Threshold analyses on combinations of testing, population size, and vaccine coverage for COVID-19 control in a university setting We simulated epidemic projections of a potential COVID-19 outbreak in a residential university population in the United States under varying combinations of asymptomatic tests (5% to 33% per day), transmission rates (2.5% to 14%), and contact rates (1 to 25), to identify the contact rate threshold that, if exceeded, would lead to exponential growth in infections. Using this, we extracted contact rate thresholds among non-essential workers, population size thresholds in the absence of vaccines, and vaccine coverage thresholds. We further stream-lined our analyses to transmission rates of 5 to 8%, to correspond to the reported levels of face-mask-use/physical-distancing during the 2020 pandemic.

Our results suggest that, in the absence of vaccines, testing alone without reducing population size would not be sufficient to control an outbreak. If the population size is lowered to 34% (or 44%) of the actual population size to maintain contact rates at 4 (or 7) among non-essential workers, mass tests at 25% (or 33%) per day would help control an outbreak. With the availability of vaccines, the campus can be kept at full population provided at least 95% are vaccinated. If vaccines are partially available such that the coverage is lower than 95%, keeping at full population would require asymptomatic testing, either mass tests at 25% per day if vaccine coverage is at 63-79%, or mass tests at 33% per day if vaccine coverage is at 53-68%. If vaccine coverage is below 53%, to control an outbreak, in addition to mass tests at 33% per day, it would also require lowering the population size to 90%, 75%, and 60%, if vaccine coverage is at 38-53%, 23-38%, and below 23%, respectively.

Threshold estimates from this study, interpolated over the range of transmission rates, can collectively help inform campus level preparedness plans for adoption of face mask/physical-distancing, testing, remote instructions, and personnel scheduling, during non-availability or partial-availability of vaccines, in the event of SARS-Cov2-type disease outbreaks.
The lost microbes of COVID-19: Bifidobacteria depletion and decreased microbiome diversity are a predictability marker of severe COVID 19, a cross sectional study ObjectiveThe study objective was to compare gut microbiome diversity and composition in SARS-CoV-2 polymerase chain reaction (PCR)-positive patients whose symptoms ranged from asymptomatic to severe, versus PCR-negative exposed controls.

DesignUsing a cross-sectional design, we performed shotgun next-generation sequencing (NGS) on stool samples to evaluate gut microbiome composition and diversity in both patients with SARS-CoV-2 PCR- confirmed infections, that had presented to Ventura Clinical Trials for care from March 2020 through October 2021, and SARS-CoV-2 PCR-negative exposed controls. Patients were classified as being asymptomatic or having mild, moderate, or severe symptoms based on NIH criteria. Exposed controls were individuals with prolonged or repeated close contact with patients with SARS-CoV-2 infection or their samples, e.g. household members of patients or frontline healthcare workers. Microbiome diversity and composition were compared between patients and exposed controls at all taxonomic levels.

ResultsCompared with controls (n=20), severely symptomatic SARS-CoV-2 infected patients (n=28) had significantly less bacterial diversity (Shannon Index, P=0.0499; Simpson Index, P=0.0581), and positive patients overall had lower relative abundances of Bifidobacterium (P<0.0001), Faecalibacterium (P=0.0077), and Roseburium (P=0.0327), while having increased Bacteroides (P=0.0075). Interestingly, there was an inverse association between disease severity and abundance of the same bacteria.

ConclusionWe hypothesize that low bacterial diversity and depletion of Bifidobacterium genera either before or after infection led to reduced pro-immune function, thereby allowing SARS-CoV-2 infection to become symptomatic. This particular dysbiosis pattern may be a susceptibility marker for symptomatic severity from SARS-CoV-2 infection and may be amenable to pre-, intra-, or post infection intervention.Keywords: SARS-CoV-2, COVID, Microbiome, Bifidobacterium, Faecalibacterium, Bacteriodes, Shannon Index, Simpson Index, Severity, Microbiota

Registrationclinicaltrials.gov NCT04031469 (PCR -) and 04359836 (PCR+)



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org.highwire.dtl.DTLVardef@173dbe8org.highwire.dtl.DTLVardef@16a75b5org.highwire.dtl.DTLVardef@55d55eorg.highwire.dtl.DTLVardef@12b2302org.highwire.dtl.DTLVardef@107663d_HPS_FORMAT_FIGEXP  M_TBL C_TBL
Plateaus, rebounds and the effects of individual behaviours in epidemics Plateaus and rebounds of various epidemiological indicators are widely reported in Covid-19 pandemics studies but have not been explained so far. Here, we address this problem and explain the appearance of these patterns. We start with an empirical study of an original dataset obtained from highly precise measurements of SARS-Cov-2 concentration in wastewater over nine months in several treatment plants around the Thau lagoon in France. Among various features, we observe that the concentration displays plateaus at different dates in various locations but at the same level. In order to understand these facts, we introduce a new mathematical model that takes into account the heterogeneity and the natural variability of individual behaviours. Our model shows that the distribution of risky behaviours appears as the key ingredient for understanding the observed temporal patterns of epidemics. Intrahost evolution of the HIV-2 capsid correlates with progression to AIDS BackgroundHIV-2 infection will progress to AIDS in most patients without treatment, albeit at approximately half the rate of HIV-1 infection. HIV-2 p26 amino acid variations are associated with lower viral loads and enhanced processing of T cell epitopes, which may lead to protective Gag-specific CTL responses common in slower disease progressors. Lower virus evolutionary rates, and positive selection on conserved residues in HIV-2 env have been associated with slower progression to AIDS. We therefore aimed to determine if intrahost evolution of HIV-2 p26 is associated with disease progression.

MethodsTwelve treatment-naive, HIV-2 mono-infected participants from the Guinea-Bissau Police cohort with longitudinal CD4+ T cell data and clinical follow-up were included in the analysis. CD4% change over time was analysed via linear regression models to stratify participants into relative faster and slower disease progressor groups. Gag amplicons of 735 nucleotides which spanned the p26 region were amplified by PCR and sequenced. We analysed p26 sequence diversity evolution, measured site-specific selection pressures and evolutionary rates, and determined if these evolutionary parameters were associated with progression status. Amino acid polymorphisms were mapped to existing p26 protein structures.

ResultsIn total, 369 heterochronous HIV-2 p26 sequences from 12 male patients with a median age of 30 (IQR: 28-37) years at enrolment were analysed. Faster progressors had lower CD4% and faster CD4% decline rates. Median pairwise sequence diversity was higher in faster progressors (5.7x10-3 versus 1.4x10-3 base substitutions per site, P<0.001). p26 evolved under negative selection in both groups (dN/dS=0.12). Virus evolutionary rates were higher in faster than slower progressors - synonymous rates: 4.6x10-3 vs. 2.3x10-3; and nonsynonymous rates: 6.9x10-4 vs. 2.7x10-4 substitutions/site/year, respectively. Virus evolutionary rates correlated negatively with CD4% change rates ({rho} = -0.8, P=0.02), but not CD4% level. However, Bayes factor (BF) testing indicated that the association between evolutionary rates and CD4% kinetics was supported by weak evidence (BF=0.5). The signature amino acid at p26 positions 6, 12 and 119 differed between faster (6A, 12I, 119A) and slower (6G, 12V, 119P) progressors. These amino acid positions clustered near to the TRIM5/p26 hexamer interface surface.

ConclusionsFaster p26 evolutionary rates were associated with faster progression to AIDS and were mostly driven by synonymous substitutions. Nonsynonymous evolutionary rates were an order of magnitude lower than synonymous rates, with limited amino acid sequence evolution over time within hosts. These results indicate the HIV-2 p26 may be an attractive vaccine or therapeutic target. Mutation burden-orthogonal tumor genomic subtypes delineate responses to immune checkpoint therapy Higher-resolution tumor-agnostic biomarkers that predict response to immune checkpoint inhibitor (ICI) therapy are needed. Mutation signatures reflect underlying oncogenic processes that can affect tumor immunogenicity, and thus potentially delineate ICI treatment response among tumor types. Systematic mutational signature analysis on all solid tumors in The Cancer Genome Atlas yielded eight distinct tumor genomic subtypes, which were characterized by smoking exposure, ultraviolet light exposure, APOBEC enzyme activity, POLE mutation, mismatch repair deficiency, homologous recombination deficiency, genomic stability, and aging. The former five subtypes were construed to form an immune-responsive group acting as candidates for ICI therapy because of their high expression of immune-related genes and enrichment in cancer types with FDA approval for ICI monotherapy. Under this hypothesis, we developed a software to classify new tumors submitted to whole-exome sequencing. A pan-cancer dataset containing 973 cases treated with ICIs and clinical response was used for validation, where the classified tumor subtypes were significantly associated with ICI response, independent of cancer type and tumor mutational burden high or low status. The new tumor subtyping method can serve as a tumor-agnostic biomarker for ICI response prediction and will improve decision making in cancer treatment.

Structured abstractO_ST_ABSBackgroundC_ST_ABSIn cancer therapy, higher-resolution tumor-agnostic biomarkers that predict response to immune checkpoint inhibitor (ICI) therapy are needed. Mutation signatures reflect underlying oncogenic processes that can affect tumor immunogenicity, and thus potentially delineate ICI treatment response among tumor types.

MethodsBased on mutational signature analysis, we developed a stratification for all solid tumors in The Cancer Genome Atlas (TCGA). Subsequently, we developed a new software (GS-PRACTICE) to classify new tumors submitted to whole-exome sequencing. Using existing data from 973 pan-cancer ICI-treated cases with outcomes, we evaluated the subtype-response predictive performance.

ResultsSystematic analysis on TCGA samples identified eight tumor genomic subtypes, which were characterized by features represented by smoking exposure, ultraviolet light exposure, APOBEC enzyme activity, POLE mutation, mismatch repair deficiency, homologous recombination deficiency, genomic stability, and aging. The former five subtypes were presumed to form an immune-responsive group acting as candidates for ICI therapy because of their high expression of immune-related genes and enrichment in cancer types with FDA approval for ICI monotherapy. In the validation cohort, the samples assigned by GS-PRACTICE to the immune-reactive subtypes were significantly associated with ICI response independent of cancer type and TMB high or low status.

ConclusionsThe new tumor subtyping method can serve as a tumor-agnostic biomarker for ICI response prediction and will improve decision making in cancer treatment.

One Sentence SummaryA novel tumor genome subtyping method based on mutation signature analysis can predict response to immune checkpoint therapy orthogonally to tumor mutational burden. Treatment interruption is a risk factor for sickness presenteeism: a large-scale cross-sectional study during the COVID-19 pandemic ObjectivesThis study examined the relationship between interruption to routine medical care during the coronavirus disease 2019 pandemic and sickness presenteeism among workers in Japan.

MethodsA cross-sectional study using data obtained from an internet monitor questionnaire was conducted. Interruption to medical care was defined based on the response "I have not been able to go to the hospital or receive treatment as scheduled." The fraction of sickness presenteeism days in the past 30 days was employed as the primary outcome. A fractional logit model was used for analysis to treat bounded data.

ResultsOf the 27,036 participants, 17,526 (65%) were workers who did not require routine medical care, 8,451 (31%) were using medical care as scheduled, and 1,059 (4%) experienced interrupted medical care. The adjusted odds ratio (aOR) of sickness presenteeism was significantly higher among workers who experienced interrupted medical care (3.44; 95% confidence interval [CI]: 3.04-3.89) than those who did not require routine medical care. In terms of symptoms, the highest aOR was observed among workers with mental health symptoms (aOR: 5.59, 95%CI: 5.04-6.20).

ConclusionsThis study suggests the importance of continuing necessary treatment during a pandemic to prevent presenteeism. I wanna live and not think about the future; What place for advance care planning for people living with severe multiple sclerosis and their families? A qualitative study BackgroundLittle is known about how people with multiple sclerosis and their families comprehend advance care planning (ACP) and its relevance in their lives.

AimTo explore under what situations, with whom, how, and why do people with MS and their families engage in ACP

MethodsWe conducted a qualitative study comprising interviews with people living with MS and their families followed by an ethical discussion group with five health professionals representing specialties working with people affected by MS and their families. Twenty-seven people with MS and 17 family members were interviewed between June 2019 and March 2020. Interviews and the ethical discussion group were audio-recorded and transcribed verbatim. Data were analysed using the framework approach.

ResultsParticipants narratives focused on three major themes :(i) planning for an uncertain future; (ii) perceived obstacles to engaging in ACP that included uncertainty concerning MS disease progression, negative previous experiences of ACP discussions and prioritising symptom management over future planning; (iii) Preferences for engagement in ACP included a trusting relationship with a health professional and that information then be shared across services. Health professionals accounts from the ethical discussion group departed from viewing ACP as a formal document to that of an ongoing process of seeking preferences and values. They voiced similar concerns to people with MS about uncertainty and when to initiate discussions. Some shared concerns of a lack of confidence when having ACP discussions.

ConclusionThese findings support the need for a whole systems strategic approach where information about the potential benefits of ACP in all its forms can be shared with people with MS. Moreover, they highlight the need for health professionals to be skilled and trained in engaging in ACP discussions and where information is contemporaneously and seamlessly shared across services. Prospectively validated disease-agnostic predictive medicine with augmented intelligence Despite numerous superhuman achievements in complex challenges1,2, standalone AI does not free life science from the long-term bottleneck of linearly extracting new knowledge from exponentially growing new data3, severely limiting the success rate of drug discovery4. Inspired by the state-of-the-art AI training methods, we trained a human-centric hybrid augmented intelligence5 (HAI) to learn a foundation model6 that extracts all-encompassing knowledge of human physiology and diseases. To evaluate the quality of HAIs extracted knowledge, we designed the public, prospective prediction of pivotal ongoing clinical trial outcomes at large scale (PROTOCOLS) challenge to benchmark HAIs real-world performance of predicting drug clinical efficacy without access to human data. HAI achieved a 10.5-fold improvement from the baseline with 99% confidence7 in the PROTOCOLS validation, readily increasing the average clinical success rate of investigational new drugs from 7.9%8 to 90% for almost any human diseases9,10. The validated HAI confirms that exponentially extracted knowledge alone is sufficient for accurately predicting drug clinical efficacy, effecting a total reversal of Erooms law4. HAI is also the worlds first clinically validated model of human aging that could substantially speed up the discovery of preventive medicine for all age-related diseases11. Our results demonstrate that disruptive breakthroughs necessitate the smallest team size to attain the largest HAI for optimal knowledge extraction from high-dimensional low-quality data space, thus establishing the first prospective proof of the previous discovery that small teams disrupt12. The global adoption of training HAI provides a well-beaten economic path to mass-produce scientific and technological breakthroughs via exponential knowledge extraction and better designs of data labels for training better-performing AI13. Meta-analytic findings on reading in children with cochlear implants This meta-analysis study aims to quantify the group differences in reading skills between children with cochlear implants and their hearing peers and between children with cochlear implants and children with hearing aids (aged between 3 to 18 years old). Of the 5,642 articles screened, 47 articles met predetermined inclusion criteria (published between 2002 and 2019). The robust variance estimation based meta-analysis models were used to synthesize all the effect sizes. Children with cochlear implants scored significantly lower than their hearing peers in phonological awareness (g = - 1.62, p < .001), vocabulary (g = -1.50, p < .001), decoding (g = -1.24, p < .001), and reading comprehension (g = -1.39, p < .001), but not for fluency (g = -.67, p = .054). Compared to children with hearing aids, children with cochlear implants scored significantly lower in phonological awareness (g = -.30, p = .028). The percentage of unilateral cochlear implant negatively impacts the group difference between children with cochlear implants and their hearing peers. Findings from this study confirm a positive shift in reading outcomes for profoundly deaf children due to cochlear implantation. Some children with cochlear implants may need additional supports in educational settings. The incidence of delirium in an acute geriatric community hospital: an observational cohort feasibility study. ObjectivesDelirium in hospitalised older adults is associated with negative health outcomes. Admission to an alternative care setting may lower the incidence of delirium. The Acute Geriatric Community Hospital (AGCH) was recently opened in the Netherlands and uses a multi-component non-pharmacological intervention strategy to prevent delirium. The objective of this study was to describe the incidence of delirium at the AGCH and compare this incidence to existing rates from literature. If a possible effect on delirium is seen in this comparison this would support conducting a larger prospectively controlled study on delirium in this new care setting.

DesignProspective cohort feasibility study; exploratory meta-analysis of proportions.

Setting and ParticipantsThe AGCH is an acute geriatric unit in a skilled nursing facility for patients aged >65 years with acute medical conditions.

MethodsDelirium assessment using the Confusion Assessment Method (CAM) upon admission and on day one, two and three or until delirium had resolved. Patients charts were reviewed if CAM was missing. In an linear mixed-effects model, the delirium incidence rate in AGCH was compared to pooled delirium incidence rates from six studies found in a high-quality review.

Results214 patients from the AGCH (mean age 81.9 years, 47% male, 12% with a history of dementia) were included in the analysis. Delirium developed in 8% (18/214) (95% confidence interval [CI] 5-13%) of patients during AGCH admission compared to 16% (95% CI 12-21%) in hospitals. Admission to the AGCH was associated with a decreased delirium incidence rate compared to the hospital control group (OR[odds ratio]= 0.49, 95% CI 0.24-0.98, p-value=0.044).

Conclusions and implicationsThe delirium incidence in the AGCH was low compared to those incidences found in general hospitals in literature. Based on these findings a controlled observational or randomized study measuring delirium in this care setting is recommended. Serum proteome analysis of systemic JIA and related pulmonary alveolar proteinosis identifies distinct inflammatory programs and biomarkers ObjectivesRecent observations in systemic Juvenile Idiopathic Arthritis (sJIA) suggest an increasing incidence of high-mortality interstitial lung disease, characterized by a variant of pulmonary alveolar proteinosis (PAP). Co-occurrence of macrophage activation syndrome (MAS) and PAP in sJIA suggested a shared pathology, but sJIA-PAP patients also commonly experience features of drug reaction such as atypical rashes and eosinophilia. We sought to investigate immunopathology and identify biomarkers in sJIA, MAS, and sJIA-PAP.

MethodsWe used SOMAscan to measure >1300 analytes in sera from healthy controls and patients with sJIA, MAS, sJIA-PAP and other related diseases. We verified selected findings by ELISA and lung immunostaining. Because the proteome of a sample may reflect multiple states (sJIA, MAS, sJIA-PAP), we used regression modeling to identify subsets of altered proteins associated with each state. We tested key findings in a validation cohort.

ResultsProteome alterations in active sJIA and MAS overlapped substantially, including known sJIA biomarkers like SAA and S100A9, and novel elevations of heat shock proteins and glycolytic enzymes. IL-18 was elevated in all sJIA groups, particularly MAS and sJIA-PAP. We also identified an MAS-independent sJIA-PAP signature notable for elevated ICAM5, MMP7, and allergic/eosinophilic chemokines, which were all previously associated with lung damage. Immunohistochemistry localized ICAM5 and MMP7 in sJIA-PAP lung. ICAM5s ability to distinguish sJIA-PAP from sJIA/MAS was independently validated.

ConclusionsSerum proteins support an sJIA-to-MAS continuum, help distinguish sJIA, sJIA/MAS, and sJIA-PAP, and suggest etiologic hypotheses. Select biomarkers, such as ICAM5, could aid in early detection and management of sJIA-PAP. Combination of Mifepristone and Methotrexate for the Treatment of Ectopic Pregnancy: A Systematic Review Protocol AimThe increase in ectopic pregnancies (EP) in recent years and their impact on female fertility forces physicians to find an effective medical treatment that can avoid surgery as soon as possible. Methotrexate and mifepristone are widely used in conservative treatments, but the effectiveness of this combination is not completely clear. Therefore, the aims in this meta-analysis are to systematically analyze the efficacy of mifepristone combined with methotrexate in the treatment of EP through existing studies and draw a conclusion, to evaluate the advantages and disadvantages of inclusion trials and propose improvement measures and scientific designing schemes.

MethodsSix databases will be searched, including PubMed, Embase, Cochrane Library, the China National Knowledge Infrastructure(CNKI), Chinese Science and Technology Periodical Database (VIP), and Wanfang Database (WF). Randomized controlled trials published up to October 2020 will be selected. Search terms include mifepristone, methotrexate, EP, and random (free word/synonym expansion). We will include trials in which the experimental group was treated with combination of mifepristone and methotrexate, and the control group was treated with mifepristone alone. Revman 5.4 will be used to evaluate the quality of the trials, and the effect model will be selected to analyze the results. Cure rate will be the main outcome index.

ResultOnly when we finish this meta analysis can we get the result.

DiscussionThe results of this study will provide evidence for the efficacy of mifepristone combined with methotrexate therapy in the treatment of EP. The site of onset of pregnancy should be taken into account.

PROSPERO registration numberCRD42021246757 Factors affecting first return to work following arthroscopic rotator cuff repair: A retrospective observational study in an occupational medicine clinic and single-surgeon practice BackgroundReturn to work (RTW) following arthroscopic rotator cuff repair (aRCR) within New South Wales (NSW), Australia, under compensable schemes has not been reported.

AimsDetermine factors affecting RTW status and time in patients treated with aRCR under state-based compensation schemes, compared to those outside such schemes.

MethodsPatients undergoing aRCR by one surgeon with minimum 1-year follow-up were grouped into those under (CP) or outside (non-CP) workers or vehicle accident compensation schemes, matched by age and gender. RTW status and time were assessed using chi-square analysis and multivariable linear regression.

ResultsOf 1054 available patients, 90 CP patients were identified with 29 consented and matched to non-CP (N=29). A higher proportion of CP patients (17.2 vs 0%, P<0.001) never returned to work and a lower proportion resumed pre-injury duties at first RTW (3 vs 52%, P<0.01). Median time to first RTW did not differ between CP and non-CP groups (5.1 vs 4.4, P=0.86). Smoking (P=0.007) and post-injury activity level (P=0.004) were significantly associated with longer time to first RTW, whereas compensation status was not.

ConclusionsCP patients undergoing aRCR in NSW are at risk of not returning to work. For those that return, there is no significant difference compared to non-CP in time to first RTW. Particularly, patient and management factors associated with extended time to first RTW have been identified. Interventions aimed at modifiable factors such as smoking cessation and increasing preoperative activity may improve future outcomes.

What is already known about this subjectO_LIWork-related injury and disease present a significant financial burden to the Australian economy ($AUD61.8billion per annum), with shoulder conditions due to body stressing accounting for 7% of this total cost (>$AUD4.2billion)
C_LIO_LIPatients receiving compensation appear to have poorer outcomes and take longer to return to work than their non-compensated counterparts, but the degree to which this occurs is variably reported in the literature
C_LIO_LIThe effect of modifiable factors on return to work status and time remain unclear, and have not previously been reported for the Australian population under the New South Wales workers compensation scheme
C_LI

What this study addsO_LIPatients receiving arthroscopic rotator cuff repair under a compensable scheme in New South Wales are at increased risk of not returning to work compared to patients presenting outside of a compensable scheme and patients in equivalent schemes internationally
C_LIO_LIPatients reporting a longer duration of symptoms and smokers are at increased risk of extended time to first return to work
C_LI

What impact this may have on practice or policyO_LIThe study has identified smoking and pre-surgery activity levels as key targets for intervention in patients receiving arthroscopic rotator cuff repair under a workers compensation scheme in New South Wales
C_LIO_LIBy further investigating whether interventions designed to modify these factors are able to favourably affect patient outcomes, there is potential to return patients to their preoperative level of work sooner
C_LI Characterization of small fiber neuropathy in hypermobile Ehlers Danlos Syndrome Ehlers Danlos syndromes (EDS) are heritable connective tissue disorders. The hypermobile form (hEDS) is the most frequent, yet the only one without an identified genetic mutation. Patients suffering from symptomatic joint hypermobility, yet not fulfilling the hEDS criteria, enter the Hypermobility Spectrum Disorder (HSD) category. In addition to musculoskeletal pain affecting joints, hEDS/HSD patients often describe painful sensations, hypoesthesia, and autonomic symptoms suggesting a neuropathic component. Small fiber neuropathy (SFN) refers to the dysfunction or damage of A-{delta} and C-fibers, which relay thermal and nociceptive information as well as mediating autonomic function. SFN has been suggested by prior studies in hEDS but these early findings (case series N[&le;]20) with sole reliance on intraepidermal nerve fiber density (IENFD) called for a larger sample combined with functional testing.

In this retrospective chart extraction from 79 hEDS/HSD patients referred to a pain center due to neuropathic pain or dysautonomia, both functional (Quantitative Sensory Testing (QST), N=79) and structural (IENFD, N=69) evaluations of small nerve fibers were analyzed in combination with clinical data and standardized questionnaires.

All the patients reported moderate to severe pain interfering with daily life. A decreased thermal detection (QST) was shown in 55/79 patients (70%) and a decreased IENFD in 54/69 patients (78%). Hence a small fiber neuropathy (both abnormal IENFD and QST) was definite in 40/69 patients (58%), possible in 23/69 patients (33%) and excluded in only 6/69 patients (9%).

These results add strong evidence for a peripheral neuropathic contribution to pain symptoms in hEDS/HSD, in addition to the known nociceptive and central sensitization components. Such neuropathic contribution could raise the hypothesis of a neurological cause of hEDS, the only EDS syndrome still without a known genetic cause. Hence, our data is leading the way to a better stratification of this very heterogeneous population, which could improve symptommanagement and expand pathophysiological research. Macular vascular complexity analysis of diabetes mellitus by swept-source optical coherence tomographic angiography PurposeTo evaluate the associations of retinal vascular complexity features, including fractal dimension (FD) and blood vessel tortuosity (BVT), with the severity of diabetic retinopathy (DR) by using noninvasive optical coherence tomographic angiography (OCTA).

MethodsThis prospective cross-sectional study recruited ocular-treatment-naive patients with type 2 diabetes mellitus (DM) registered in the community of Guangzhou, China. OCTA was used to obtain the measurements of FD and BVT in the superficial capillary plexus (SCP) and the deep capillary plexus (DCP). Univariate and multivariate linear regression was used to analyse the correlation of FD and BVT in different layers with DR severity.

ResultsA total of 1282 patients with DM (1282 eyes), with a mean age of 64.2{+/-}7.8 years, were included. FD in the DCP decreased and BVT in the DCP increased in DR patients compared to non-DR patients, even after adjusting for confounding factors (P< 0.05). Trend analysis showed a significant decrease in the FD values as the DR progressed, while the BVT progressively increased with worsening DR severity (P< 0.01). The FD in DCP had a statistically significant positive correlation with FD in SCP and a negative correlation with BVT in SCP and BVT in DCP in all of the participants, including the non-DR group, moderate DR group and severe DR group (P< 0.01).

ConclusionFD and BVT determined using OCTA might be useful parameters for objectively distinguishing DR from non-DR and indicating DR progression. Macronutrient mass intake explains deferential weight and fat loss in isocaloric diets Differential weight and fat losses under isocaloric diets of distinct macronutrient composition are well-documented findings in obesity research.1-6 Such data are considered a result of inadequate methodology as it disagree with the energy balance theory.7 A recent mathematical analysis of this paradigm has found, however, serious analytical contradictions in its foundations.8 As an alternative, a mass balance model was proposed to explain the aforesaid body composition alterations. Here, we expand on this observation by contrasting both models. We show that mass balance explains a wide range of fending experiments including those concurring with the energy balance principle. The latter, however, is less flexible and results in poor forecasts in settings consistent with mass balance. The energy balance theory is thus an unsatisfactory model of body composition changes. Consequently, by shifting to a mass balance paradigm of obesity a much deeper understanding of this disease may follow in the near future. A Randomised Trial of a Wearable UV dosimeter for Skin Cancer Prevention BackgroundNon-melanoma skin cancer (NMSC) is the most prevalent cancer in the United States, affecting 5 million people and costing $8.1 billion per year. Despite well-defined guidelines on ultraviolet radiation (UVR) avoidance, it remains difficult for people to assess their individual exposure, as UVR is invisible and the onset of symptoms due to UVR damage are delayed.

MethodsIn a prospective, randomized-controlled trial, 97 patients with a history of actinic keratoses were enrolled from March 2018 to July 2018 and followed over 6 months. 50 patients were given a wearable device that measured UV exposure and a smartphone application that provided both real-time and cumulative UV exposure information, and 47 patients were provided with UV protection counseling by a dermatologist.

ResultsWe observed a significant decrease in the incidence rate of NMSC in the intervention group compared to the control group over 3 months (p = 0.02). We did not observe a significant decrease in the incidence rate of actinic keratoses (AK) in the intervention group compared to the control group. The observed clinical benefit was not accompanied by psychological side effects such as anxiety and depression.

ConclusionsThis study suggests that providing real-time UV exposure data using a wearable UV dosimeter is a safe and effective behavioral change strategy to prevent NMSC. (Funded by the National Cancer Institute, contract HHSN261201700005C; ClinicalTrials.gov number NCT03315286.) SARS-CoV-2 Acquisition and Immune Pathogenesis Among School-Aged Learners in Four Diverse Schools BackgroundUnderstanding SARS-CoV-2 infection in children is necessary to reopen schools safely.

MethodsWe measured SARS-CoV-2 infection in 320 learners [10.5 {+/-} 2.1(sd); 7-17 y.o.] at four diverse schools with either remote or on-site learning. Schools A and B served low-income Hispanic learners; school C served many special-needs learners; and all provided predominantly remote instruction. School D served middle- and upper-income learners, with predominantly on-site instruction. Testing occurred in the fall (2020), and 6-8 weeks later during the fall-winter surge (notable for a tenfold increase in COVID-19 cases). Immune responses and mitigation fidelity were also measured.

ResultsWe found SARS-CoV-2 infections in 17 learners only during the surge. School A (97% remote learners) had the highest infection (10/70, 14.3%, p<0.01) and IgG positivity rates (13/66, 19.7%). School D (93% on-site learners) had the lowest infection and IgG positivity rates (1/63, 1.6%). Mitigation compliance [physical distancing (mean 87.4%) and face covering (91.3%)] was remarkably high at all schools. Documented SARS-CoV-2-infected learners had neutralizing antibodies (94.7%), robust IFN-{gamma}+ T cell responses, and reduced monocytes.

ConclusionSchools can implement successful mitigation strategies across a wide range of student diversity. Despite asymptomatic to mild SARS-CoV-2 infection, children generate robust humoral and cellular immune responses.

Key PointsO_LISuccessful COVID-19 mitigation was implemented across a diverse range of schools.
C_LIO_LISchool-associated SARS-CoV-2 infections reflect regional rates rather than remote or on-site learning.
C_LIO_LISeropositive school-aged children with asymptomatic to mild SARS-CoV-2 infections generate robust humoral and cellular immunity.
C_LI Cognitive impairment and functional change in COVID-19 patients undergoing inpatient rehabilitation Cognitive impairment is increasingly recognized as a sequela of COVID-19. It is unknown how cognition changes and relates to functional gain during inpatient rehabilitation. We administered the Montreal Cognitive Assessment (MoCA) at admission to 77 patients undergoing inpatient rehabilitation for COVID-19 in a large U.S. academic medical center. 45 patients were administered the MoCA at discharge. Functional gain was assessed by change in the Quality Indicator for Self-Care (QI-SC). In the full sample, 80.5% of patients exhibited cognitive impairment on admission, which was associated with prior delirium. Among 45 patients with retest data, there were significant improvements in MoCA and QI-SC. QI-SC score gain was higher in patients who made clinically meaningful changes on the MoCA, an association that persisted after accounting for age and delirium history. Cognitive impairment is frequent among COVID-19 patients, but improves over time and is associated with functional gain during inpatient rehabilitation. Remote exposure to secondhand tobacco smoke is associated with lower exercise capacity through effects on oxygen pulse, a proxy of cardiac stroke volume BackgroundPast exposure to secondhand tobacco smoke (SHS) is associated with exercise limitation. Pulmonary factors including air trapping contribute to this limitation but the contribution of cardiovascular factors is unclear.

ObjectiveTo determine contribution of cardiovascular mechanisms to SHS-associated exercise limitation.

MethodsWe examined the cardiovascular responses to maximum effort exercise in 245 never-smokers with remote, prolonged occupational exposure to SHS and no known history of cardiovascular disease. We estimated the contribution of oxygen-pulse (proxy for cardiac stroke volume) and changes in systolic (SBP) and diastolic blood pressures (DBP) and heart rate (HR) towards exercise capacity, and examined whether the association of SHS with exercise capacity was mediated through these variables.

ResultsAt peak exercise (highest workload completed [WattsPeak]=156{+/-}46 watts [135{+/-}33 %predicted]), oxygen consumption (VO2Peak) and oxygen-pulse (O2-PulsePeak) were 1,557{+/-}476 mL/min (100{+/-}24 %predicted) and 11.0{+/-}3.0 mL/beat (116{+/-}25 %predicted), respectively, with 29% and 3% participants not achieving their predicted normal range. Oxygen saturation at peak exercise was 98{+/-}1% and remained >93% in all participants. Sixty-six percent showed hypertensive response to exercise. In models adjusted for covariates, WattsPeak was associated directly with O2-PulsePeak, HRPeak, and SBPPeak and inversely with SHS, air trapping (RV/TLC), and rise of SBP over workload (all P<0.01). Moreover, SHS exposure association with WattsPeak was substantially (41%) mediated through its effect on O2-PulsePeak (P<0.038). Although not statistically significant, a considerable proportion (36%) of air trapping effect on WattsPeak seemed to be mediated through O2-PulsePeak (P=0.078). The likelihood of having baseline respiratory symptoms (modified Medical Research Council score [&ge;]1) was associated with steeper rise in SBP over workload (P<0.01).

ConclusionIn a never-smoker population with remote exposure to SHS, abnormal escalation of afterload and an SHS-associated reduction in cardiac output contributed to lower exercise capacity.

Key messagesO_ST_ABSWhat is the key question?C_ST_ABSWhat are the cardiovascular health effects of past exposure to secondhand tobacco smoke in never-smokers? How do pulmonary and cardiovascular systems interact in this setting?

What is the bottom line?Healthy never-smokers with history of remote past exposure to secondhand tobacco smoke have an abnormal cardiovascular response to exercise, which is characterized by a stroke volume and thus an exercise capacity that are reduced proportional to their years of exposure to secondhand tobacco smoke.

Why read on?The abnormal cardiovascular response to exercise in this population reveals the presence of an occult or subclinical pathology that impairs the cardiopulmonary functional reserve and reduces the efficiency of bodys oxygen delivery machinery, which could be disadvantageous during the times of increased cardiopulmonary output demands as in physiological distress or disease. A Cross-Sectional Examination of Conflict-of-Interest Disclosures of Physician-Authors Publishing in High-Impact US Medical Journals ObjectiveTo assess the accuracy of self-reported financial conflict-of-interest (COI) disclosures in the New England Journal of Medicine (NEJM) and Journal of the American Medical Association (JAMA) within the requisite disclosure period prior to article submission.

DesignCross-sectional investigation.

Data SourcesOriginal clinical-trial research articles published in NEJM (n = 206) or JAMA (n = 188) from January 1 to December 31, 2017; self-reported COI disclosure forms submitted to NEJM or JAMA with the authors published articles; Open Payments website (from database inception; latest search: August 2019).

Main outcome measuresFinancial data reported to Open Payments from 2014 to 2016 (time period that included all subjects requisite disclosure windows) were compared to self-reported disclosure forms submitted to the journals. Payments were defined as those not associated with a research study or formal research funding. Payment types were categorized as "disclosed," "undisclosed," "indeterminate," or "unrelated."

ResultsThirty-one articles from NEJM and 31 articles from JAMA met inclusion criteria. The physician-authors (n = 118) received a combined total of $7.48 million. Of the 106 authors (89.8%) who received payments, 86 (81.1%) received undisclosed payments. The top 23 most highly compensated received $6.32 million, of which $3.00 million (47.6%) was undisclosed. Disclosure rates were the equivalent between the top 23 and the entire sample.

ConclusionsHigh payment amounts, as well as high proportions of undisclosed financial compensation, regardless of amount received, comprised potential COIs for two influential US medical journals. Further research is needed to explain why such high proportions of general payments were undisclosed and whether journals that rely on self-reported COI disclosure need to reconsider their policies. A general computational framework for COVID-19 modelling with applications to testing varied interventions in education environments We construct a spatially-compartmental individual-based model of the spread of Covid-19 in indoor spaces. The model can be used to predict the infection rates in a variety of locations when various non-pharmaceutical interventions (NPIs) are introduced. Tasked by the Welsh Government, we apply the model to secondary schools and Further and Higher Education environments. Specifically, we consider student populations mixing in a classroom and in halls of residence. We focus on assessing the potential efficacy of Lateral Flow Devices (LFDs) when used in broad-based screens for asymptomatic infection or in  test-to-release scenarios in which individuals who have been exposed to infection are released from isolation given a negative result. LFDs are also compared to other NPIs; we find that, although LFD testing can be used to mitigate the spread of Covid-19, it is more effective to invest in personal protective equipment, e.g. masks, and in increasing ventilation quality. In addition, we provide an open-access and user-friendly online applet that simulates the individual-based model, complete with user tutorials to encourage the use of the model to aid educational policy decisions as input infection data evolves (https://bit.ly/CV19_INTER_IBM). Elevated Levels of IL-6 in IgA Nephropathy patients are induced by an Epigenetically Driven Mechanism Triggered by Viral and Bacterial RNA Recently, a several models has been proposed to describe the pathogenesis of Immunoglobulin A nephropathy (IgAN), and among them the multihit and the gut-microbiota. These models explain the pathogenesis of IgAN caused by the production of aberrant IgA, but it is believed further predisposing factors are present, including immunological, genetic, environmental, or nutritional factors that can influence the pathogenesis and that could be useful for development of precision nephrology and personalized therapy.

Newly, the role of IL-6 in pathogenesis is becoming increasingly important. It is essential for glomerular immunoglobulin A deposition and the development of renal pathology in Cd37-deficient mice, even if the reason why levels of IL-6 are elevated in IgAN patients is not well understood. One attainable hypothesis on high levels of IL-6 in IgAN comes out from our recent whole genome DNA methylation screening in IgAN patients, that identified, among others, a hypermethylated region comprising Vault RNA 2-1 (VTRNA2-1), a non-coding RNA also known as precursor of miR-886 (pre-mi-RNA). Consistently, the VTRNA2-1 expression was found down-regulated in IgAN patients.

Here we confirm that VTRNA2-1 is low expressed in IgAN subjects compared to HS and we found that also in transplanted IgAN patients (TP-IgAN), compared to non IgAN transplanted patients (TP), the VTRNA2-1 transcript was expressed at level very low. We found that in IgAN patients with downregulated VTRNA2-1, PKR is overactivated, coherently with the role of the VTRNA2-1 that binds to PKR and inhibits its phosphorylation. The loss of the VTRNA2-1 natural restrain causes, in turn, the activation of CREB by PKR. We found CREB, a classical cAMP-inducible CRE-binding factor interacting with a region of the IL-6 promoter and leading to IL-6 production, overactivated both in IgAN and in TP-IgAN patients. Effectively, in the same patients, we found elevated levels of IL-6 correlating with CREB and PKR phosphorylation.

Since PKR is normally activated by bacterial and viral RNA we hypothesized that these microrganisms can further activate the PKR/CREB/IL-6 pathway leading to an excess of IL-6 production, explaining both the high levels of IL-6, both infection involvement in the disease, both cases of IgAN associated with COVID-19 infection and with COVID-19 RNA-vaccination, and recent data showing microbiota involvment in IgAN.

Effectively, we found that Effectively, we sfound that both the RNA poly(I:C) and the COVID-19 RNA-vaccine stimulation significantly increase the IL-6 levels in IgAN patient PBMCs.

The PKR/CREB/IL-6 pathway may be very important also in the setting of renal transplantation. We found that this pathway is upregulated also in IgAN transplanted patients. Recent studies showed that the cumulative risk of IgA nephropathy recurrence increases after transplant and is associated with a 3.7-fold greater risk of graft loss. Finally, we showed that the IL-6 secretion can be reduced by the PKR inhibitor imoxin.

In conclusion, the discovery of the upregulated VTRNA2-1/PKR/CREB/IL-6 pathway in IgAN patients may provide novel approach to treat the disease and may be useful for development of precision nephrology and personalized therapy, possibly by checking the VTRNA2-1 methylation level in IgAN patients. GWAS of Retinal Vessel Tortuosity Identifies 173 Novel Loci Revealing Genes and Pathways Associated with Vascular Pathomechanics and Diseases BackgroundFundus images allow for non-invasive assessment of the retinal vasculature whose features provide important information on health. Blood vessel tortuosity is a morphological feature associated with many diseases including hypertension.

MethodsWe analyzed 116 639 fundus images of suitable quality from 63 662 participants from three cohorts, namely the UK Biobank (n = 62 751), SKIPOGH (n = 397), and OphtalmoLaus (n = 512). We used a fully automated image processing pipeline to annotate vessels and a deep learning algorithm to determine the vessel type, characterizing these subjects in terms of their median retinal vessel tortuosity specific to arteries and to veins. Tortuosity was measured by the distance factor (the length of a vessel segment over its chord length), as well as measures that integrate over vessel curvature. Using these measures as traits, we performed the largest genome-wide association study (GWAS) of vessel tortuosity to date. We assessed gene set enrichment using the novel high-precision statistical method PascalX.

ResultsHigher tortuosity was significantly associated with higher incidence of angina, myocardial infarction, stroke, deep vein thrombosis, and hypertension. We identified 175 significantly associated genetic loci in the UK Biobank; 173 of these were novel and 4 replicated in our second, much smaller, meta-cohort. We estimated heritability at [~]25% using linkage disequilibrium score regression. Vessel type specific GWAS revealed 114 loci for arteries and 63 for veins. Genes with significant association signals included COL4A2, ACTN4, LGALS4, LGALS7, LGALS7B, TNS1, MAP4K1, EIF3K, CAPN12, ECH1, and SYNPO2. These tortuosity genes were overexpressed in arteries and heart muscle and linked to pathways related to the structural properties of the vasculature. We demonstrated that tortuosity loci served pleiotropic functions as cardiometabolic disease variants and risk factors. Concordantly, Mendelian randomization revealed causal effects between tortuosity, BMI and LDL.

ConclusionsSeveral alleles associated with retinal vessel tortuosity point to a common genetic architecture of this trait with cardiovascular diseases and metabolic syndrome. Our results shed new light on the genetics of vascular diseases and their pathomechanisms and highlight how GWASs and heritability can be used to improve phenotype extraction from high-dimensional data, such as images.

Clinical PerspectiveO_ST_ABSWhat is new?C_ST_ABSO_LIWe automatically estimated arterial and venous tortuosity in over 100k retinal fundus images using image analysis and deep learning.
C_LIO_LIGWAS revealed 173 novel loci.
C_LIO_LIMendelian randomization showed that increased venous tortuosity reduces BMI whereas elevated LDL levels reduce the tortuosity of both arteries and veins.
C_LIO_LIMeasuring tortuosity in terms of the distance factor, which is sensitive to total vessel elongation, had higher heritability and more associated loci than other tortuosity measures that are sensitive to local vessel bending.
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What are the clinical implications?O_LITortuosity genes were overexpressed in the aorta, tibial artery, coronary artery, and in two heart tissues.
C_LIO_LIHigher tortuosity was associated with higher incidence of angina, myocardial infarction, stroke, deep vein thrombosis and hypertension.
C_LIO_LIWe demonstrated a shared genetic architecture between retinal tortuosity and certain diseases related to the vasculature, and the associations included several cardiometabolic disease variants and risk factors. Further research is needed to investigate the potential of the retinal vessel tortuosity as a clinically relevant biomarker for cardiovascular disease and metabolic syndrome.
C_LIO_LIEnriched pathways include a well-known therapeutic target for ocular diseases (VEGFA-VEGFR2) affecting tissue remodeling. We highlight several transcription factors as interesting targets for further experimentation.
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