The kidney releases a non-polymerizing form of Uromodulin in the urine and circulation that retains the external hydrophobic patch domain Uromodulin (Tamm-Horsfall protein, THP) is a glycoprotein uniquely produced in the kidney. It is released by cells of the thick ascending limbs (TAL) apically in the urine, and basolaterally in the renal interstitium and systemic circulation. Processing of mature urinary THP, which polymerizes into supra-molecular filaments, requires cleavage of an external hydrophobic patch (EHP) at the C terminus. However, THP in the circulation is not polymerized, and it remains unclear if non-aggregated forms of THP exist natively in the urine. We propose that an alternative processing path, which retains the EHP domain, can lead to a non-polymerizing form of THP. We generated an antibody that specifically recognizes THP with retained EHP (THP+EHP) and established its presence in the urine in a non-polymerized native state. Proteomic characterization of urinary THP+EHP revealed its C-terminus to end at F617. In the human kidney, THP+EHP was not only detected in TAL cells, but also diffusely in the renal parenchyma. Using immunoprecipitation followed by proteomic sequencing and immunoblotting, we then demonstrated that serum THP has also retained EHP. In a small cohort of patients at risk for acute kidney injury (AKI), admission urinary THP+EHP was significantly lower in patients who subsequently developed AKI during hospitalization. Our findings uncover novel insights into uromodulin biology by establishing the presence of an alternative path for cellular processing, which could explain the release of non-polymerizing THP in the circulation. Larger studies are needed to establish the utility of urinary THP+EHP as a sensitive biomarker of kidney health and susceptibility to injury.
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.
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.) COVID Outcome Prediction in the Emergency Department (COPE): Development and validation of a model for predicting death and need for intensive care in COVID-19 patients Background and aimCOVID-19 is putting extraordinary pressure on emergency departments (EDs). To support decision making in the ED, we aimed to develop a simple and valid model for predicting mortality and need for intensive care unit (ICU) admission in suspected COVID-19 patients.

MethodsFor model development, we retrospectively collected data of patients who were admitted to 4 large Dutch hospitals with suspected COVID-19 between March and August 2020 (first wave of the pandemic). Based on prior literature we considered quickly and objectively obtainable patient characteristics, vital parameters and blood test values as predictors. Logistic regression analyses with post-hoc uniform shrinkage was used to obtain predicted probabilities of in-hospital death and of the need for ICU admission, both within 28 days after hospital admission. We assessed model performance (Area Under the ROC curve (AUC); calibration plots) with temporal validation in patients who presented between September and December 2020 (second wave). We used multiple imputation to account for missing values.

ResultsThe development data included 5,831 patients, of whom 629 (10.8%) died and 5,070 (86.9%) were discharged within 28 days after admission. ICU admission was fully recorded for 2,633 first wave patients in 2 hospitals, with 214 (8%) ICU admissions within 28 days. A simple model - COVID Outcome Prediction in the Emergency Department (COPE) - with age, respiratory rate, C-reactive protein, lactic dehydrogenase, albumin and urea captured most of the ability to predict death. COPE was well-calibrated and showed good discrimination in 3,252 second wave patients (AUC in 4 hospitals: 0.82 [0.78; 0.86]; 0.82 [0.74; 0.90]; 0.79 [0.70; 0.88]; 0.83 [0.79; 0.86]). COPE was also able to identify patients at high risk of needing IC in 706 second wave patients with complete information on ICU admission (AUC: 0.84 [0.78; 0.90]; 0.81 [0.66; 0.95]). The models are implemented in web-based and mobile applications.

ConclusionCOPE is a simple tool that is well able to predict mortality and need for ICU admission for patients who present to the ED with suspected COVID-19 and may help patients and doctors in decision making.

CONTRIBUTION TO THE LITERATUREO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIPrediction models have the potential to support decision making about hospital admission of patients presenting to the emergency department with suspected COVID-19
C_LIO_LIMost currently available models that were independently assessed contain a high risk of bias
C_LIO_LIPromising models were developed in different patient selections and included predictors that are not quickly and objective obtainable in emergency departments
C_LI

What this study addsO_LIA simple and objective tool ("COPE") is well able to predict mortality and need for ICU admission for patients who present to the ED with suspected COVID-19
C_LIO_LICOPE may support ED physicians to identify high-risk patients - i.e. those at high risk of deterioration and/or death - requiring treatment in the ICU, intermediate-risk patients requiring admission to the clinical ward, and low-risk patients who can potentially be sent home
C_LI Autism in gifted youth is associated with low processing speed and high verbal ability BackgroundHigh cognitive ability is an almost universally positive prognostic indicator in the context of neurodevelopmental, neuropsychiatric, and neurodegenerative conditions. However, "twice-exceptional" individuals, those who demonstrate exceptionally high cognitive ability (gifted) and exhibit profound behavioral and mental health challenges, are a striking exception to this rule.

MethodsWe digitized the clinical records of N=1,074 clients from a US-based specialty clinic serving gifted students. This included a broad array of diagnostic, cognitive, achievement, and behavioral data, including self, teacher, and parent reported items. We conducted both hypothesis-driven and unsupervised learning analyses to 1) identify characteristics whose association with full-scale IQ (FSIQ) was dependent on autism diagnosis and 2) identify cognitive archetypes associated with autism diagnosis and related behaviors. We tested the generalization of our findings using data from the SPARK (N=17,634) and ABCD studies (N=10,602).

ResultsAutistic individuals with IQ >= 120 were nearly 15 times more likely to enter adulthood undiagnosed compared to lower-IQ (IQ < 70) counterparts. Self-reported sense of inadequacy was most strongly associated with increasing FSIQ specifically among autistic clients (beta=0.3, 95% CI:[0.15,0.45], p=7.1x10-5). Similarly, self, parent, and teacher reports of anxiety increased with FSIQ (all p<0.05) in autistic individuals, in striking opposition to the ameliorating effect of FSIQ seen in non-autistic individuals. We uncovered a pattern of decreased processing speed (PS) coupled with very high verbal comprehension (VC), a PS/VC discrepancy, that was associated with autism, inattention, and internalizing problems. Similar cognitive-behavioral links were also observed in the ABCD study. Finally, we found a significant association between the PS/VC discrepancy and polygenic risk for autism in the ABCD sample (t=2.9, p=0.004).

ConclusionsOur results suggest that autistic individuals with exceptional ability are underserved and suffer disproportionately from high anxiety and low self-worth. In addition, elevated IQ with a significant PS/VC discrepancy appears to be a clinically and genetically meaningful biotype linked to autism. Airway management, procedural data, and mortality records of patients undergoing surgery for mucormycosis associated with coronavirus disease (COVID-19) In India, the second wave of coronavirus disease (COVID -19) was associated with a distinct surge in cases of invasive fungal infection with mucormycosis. This disease was seen typically in the sinonasal form in COVID-19 patients. Uncontrolled diabetes, steroid use in COVID-19 treatment, etc. were some of the postulated risk factors for the association of COVID 19 and Mucormycosis. The management plan of these cases included surgical debridement, systemic antifungal therapy, sugar control, and management of antifungal related systemic adverse effects. In this retrospective case record review, we aimed to evaluate the airway management plan, demographics, and overall outcomes in patients undergoing surgical resection for COVID-19 associated mucormycosis. Forty-one (71.9 %) patients had a diagnosis of sino-nasal mucormycosis, fourteen (24.6%) had a diagnosis of rhino-orbital mucormycosis, and 2 patients (3.5%) were diagnosed with palatal mucormycosis. Total 44 (77.19 %) patients had co-morbidities. The most common co-morbidity was Diabetes Mellitus 42 (73.6%), followed by hypertension 21 (36.84%) and Acute kidney injury 14 (28.07%). We used the intubation difficulty scale score to assess intubating conditions. Intubation was easy to slightly difficult in 53 out of 57 patients. In our study, mortality occurred in 7 (12.28 %) patients. The median mortality time was 60 (range, 27-74) days. The median time to hospital discharge was 53.5 (range,10-85) days. Managing COVID-19 on its own is challenging and additional mucormycosis can lead to increased morbidity and mortality. Despite challenges and risks, timely and meticulous interventions can reduce complications. Hyperreflective foci, OCT progression indicators in age-related macular degeneration, include transdifferentiated retinal pigment epithelium PurposeBy optical coherence tomography (OCT) imaging, hyperreflective foci (HRF) indicate progression risk for advanced age-related macular degeneration (AMD) and are in part attributable to ectopic retinal pigment epithelium (RPE). We hypothesized that ectopic RPE are molecularly distinct from in-layer cells and that their cross-retinal course follows Muller glia.

MethodIn clinical OCT (61 eyes, 44 AMD patients, 79.4 {+/-} 7.7 years; 29 female; follow-up = 4.7 {+/-} 0.9 years) one HRF type, RPE plume, was reviewed. Twenty eyes of 20 donors characterized by ex vivo OCT were analyzed by histology (normal, 4; early/intermediate AMD, 7; geographic atrophy (GA), 6; 3 neovascular AMD (nvAMD). Cryosections were stained with antibodies to retinoid (RPE65, CRALPB) and immune (CD68, CD163) markers. In published RPE cellular phenotypes, red immunoreactivity was assessed semi-quantitatively by one observer (none, some cells, all cells).

ResultsTrajectories of RPE plume and cellular debris paralleled Muller glia, whether ordered or subsident, near atrophy borders. RPE corresponding to HRF lost immunoreactivity for retinoid markers and gained immunoreactivity for immune markers. Aberrant immunoreactivity appeared in individual in-layer RPE cells and extended to all abnormal phenotypes. Muller glia remained CRALBP-positive. Plume cells approached and contacted retinal capillaries.

ConclusionGain- and loss-of-function starts with individual in-layer RPE cells and extends to all abnormal phenotypes. Down-regulated RPE retinoid handling may impair rod vision while Muller glia sustain cone vision. Evidence for RPE transdifferentiation, possibly due to ischemia, supports a proposed process of epithelial-mesenchyme transition. Data can propel new biomarkers and therapeutic strategies for AMD.

PrecisHyperreflective foci (HRF) are OCT progression risk indicators in age-related macular degeneration. Abnormal RPE cells including some that correspond to HRF lose immunoreactivity for retinoid markers and gain immunoreactivity for immune markers, indicating molecular transdifferentiation. Statistical modeling for quality risk assessment of clinical trials: follow-up at the era of remote auditing BackgroundAs investigator site audits have largely been conducted remotely during the COVID-19 pandemic, remote quality monitoring has gained some momentum. To further facilitate the conduct of remote Quality Assurance (QA) activities for clinical trials, we developed new quality indicators, building on a previously published statistical modeling methodology.

MethodsWe modeled the risk of having an audit or inspection finding using historical audits and inspections data from 2011 - 2019. We used logistic regression to model finding risk for 4 clinical impact factor (CIF) categories: Safety Reporting, Data Integrity, Consent and Protecting Endpoints.

ResultsWe could identify 15 interpretable factors influencing audit finding risk of 4 out of 5 CIF categories. They can be used to realistically predict differences in risk between 25 and 43% for different sites which suffice to rank sites by audit and inspection finding risk.

ConclusionContinuous surveillance of the identified risk factors and resulting risk estimates could be used to complement remote QA strategies for clinical trials and help to manage audit targets and audit focus also in post-pandemic times. 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. Dental biofilm microbiota dysbiosis is associated with the risk of acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation Acute graft-versus-host disease (aGVHD) is one of the major causes of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recently, aGVHD onset was linked to intestinal microbiota (IM) dysbiosis. However, other bacterial-rich gastrointestinal sites, such as the mouth, which hosts several distinctive microbiotas, may also impact the risk of GVHD. The dental biofilm microbiota (DBM) is highly diverse and, like the IM, interacts with host cells and modulates immune homeostasis. We characterized changes in the DBM of patients during allo-HSCT and evaluated whether the DBM could be associated with the risk of aGVHD. DBM dysbiosis during allo-HSCT was marked by a gradual loss of bacterial diversity and changes in DBM genera composition, with commensal genera reductions and potentially pathogenic bacteria overgrowths. High Streptococcus and high Corynebacterium relative abundance at preconditioning were associated with a higher risk of aGVHD (67% vs. 33%; HR = 2.89, P = 0.04 and 73% vs. 37%; HR = 2.74, P = 0.04, respectively), while high Veillonella relative abundance was associated with a lower risk of aGVHD (27% vs. 73%; HR = 0.24, P < 0.01). Enterococcus faecalis bloom during allo-HSCT was observed in 20% of allo-HSCT recipients and was associated with a higher risk of aGVHD (100% vs. 40%; HR = 4.07, P < 0.001) and severe aGVHD (60% vs. 12%; HR = 6.82, P = 0.01). To the best of our knowledge, this is the first study demonstrating that DBM dysbiosis is associated with the aGVHD risk after allo-HSCT. Generalized Prediction of Hemodynamic Shock in Intensive Care Units Early prediction of hemodynamic shock in the ICU can save lives. Several studies have leveraged a combination of vitals, lab investigations, and clinical data to construct early warning systems for shock. However, these have a limited potential of generalization to diverse settings due to reliance on non-real-time data. Monitoring data from vitals can provide an early real-time prediction of Hemodynamic shock which can precede the clinical diagnosis to guide early therapy decisions. Generalization across age and geographical context is an unaddressed challenge. In this retrospective observational study, we built real-time shock prediction models generalized across age groups (adult and pediatric), ICU-types, and geographies. We trained, validated, and tested a shock prediction model on the publicly available eICU dataset on 208 ICUs across the United States. Data from 156 hospitals passed the eligibility criteria for cohort building. These were split hospital-wise in a five-fold training-validation-test set. External validation of the model was done on a pediatric ICU in New Delhi and MIMIC-III database with more than 0.23 million and one million patient-hours vitals data, respectively. Our models identified 92% of all the shock events more than 8 hours in advance with AUROC of 86 %(SD= 1.4) and AUPRC of 93% (SD =1.2) on the eICU testing set. An AUROC of 87 % (SD =1.8), AUPRC 92 % (SD=1.6) were obtained in external validation on the MIMIC-III cohort. The New Delhi Pediatric SafeICU data achieved an AUROC of 87 % (SD =4) AUPRC 91% (SD=3), despite being completely different geography and age group. In this first, we demonstrate a generalizable model for predicting shock, and algorithms are publicly available as a pre-configured Docker environment at https://github.com/tavlab-iiitd/ShoQPred. PENet: Continuous-Valued Pulmonary Edema Severity Prediction On Chest X-ray Using Siamese Convolutional Networks For physicians to take rapid clinical decisions for patients with congestive heart failure, the assessment of pulmonary edema severity in chest radiographs is vital. While deep learning has been promising in detecting the presence or absence, or even discrete grades of severity, of such edema, prediction of the continuous-valued severity yet remains a challenge. Here, we propose PENet, a deep learning framework to assess the continuous spectrum of pulmonary edema severity from chest X-rays. We present different modes of implementing this network, and demonstrate that our best model outperforms that of earlier work (mean area under the curve of 0.91 over 0.87, for nine comparisons), while saving training data and computation. In depth analysis of patients with severe SARS-CoV-2 in sub-Saharan Africa demonstrates distinct clinical and immunological profiles Although the COVID-19 pandemic has left no country untouched there has been limited research to understand clinical and immunological responses in African populations. Here we comprehensively characterise patients hospitalised with suspected or confirmed COVID-19, and healthy community controls. PCR-confirmed COVID-19 participants were more likely to receive dexamethasone and a beta-lactam antibiotic, and survive to hospital discharge than PCR-/IgG+ and PCR-/IgG-participants. PCR-/IgG+ participants exhibited a nasal and systemic cytokine signature analogous to PCR-confirmed COVID-19 participants, but increased propensity for Staphylococcus aureus and Streptococcus pneumoniae colonisation. We did not find evidence that HIV co-infection in COVID-19 participants was associated with mortality or altered cytokine responses. The nasal immune signature in PCR-/IgG+ and PCR-confirmed COVID-19 participants was distinct and predominated by chemokines and neutrophils. In addition, PCR-/IgG+ individuals with high COVID-19 clinical suspicion had inflammatory profiles analogous to PCR-confirmed disease and potentially represent a target population for COVID-19 treatment strategies. Serum Vitamin D levels are associated with increased COVID-19 severity and mortality independent of whole-body and visceral adiposity INTRODUCTIONCoronavirus disease (COVID-19) is a global pandemic. Vitamin D deficiency has been associated with susceptibility to infectious disease. In this study, the association between COVID-19 outcomes and vitamin D levels in patients attending a COVID-19 reference center in Mexico City are examined.

METHODSConsecutive patients with confirmed COVID-19 were evaluated. All patients underwent clinical evaluation and follow-up, laboratory measurements and a thoracic computerized tomography, including the measurement of epicardial fat thickness. Low vitamin D was defined as levels <20ng/mL (<50nmol/L) and deficient Vitamin D as a level [&le;]12ng/mL (<30nmol/L)

RESULTSOf the 551 patients included, low vitamin D levels were present in 45.6% and deficient levels in 10.9%. Deficient Vitamin D levels were associated with mortality (HR 2.11, 95%CI 1.24-3.58, p=0.006) but not with critical COVID-19, adjusted for age, sex, body-mass index and epicardial fat. Using model-based causal mediation analyses the increased risk of COVID-19 mortality conferred by low vitamin D levels was partly mediated by its effect on D-dimer and cardiac ultrasensitive troponins. Notably, increased risk of COVID-19 mortality conferred by low vitamin D levels was independent of BMI and epicardial fat.

CONCLUSIONVitamin D deficiency ([&le;]12ng/mL or <30nmol/L), is independently associated with COVID-19 mortality after adjustment for visceral fat (epicardial fat thickness). Low vitamin D may contribute to a pro-inflammatory and pro-thrombotic state, increasing the risk for adverse COVID-19 outcomes. The Association of Opening K-12 Schools with the Spread of COVID-19 in the United States: County-Level Panel Data Analysis AO_SCPLOWBSTRACTC_SCPLOWThis paper empirically examines how the opening of K-12 schools and colleges is associated with the spread of COVID-19 using county-level panel data in the United States. Using data on foot traffic and K-12 school opening plans, we analyze how an increase in visits to schools and opening schools with different teaching methods (in-person, hybrid, and remote) is related to the 2-weeks forward growth rate of confirmed COVID-19 cases. Our debiased panel data regression analysis with a set of county dummies, interactions of state and week dummies, and other controls shows that an increase in visits to both K-12 schools and colleges is associated with a subsequent increase in case growth rates. The estimates indicate that fully opening K-12 schools with in-person learning is associated with a 5 (SE = 2) percentage points increase in the growth rate of cases. We also find that the positive association of K-12 school visits or in-person school openings with case growth is stronger for counties that do not require staff to wear masks at schools. These results have a causal interpretation in a structural model with unobserved county and time confounders. Sensitivity analysis shows that the baseline results are robust to timing assumptions and alternative specifications. Determinants and trends of COVID-19 vaccine hesitancy and vaccine uptake in a national cohort of U.S. adults: a longitudinal cohort study We estimated the trends and correlates of vaccine hesitancy, and its association with subsequent vaccine uptake among 5,458 adults in the United States. Participants belonged to the CHASING COVID Cohort, a national longitudinal study. Trends and correlates of vaccine hesitancy were examined longitudinally in eight interview rounds from October 2020 to July 2021. We also estimated the association between willingness to vaccinate and subsequent vaccine uptake through July 2021. Vaccine delay and refusal decreased from 51% and 8% in October 2020 to 8% and 6% in July 2021, respectively. Compared to Non-Hispanic (NH) White participants, NH Black and Hispanic participants had higher adjusted odds ratios (aOR) for both vaccine delay (aOR: 2.0 [95% CI: 1.5, 2.7] for NH Black and 1.3 [95% CI: 1.0, 1.7] for Hispanic) and vaccine refusal (aOR: 2.5 [95% CI: 1.8, 3.6] for NH Black and 1.4 [95% CI: 1.0, 2.0] for Hispanic) in June 2021. COVID-19 vaccine hesitancy was associated with lower odds of subsequent vaccine uptake (aOR: 0.15, 95% CI: 0.13, 0.18 for vaccine-delayers and aOR: 0.02; 95% CI: 0.01, 0.03 for vaccine-refusers compared to vaccine-willing participants), adjusted for sociodemographic factors and COVID-19 history. Vaccination awareness and distribution efforts should focus on vaccine delayers. 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. Simple risk scores to predict hospitalization or death in outpatients with COVID-19 including the Omicron variant ImportanceOutpatient physicians need guidance to support their clinical decisions regarding management of patients with COVID-19, in particular whether to hospitalize a patient and if managed as an outpatient, how closely to follow them.

ObjectiveTo develop and prospectively validate a clinical prediction rule to predict the likelihood of hospitalization for outpatients with COVID-19 that does not require laboratory testing or imaging.

DesignDerivation and temporal validation of a clinical prediction rule, and prospective validation of two externally derived clinical prediction rules.

SettingPrimary and Express care clinics in a Pennsylvania health system.

ParticipantsPatients 12 years and older presenting to outpatient clinics who had a positive polymerase chain reaction test for COVID-19.

Main outcomes and measuresClassification accuracy (percentage in each risk group hospitalized) and area under the receiver operating characteristic curve (AUC).

ResultsOverall, 7.4% of outpatients in the early derivation cohort (5843 patients presenting before 3/1/21) and 5.5% in the late validation cohort (3806 patients presenting 3/1/21 or later) were ultimately hospitalized. We developed and temporally validated three risk scores that all included age, dyspnea, and the presence of comorbidities, adding respiratory rate for the second score and oxygen saturation for the third. All had very good overall accuracy (AUC 0.77 to 0.78) and classified over half of patients in the validation cohort as very low risk with a 1.7% or lower likelihood of hospitalization. Two externally derived risk scores identified more low risk patients, but with a higher overall risk of hospitalization (2.8%).

Conclusions and relevanceSimple risk scores applicable to outpatient and telehealth settings can identify patients with very low (1.6% to 1.7%), low (5.2% to 5.9%), moderate (14.7% to 15.6%), and high risk (32.0% to 34.2%) of hospitalization. The Lehigh Outpatient COVID Hospitalization (LOCH) risk score is available online as a free app: https://ebell-projects.shinyapps.io/LehighRiskScore/. Deep learning for caries detection using optical coherence tomography Early detection of dental caries has been one of the most predominant topics studied over the last few decades. Conventional examination through visual-tactile inspection and radiography can be inaccurate and destructive to the tooth structure. The development of optical coherence tomography (OCT) has given dentistry an alternative diagnostic technique, which has been proven by numerous studies, that it has better sensitivity, specificity, and non-invasive characteristics. The growing popularity of artificial intelligence (AI) also contributes to a more efficient and effective way of image-based detection and decision-making. However, previous studies, which have attempted to employ AI for caries assessment, did not incorporate high-quality ground truth data. Therefore, this study aims to bypass this issue and highlights the importance of high-quality data. A two-phase study was carried out to explore different methods for caries detection. Initially, the comparison of caries detection based on OCT and apical radiography by 5 experienced clinicians was conducted. Then, five convolutional neural networks (CNNs), including AlexNet, VGG-16, ResNet-152, Xception, and ResNext-101, in the scope of AI were employed to detect caries and compared with the findings of the 5 clinicians. The data was preprocessed and labeled with the ground truth corresponding to microcomputed tomography (micro-CT) with rigorous definition. The weighted Kappa statistics suggested that OCT ({varkappa}= .699, SD = .090) showed a higher accuracy rate than radiography ({varkappa}= .407, SD = .049), and CNNs ({varkappa}= .860, SD = .049) were rated higher than clinicians ({varkappa}= .679, SD = .113), both at a .05 significance level. The best result was carried out by ResNet-152, which demonstrated a high accuracy rate of 95.21% and a sensitivity of 98.85%. These findings illustrate the importance of ground truth data for AI training and the potential of deep CNN algorithms combined with OCT for diagnosing dental caries. 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. 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 SARS-CoV-2 Variant of Concern 202012/01 has about twofold replicative advantage and acquires concerning mutations The novel SARS-CoV-2 Variant of Concern (VOC)-202012/01 (also known as B.1.1.7), first collected in United Kingdom on September 20, 2020, is a rapidly growing lineage that in January 2021 constituted 86% of all SARS-CoV-2 genomes sequenced in England. The VOC has been detected in 40 out of 46 countries that reported at least 50 genomes in January 2021. We have estimated that the replicative advantage of the VOC is in the range 1.83-2.18 [95% CI: 1.71-2.40] with respect to the 20A.EU1 variant that dominated in England in November 2020, and in range 1.65-1.72 [95% CI: 1.46-2.04] in Wales, Scotland, Denmark, and USA. As the VOC strain will likely spread globally towards fixation, it is important to monitor its molecular evolution. We have estimated growth rates of expanding mutations acquired by the VOC lineage to find that the L18F substitution in spike has initiated a substrain of high replicative advantage in relation to the remaining VOC substrains. The L18F substitution is of significance because it has been found to compromise binding of neutralizing antibodies. Of concern are immune escape mutations acquired by the VOC: E484K, F490S, S494P (in the receptor binding motif of spike) and Q677H, Q675H (in the proximity of the polybasic cleavage site at the S1/S2 boundary). These mutants may hinder efficiency of existing vaccines and expand in response to the increasing after-infection or vaccine-induced seroprevalence. Decoding hand and wrist movement intention from chronic stroke survivors with hemiparesis using a user-friendly, wearable EMG-based neural interface Prosthetics and orthotics have been recognized for decades as a potential means to restore hand function and independence to individuals living with impairment due to stroke. However, 75% of stroke survivors, caregivers, and health care professionals (HCP) believe current practices are insufficient, specifically calling out the upper extremity as an area where innovation is needed to develop highly usable prosthetics/orthotics for the stroke population. A promising method for controlling upper limb technologies is to infer movement intent non-invasively from surface electromyography (EMG) activity. While this approach has garnered significant attention in the literature, existing technologies are often limited to research settings and struggle to meet stated user needs. To address these limitations, we have developed the NeuroLife(R) EMG System, which consists of a wearable forearm sleeve with 150 embedded electrodes and associated hardware and software to record and decode surface EMG. Here, we demonstrate accurate decoding of 12 functional hand, wrist, and forearm movements, including multiple types of grasps from participants with varying levels of chronic impairment from stroke, with an overall accuracy of 77.1{+/-}5.6%. Importantly, we demonstrate the ability to decode a subset of 3 fundamental movements in individuals with severe hand impairment at 85.4{+/-}6.4% accuracy, highlighting the potential as a control mechanism for assistive technologies. Feedback from stroke survivors who tested the system indicates that the sleeves design meets various user needs, including being comfortable, portable, and lightweight. The sleeve is in a form factor such that it can be used at home without an expert technician and can be worn for multiple hours without discomfort. Taken together, the NeuroLife EMG System represents a platform technology to record and decode high-definition EMG for the eventual real-time control of assistive devices in a form factor designed to meet user needs.