title: Immunogenicity and safety of an inactivated SARS-CoV-2 vaccine in people living with HIV-1

abstract:
BackgroundIt has been proven that inactivated COVID-19 vaccines are safe and effective in general population with intact immunity. However, their safety and immunogenicity have not been demonstrated in people living with HIV (PLWH).

Methods42 HIV-1 infected individuals who were stable on cART and 28 healthy individuals were enrolled in this study. Two doses of an inactivated COVID-19 vaccine (BIBP-CorV) were given 4 weeks apart. The safety and reactogenicity of the vaccine were evaluated by observing clinical adverse events and solicited local and systemic reactions. Humoral responses were measured by anti-spike IgG ELISA and surrogate neutralization assays. Cell-mediated immune responses and vaccine induced T cell activation were measured by flow cytometry.

FindingsAll the HIV-1 infected participants had a CD4+ T cell count of above 200 cells/L both at baseline and 4 weeks after vaccination. No solicited adverse reaction was observed among all participants. Similar binding antibody, neutralizing antibody and S protein specific T cell responses were elicited in PLWH and healthy individuals. Further analyses showed that PLWH with low baseline CD4+/CD8+ T cell ratios (<0{middle dot}6) generated lower antibody responses after vaccination than PLWH with medium (0{middle dot}6[~]1{middle dot}0) or high ([≥]1{middle dot}0) baseline CD4+/CD8+ T cell ratios (P<0{middle dot}01). The CD3+, CD4+ and CD8+ T cell counts of PLWH decreased significantly after vaccination, but it did not lead to any adverse clinical manifestation. Moreover, we found that the general burden of HIV-1 among the PLWH cohort decreased significantly (P=0{middle dot}0192) after vaccination. And the alteration of HIV-1 viral load was not significantly associated with the vaccine induced CD4+ T cell activation.

InterpretationOur data demonstrate that the inactivated COVID-19 vaccine is safe and immunogenic in PLWH who are stable on cART with unsuppressed CD4 counts.

FundingThis work was funded by the National Natural Science Foundation of China (Grant No. 81971559, 82041010).

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSThe safety and efficacy of inactivated COVID-19 vaccines have been validated in general population with intact immunity. However, their safety and immunogenicity have not been demonstrated in people living with HIV (PLWH).

Added value of this studyOur study provides the first evidence to show humoral and cellular immune responses to an inactivated vaccine in PLWH who have been stable on cART with good CD4 cell counts. We found that participants with HIV-1 generated antibody and T cell responses comparable with those of healthy individuals after two-dose vaccination. The baseline CD4/CD8 ratios while not the absolute CD4+ T cell counts were shown to be associated with the magnitudes of vaccine induced antibody responses. Moreover, we showed that the vaccine induced T cell activation did not increase the viral burden in PLWH on cART. On the contrary, the levels of plasma HIV-1 RNA decreased among a significant percentage of PLWH.

Implications of all the available evidenceOur data demonstrate that the inactivated COVID-19 vaccine is safe and immunogenic in PLWH who are stable on cART with unsuppressed CD4 counts and indicate that this vaccine might be protective and efficacious against COVID-19 for people with HIV.

category: hiv aids


title: Real-world clinical performance of SARS-CoV-2 point-of-care diagnostic tests: a systematic review of available trials as per April, 4, 2021

abstract:
Point-of-care assays offer a decentralized and fast solution to the diagnosis of SARS-CoV-2, providing benefits for patients, healthcare workers and healthcare facilities. This technology has the potential to prevent outbreaks, enable fast adoption of potentially life-saving measures and improve hospital workflow. While reviews regarding the laboratory performance of those assays exist, a review focused on the real-life clinical performance and true point-of-care feasibility of those platforms is missing. Therefore, the objective of this study is to help clinicians, healthcare providers and organizations to understand the real-life performance of point-of-care assays, aiding in their implementation in decentralised, true point-of-care facilities, or inside hospitals. 1246 studies were screened in 3 databases and 87 studies were included, evaluating 27 antigen tests and 11 nucleic-acid amplification platforms deemed feasible for true point-of-care placement. We excluded studies that used processed samples, pre-selected populations, archived samples and laboratory-only evaluations and strongly favored prospective trial designs. We also investigated package inserts, instructions for use, comments on published studies and manufacturers websites in order to assess feasibility of point-of-care placement and additional information of relevance to the end-user. Apart from performance in the form of sensitivity and specificity, we present information on time to results, hands-on time, kit storage, machine operating conditions and regulatory status. To the best of our knowledge, this is the first review to systematically compare point-of-care test performance in real-life clinical practice. We found the performance of tests in clinical practice to be markedly different from the manufacturers reported performance and laboratory- only evaluations in the majority of scenarios. Our findings may help in the decision-making process related to SARS-CoV-2 test in real-life clinical settings.

Rationale for the reviewA review focused on the real-life clinical performance and point-of-care feasibility of SARS-CoV-2 diagnostic platforms is missing, impairing the ability of individuals, healthcare providers and test providers to make informed decisions.

Objective(s) or question(s) the review addressesThe objective of this study is to help clinicians, healthcare providers and organizations to understand the real-life performance of point-of-care assays, aiding in their implementation in decentralised, true point-of-care facilities or in complex healthcare environments.

category: infectious diseases


title: Field clinical performance of SARS-CoV-2 point-of-care diagnostic tests: a living systematic review of trials up to 17th of August, 2021


title: Depressive symptoms are associated with cigarette smoking among tuberculosis patients in Botswana

abstract:
BackgroundResearchers have increasingly recognized the adverse effects of smoking on tuberculosis (TB) outcomes. Smoking may be a maladaptive coping mechanism for depression and anxiety among TB patients; however, this association has not yet been investigated.

Design/MethodsWe conducted a cross-sectional study among newly diagnosed TB patients between January and December 2019 in Gaborone, Botswana, and evaluated factors associated with cigarette smoking. Using the Patient Health Questionnaire-9 and the Zung Self-Rating Anxiety scale, we collected depression and anxiety scores, respectively; scores of [≥]10 indicate depression and scores of [≥]36 indicate anxiety. We performed Poisson regression analyses with robust variance to examine whether depression and anxiety were associated with smoking.

ResultsOne hundred and eighty participants with TB were enrolled from primary health clinics. Among all enrollees, depression was reported in 46 (27.1%) participants, while anxiety was reported in 60 (44.4%) participants. Overall, 45 (25.0%) participants reported current smoking, and the median number of cigarettes per day was 10. Depressive symptoms were associated with a higher prevalence of smoking (aPR: 1.82; 95% CI = 1.11, 3.01) after adjusting for sex, HIV status, food insecurity, anxiety, and income. The association between anxiety symptoms and cigarette smoking did not reach statistical significance (aPR 1.26; 95% CI: 0.78-2.05).

ConclusionsWe found the association between depressive symptoms and smoking among TB patients in Botswana to be significant and the association between anxiety symptoms and cigarette smoking insignificant. Future studies should further investigate these associations when addressing TB care.


title: A system biology approach identifies candidate drugs to reduce mortality in severely ill COVID-19 patients

abstract:
Despite the availability of highly efficacious vaccines, Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) lacks effective drug treatment which results in a high rate of mortality. To address this therapeutic shortcoming, we applied a system biology approach to the study of patients hospitalized with severe COVID. We show that, at the time of hospital admission, patients who were equivalent on the clinical ordinal scale displayed significant differential monocyte epigenetic and transcriptomic attributes between those who would survive and those who would succumb to COVID-19. We identified mRNA metabolism, RNA splicing, and interferon signaling pathways as key host responses overactivated by patients who would not survive. Those pathways are prime drug targets to reduce mortality of critically ill COVID-19 patients leading us to identify Tacrolimus, Zotatifin, and Nintedanib as three strong candidates for treatment of severely ill patients at the time of hospital admission.

TeaserEpigenetics distinguishes COVID-19 survivors already at hospital admission: lessons for drug repurposing.


title: Hydroxychloroquine inhibits proteolytic processing of endogenous TLR7 protein in human primary plasmacytoid dendritic cells

abstract: Toll-like receptor 7 (TLR7) triggers antiviral immune responses through its capacity to recognize single-stranded RNA. Proteolytic cleavage of TLR7 protein is required for its functional maturation in the endosomal compartment. Structural studies demonstrated that the N- and C-terminal domains of TLR7 are connected and involved in ligand binding after cleavage. Hydroxychloroquine (HCQ), an antimalarial drug, has been studied for its antiviral effects. HCQ increases pH in acidic organelles and has been reported to potently inhibit endosomal TLR activation. Whether HCQ can prevent endogenous TLR7 cleavage in primary immune cells, such as plasmacytoid dendritic cells (pDCs), had never been examined. Here, using a validated anti-TLR7 antibody suitable for biochemical detection of native TLR7 protein, we show that HCQ-treatment of fresh PBMCs, CAL-1 leukemic and primary human pDCs inhibits TLR7 cleavage and results in accumulation of full-length protein. As a consequence, we observe an inhibition of pDC activation in response to TLR7 stimulation with synthetic ligands and viruses including inactivated SARS-CoV2, which we show herein activates pDCs through TLR7-signaling. Together, our finding suggests that the major pathway by which HCQ inhibits ssRNA-sensing by pDCs may rely on its capacity to inhibit endosomal acidification and the functional maturation of TLR7 protein.

category: allergy and immunology


title: Adult mortality in children exposed to state care: systematic review and meta-analysis of prospective cohort studies

abstract:
BackgroundRemoval from family of origin to placement in state care is a highly challenging and increasingly prevalent childhood experience. The purpose of this report was to synthesise published and unpublished prospective evidence on adult mortality in people with a history of state care in early life.

MethodsFor this systematic review and meta-analysis, we searched PubMed and Embase from their inception to May 31st 2021, extracting standard estimates of association and variance from qualifying studies. We augmented these findings with analyses of unpublished individual-participant data from the 1958 and 1970 Birth Cohort Studies (total N = 21,936). Study-specific estimates were aggregated using random-effect meta-analysis. The Cochrane Risk of Bias Tool was used to assess study quality. This review is PROSPERO-registered (CRD42021254665).

FindingsWe identified 209 potentially eligible published articles, of which 11 prospective cohort studies from the UK, Sweden, Finland, the USA, and Canada met the inclusion criteria (2 unpublished). In 2,273,998 individuals (10 studies), relative to those without a care history in childhood, those who were exposed had 2.5 times the risk of total mortality in adulthood (summary rate ratio; 95% confidence interval: 2.58; 1.96 to 3.39), study-specific estimates varying between 1.53 and 5.77 (I2=92%). Despite some attenuation, this association held following adjustment for other measures of early life adversity; extended into middle- and older-age; was stronger in higher quality studies; and was of equal magnitude according to sex and geographical region. There was a suggestion of sensitive periods of exposure to care, whereby individuals who entered public care for the first time in adolescence (3.54; 2.00 to 6.29) experienced greater rates of total mortality than those doing so earlier in the life course (1.69; 1.35 to 2.12). In five studies capturing 1,524,761 individuals (5 studies), children in care had more than three times the risk of competed suicide in adulthood (3.37; 2.64 to 4.30) with study-specific estimates ranging between 2.42 and 5.85 (I2=68%). The magnitude of this relationship was weaker after adjustment for multiple covariates; in men versus women; and in lower quality studies.

InterpretationThe excess rates of total and suicide mortality in children exposed to state care suggest child protection systems and social policy following care graduation are insufficient to mitigate the effects of the adverse experiences of care itself and the social disadvantage that preceded it.

FundingNone.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSExposure to state care during childhood has emerging links with an array of unfavourable social, psychological, and behavioural characteristics in early adulthood. We searched PubMed and Embase from their inception to May 31st 2021 for studies examining whether care is also related to elevated rates of adult mortality. While we identified a series of relevant studies, there was no synthesis of this evidence. Few studies utilised a prospective design such that the assessment of care was made in childhood, so avoiding biases of distant retrospective recall. There was also a lack of clarity regarding: the role of confounding factors; the influence of the timing of care entry on mortality; whether the impact of care extended into middle-age and beyond; and, as has been hypothesised, if men with a care history have a greater vulnerability than women.

Added value of this studyWe conducted a systematic review to synthesis evidence on adult mortality risk in children placed in state care. Drawing also on unpublished resources to complement the findings of published studies, a total of 10 studies consistently showed that exposure to state care in childhood was associated with more than a doubling in the risk of total mortality. This association, while attenuated, held following statistical adjustment for other early life risk factors, including other adversities; extended into later adulthood such that it did not exclusively occur immediately following graduation from care; was stronger in better designed studies; and was of equal magnitude in men and women. There was also a suggestion of sensitive periods of exposure to care, whereby individuals who entered public care for the first time in adolescence experienced greater rates of total mortality in adulthood than those doing so earlier in the life course. The magnitude of the association between childhood care and adult risk of completed suicide (5 studies) were somewhat higher than for total mortality. This relationship was not completely explained by control for other early life risk factors; and the magnitude was somewhat weaker in lower quality studies, and in men versus women. There were too few studies to explore the impact of care on other causes of mortality.

Implications of all the available evidenceIn recent years there has been a secular rise in the prevalence of children in state care in western societies. This excess mortality risk in this group did not appear to be attributable to other measures of adversity, suggesting that, in the countries studied, child protection systems and social policy following care graduation are insufficient to mitigate the effects of the adverse experiences of care itself and the unfavourable events that preceded it.

category: epidemiology


title: Health-Related Quality of Life and psychological distress of adolescents during the COVID-19 pandemic in Geneva

abstract:
AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSPurposeC_ST_ABSOur objective was to assess adolescents Health-Related Quality of Life (HRQoL) and psychological distress, from their own and their parents perspective, and to examine associated risk factors during the COVID-19 pandemic in Geneva, Switzerland.

MethodsA random sample of adolescents, aged 14-17 years, and their families was invited to a serosurvey in November and December 2020. Adolescents HRQoL was evaluated using the validated adolescent-reported KIDSCREEN-10 and parent-reported KINDL(R) scales. Psychological distress was assessed with self-reported sadness and loneliness, and using the KINDL(R) emotional well-being scale. Risk factors for adolescents low HRQoL and psychological distress were identified using generalized estimating equations and both adolescents and their parents perceptions were compared.

ResultsAmong 240 adolescents, 11% had a low HRQoL, 35% reported sadness and 23% reported loneliness. Based on parents perception, 12% of the adolescents had a low HRQoL and 16% a low emotional well-being. Being a girl (aOR=3.29; 95%CI: 1.64-6.57), increased time on social media (aOR=2.05; 95%CI: 1.08-3.88), parents average to poor mood (aOR=2.81; 95%CI: 1.21-6.56) and average to poor household financial situation (aOR=2.30; 95%CI: 1.00-5.29) were associated with an increased risk of sadness. Mismatches between adolescents and their parents perception of HRQoL were more likely for girls (aOR=2.88; 95%CI: 1.54-5.41) and in households with lower family well-being (aOR=0.91; 95%CI: 0.86-0.96).

ConclusionA meaningful proportion of adolescents experienced low well-being during the second wave of COVID-19. Adolescents living in underprivileged or distressed families seemed particularly affected. Monitoring is necessary to evaluate the long-term effects of the pandemic on adolescents.

Implications and ContributionThis study describes the psychological well-being of a population-based sample of adolescents in Geneva, Switzerland amid the COVID-19 pandemic, and identifies adolescents at risk of distress. This study provides further insight by comparing adolescents well-being as reported by themselves and their parents.


title: Monitoring the COVID-19 immunisation programme through a National Immunisation Management System- Englands experience

abstract:
In England, the National Immunisation Management System (NIMS) has been used to deliver COVID-19 vaccinations across England, monitor vaccine coverage, and assess vaccine effectiveness and safety.

The NIMS was developed by a joint collaboration between a range of health and digital government agencies. Vaccinations delivered at large vaccination sites, pharmacies, hospitals and in primary care are entered on a point of care application which is verified using the unique NHS number in a centralised system containing information for everyone resident and registered with a GP in England. Vaccination details and additional data from hospital and GP records (such as priority groups) are sent to NHS Digital for data linkage. The NIMS constantly receives updated details from NHS Digital for all individuals and these data are provided to Public Health England (PHE) in a secure environment.

PHE primarily use the NIMS for vaccine coverage, vaccine effectiveness and safety. Daily access to individual-level vaccine data has allowed PHE to rapidly and accurately estimate vaccine coverage and provide some of the worlds first vaccine effectiveness estimates.

Other countries evaluating the roll-out and effect of COVID-19 vaccine programmes should consider a vaccine register or immunisation information system similar to the NIMS.


title: Long-term low-dose acetylsalicylic use shows protective potential for the development of both vascular dementia and Alzheimer's disease in patients with coronary heart disease but not in other individuals from the general population: results from two large cohort studies

abstract:
ObjectivesTo investigate the association between long term low-dose acetylsalicylic acid (LDASA) use and the development of all-cause dementia, Alzheimers disease (AD) and vascular dementia (VD).

DesignMeta-analysis of individual participant data from two prospective cohort studies.

SettingCommunity-dwelling older adults from Germany (ESTHER) and United Kingdom (UK Biobank).

Participants5,258 ESTHER and 305,394 UK Biobank participants who were 55 years or older and completed drug assessment were included for analysis.

Main outcome measuresCox regression models with inverse probability of treatment weighting to model the underlying cardiovascular risk were used to assess the associations of LDASA use with all-cause dementia, AD and VD incidence.

Results476 cases of all-cause dementia, 157 cases of AD and 183 cases of VD were diagnosed over a median of 14.3 years of follow-up in ESTHER. In the UK Biobank, 5,584 participants were diagnosed with all-cause dementia, 2,029 with AD and 1,437 with VD over a median of 11.6 years. The meta-analysis of both cohorts revealed a weak reduction in hazards for all-cause dementia (HR [95% CI]: 0.96 [0.93 to 0.99]). The strongest protective effect of LDASA was observed in participants with coronary heart disease (CHD) in both cohorts, and a significant interaction was detected. In particular, in meta-analysis, a 31% reduction in hazard for AD, 69% for VD and 34% for all-cause dementia were observed (HR [95% CI]: 0.69 [0.59 to 0.80], 0.31 [0.27 to 0.35], 0.46 [0.42 to 0.50], respectively). Furthermore, compared to non-users, users of LDASA for 10 years or longer (who likely use it because they have CHD or a related diagnosis putting them at an increased risk for cardiovascular events) demonstrated a strong protective effect on all dementia outcomes, especially for VD (HR [95% CI]: 0.48 [0.42 to 0.56]) whereas no protective associations were observed with shorter LDASA use.

ConclusionsThe protective potential of LDASA for all-cause dementia, AD and VD seems to strongly depend on pre-existing CHD and the willingness of patients to take it for a minimum of ten years.


title: Information Theoretic Model Selection for Accurately Estimating Unreported COVID-19 Infections

abstract: Estimating the true magnitude of infections was one of the significant challenges in combating the COVID-19 outbreak early on. Our inability in doing so allowed unreported infections to drive up disease spread in numerous regions in the US and worldwide. Even today, identifying the true magnitude (the number of total infections) is still challenging, despite the use of surveillance-based methods such as serological studies, due to their costs and biases. This paper proposes an information theoretic approach to estimate total infections accurately. Our approach is built on top of ordinary differential equations based epidemiological models, which have been used extensively in understanding the dynamics of COVID-19, and aims to estimate the true total infections and a parameterization that "best describes" the observed reported infections. Our experiments show that the parameterization learned by our framework leads to a better estimation of total infections and forecasts of the reported infections compared to a "baseline" parameterization, which is learned via usual model calibration. We also demonstrate that our framework can be leveraged to simulate what-if scenarios with non-pharmaceutical interventions. Our results also support earlier findings that most COVID-19 infections were unreported and non-pharmaceutical interventions indeed helped mitigate the COVID-19 outbreak. Our approach gives a general method to use information theoretic techniques to improve epidemic modeling, which can also be applied to other diseases.


title: Health-care workers in gastrointestinal endoscopy are at higher risk for SARS-CoV-2 infection compared to other aerosol-generating disciplines

abstract:
ObjectiveHealthcare workers (HCW) are at high risk of SARS-CoV-2 infection due to exposure to potentially infectious material, especially during aerosol-generating procedures (AGP). We aimed to investigate the prevalence of infection among HCW in medical disciplines with AGP.

DesignA nationwide questionnaire-based study in in- and outpatient settings was conducted between 12/16/2020 and 01/24/2021. Data on SARS-CoV-2 infections among HCW and potential risk factors were investigated.

Results2,070 healthcare facilities with 25,113 employees were included in the study. Despite a higher rate of pre-interventional testing, clinics treated three times more confirmed SARS-CoV-2 cases than private practices (28.8% vs. 88.4%, p<0.001). Overall infection rate among HCW accounted for 4.7%. Multivariate analysis revealed that ZIP-regions having comparably higher incidences were significantly associated with increased risk of infection. Furthermore, clinical setting and the GIE specialty have more than double the risk of infection (OR 2.63; 95% CI 2.501-2.817, p<0.01 and OR 2.35; 95% CI 2.245-2.498, p<0.01). The number of procedures performed per day was also significantly associated with an increased risk of infection (OR 1.01; 95% CI 1.007-1.014), p<0.01). No treatment of confirmed SARS-CoV-2 cases was tending to lower the risk of infection (OR 0.72; 95% CI 0.507-1.025, p=0.068).

ConclusionHCW in GIE seem to be at higher risk of infection than those in other AGP, especially in the clinical setting. Regions having comparably higher incidences as well as the number of procedures performed per day were also significantly associated with increased risk of infection.

Significance of this studyO_ST_ABSWhat is already known on this subject?C_ST_ABSHealth care workers, especially those exposed to aerosol generating procedures, are assumed to have an increased risk of SARS-CoV-2 infection. However, data confirming this are lacking, especially for the outpatient care setting.

What are the new findings?Health care workers in gastrointestinal endoscopy have a higher risk of SARS-CoV-2-infection than in other AGPs. This risk is particularly higher

- in clinical settings compared to private practices
- in regions having comparably higher incidences
- the more procedures are performed per day

How might it impact on clinical practice in the foreseeable future?Our study suggests making additional efforts to protect HCW in the gastrointestinal work field.

category: gastroenterology


title: Human Milk Antibodies Elicited by BNT162b2 Vaccination Target have reduced activity against SARS-CoV-2 Variants of Concern

abstract:
We detected the presence of SARS-CoV-2 specific IgA against all major VOCs in milk out to 6 weeks after D2 of BNT162b2. These likely confer some protection to the breastfed infants, who are ineligible for vaccination and are at risk of severe COVID-19.

However, we detected significantly reduced milk IgA binding to VOCs, including the globally dominant Delta variant, suggesting reduced protection for breastfeeding infants. Additionally, these antibodies were significantly reduced by as early as 4-6 weeks after D2.

category: pediatrics


title: Alterations in resting-state activity and functional connectivity in children with 22q11.2 deletion syndrome

abstract:
BackgroundWhile genetic risk factors for psychiatric and neurodevelopmental disorders have been identified, the neurobiological route from genetic risk to neuropsychiatric outcome remains unclear. 22q11.2 deletion syndrome (22q11.2DS) is a copy number variant (CNV) syndrome associated with high rates of neurodevelopmental and psychiatric disorders including autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD) and schizophrenia. Alterations in neural integration and cortical connectivity have been linked to the spectrum of neuropsychiatric disorders seen in 22q11.2DS and may be a mechanism by which the CNV acts to increase risk. Despite this, few studies have investigated electrophysiological activity and connectivity in this high-risk group.

MethodsMagnetoencephalography (MEG) was used to investigate resting-state cortical oscillatory patterns in 34 children with 22q11.2DS and 25 controls aged 10-17 years old. Oscillatory activity and functional connectivity across six frequency bands were compared between groups. Regression analyses were used to explore the relationships between these measures, IQ and neurodevelopmental symptoms.

ResultsChildren with 22q11.2DS had atypical oscillatory activity and functional connectivity across multiple frequency bands. In the 22q11.2DS group, low frequency (alpha band) activity was positively associated with cognitive ability, while connectivity was negatively associated with ASD and ADHD symptoms. Frontal high frequency (gamma band) activity and connectivity were positively associated with ASD and ADHD symptoms respectively, while posterior gamma activity was negatively associated with ASD symptoms.

ConclusionsThese findings highlight that haploinsufficiency at the 22q11.2 locus alters both local and long-range cortical circuitry, which could be a mechanism underlying neurodevelopmental vulnerability in this high risk group.

category: psychiatry and clinical psychology


title: Psychedelic mushrooms in the USA: Knowledge, patterns of use and association with health outcomes

abstract:
IntroductionPopular media coverage, including of recent positive late stage clinical trials in depression and PTSD, and decriminalization initiatives, are transforming the public perception of psychedelics. However, little is known about levels of knowledge and personal use of psychedelic mushroom(s) (PM) among American adults.

MethodsWe examined PM use and various measures of health status, quality of life and self-reported mental health outcome measures obtained through a national on-line, cross-sectional survey of adults with a demographic composition representative of the US adult population by region, gender, age, and race (weighted N = 251,297,495) from November 2020-March 2021.

ResultsGeneral mental health and well-being was a popular reason for PM use (63.6%). PM users were less likely to be overweight than non-users, but overall quality of life (VR-12) was lower for mental health (39.5 vs 45.5). PM users reported significantly higher levels of anxiety (GAD-7 scores of 9.6 vs 5.9) and depression (PHQ-9 scores of 11.2 vs 6.8). They were less likely to have health insurance [OR=0.50 (0.35-0.72)], but reported significantly more healthcare services utilization.

Discussion and ConclusionsThere is a mismatch between our findings of an association between PM use and poor mental health outcomes, and current discourse on the positive health benefits of PM consumption. A significant number of Americans are already "self medicating" with PM and further research to understand the role of anecdotal knowledge and pseudoscientific information in PM uptake. There is an urgent need for a PM use-related national harm reduction strategy.


title: Body fat volumes and distribution in chronic schizophrenia compared to healthy controls; a cross-sectional MR study

abstract: People with schizophrenia show higher risk for abdominal obesity than the general population, which could contribute to excess mortality. However, it is unclear whether this is driven by alterations in abdominal fat partitioning. Here, we test the hypothesis that individuals with schizophrenia show a higher proportion of visceral to total body fat measured using MRI. We recruited 38 patients with schizophrenia and 38 healthy controls matched on age, sex, ethnicity and body mass index. We found no significant difference in body fat distribution between groups, suggesting that increased abdominal obesity in schizophrenia is not associated with altered fat distribution.


title: The impact of health literacy-sensitive design and heart age in a cardiovascular disease prevention decision aid: randomised controlled trial and end user testing

abstract:
IntroductionShared decision making is as an essential principle for cardiovascular disease (CVD) prevention, where asymptomatic people are considering lifelong medication and lifestyle changes. This project aimed to develop and evaluate the first literacy-sensitive CVD prevention decision aid (DA) developed for people with low health literacy, and investigate the impact of literacy-sensitive design and heart age.

MethodsWe developed the standard DA based on international standards. The literacy-sensitive version included simple language, supporting images, white space and a lifestyle action plan. A randomised trial included 859 people aged 45-74 using a 3 (DA: standard, literacy-sensitive, control) x 2 (heart age: heart age + percentage risk, percentage risk only) factorial design, with outcomes including prevention intentions/behaviours, gist/verbatim knowledge of risk, credibility, emotional response and decisional conflict. We iteratively improved the literacy-sensitive version based on end user testing interviews with 20 people with varying health literacy levels.

ResultsImmediately post-intervention (n=859), there were no differences between the DA groups on any outcome. The heart age group was less likely to have a positive emotional response, perceived the message as less credible, and had higher gist/verbatim knowledge of heart age risk but not percentage risk. After 4 weeks (n=596), the DA groups had better gist knowledge of percentage risk than control. The literacy-sensitive decision aid group had higher fruit consumption, and the standard decision aid group had better verbatim knowledge of percentage risk. Verbatim knowledge was higher for heart age than percentage risk amongst those who received both.

DiscussionThe literacy-sensitive DA resulted in increased knowledge and lifestyle change for participants with varying health literacy levels and CVD risk results. Adding heart age did not increase lifestyle change intentions or behaviour but did affect psychological outcomes, consistent with previous findings.

MeSH TermsHealth Literacy, Cardiovascular Diseases, Decision Making (Shared), Life Style, Decision Support Techniques

category: public and global health


title: Predictors of COVID-19 vaccine uptake in healthcare workers: a cross-sectional study in Greece

abstract:
BackgroundThe role of healthcare workers (HCWs) in the general public health is crucial and their decision to vaccinate against the COVID-19 can have a positive impact on the general population facilitating widespread COVID-19 vaccine uptake.

ObjectiveTo estimate the uptake of a COVID-19 vaccine in HCWs and to expand our knowledge regarding the predictors of COVID-19 vaccine uptake.

MethodsAn on-line cross-sectional study was conducted in Greece during August 2021. We collected socio-demographic data of HCWs and we measured attitudes towards vaccination and COVID-19, knowledge and trust. We used a convenience sample since we distributed the questionnaire through social media and e-mails.

ResultsStudy population included 855 HCWs. The majority of HCWs were vaccinated against the COVID-19 (91.5%). According to multivariate analysis, females, HCWs without a previous COVID-19 diagnosis, and HCWs with previous seasonal influenza vaccination history had a greater probability to take a COVID-19 vaccine. Also, increased self-perceived knowledge regarding COVID-19 and increased trust in COVID-19 vaccines and government regarding the information about the COVID-19 vaccines were associated with COVID-19 vaccine uptake. On the other hand, HCWs with more concerns about the side-effects of COVID-19 vaccination were more reluctant to take a COVID-19 vaccine.

ConclusionsOur study provides a timely assessment of COVID-19 vaccination status among HCWs and identifies specific factors associated with COVID-19 vaccine uptake. By understanding these factors, policy makers and scientists will be able to develop novel strategies to improve COVID-19 vaccine uptake among HCWs.


title: Deep Learning in Opthalmology: Iris Melanocytic Tumor Intelligent Diagnosis

abstract: Recently, Convolutional neural networks (CNN) have shown a growth due to their ability of learning different level image representations that helps in image classification in different fields. These networks have been trained on millions of images, so they gained a powerful ability of extracting the rightful features from input images, which results in accurate classification. In this research, we investigate the effects of transfer learning based convolutional neural networks for the iris tumor malignancy identification as it is notoriously hard to distinguish an iris nevus from an iris tumor. Features are transferred from a CNN trained on a source task, i.e. ImageNet, to a target task, i.e. iris tumor datasets. We transfer features learned from AlexNet and VGG-16 that are trained on ImageNet, to classify three different iris images types which are: iris nevus unaffected, iris cysts, and iris melanocytic tumors. The employed pre-trained models are modified by replacing their feedforward neural network classifier, Softmax, by a support vector machine (SVM) that is expected to slightly boost their performance (AlexNet-SVM and VGG16-SVM). All employed models are trained (fine-tuned) on a 60% of the available large dataset of iris images in order to investigate their power of generalization when trained using large amount of data. The networks are also tested on 40% of the data. The best performance was achieved by the VGG16-SVM which scored a high accuracy of 96.27% and strong features extraction capability as compared to the other models. Experimentally, it was seen that adding SVM contributed in improving the network performance compared to original models which use a feedforward neural network classifier.

category: radiology and imaging


title: Childhood Asthma and COVID-19: A Nested Case-Control Study

abstract:
BackgroundMost pediatric studies of asthma and COVID-19 to date have been ecological, which offer limited insight. We evaluated the association between asthma and COVID-19 at an individual level.

MethodsUsing data from prospective clinical registries, we conducted a nested case-control study comparing three groups: children with COVID-19 and underlying asthma ("A+C" cases); children with COVID-19 without underlying disease ("C+" controls); and children with asthma without COVID-19 ("A+" controls).

ResultsThe cohort included 142 A+C cases, 1110 C+ controls, and 140 A+ controls. A+C cases were more likely than C+ controls to present with dyspnea and wheezing, to receive pharmacologic treatment including systemic steroids (all p<0.01), and to be hospitalized (4.9% vs 1.7%, p=0.01). In the adjusted analysis, A+C cases were nearly 4 times more likely to be hospitalized than C+ controls (adjusted OR=3.95 [95%CI=1.4-10.9]); however, length of stay and respiratory support level did not differ between groups. Among A+C cases, 8.5% presented with an asthma exacerbation and another 6.3% developed acute exacerbation symptoms shortly after testing positive for SARS-CoV-2. Compared to historic A+ controls, A+C cases had less severe asthma, were less likely to be on controller medications, and had better asthma symptom control (all p<0.01).

ConclusionsIn our cohort, asthma was a risk factor for hospitalization in children with COVID-19, but not for worse COVID-19 outcomes. SARS-CoV-2 does not seem to be a strong trigger for pediatric asthma exacerbations. Asthma severity was not associated with higher risk of COVID-19.

Key messagesIn this pediatric cohort, asthma was a risk factor for hospitalization in children with COVID-19, but not for worse COVID-19 outcomes. Baseline asthma severity was not associated with higher risk of COVID-19, and SARS-CoV-2 did not seem to be a strong trigger for pediatric asthma exacerbations.

category: respiratory medicine


title: Hemoglobin levels among male agricultural workers: analyses from the Demographic and Health Surveys to investigate a marker for chronic kidney disease of uncertain etiology

abstract:
BackgroundChronic kidney disease of uncertain etiology (CKDu) has been found at high frequency in several lowland agricultural areas. Whether CKDu occurs in other countries with large agricultural populations remains uncertain, primarily due to lack of systematic data on kidney function. Hemoglobin (Hgb) levels are an ancillary marker for kidney dysfunction. We estimate the causal effect of agricultural work on Hgb level in men. A causal effect may indicate the presence of CKDu.

MethodsWe use Demographic and Health Surveys (DHS) data from seven African and Asian countries to estimate the causal effect of agricultural work on altitude-adjusted Hgb levels after adjusting for seven measured confounders. To assess potential bias due to unmeasured socioeconomic differences, we use multiple control groups that differ in non-agricultural occupation. We conduct sensitivity analyses to assess the robustness of our causal conclusions to unmeasured confounding.

ResultsData were available for 41,180 agricultural workers and 55,705 non-agricultural workers. On average, Hgb levels were 0.09 g/dL lower among agricultural workers compared to matched controls. Significant effects were observed in Ethiopia, India, Lesotho, and Senegal, with effects from 0.07 to 0.30 g/dL lower hemoglobin among agricultural workers.

ConclusionsWe find evidence that men engaged in agricultural work in four of the seven countries studied have modestly lower Hgb levels compared with comparable men. Since underlying kidney disease could be a potential explanation for this finding, our data support consideration to integrating kidney function assessments within DHS surveys and other population-based surveys.

category: nephrology


title: Serum NfL in spinocerebellar ataxia type 1 is increased already at the preataxic stage, correlating with proximity to clinical onset

abstract:
Background and ObjectivesNeurofilament light (NfL) appears a promising fluid biomarker in repeat-expansion spinocerebellar ataxias (SCAs), with piloting studies in mixed SCA cohorts suggesting that NfL might be increased at the ataxic stage of spinocerebellar ataxia type 1 (SCA1). We here hypothesised that NfL is increased not only at the ataxic stage of SCA1, but also at its - likely most treatment-relevant - preataxic stage.

MethodsWe assessed serum (sNfL) and cerebrospinal fluid (cNfL) levels of NfL in both preataxic and ataxic SCA1, leveraging a multicentric cohort of 40 SCA1 carriers (23 preataxic, 17 ataxic) and >80 controls, and clinical follow-up data including actually observed (rather than only predicted) conversion to the ataxic stage (11 carriers).

ResultssNfL levels were increased with high age-corrected effect sizes at the preataxic (r=0.62) and ataxic stage (r=0.63), paralleling increases of cNfL levels. In preataxic subjects, sNfL levels increased with proximity to predicted ataxia onset, with significant sNfL elevations already 5 years before onset, and confirmed in preataxic subjects with actually observed ataxia onset. sNfL increases were detected already in preataxic SCA1 subjects without volumetric atrophy of cerebellum or pons, suggesting that sNfL might be more sensitive to early preataxic neurodegeneration than the currently known most change-sensitive regions in volumetric MRI. Using longitudinal sNfL measurements, we estimated sample sizes for clinical trials using the reduction of sNfL as endpoint.

ConclusionssNfL levels might thus provide easily accessible peripheral biomarkers in both preataxic and ataxic SCA1, allowing stratification of preataxic subjects regarding proximity-to-onset, early detection of neurodegeneration even before volumetric MRI alterations, and potentially capture of treatment response in clinical trials.

category: neurology


title: Surgical Resection, Radiotherapy, And Percutaneous Thermal Ablation for Treatment of Stage 1 Non-Small Cell Lung Cancer: A Systematic Review and Network Meta-Analysis

abstract:
IntroductionNon-small cell lung cancer (NSCLC) makes up the majority of lung cancer cases. Currently surgical resection of the affected lung parenchyma is the gold standard of treatment. However, as patients are becoming medically more complex and presenting with more advanced disease, minimally invasive image guided percutaneous ablations are gaining popularity. Therefore, comparison of surgical, ablative, and second-line external beam therapies will help clinicians, as management of NSCLC changes. We will conduct a meta-analysis, reviewing literature investigating these therapies in adult patients diagnosed with Stage I NSCLC (tumor ranging from 0-5 cm, with no hilar nor mediastinal nodal involvement, confirmed either through cytology or histology regardless of type).

Methods and AnalysisWe will search electronic databases from their inception to January 2021 to identify randomized controlled trials (RCTs), cluster-RCTs, and cohort studies comparing the survival and clinical outcomes between any two interventions (lobectomy, wedge resection, radiofrequency ablation (RFA), microwave ablation (MWA), cryoablation and consolidated radiation therapies (EBRT, SBRT and 3D-CRT). The primary outcomes will include: cancer-specific survival (CSS), lung disease free survival, locoregional recurrence, death, toxicity, and non-target organ injury. In addition to the electronic databases, we will search for published and unpublished studies in trial registries and will review the references of included studies for possible inclusion in this review. Risk of bias will be assess using tools developed by the Cochrane collaboration. Two reviewers will independently assess the eligibility of studies and conduct the corresponding risk-of-bias assessments. For each outcome, given a sufficient number of studies, we will conduct a network meta-analysis. Finally, we will use the Confidence in Network meta-analysis (CINeMA) tool to assess the quality of the evidence for each of the primary outcomes.

Ethics and DisseminationWe aim to share our findings through high-impact peer review. As interventional techniques become more popular, it will be important for all providers in multi-disciplinary teams focused on care of these patients to receive continuing medical education on related to these interventions. Data synthesized in this study will be made available to readers.

category: oncology


title: Retinal oxygen delivery and extraction in ophthalmologically healthy subjects with different blood pressure status

abstract:
PurposeTo compare retinal oxygen delivery (DO2) and extraction (VO2) in ophthalmologically healthy subjects with different blood pressure (BP) status.

MethodsIn this case-control study, we prospectively included 93 eyes of 93 subjects (age 50-65) from a large-scale population-based Dutch cohort (n=167,000) and allocated them to four groups (low BP, normal BP [controls], treated arterial hypertension [AHT], untreated AHT). We estimated vascular calibers from fundus images and fractal dimension (FD) from optical coherence tomography angiography scans. We combined calibers, FD, BP, and intraocular pressure measurements in a proxy of total retinal blood flow (RBF), using a validated Poiseuille-based model. We measured arterial and venous oxygen saturations (SaO2, SvO2) with a two-wavelength scanning laser ophthalmoscope. We calculated DO2 and VO2 from RBF, SaO2, and SvO2. We compared DO2 and VO2 between groups and investigated the DO2-VO2 association.

ResultsDO2 and VO2 were different between groups (P=0.009, P=0.036, respectively). In post hoc analysis, the low BP group had lower DO2 than the untreated AHT group (P=4.9{middle dot}10-4), while both the low BP group and the treated AHT group had lower VO2 than the untreated AHT group (P=0.021, P=0.034, respectively). There was a significant DO2-VO2 correlation (Robs=0.65, bobs=0.51, P=2.4{middle dot}10-12). After correcting for shared measurement error, the slope was no longer significant (bcor=0.19, P=0.29), while the correlation coefficient could not be calculated.

ConclusionsDO2 and VO2 were altered in ophthalmologically healthy subjects with different BP status. Future studies could elucidate whether these changes can explain the increased risk of several ophthalmic pathologies in those subjects.

category: ophthalmology


title: SARS-CoV-2 Delta variant of concern in Brazil - multiple introductions, communitary transmission, and early signs of local evolution

abstract: The dissemination of the Delta VOC in Brazil is still unclear, despite the frequent reports of isolated cases from different Brazilian states. In this report we characterize the dissemination of the Delta VOC in Brazil and where the introductions of this lineage fall within the global Delta phylogeny. We also examined the mutational profile of the largest clade within the Brazilian Delta VOCs, with a focus on samples which were obtained in the State of Sao Paulo, and especially in the city of Sao Paulo, the largest metropolis of South America, and a national and international transportation hub.

category: genetic and genomic medicine


title: Toward Using Twitter Data to Monitor Covid-19 Vaccine Safety in Pregnancy

abstract:
BackgroundCoronavirus Disease 2019 (Covid-19) during pregnancy is associated with an increased risk of maternal death, intensive care unit (ICU) admission, and preterm birth; however, many people who are pregnant refuse to receive Covid-19 vaccination because of a lack of safety data.

ObjectiveThe objective of this preliminary study was to assess whether we could identify (1) users who have reported on Twitter that they received Covid-19 vaccination during pregnancy or the periconception period, and (2) reports of their pregnancy outcomes.

MethodsWe searched for reports of Covid-19 vaccination in a large collection of tweets posted by users who have announced their pregnancy on Twitter. To help determine if users were vaccinated during pregnancy, we drew upon a natural language processing (NLP) tool that estimates the timeframe of the prenatal period. For users who posted tweets with a timestamp indicating they were vaccinated during pregnancy, we drew upon additional NLP tools to help identify tweets that report their pregnancy outcomes.

ResultsUpon manually verifying the content of tweets detected automatically, we identified 150 users who reported on Twitter that they received at least one dose of Covid-19 vaccination during pregnancy or the periconception period. Among the 60 completed pregnancies, we manually verified at least one reported outcome for 45 (75%) of them.

ConclusionsGiven the limited availability of data on Covid-19 vaccine safety in pregnancy, Twitter can be a complementary resource for potentially increasing the acceptance of Covid-19 vaccination in pregnant populations. Directions for future work include developing machine learning algorithms to detect a larger number of users for observational studies.

category: health informatics


title: Development and evaluation of a machine learning-based in-hospital COvid-19 Disease Outcome Predictor (CODOP): a multicontinental retrospective study

abstract:
BackgroundMore contagious SARS-CoV-2 virus variants, breakthrough infections, waning immunity, and sub-optimal rates of COVID-19 vaccination account for a new surge of infections leading to record numbers of hospitalizations and deaths in several European countries. This is a particularly concerning scenario for resource-limited countries, which have a lower vaccination rate and fewer clinical tools to fight against the next pandemic waves. There is an urgent need for clinically valuable, generalizable, and parsimonious triage tools assisting the appropriate allocation of hospital resources. We aimed to develop and extensively validate CODOP, a machine learning-based tool for accurately predicting the clinical outcome of hospitalized COVID-19 patients.

MethodsCODOP was built using modified stable iterative variable selection and linear regression with lasso regularisation. To avoid generalization problems, CODOP was trained and tested with three time-sliced and geographically distinct cohorts encompassing 40 511 blood-based analyses of COVID-19 patients from more than 110 hospitals in Spain and the USA during 2020-21. We assessed the discriminative ability of the model using the Area Under the Receiving Operative Curve (AUROC) as well as horizon and Kaplan-Meier risk stratification analyses. To reckon the fluctuating pressure levels in hospitals through the pandemic, we offer two online CODOP calculators suited for undertriage or overtriage scenarios. We challenged their generalizability and clinical utility throughout an evaluation on a cohort of patients hospitalized in five hospitals from three Latin American countries.

FindingsCODOP uses 12 clinical parameters commonly measured at hospital admission and associated with the pathophysiology of COVID-19. CODOP reaches high discriminative ability up to nine days before clinical resolution (AUROC: 0{middle dot}90-0{middle dot}96, 95% CI 0{middle dot}879-0{middle dot}970), it is well calibrated, and it enables an effective dynamic risk stratification during hospitalization. The two CODOP online calculators demonstrate their potential for triage decisions when challenged with the distinctive Latin American evaluation cohorts (73-100% sensitivity and 84-100% specificity).

InterpretationThe high predictive performance of CODOP in geographically disperse patient cohorts and the easiness-of-use, strongly suggest its clinical utility as a global triage tool, particularly in resource-limited countries.

FundingThe Max Planck Society.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe have searched PubMed for articles about the existence of in-hospital COVID-19 mortality predictive models, using the search terms "coronavirus", "COVID-19", "risk", "death", "mortality", and "prediction", focusing on studies published between March 1, 2020 and 31 August, 2021. The studies we identified generally used small-medium size cohorts of patients that are geographically restricted to small regions of the developed world (many times, to the same city). We havent found studies that challenged their models in extended cohorts of patients from very distinct health system populations, particularly from resource-limited countries. Further, most of the previous models are rigid by not acknowledging the fluctuating availability of hospital resources during the pandemic (e.g., beds, oxygen supply). These and other limitations have been pointed out by expert reviews indicating that published in-hospital COVID-19 mortality predictive models are subject to high risk of bias, report an over-optimistic performance, and have limited clinical value in assisting daily triage decisions. A parsimonious, accurate and extensively validated model is yet to be developed.

Added value of this studyWe analysed clinical data from different cohorts totalling 21 607 COVID-19 patients treated in more than 110 hospitals in Spain and the USA during three different pandemic waves extending from February 2020 to April 2021. The new CODOP in-hospital mortality prediction model is based on 11 blood biochemistry parameters (representing main biological pathways involved in the pathogenesis of SARS-CoV-2) plus Age, all of them commonly measured upon hospitalization. CODOP accurately predicted mortality risk up to nine days before clinical resolution (AUROC: 0{middle dot}90-0{middle dot}96, 95% CI 0{middle dot}879-0{middle dot}970), it is well calibrated, and it enables an effective dynamic risk stratification during hospitalization. We offer two online CODOP calculator subtypes (https://gomezvarelalab.em.mpg.de/codop/) tailored to overtriage and undertriage scenarios. The online calculators were able to reach the desired prediction performance in five independent evaluation cohorts gathered in hospitals of three Latin American countries from March 7th 2020 to June 7th 2021.

Implications of all the available evidenceWe present here a highly accurate, parsimonious and extensively validated COVID-19 in-hospital mortality prediction model, derived from working with the largest number and the most geographically extended representation of patients and health systems to date.

The rigorous analytical methods, the generalizability of the model in distinct world regions, and its flexibility to reckon with the changing availability of hospital resources point to CODOP as a clinically useful tool potentially improving the outcome prediction and the management of COVID-19 hospitalized patients.


title: COVID-19 vaccine hesitancy and vaccine passports: Vaccination or restriction?

abstract:
ObjectivesWhile the development of vaccines against the novel coronavirus (COVID-19) brought the hope of establishing herd immunity, which might help end the global pandemic, vaccine hesitancy can hinder the progress towards herd immunity. In this study, we assess the determinants of vaccine hesitancy, reasons for hesitation, and effectiveness of vaccine passports in relaxing public health restrictions.

MethodsThrough an online survey that includes a conjoint experiment of a demographically representative sample of 5,000 Japanese adults aged 20-74, we assess the determinants of vaccine hesitancy, reasons for hesitation, and effectiveness of hypothetical vaccine passports.

ResultsWe found that about 30% of respondents did not intend to vaccinate or have not yet decided, with major reasons for vaccine hesitancy being related to concerns about the safety and side effects of the vaccine. In line with previous findings, younger age, lower socioeconomic status, and psychological factors such as weaker COVID-19 fear were associated with vaccine hesitancy. The easing of public health restrictions such as travel, wearing face masks, and dining out at night was associated with an increase in vaccine acceptance by 4-10%.

ConclusionVaccine hesitancy can be reduced by mitigating the concerns about vaccine safety and side effects, as well as by relaxing public health restrictions. However, the feasibility of vaccine passports needs to be sufficiently assessed, taking the ethical issues of passports and the public health impacts of the relaxation of restrictions into careful consideration.

Strengths and limitations of this study{square} This study includes timely data on COVID-19 vaccine hesitancy, obtained from a demographically representative sample of 5,000 Japanese adults.
{square}A conjoint experiment allows assessing the effectiveness of easing public health restrictions on vaccine acceptance.
{square}Actual behaviour may diverge from the survey responses or fluctuate due to the pandemic situation and the timing of the survey.
{square}Results may not be applicable in other countries, since the pandemic situation, government responses to the pandemic, and reasons for vaccine hesitancy can vary across countries.

category: health policy


title: Vaccination or restriction?: COVID-19 vaccine hesitancy and vaccine passports


title: University patenting and licensing practices in the United Kingdom during the COVID-19 pandemic - implications for global equitable access to COVID-19 health technologies

abstract: Universities play a vital role in biomedical innovation during the COVID-19 pandemic, and decisions made during technology transfer may affect affordability, accessibility, and availability of health technologies downstream. We investigated the measures the top 35 UK universities receiving most Medical Research Council funding have taken in technology transfer to ensure global equitable access to health technologies. We sent Freedom Of Information (FOI) requests and analysed universities websites, to (i.) assess institutional strategies on the patenting and licensing of COVID-19-related health technologies, (ii.) identify all COVID-19-related health technologies licensed or patented, and (iii.) record whether universities engaged with the Open-COVID pledge, COVID-19 Technology Access Pool (C-TAP), or Association of University Technology Managers (AUTM) COVID-19 licensing guidelines. Except for the Universities of Oxford and Edinburgh, UK universities have not updated their institutional strategies during the pandemic. Nine universities licensed 22 COVID-19 health technologies. Imperial College London disclosed 10 patents relevant to COVID-19. No UK universities participate in the Open-COVID Pledge or C-TAP, but discussions are ongoing. The University of Bristol signed up to the AUTM guidelines. Despite several important COVID-19 health technologies being developed by UK universities, our findings suggest minimal engagement with measures that may promote equitable access downstream. We suggest that universities review their technology transfer policies and implement global equitable access strategies for COVID-19 health technologies. We furthermore propose that public and charitable funders can play a larger role in encouraging universities to adopt such practices, by making access and transparency clauses a mandatory condition for receiving public funds for research.


title: A Data-Driven Framework for Identifying Intensive Care Unit Admissions Colonized with Multidrug-Resistant Organisms

abstract: The rising prevalence of multi-drug resistant organisms (MDROs), such as Methicillin-resistant Staphylococcus aureus (MRSA), Vancomycin-resistant Enterococci (VRE), and Carbapenem-resistant Enterobacteriaceae (CRE), is an increasing concern in healthcare settings. Leveraging electronic healthcare record data, we developed a data-driven framework to predict MRSA, VRE, and CRE colonization upon intensive care unit admission (ICU), and identify the associated socio-demographic and clinical factors using logistic regression (LR), random forest (RF), and XGBoost algorithms. We performed threshold optimization for converting predicted probabilities into binary predictions and identified the cut-off maximizing the sum of sensitivity and specificity. We achieved the following sensitivity and specificity values with the best performing models: 80% and 66% for VRE with LR, 73% and 77% for CRE with XGBoost, 76% and 59% for MRSA with RF, and 82% and 83% for MDRO (i.e., VRE or CRE or MRSA) with RF. Further, we identified several predictors of MDRO colonization, including long-term care facility exposure, current diagnosis of skin/subcutaneous tissue or infectious/parasitic disease, and recent isolation precaution procedures before ICU admission. Our data-driven modeling framework can be used as a clinical decision support tool for timely predictions, identification of high-risk patients, and selective and timely use of infection control measures in ICUs.

category: health systems and quality improvement


title: Virological and Serological Characterization of SARS-CoV-2 Infections Diagnosed After mRNA BNT162b2 Vaccination.

abstract: Coronavirus disease 2019 (COVID-19) vaccines are proving to be very effective in preventing severe illness; however, although rare, post-vaccine infections have been reported. The present study describes 94 infections (47.9% symptomatic, 52.1% asymptomatic), occurred in Lazio Region (Central Italy) in the first trimester 2021, after first or second dose of mRNA BNT162b2 vaccine. Median viral load at diagnosis was independent from number and time of vaccine dose administration, despite the higher proportion of samples with low viral load observed in fully vaccinated individuals. More importantly, infectious virus was cultured from NPS collected from both asymptomatic and symptomatic vaccinated individuals, suggesting that, at least in principle, they can transmit the infection to susceptible people. The majority of the post-vaccine infections here reported, showed pauci/asymptomatic clinical course, confirming the impact of vaccination on COVID-19 disease. Most cases (78%) showed infection in presence of neutralizing antibodies at the time of infection diagnosis, presumably attributable to vaccination, due to the concomitant absence of anti-N IgG in most cases. The proportion of post-vaccine infections attributed either to Alpha and Gamma VOCs was similar to the proportion observed in the contemporary unvaccinated population in Lazio region. In addition, mutational analysis did not suggest enrichment of a defined set of Spike protein substitutions depending on the vaccination status. Characterization of host and virus factors associated with vaccine breakthrough, coupled with intensive and continuous monitoring of involved viral strains, is crucial to adopt informed vaccination strategies.

category: infectious diseases


title: mRNA-1273 vaccine (Moderna): a better option than BNT162b2 (Pfizer) in kidney transplant recipients and dialysis patients?

abstract: In this study of the humoral immune response after the SARS-CoV-2 mRNA vaccination, low seroconversion rates were noted in both kidney transplant recipients and dialysis patients after first dose administration. While in DP the seroconversion rate levelled up to 92.8% after a second dose of SARS-CoV-2 mRNA vaccination, KTR stayed behind with a seroconversion rate of 62.4%. Futhermore, vaccination with the mRNA-1273 vaccine (Moderna) resulted in both higher seroconversion rates and mean log-transformed antibody titer concentrations compared to BNT162b2 (Pfizer).


title: Design and implementation of multiplexed amplicon sequencing panels to serve genomic epidemiology of infectious disease: a malaria case study

abstract: Multiplexed PCR amplicon sequencing (AmpSeq) is an increasingly popular application for cost-effective monitoring of threatened species and managed wildlife populations, and shows strong potential for genomic epidemiology of infectious disease. AmpSeq data for infectious microbes can inform disease control in multiple ways, including measuring drug resistance marker prevalence, distinguishing imported from local cases, and determining the effectiveness of therapeutics. We describe the design and comparative evaluation of two new AmpSeq assays for Plasmodium falciparum malaria parasites: a four-locus panel ( 4CAST) composed of highly diverse antigens, and a 129-locus panel ( AMPLseq) composed of drug resistance markers, highly diverse loci for measuring relatedness, and a locus to detect Plasmodium vivax co-infections. We explore the performance of each panel in various public health use cases with in silico simulations as well as empirical experiments. We find that the smaller 4CAST panel performs reliably across a wide range of parasitemia levels without DNA pre-amplification, and could be highly informative for evaluating the number of distinct parasite strains within samples (complexity of infection), and distinguishing recrudescent infections from new infections in therapeutic efficacy studies. The AMPLseq panel performs similarly to two existing panels of comparable size for relatedness measurement, despite differences in the data and approach used for designing each panel. Finally, we describe an R package (paneljudge) that facilitates design and comparative evaluation of AmpSeq panels for relatedness estimation, and we provide general guidance on the design and implementation of AmpSeq panels for genomic epidemiology of infectious disease.


title: Epidemiology, clinical presentation and management of COVID-19 associated Mucormycosis: A single center experience from Pune, Western India.

abstract:
BackgroundThe second COVID-19 wave in India, triggered by the Delta variant,has been associated with an unprecedented increase in cases of COVID-19 associated Mucormycosis(CAM), mainly Rhino-orbito-cerebral mucormycosis(ROCM).The primary reason appears to be an unusual alignment of multiple risk factors in patients like prevalence of hypoxia, uncontrolled diabetes mellitus, indiscriminate use of steroids, high iron levels and immune dysfunction.

MethodsThis retrospective cohort study was conducted at Noble hospital and Research Centre (NHRC), Pune, Western India between 1st April 2020 and 1st August 2021 to identify patients admitted with CAM. The primary endpoint was incidence of all cause mortality due to CAM. Secondary outcomes studied were need for mechanical ventilation and intensive care unit(ICU) admission. Baseline and time dependent risk factors significantly associated with death due to CAM were identified by Relative risk estimation.

Results59 patients were diagnosed with Mucormycosis at NHRC (58 ROCM, 1 Renal (disseminated) mucormycosis). Median age of the cohort was 52(IQR: 41,61) years and it included 20.3% females. Median duration from first positive COVID-19 RT PCR test to diagnosis of Mucormycosis was 17(IQR: 12,22) days. 90% patients were diabetic with 30% being newly diagnosed at the time of COVID-19 admission and 89% having uncontrolled sugar level (HbA1c > 7%). All patients were prescribed steroids during treatment for COVID-19. 56% patients were prescribed steroids for non-hypoxemic, mild COVID (irrational steroid therapy) while in 9%, steroids were indicated but were prescribed in inappropriately high dose. Majority of the patients were treated with a combination of surgical debridement(94%), intravenous Amphotericin B(91%) and concomitant oral Posoconazole therapy(95.4%). 74.6% patients were discharged after clinical and radiologic recovery while 25.4% (15 patients) died. On Relative risk analysis, CT severity score during COVID-19 admission [≥]18 (p=0.017), presence of orbital symptoms(p=0.002), presence of diabetic ketoacidosis(p=0.011) and cerebral involvement by Mucor(p=0.0004) were associated with increased risk of death. Duration of Amphotericin B therapy of [≥] 21 days was associated with statistically significant reduction in mortality(p=0.002).

ConclusionsCAM is an uncommon, rapidly progressive, angioinvasive, opportunistic fungal infection which is fatal if left untreated. Combination of surgical debridement and antifungal therapy leads to clinical and radiologic improvement in majority of cases.


title: Viral loads and profile of the patients infected with SARS-CoV-2 Delta, Alpha or R.1 variants in Tokyo

abstract: The rapid spread of the Delta variant of SARS-CoV-2 became a serious concern worldwide in summer 2021. We examined the copy number and variant types of all SARS-CoV-2-positive patients who visited our hospital from February to August 2021 using PCR tests. Whole genome sequencing was performed for some samples. The R.1 variant (B.1.1.316) was responsible for most infections in March, replacing the previous variant (B.1.1.214); the Alpha (B.1.1.7) variant caused most infections in April and May; and the Delta variant (B.1.617.2) was the most prevalent in July and August. There was no significant difference in copy numbers among the previous variant cases (n=29, median 3.0x104 copies/L), R.1 variant cases (n=28, 2.1x105 copies/L), Alpha variant cases (n=125, 4.1x105 copies/L), and Delta variant cases (n=106, 2.4x105 copies/L). Patients with Delta variant infection were significantly younger than those infected with R.1 and the previous variants, possibly because many elderly individuals in Tokyo were vaccinated between May and August. There was no significant difference in mortality among the four groups. Our results suggest that the increased infectivity of Delta variant may be caused by factors other than the higher viral loads. Clarifying these factors is important to control the spread of Delta variant infection.


title: HUMORAL AND CELLULAR IMMUNOGENICITY and SAFETY UP TO 4 MONTHS AFTER VACCINATION WITH BNT162B2 mRNA COVID-19 VACCINE IN HEART AND LUNG TRANSPLANTED YOUNG ADULTS

abstract:
BackgroundImmunizations among vulnerable population, including solid organ transplant recipients (SOT), present suboptimal responses at vaccination and over time. We investigated safety and immunogenicity of the BNT162B2 mRNA COVID-19 vaccine in 34 SOT young adults as compared to 36 healthy controls (HC).

Methodsimmunogenicity was measured through the analysis of anti SARS-CoV2 IgG Antibodies and antigen specific CD4 T cells (CD40L+), detected by flow cytometry before vaccination, 21 days after priming (T21), 7 days after booster dose (T28) and 2-4 months after priming (T120). Baseline T and B cell immune phenotype was deeply investigated. The safety profile was investigated by close monitoring and self-reported diary.

ResultsAnti-S and anti-Trimeric Ab responses were significantly lower in SOT vs HC at T21 (p<0.0001) and at T28 (p<0.0001). Ten out of 34 SOT (29%) at T28 and 3 out of 33 (9%) at T120 had undetectable SARS-CoV-2 IgG. The analysis of SARS-CoV-2 specific CD4 T cells showed lower CD40L expression after in vitro stimulation in SOT compared to HC. Lower frequencies of memory B cells were found in patients not responding to vaccination. Lack of seroconversion was higher in patients treated with mycophenolate (p=0.0005). The vaccination was safe and well tolerated. Only short-term adverse events, were reported and no hospitalization or graft rejection were observed after vaccinations.

ConclusionsThese data show that SOT have a suboptimal immune response following mRNA vaccinations as compared to HC. Alternative strategies should be investigated to improve the immunization against SARS-CoV-2 in these patients.


title: Long Term Accuracy of SARS-CoV-2 Interferon-γ Release Assay and its Application in Household Investigation

abstract:
BackgroundAn immunodiagnostic assay that sensitively detects a cell-mediated immune response to SARS-CoV-2 is needed for epidemiological investigation and for clinical assessment of T cell-mediated immune response to vaccines, particularly in the context of emerging variants that might escape antibody responses.

MethodsThe performance of a whole blood interferon-gamma (IFN-{gamma}) release assay (IGRA) for the detection of SARS-CoV-2 antigen-specific CD4 and CD8 T cells was evaluated in COVID-19 convalescents tested serially up to 10 months post-infection and in healthy blood donors. SARS-CoV-2 IGRA was applied in contacts of households with index cases. Freshly collected blood in the lithium heparin tube was left unstimulated, stimulated with a SARS-CoV-2 peptide pool, and stimulated with mitogen.

ResultsThe overall sensitivity and specificity of IGRA were 84.5% (153/181; 95% confidence interval [CI] 79.0-89.0) and 86.6% (123/142; 95% CI;80.0-91.2), respectively. The sensitivity declined from 100% (16/16; 95% CI 80.6-100) at 0.5-month post-infection to 79.5% (31/39; 95% CI 64.4-89.2) at 10 months post-infection (P<0.01). The IFN-{gamma} response remained relatively robust at 10 months post-infection (3.8 vs. 1.3 IU/mL, respectively). In 14 households, IGRA showed a positivity rate of 100% (12/12) and 65.2% (15/23), and IgG of 50.0% (6/12) and 43.5% (10/23) in index cases and contacts, respectively, exhibiting a difference of +50% (95% CI +25.4-+74.6) and +21.7% (95% CI, +9.23-+42.3), respectively. Either IGRA or IgG was positive in 100% (12/12) of index cases and 73.9% (17/23) of contacts.

ConclusionsThe SARS-CoV-2 IGRA is a useful clinical diagnostic tool for assessing cell-mediated immune response to SARS-CoV-2.

Key pointsSARS-CoV-2 immunodiagnostics are needed to identify infected individuals in order to understand the transmission dynamics of emerging variants and to assess vaccine response. Interferon-gamma release assay maintains sensitivity 10 months post-infection in convalescents and detects more household contacts than IgG.


title: Vitamin D and socioeconomic deprivation mediate COVID-19 ethnic health disparities

abstract: Ethnic minorities in developed countries suffer a disproportionately high burden of COVID-19 morbidity and mortality, and COVID-19 ethnic disparities have been attributed to social determinants of health. Vitamin D has been proposed as a modifiable risk factor that could mitigate COVID-19 health disparities. We investigated the relationship between vitamin D and COVID-19 susceptibility and severity using the UK Biobank, a large progressive cohort study of the United Kingdom population. Structural equation modelling was used to evaluate the ability of vitamin D, socioeconomic deprivation, and other known risk factors to mediate COVID-19 ethnic health disparities. Asian ethnicity is associated with higher COVID-19 susceptibility, compared to the majority White population, and Asian and Black ethnicity are both associated with higher COVID-19 severity. Socioeconomic deprivation mediates all three ethnic disparities and shows the highest overall signal of mediation for any COVID-19 risk factor. Vitamin supplements, including vitamin D, mediate the Asian disparity in COVID-19 susceptibility, and serum 25-hydroxyvitamin D (calcifediol) levels mediate Asian and Black COVID-19 severity disparities. Several measures of overall health also mediate COVID-19 ethnic disparities, underscoring the importance of comorbidities. Our results support ethnic minorities use of vitamin D as both a prophylactic and a supplemental therapeutic for COVID-19.


title: Metabolite-based dietary supplementation in human type 1 diabetes is associated with microbiota and immune modulation

abstract:
BackgroundShort-chain fatty acids (SCFAs) produced by the gut microbiota have beneficial anti-inflammatory and gut homeostasis effects and prevent type 1 diabetes (T1D) in mice. Reduced SCFA production indicates a loss of beneficial bacteria, commonly associated with chronic autoimmune and inflammatory diseases, including T1D and type 2 diabetes. Here we addressed whether a metabolite-based dietary supplement has an impact on humans with T1D. We conducted a single-arm pilot-and-feasibility trial with high-amylose maize resistant starch modified with acetate and butyrate (HAMSAB) to assess safety, while monitoring changes in the microbiota in alignment with modulation of the immune system status.

ResultsHAMSAB supplement was administered for six weeks with follow-up at 12 weeks in adults with long-standing T1D. Increased concentrations of SCFA acetate, propionate, and butyrate in stools and plasma were in concert with a shift in the composition and function of the gut microbiota. While glucose control and insulin requirements did not change, subjects with the highest SCFA concentrations exhibited the best glycemic control. Bifidobacterium longum, Bifidobacterium adolescentis, and vitamin B7 production correlated with lower HbA1c and basal insulin requirements. Circulating B and T cells developed a more regulatory phenotype post-intervention.

ConclusionChanges in gut microbiota composition, function, and immune profile following six weeks of HAMSAB supplementation were associated with increased SCFAs in stools and plasma. The persistence of these effects suggests that targeting dietary SCFAs may be a mechanism to alter immune profiles, promote immune tolerance and improve glycemic control for the treatment of T1D.

Trial registrationACTRN12618001391268. Registered 20 August 2018, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=375792

category: endocrinology


title: Efficacy of SARS-CoV-2 wastewater surveillance for detection of COVID-19 at a residential private college

abstract: Many colleges and universities utilized wastewater surveillance testing for SARS-CoV-2 RNA as a tool to help monitor and mitigate the COVID-19 pandemic on campuses across the United States during the 2020-2021 academic year. We sought to assess the efficacy of one such program by analyzing wastewater RNA load data in relation to SARS-CoV-2 cases identified through individual surveillance testing. Almost 80% of the cases on campus were associated with positive wastewater tests, resulting in an overall positive predictive value of [~]79% (Chi square 48.1, Df = 1, p < 0.001). However, half of the positive wastewater samples occurred in the two weeks following the return of a student to the residence hall following isolation, and therefore were not useful in predicting new infections. When these samples were excluded, the positive predictive value of a positive wastewater sample was [~]54%. Overall, we conclude that the continued shedding of viral RNA by patients past the time of potential transmission confounds the identification of new cases using wastewater surveillance, and decreases its effectiveness in managing SARS-CoV-2 infections on a residential college campus.

category: epidemiology


title: Genomic Surveillance in Japan of AY.29--A New Sub-lineage of SARS-CoV-2 Delta Variant with C5239T and T5514C Mutations

abstract: In the present study, we report a new sub-lineage of the SARS-CoV-2 Delta variant called AY.29, which has C5239T and T5514C mutations. We investigated the monthly trend of AY.29 in Japan within 37,737 Delta variants downloaded on October 2, 2021. Among the total Japanese Delta variants, the AY.29 sub-lineage accounted for 95.1%. In terms of monthly trends, the sequences became predominant in June, and accounted for 95.4%, 97.6% and 90.5% of the reported sequences in July, August and September, respectively. Furthermore, the number of Delta variants imported from abroad during the Tokyo 2020 Olympics and Paralympics (held in August 2021) was extremely low during the fifth wave in Japan. Therefore, the epidemic of the new Delta variant is attributable to a newly occurring mutation in Japan.


title: Ontogeny of plasma lipid metabolism in pregnancy and early childhood: a longitudinal population study

abstract:
BackgroundThere is mounting evidence that in utero and early life exposures may predispose an individual to metabolic disorders in later life; and dysregulation of lipid metabolism is critical in such outcomes. However, there is limited knowledge about lipid metabolism and factors causing lipid dysregulation in early life that could result in adverse health outcomes in later life. In this study, we aim to understand the lipid metabolism in pregnancy, and from birth to four years.

Methods and findingsWe performed comprehensive lipid profiling of 1074 mother-child dyads in the Barwon Infant Study (BIS), a population based pre-birth cohort and measured 776 distinct lipid species across 42 lipid classes using ultra high-performance liquid chromatography (UHPLC). We measured lipids in 1032 maternal serum samples at 28 weeks gestation, 893 cord serum samples at birth, 793, 735, and 511 plasma samples at six, twelve months, and four years, respectively. The lipidome differed between mother and newborn and changed markedly with increasing postnatal age. Cord serum was enriched with long chain poly-unsaturated fatty acids (LC-PUFAs), and corresponding cholesteryl esters relative to the maternal serum. Alkenyl-phosphatidylethanolamine species containing LC-PUFAs increased with postnatal age, whereas the corresponding lysophospholipids and triglycerides decreased. We performed regression analyses to investigate the associations of cord serum lipid species with birth factors: gestational age, birth weight, mode of birth and duration of labor. Majority of the cord serum lipids were strongly associated with gestational age and birth weight, with most lipids showing opposing associations. Each mode of birth showed an independent association with cord serum lipids.

ConclusionsThere were marked changes in the plasma lipidome over the first four years of life. This study sheds light on lipid metabolism in infancy and early childhood and provide a framework to define the relationship between lipid metabolism and health outcomes in early childhood.

Funding StatementThis work was supported by the A*STAR-NHMRC joint call funding (1711624031).


title: Modeling the systemic risks of COVID-19 on the wildland firefighting workforce

abstract: Wildfire management in the US relies on a complex nationwide network of shared resources that are allocated based on regional need. While this network bolsters firefighting capacity, it may also provide pathways for COVID-19 transmission between fire sites. We develop an agent-based model of COVID-19 built on historical wildland fire assignments using detailed dispatch data from 2016-2018, which form a network of firefighters dispersed spatially and temporally across the US. We use this model to simulate SARS-CoV-2 transmission under several intervention scenarios including vaccination and social distancing. We find vaccination and social distancing are effective at reducing transmission at fire incidents. Under a scenario assuming High Compliance with recommended mitigations (including vaccination), infection rates, number of outbreaks, and worker days missed are effectively negligible. Under a contrasting Low Compliance scenario, it is possible for cascading outbreaks to emerge leading to relatively high numbers of worker days missed. The current set of interventions in place successfully mitigate the risk of cascading infections between fires, and off-assignment infection may be the dominant infection concern in the 2021 season. COVID-19 control measures in place in wildfire management are highly beneficial at decreasing both the health and resource impacts of the ongoing pandemic.


title: Medication Management at Home and Medication Adherence in Older Patients with Polypharmacy: In-Depth Interviews with Home Visits

abstract:
BackgroundOlder patients with multiple non-communicable diseases (NCDs) usually require [≥]5 concurrent medications or polypharmacy. Medication adherence is the main concern in these patients. Medication management at home may play an important role in medication adherence; yet, unlike other factors, the topic has not been well examined.

ObjectiveThis study aims to explore how medication management at home affects medication adherence qualitatively.

MethodsWe conducted home visits and in-depth interviews with 19 patients aged [≥]60 years with polypharmacy and took photos of medication storage locations. Transcripts were analyzed using thematic content analysis.

ResultsOf the 19 patients (mean age=69 years), nine reported good medication adherence. Two themes emerged: medication management at home and factors affecting medication adherence. Medication management at home comprised three subthemes: a medication storage system, a medication sorting system, and remaining medications. Some patients with medication nonadherence removed medications from blister packages. Other factors affecting medication adherence included knowledge, attitude, and lifestyles. All the patients had a positive attitude towards medication adherence; however, misunderstanding about medication administration prevented them from adhering to medications.

ConclusionMedication management at home for the elderly with polypharmacy affected medication adherence. Health professionals should explore how patients manage medications at home and their knowledge about medication administration to improve medication adherence.

Key messages- Older patients had their own medication management system.
- Removing medications from blister packages was associated with medication nonadherence.
- Unintentional medication nonadherence was common in older patients engaging in outdoor activities.

category: primary care research


title: Did the COVID-19 pandemic result in more family physicians stopping practice? Results from Ontario, Canada

abstract:
PurposeTo understand changes in family physician practice patterns and whether more family physicians stopped working during the COVID-19 pandemic compared to previous years.

MethodsWe analyzed administrative data from Ontario, Canada two ways: cross-sectional and longitudinal. First, we identified the percentage and characteristics of all family physicians who had a minimum of 50 billing days in 2019 but no billings during the first six months of the pandemic. Second, for each year from 2010 to 2020, we calculated the percentage of physicians who billed for services in the first quarter of the calendar year but submitted no bills between April and September of the given year.

ResultsWe found 3.1% of physicians working in 2019 (N=385/12,247) reported no billings in the first six months of the pandemic. Compared with other family physicians, a higher portion were age 75 or older (13.0% vs. 3.4%, p<0.001), had fee-for-service reimbursement (38% vs 25%, p<0.001), and had a panel size under 500 patients (40% vs 25%, p<0.001). Between 2010 and 2019, an average of 1.6% of physicians who practiced in the first quarter had no billings in each of the second and third quarters of the calendar year compared to 3.0% in 2020 (p<0.001).

ConclusionsApproximately twice as many family physicians stopped work in Ontario, Canada during COVID-19 compared to previous years, but the absolute number was small and those who did had smaller patient panels. More research is needed to understand the impact on primary care attachment and access to care.


title: Mortality in Rural Coastal Kenya measured using the Kilifi Health and Demographic Surveillance System: A 16-year descriptive analysis

abstract:
BackgroundThe Kilifi Health and Demographic Surveillance System (KHDSS) was established in 2000 to define the incidence and prevalence of local diseases and evaluate the impact of community-based interventions. KHDSS morbidity data have been reported comprehensively but mortality has not been described. This analysis describes mortality in the KHDSS over 16 years.

MethodsWe calculated mortality rates from 2003-2018 in four intervals of equal duration and assessed differences in mortality across these intervals by age and sex. We calculated the period survival function and median survival using the Kaplan-Meier method and mean life expectancies using abridged life tables. We estimated trend and seasonality by decomposing a time series of monthly mortality rates. We used choropleth maps and random effects Poisson regression to investigate geographical heterogeneity.

ResultsMortality declined by 36% overall between 2003-2018 and by 59% in children aged <5 years. Most of the decline occurred between 2003 and 2006. Among adults, the greatest decline (49%) was observed in those aged 15-54 years. Life expectancy at birth increased by 12 years. Females outlived males by 6 years. Seasonality was only evident in the 1-4 year age group in the first four years. Geographical variation in mortality was +/-10% of the median value and did not change over time.

ConclusionsBetween 2003-2018 mortality among children and young adults has improved substantially. The steep decline in 2003-2006 followed by a much slower reduction thereafter suggests improvements in health and wellbeing have plateaued in the last 12 years. However, there is substantial inequality in mortality experience by geographical location.


title: COVID-19 Vaccine Hesitancy in India: An Exploratory Analysis

abstract: Vaccine hesitancy is context specific and varies over time and space. Therefore, strategies to tackle vaccine hesitancy based on evidence from high income countries are unlikely to serve the purpose adequately in LMICs. We use district level evidence on COVID-19 vaccine uptake rates from an LMIC - India to provide evidence of COVID-19 vaccine hesitancy. We argue that vaccination rates during the different phases of COVID-19 vaccination across the districts is likely to be related to vaccine hesitancy. Districts with larger rural population and lower literacy rates had lower vaccination rates. High past child immunization rates were positively correlated with COVID-19 vaccination uptake. Across the four phases of vaccination drive, vaccine hesitancy was the highest during the third phase of the vaccination drive, and therefore the above correlations were strongest during the third and the fourth phase. Measures of family planning indicators too seem to be correlated with vaccine uptakes during the third phase which indicate the regions most susceptible to vaccine hesitancy.


title: Effect of Pre-Exercise Caffeine Intake on Endurance Performance and Core Temperature Regulation During Exercise in the Heat: A Systematic Review with Meta-Analysis

abstract:
BackgroundHeat is associated with physiological strain and endurance performance (EP) impairments. Studies have investigated the impact of caffeine intake upon EP and core temperature (CT) in the heat, but results are conflicting. There is a need to systematically determine the impact of pre-exercise caffeine intake in the heat.

ObjectiveUse a meta-analytical approach to determine the effect of pre-exercise caffeine intake on EP and CT in the heat.

DesignSystematic review with meta-analysis.

Data sourcesFour databases and cross-referencing.

Data analysisWeighted mean effect summaries using random-effects models for EP and CT, as well as meta regressions with robust standard errors to explore confounders.

Study selectionPlacebo-controlled, randomized studies in adults ([≥] 18 yrs old) with caffeine intake at least 30 min before endurance exercise [≥] 30 min, performed in ambient conditions [≥] 27{degrees}C.

ResultsRespectively 6 and 12 studies examined caffeines impact on EP and CT, representing 52 and 205 endurance-trained individuals. On average, 6 mg/kg body mass of caffeine were taken 1 h before exercises of [~] 70 min conducted at 34{degrees}C and 47% relative humidity. Caffeine supplementation improved EP by 2.0 {+/-} 0.7% (95% CI: 0.6 to 3.5%) and increased the rate of change in CT by 0.10 {+/-} 0.04{degrees}C/h (95% CI: 0.03 to 0.16{degrees}C/h), compared with the ingestion of a placebo.

ConclusionCaffeine ingestion of 6 mg/kg body mass [~] 1 h before an exercise in the heat provides a worthwhile improvement in EP of 2%, while trivially increasing the rate of change in CT by 0.10{degrees}C/h.

category: sports medicine


title: PERIPHERAL ARTERIOVENOUS MALFORMATIONS AND THEIR RESPONSE TO TREATMENT MODALITIES: A SINGLE SURGEON'S EXPERIENCE AT TERTIARY CARE HOSPITALS

abstract:
BackgroundPeripheral arteriovenous malformations (AVMs) are congenital defects resulting in abnormal connections between veins and arteries. We investigated a group of patients with peripheral AVMs to determine whether there were any gender differences in disease presentation and the response of AVMs to various modalities of treatment.

MethodologyThe patients in this cross-sectional study were divided into two groups based on gender and their demographic data, clinical presentation at the time of diagnosis and response to treatment was assessed. Both surgical and nonsurgical treatment options were used. Nonsurgical options employed in the study included immunotherapy, embolotherapy and ultrasound-guided foam sclerotherapy (UGFS)

ResultsOut of 43 patients, 74.4% were females with a male to female ratio of 1:3. The mean age at presentation in males was 27 years and 17 years in females. 60% of the male patients presented with high-flow AVMs while 81% of the female patients presented with low-flow lesions instead. Half of the AVMs in males were on the trunk whereas, in females, 93.9% were on the extremities. UGFS alone was used in 95.3% of patients while 32.5% of patients underwent UGFS followed by surgical excision. One patient was treated with sirolimus. In 4.6% of cases, embolization followed by surgical excision was performed. Recurrence was recorded in 20.9% of cases.

ConclusionsThe clinical presentation of AVMs is notably different among the two genders. Sclerotherapy and embolotherapy proved to be effective treatment options. Larger studies, however, are needed to substantiate these claims.

category: surgery


title: Startle responses in Duchenne muscular dystrophy: a novel biomarker of brain dystrophin deficiency

abstract:
Duchenne muscular dystrophy (DMD) is characterised by loss of dystrophin in muscle. Patients affected by DMD also have variable degree of intellectual disability and neurobehavioural co-morbidities. In contrast to muscle, in which a single full-length isoform (Dp427) is produced, multiple dystrophin isoforms are produced in the brain, and their deficiency accounts for the variability of CNS manifestations, with increased risk of comorbidities in patients carrying mutations affecting the 3 end of gene, disrupting the shorter Dp140 and Dp71 isoforms. The mdx mouse model of DMD lacks Dp427 in muscle and CNS and exhibits exaggerated startle responses to threat, linked to the deficiency of dystrophin in limbic structures such as the amygdala, which normalise with postnatal brain dystrophin-restoration therapies. A pathological startle response is not a recognised feature of DMD, and its characterisation has implications for improved clinical management and translational research.

To investigate startle responses in DMD, we used a novel fear-conditioning task in an observational study of 56 males aged 7-12 years (31 DMD, mean age 9.7{+/-}1.8 years; 25 Controls, mean age 9.6{+/-}1.4 years). Trials of two neutral visual stimuli were presented to participants: one  safe cue presented alone; one  threat cue paired with an aversive noise to enable conditioning of physiological startle responses (skin conductance response, SCR; heart rate, HR). Retention of conditioned physiological responses was subsequently tested with presentation of both cues without the aversive noise in an  extinction phase. Primary outcomes were the magnitude of the initial unconditioned SCR and HR change responses to the aversive  threat and acquisition and retention of conditioned responses after conditioning. Secondary outcomes were neuropsychological measures and genotype associations.

The initial (unconditioned) mean SCR to threat was greater in DMD than Controls (Mean difference 3.0 {micro}S (95% CI 1.0, 5.1), P=.004), associated with a significant threat-induced bradycardia only in the DMD group (mean difference -5.6 bpm (95% CI 0.51, 16.9); P=.04). DMD participants found the task more aversive than Controls, consequently early termination during the extinction phase occurred in 26% of the DMD group (vs. 0% Controls; P=.007).

This study provides the first evidence that boys with DMD show increased unconditioned startle responses to threat, similar to the mdx mouse phenotype that also responds to brain dystrophin restoration. Our study provides new insights into the neurobiology underlying the complex neuropsychiatric co-morbidities in DMD and defines an objective measure of this CNS phenotype, which will be valuable for future CNS-targeted dystrophin-restoration studies.