total of 1516 adults provided complete responses to our online questionnaire sent out in August 2021. Information about self-reported PA categories, sporting behavior, barriers to PA, and COVID-19 vaccination status were gathered. Main analyses were done using multiple linear regression adjusted for relevant parameters.

ResultsWe found a significant association of vaccination status with total PA (p = .011), vigorous PA (p = .015), and moderate PA (p = .001) but not transport-related PA or sedentary time. Unvaccinated adults tended to have more total and vigorous PA than those vaccinated once (ratios of geometric means: 1.34 and 1.60, respectively) or twice (1.22 and 1.09, respectively). Yet, not sufficient evidence was available to confirm this. There was no between-group difference in the contribution of leisure time, work-related, or transport-related PA to total PA. Vaccination status was not associated with sporting behavior except for jogging as the primary intensive type of sports. Finally, there were no significant differences in any of the COVID-19 specific barriers to PA between groups.

ConclusionOur data showed that vaccination status is associated with PA even in summer, where the number of COVID-19 cases was low and the severity of safety measures was mild. These findings may enhance future research and improve/extend COVID-19-specific PA guidelines.


title: Genetic modifiers of Huntington's disease differentially influence motor and cognitive domains

abstract: Genome-wide association studies (GWAS) of Huntingtons disease (HD) have identified six DNA maintenance gene loci (among others) as modifiers and implicated a two step-mechanism of pathogenesis: somatic instability of the causative HTT CAG repeat with subsequent triggering of neuronal damage. The largest studies have been limited to HD individuals with a rater-estimated age at motor onset. To capitalize on the wealth of phenotypic data in several large HD natural history studies, we have performed algorithmic prediction using common motor and cognitive measures to predict age at other disease landmarks as additional phenotypes for GWAS. Combined with imputation using the Trans-Omics for Precision Medicine reference panel, predictions using integrated measures provided objective landmark phenotypes with greater power to detect most modifier loci. Importantly, substantial differences in the relative modifier signal across loci, highlighted by comparing common modifiers at MSH3 and FAN1, revealed that individual modifier effects can act preferentially in the motor or cognitive domains. Individual components of the DNA maintenance modifier mechanisms may therefore act differentially on the neuronal circuits underlying the corresponding clinical measures. In addition, we identified new modifier effects at the PMS1 and PMS2 loci and implicated a potential new locus on chromosome 7. These findings indicate that broadened discovery and characterization of HD genetic modifiers based on additional quantitative or qualitative phenotypes offers not only the promise of in-human validated therapeutic targets, but also a route to dissecting the mechanisms and cell types involved in both the somatic instability and toxicity components of HD pathogenesis.


title: Genomic Landscape of Lymphatic Malformations: A Case Series and Response to the PI3Kα Inhibitor Alpelisib in an N-of-One Clinical Trial

abstract:
BackgroundLymphatic malformations (LMs) often pose treatment challenges due to a large size or a critical location that could lead to disfigurement, and there are no standardized treatment approaches for either refractory or unresectable cases.

MethodsWe examined the genomic landscape of a patient cohort of LMs (n=30 cases) that underwent comprehensive genomic profiling (CGP) using a large-panel next generation sequencing (NGS) assay. Immunohistochemical analyses were completed in parallel.

ResultsThese LMs had low mutational burden with hotspot PIK3CA mutations and NRAS mutations being most frequent, and mutually exclusive. All LM cases with Kaposi sarcoma-like (kaposiform) histology had NRAS mutations. One index patient presented with subacute abdominal pain and was diagnosed with a large retroperitoneal lymphatic malformation harboring a somatic PIK3CA gain-of-function mutation (H1047R). The patient achieved a rapid and durable complete response to the PI3K inhibitor alpelisib within the context of a personalized N-of-1 clinical trial (NCT03941782). In translational correlative studies, canonical PI3K pathway activation was confirmed by immunohistochemistry and human LM-derived lymphatic endothelial cells carrying an allele with an activating mutation at the same locus were sensitive in vitro to alpelisib in a concentration-dependent manner.

ConclusionsOur findings establish that LM patients with conventional or kaposiform histology have distinct, yet targetable, driver mutations.

FundingR.P. and W.A. are supported by awards from the Levy-Longenbaugh Fund. S.G. is supported by awards from the Hugs for Brady Foundation. This work has been funded in part by the NCI Cancer Center Support Grants (CCSG; P30) to the University of Arizona Cancer Center (CA023074), the University of New Mexico Comprehensive Cancer Center (CA118100), and the Rutgers Cancer Institute of New Jersey (CA072720). B.K.M. was supported by National Science Foundation via Graduate Research Fellowship DGE-1143953.

Clinical trial numberNCT03941782


title: Performance evaluation of novel fluorescent-based lateral immune flow assay (LIFA) for rapid detection and quantitation of total anti-SARS-CoV-2 S-RBD binding antibodies in infected individuals

abstract:
1.BackgroundThe vast majority of the commercially available LFIA is used to detect SARS-CoV-2 antibodies qualitatively. Recently, a novel fluorescence-based LIFA test was developed for quantitative measurement of the total binding antibody units (BAU/mL) against the receptor-binding domain of the SARS-CoV-2 spike protein (S-RBD).

AimTo evaluate the performance of the fluorescence LIFA Finecare 2019-nCoV S-RBD test along with its reader (Model No.: FS-113).

MethodsPlasma from 150 RT-PCR confirmed-positive individuals and 100 pre-pandemic samples were tested by FinCare to access sensitivity and specificity. For qualitative and quantitative validation of the FinCar measurements, the BAU/mL results of FinCare were compared with results of two reference assays: the surrogate virus-neutralizing test (sVNT, GenScript, USA), and the VIDAS(R)3 automated assay (BioMerieux, France).

ResultsFinecare showed 92% sensitivity and 100% specificity compared to PCR. Cohens Kappa statistic denoted moderate and excellent agreement with sVNT and VIDAS(R)3, ranging from 0.557 (95% CI: 0.32-0.78) to 0.731 (95% CI: 0.51-0.95), respectively. A strong correlation was observed between Finecare/sVNT (r=0.7, p<0.0001) and Finecare/VIDAS(R)3 (r=0.8, p<0.0001).

ConclusionFinecare is a reliable assay and can be used as a surrogate to assess binding and neutralizing antibody response post-infection or vaccination, particularly in none or small laboratory settings.

category: infectious diseases


title: Convolution Neural Networks for Point-of-Care Diagnostics of Bacterial Infections in Blood

abstract: A droplet of blood, when evaporated on a surface, leaves dried residue--the fractal patterns formed on the dried residues can act as markers for infection present in the blood. Exploiting the unique patterns found in the residues of a naturally dried droplet of blood, we propose a Point-of-Care (POC) diagnostic tool for detecting broad-spectrum of bacterial infections (such as Enterobacter aerogenes, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa, Salmonella Typhi) in blood. The diagnosis process we propose is straightforward and can be performed with the following steps: A droplet of blood (healthy or infected) of volume range 0.5 to 2 l is allowed to dry on a clean glass surface and is imaged using a conventional optical microscope. A computer algorithm based on the framework of convolution neural network (CNN) is used to classify the captured images of dried blood droplets according to the bacterial infection. In total, our multiclass model reports an accuracy of 92% for detecting six bacterial species infections in the blood (with control being the uninfected or healthy blood). The high accuracy of detecting bacteria in the blood reported in this article is commensurate with the standard bacteriological tests. Thus, this article presents a proof-of-concept of a potential futuristic tool for a rapid and low-cost diagnosis of bacterial infection in the blood.


title: Fully Vaccinated and Boosted Patients Requiring Hospitalization for COVID-19: an Observational Cohort Analysis

abstract:
ObjectiveReal-world data on the effectiveness of boosters against COVID-19, especially as new variants continue to emerge, is limited. It is our objective to assess demographic, clinical, and outcome variables of patients requiring hospitalization for severe SARS-CoV-2 infection comparing fully vaccinated and boosted (FV&B) and unvaccinated (UV) patients.

MethodsThis multicenter observational cohort analysis compared demographic, clinical, and outcome variables in FV&B and UV adults hospitalized for COVID-19. A sub-analysis of FV&B patients requiring intensive care (ICU) care versus non-ICU care was performed to describe and analyze common symptom presentations, initial vital signs, initial laboratory workup, and pertinent medication use in these two groups.

ResultsBetween August 12th, 2021 and December 6th, 2021, 4,571 patient encounters had a primary diagnosis of COVID-19 and required inpatient treatment at an acute-care hospital system in Southeastern Michigan. Of the 4,571 encounters requiring hospitalization, 65(1.4%) were FV&B and 2,935(64%) were UV. FV&B individuals were older (74 [67, 81] vs 58 [45, 70]; p <0.001) with a higher proportion of immunocompromised individuals (32.3% vs 10.4%; p<0.001). Despite a significantly higher baseline risk of in-hospital mortality in the FV&B group compared to the UV (Elixhauser 16 vs 8 (p <0.001)), there was a trend toward lower in-hospital mortality (7.7% vs 12.1%; p=0.38) among FV&B patients. Other severe outcomes followed this same trend, with 7.7% of FV&B vs 11.1% UV patients needing mechanical ventilation and 4.6% vs 10.6% of patients needing vasopressors in each group, respectively (p=0.5 and 0.17).

ConclusionsFully vaccinated and boosted individuals requiring hospital-level care for breakthrough COVID-19 tended to have less severe outcomes despite appearing to be higher risk at baseline when compared to unvaccinated individuals during the same time period. Specifically, there was a trend that FV&B group had lower rates of mechanical ventilation, use of vasopressors, and in-hospital mortality. As COVID-19 continues to spread, larger expansive trials are needed to further identify risk factors for severe outcomes among the FV&B population.


title: Knowledge, Attitude, Practices, and Determinants of Them towards Tuberculosis in Bangladesh: A Cross-sectional Study

abstract:
IntroductionTuberculosis (TB) is an infectious disease that causes thousands of deaths in Bangladesh. Bangladesh is one of the high-risk countries among 30 high TB burden countries. In this study, we aimed to assess the knowledge, practices, attitudes towards TB, and the factors associated with them in the general population of Bangladesh.

MethodA web-based anonymous cross-sectional survey was conducted among the general population in Bangladesh. A comprehensive consent statement was included at the beginning of the survey by explaining the studys intent, types of questions, anonymous and voluntary nature. Analysis was carried out using the chi-square test and univariate and multivariate logistic regression.

ResultsAmong 1,180 eligible respondents, 58.64% were males, and 62.37% were married. The majority of the participants (78.28%) were aged between 15 to 44 years. Overall adequate knowledge, favorable attitudes, and good practices about TB were found respectively in 47.8%, 44.75%, and 31.19% of the general population of Bangladesh. Almost the same sets of associated factors were found to influence adequate knowledge, favorable attitudes, and good practices towards TB among general people. Males, young, unmarried, respondents with higher education, and urban respondents were more likely to have adequate knowledge, favorable attitudes, and good practices towards TB.

ConclusionPolicymakers need to design programs and interventions to improve knowledge, attitudes, and good practices towards TB among the general people by focusing on vulnerable groups such as females, young and older people, people who live in the rural areas, and illiterate/less educated people.

Key QuestionsO_ST_ABSWhat is already known?C_ST_ABSO_LITB is highly prevalent in Bangladesh. It is among the 30 most-affected countries globally by TB and carries almost 4% of the global TB burden.
C_LIO_LIOne of the significant probable obstacles to preventing, controlling, and eliminating tuberculosis is a lack of knowledge and understanding about the disease and a negative attitude toward it. Additionally, there are numerous misconceptions about the etiology and route of transmission of the disease in Bangladesh.
C_LI

What are the new findings?O_LIA low level of appropriate knowledge, positive attitudes, and good practices were found in the study.
C_LIO_LIOverall, adequate knowledge, favorable attitudes, and good practices about tuberculosis were discovered only in 47.8%, 44.75%, and 31.19%, respectively, of Bangladeshs general population. Males, those who are young and unmarried, those with a higher level of education, and those who live in urban areas were more likely to have enough knowledge, favorable attitudes, and appropriate practices about tuberculosis.
C_LI

What do the new findings imply?O_LIBangladesh showed little progress in fighting against TB in the recent past. Therefore, government and policymakers should renew their efforts to improve knowledge, attitudes, and practices as an essential step to achieve stipulated TB goals.
C_LIO_LIFurther studies are required that also include TB patients, healthcare workers, and community influencers.
C_LI


title: Evaluation of Commercial Anti-SARS-CoV-2 Neutralizing Antibody Assays in seropositive subjects

abstract: The virus neutralization test (VNT) is the reference for the assessment of the functional ability of neutralizing antibodies (NAb) to block SARS-CoV-2 entry into cells. New competitive immunoassays measuring antibodies preventing interaction between the spike protein and its cellular receptor are proposed as surrogate VNT (sVNT). We tested three commercial sVNT (a qualitative immunochromatographic test and two quantitative immunoassays named YHLO and TECO) together with a conventional anti-spike IgG assay (bioMerieux) in comparison with an in-house plaque reduction neutralization test (PRNT50) using the original 19A strain and different variants of concern (VOC), on a panel of 306 sera from naturally-infected or vaccinated patients. The qualitative test was rapidly discarded because of poor sensitivity and specificity. Areas under the curve of YHLO and TECO assays were, respectively, 85.83 and 84.07 (p-value >0.05) using a positivity threshold of 20 for PRNT50, and 95.63 and 90.35 (p-value =0.02) using a threshold of 80. However, the performances of YHLO and bioMerieux were very close for both thresholds, demonstrating the absence of added value of sVNT compared to a conventional assay for the evaluation of the presence of NAb in seropositive subjects. In addition, the PRNT50 assay showed a reduction of NAb titers towards different VOC in comparison to the 19A strain that could not be appreciated by the commercial tests. Despite the good correlation between the anti-spike antibody titer and the titer of NAb by PRNT50, our results highlight the difficulty to distinguish true NAb among the anti-RBD antibodies with commercial user-friendly immunoassays.


title: Breast milk exposure is associated with cortical maturation in preterm infants

abstract:
ObjectiveBreast milk exposure is associated with improved neurocognitive outcomes following preterm birth but the neural substrates linking nutrition with outcome are uncertain. By combining nutritional data with brain MRI, we tested the hypothesis that high versus low breast milk exposure in preterm infants during neonatal care results in a cortical morphology that more closely resembles that of infants born at term.

MethodsWe studied 135 preterm (mean gestational age 30+2 weeks, range 22+1 to 32+6) and 77 term-born infants (mean gestational age 39+4 weeks, range 36+3 to 42+1). Nutritional data was collected from birth until hospital discharge to identify the proportion of days preterm infants received exclusive breast milk. Structural and diffusion MRI were performed at term-equivalent age. Cortical indices (volume, thickness, surface area, gyrification index, sulcal depth, curvature) and water diffusion parameters (fractional anisotropy, mean diffusivity, radial diffusivity, axial diffusivity, neurite density index, orientation dispersion index) were compared between preterm infants who received exclusive breast milk for <75% of inpatient days (n=68), preterm infants who received exclusive breast milk for [≥]75% of inpatient days (n=67) and term-born controls (n=77).

ResultsHigh breast milk exposure was associated with reduced cortical gray matter volume (d=0.47, p=0.014), thickness (d=0.42, p=0.039) and radial diffusivity (d=0.38, p=0.039), and increased fractional anisotropy (d=0.38, p=0.037) after adjustment for age at MRI.

InterpretationHigh versus low breast milk exposure in the weeks following preterm birth is associated with a cortical imaging phenotype that more closely resembles the brain morphology of healthy infants born at term.

category: pediatrics


title: Radiological follow-up of adults hospitalised with pneumonia and SARS-CoV-2 infection, in Bristol UK, during the COVID19 pandemic

abstract: For patients with pneumonia and COVID19 repeating chest radiography is recommend in current British Thoracic Society (BTS) guidelines. Over two distinct time periods during the COVID19 pandemic (Aug-Dec 2020, Jun-Aug 2021) we undertook an audit of 829 patients hospitalised with infective radiological change (pneumonia=481, COVID19=348). 654/829 patients (79%) required radiological follow-up under BTS guideline criteria. 414/654 (63%) were planned, 322/654 (49%) occurred and, of patients receiving radiological follow-up, most occurred within BTS timelines (86%). Further audits should be conducted to ensure BTS guidelines adherence, to avoid delay in diagnosing underlying malignancy or chronic lung disease.


title: Cardiovascular disease protein biomarkers are associated with kidney function: the Framingham Heart Study

abstract:
BackgroundBiomarkers common to chronic kidney disease (CKD) and cardiovascular disease (CVD) may reflect early impairments underlying both diseases.

MethodsWe evaluated associations of 71 CVD-related plasma proteins measured in 2,873 Framingham Heart Study (FHS) Offspring cohort participants with cross-sectional continuous eGFR and with longitudinal change in eGFR from baseline to follow-up ({Delta}eGFR). We also evaluated the associations of the 71 CVD proteins with the following dichotomous secondary outcomes: prevalent CKD stage [≥]3 (cross-sectional), new-onset CKD stage [≥]3 (longitudinal), and rapid decline in eGFR (longitudinal). Proteins significantly associated with eGFR and {Delta}eGFR were subsequently validated in 3,951 FHS Third Generation cohort participants and were tested using Mendelian randomization (MR) analysis to infer putatively causal relations between plasma protein biomarkers and kidney function.

ResultsIn cross-sectional analysis, 37 protein biomarkers were significantly associated with eGFR at FDR<0.05 in the FHS Offspring cohort and 20 of these validated in the FHS Third Generation cohort at p<0.05/37. In longitudinal analysis, 27 protein biomarkers were significantly associated with {Delta}eGFR at FDR<0.05 and 12 of these were validated in the FHS Third Generation cohort at p<0.05/27. Additionally, 35 protein biomarkers were significantly associated with prevalent CKD, five were significantly associated with new-onset CKD, and 17 were significantly associated with rapid decline in eGFR. MR suggested putatively causal relations of melanoma cell adhesion molecule (MCAM; -0.011{+/-}0.003 mL/min/1.73m2, p=5.11E-5) and epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1; - 0.006{+/-}0.002 mL/min/1.73m2, p=0.0001) concentration with eGFR.

Discussion/ConclusionsEight protein biomarkers were consistently associated with eGFR in cross-sectional and longitudinal analysis in both cohorts and may capture early kidney impairment; others were implicated in association and causal inference analyses. A subset of CVD protein biomarkers may contribute causally to the pathogenesis of kidney impairment and should be studied as targets for CKD treatment and early prevention.


title: Task-Induced Mental Fatigue and Motivation Influence Listening Effort as Measured by the Pupil Dilation in a Speech-in-Noise Task

abstract:
ObjectivesListening effort and fatigue are common complaints among individuals with hearing impairment (HI); however, the underlying mechanisms, and relationships between listening effort and fatigue are not well understood. Recent quantitative research suggests that the peak pupil dilation (PPD), which is commonly measured concurrent to the performance of a speech-in-noise task as an index of listening effort, may be informative of daily-life fatigue, but it remains unknown whether the same is true for task-induce fatigue. As fatigue effects are known to manifest differently depending on motivation, the main aim of the present study was to experimentally investigate the interactive effects of task-induced fatigue and motivation on the PPD.

DesignIn a pre-/post-fatigue within-subject design, 18 participants with normal hearing (NH) engaged in a 98-trial-long speech-in-noise task (the  load sequence, approximately 40 min. long), which either excluded or included additional memory demands (light vs. heavy load sequence). Before and after the load sequence, baseline pupil diameter (BPD) and PPD were measured during shorter  probe blocks of speech-in-noise tasks. In these probe blocks, if participants correctly repeated more than 60% of the keywords, they could win vouchers of either 20 or 160 Danish krones worth (low incentive vs. high incentive). After each probe block, participants reported their invested effort, tendency for quitting, and perceived performance.

ResultsThe BPD in anticipation of listening declined from pre-to post-load sequence, suggesting an overall decrease in arousal, but the decline did not scale with the magnitude of the load sequence, nor with the amount of monetary incentive. Overall, there was larger pre-to post-load sequence decline in PPD when the load sequence was heavy and when the monetary incentives were low. Post-hoc analyses showed that the decline in PPD was only significant in the heavy-load sequence-low reward condition. The speech-in-noise task performance, self-reported effort, and self-reported tendency to quit listening did not change with the experimental conditions.

ConclusionsThis is the first study to investigate the influence of task-induced fatigue on BPD and PPD. Whereas BPD was not sensitive to the magnitude of previous load sequence and monetary incentives, the decline in PPD from pre-to post-load sequence was significant after the heavy load sequence when the offered monetary incentives were low. This result supports the understanding that fatigue and motivation interactively influence listening effort.

category: otolaryngology


title: COVID-19-Associated Hospitalizations Among Children Less Than 12 Years of Age in the United States

abstract:
ObjectivesTo describe the characteristics, healthcare resource use and costs associated with initial hospitalization and readmissions among pediatric patients with COVID-19 in the US.

MethodsHospitalized pediatric patients, 0-11 years of age, with a primary or secondary discharge diagnosis code for COVID-19 (ICD-10 code U07.1) were selected from 1 April 2020 through 30 September 2021 in the US Premier Healthcare Database Special Release (PHD SR). Patient characteristics, hospital length of stay (LOS), in-hospital mortality, hospital costs, hospital charges, and COVID-19-associated readmission outcomes were evaluated and stratified by age groups (0-4, 5-11), four COVID-19 disease progression states based on intensive care unit (ICU) and invasive mechanical ventilation (IMV) usage, and three sequential calendar periods. Sensitivity analyses were performed using the US HealthVerity claims database and restricting the analyses to primary discharge code.

ResultsAmong 4,573 hospitalized pediatric patients aged 0-11 years, 68.0% were 0-4 years and 32.0% were 5-11 years, with a mean (median) age of 3.2 (1) years; 56.0% were male, and 67.2% were covered by Medicaid. Among the overall study population, 25.7% had immunocompromised condition(s), 23.1% were admitted to the ICU and 7.3% received IMV. The mean (median) hospital LOS was 4.3 (2) days, hospital costs and charges were $14,760 ($6,164) and $58,418 ($21,622), respectively; in-hospital mortality was 0.5%. LOS, costs, charges, and in-hospital mortality increased with ICU admission and/or IMV usage. In total, 2.1% had a COVID-19-associated readmission. Study outcomes appeared relatively more frequent and/or higher among those 5-11 than those 0-4. Results using the HealthVerity data source were generally consistent with main analyses.

LimitationsThis retrospective administrative database analysis relied on coding accuracy and inpatient admissions with validated hospital costs.

ConclusionsThese findings underscore that children aged 0-11 years can experience severe COVID-19 illness requiring hospitalization and substantial hospital resource use, further supporting recommendations for COVID-19 vaccination.


title: Modern lineages of Mycobacterium tuberculosis were recently introduced in western India and demonstrate increased transmissibility

abstract:
BackgroundMycobacterium tuberculosis (Mtb) transmissibility may vary between lineages (or variants) and this may contribute to the slow decline of tuberculosis (TB) incidence. The objective of our study was to compare transmissibility across four major lineages (L1-4) of Mtb among participants from two cohort studies in Pune, India.

MethodsWe performed whole-genome sequencing (WGS) of Mtb sputum culture-positive isolates from participants in two prospective cohort studies of adults with pulmonary TB seeking care at public treatment centers in Pune, Maharashtra. We performed genotypic susceptibility prediction for both first- and second-line drugs using a previously validated random forest model. We used single nucleotide substitutions (SNS) and maximum likelihood estimation to build isolate phylogenies by lineage. We used Bayesian molecular dating to estimate ancestral node ages and compared tree characteristics using a two-sample Kolmogorov-Smirnov (KS) test.

ResultsOf the 642 isolates from distinct study participants that underwent WGS, 612 met sequence quality criteria. The median age of the 612 participants was 31 years (IQR 24.4-44.2), the majority were male (64.7%) and sputum smear-positive (83.3%), and 6.7% had co-infection with HIV. Most isolates belonged to L3 (44.6%). The majority (61.1%) of multidrug-resistant isolates (MDR, resistant to isoniazid and rifampin) belonged to L2 (P < 0.001 [Fishers Exact]). There was no significant difference in host characteristics between participants infected with the four major lineages. In phylogenetic analysis, we measured shorter terminal branch lengths in the L2 tree compared to L1 and L3 trees indicating less time elapsing between transmission and sampling and higher transmissibility (median branch lengths: L2 - 3.3, L3 - 7.8, p <0.001). Branching times for L2 and L4 were more recent than L1 and L3 indicating recent introduction into the region (p < 0.01 [KS test]).

ConclusionModern Mtb lineages (L2 and L4) were more recently introduced in western India, compared to older lineages (L1 and L3). L2 shows a higher frequency of drug-resistance and higher transmissibility. Our findings highlight the need for contact tracing around cases of TB due to L2, and heightened surveillance of TB antibiotic resistance in India.