Increasing coordination and responsivity of emotion-related brain regions with a heart rate variability biofeedback randomized trial Heart rate variability is a robust biomarker of emotional well-being, consistent with the shared brain networks regulating emotion regulation and heart rate. While high heart rate oscillatory activity clearly indicates healthy regulatory brain systems, can increasing this oscillatory activity also affect brain function? To test this possibility, we randomly assigned 106 young adult participants to one of two 5-week interventions involving daily biofeedback that either increased heart rate oscillations (Osc+ condition) or had little effect on heart rate oscillations (Osc- condition) and examined effects on brain activity during rest and during regulating emotion. While there were no significant changes in the right amygdala-medial prefrontal cortex (MPFC) functional connectivity (our primary outcome), the Osc+ intervention increased left amygdala-MPFC functional connectivity and functional connectivity in emotion-related resting-state networks during rest. It also increased down-regulation of activity in somatosensory brain regions during an emotion regulation task. The Osc- intervention did not have these effects. In this healthy cohort, the two conditions did not differentially affect anxiety, depression or mood. These findings indicate that heart rate oscillatory activity not only provides a measure of the current state of regulatory brain systems but also changes emotion network coordination in the brain.

Significance StatementPeople whose breathing makes their heart rate oscillate more (leading to higher heart rate variability or HRV) generally have better regulated emotion. Thus, HRV may indicate functioning of brain networks regulating emotion and internal body states. But heart rate oscillations may not only reflect brain regulatory networks but also help shape these networks. We randomly assigned participants to practice either increasing heart rate oscillations using slow-paced breathing or decreasing them using personalized strategies. Daily practice increasing heart rate oscillations affected brain activity in emotion-related networks even during times when participants breathed no differently than the comparison group. Thus, HRV is more than just an outcome measure--it can help shape the subsequent functioning of emotion-related brain networks.
Modelling the laminar connectome of the human brain The human connectome is the complete structural description of the network of connections and elements that form the  wiring diagram of the brain. Due to the current scarcity of information regarding laminar end points of white matter tracts inside cortical grey matter, tractography remains focused on cortical partitioning into regions, while ignoring radial partitioning into laminar components. To overcome this biased representation of the cortex as a single homogenous unit, we use a recent data-derived model of cortical laminar connectivity, which has been further explored and corroborated in the macaque brain by comparison to published studies. The model integrates multimodal MRI imaging datasets of both white matter connectivity and grey matter laminar composition into a laminar-level connectome. In this study we model the laminar connectome of healthy human brains (N=30) and explore them via a set of neurobiologically meaningful complex network measures. Our analysis demonstrates a subdivision of network hubs that appear in the standard connectome into each individual component of the laminar connectome, giving a fresh look into the role of laminar components in cortical connectivity and offering new prospects in the fields of both structural and functional connectivity.
Using controlled interrupted time series to estimate the population-level effects of Ontario's recently implemented overdose prevention sites and consumption and treatment services BackgroundOntario recently implemented overdose prevention sites and consumption and treatment services (OPS/CTS) to stem the harms of the opioid epidemic. We tested whether operating any site improved local opioid-related health service use and mortality rates.

MethodsWe used monthly counts of all opioid-related emergency department (ED) visits, hospitalizations, and deaths between January 2014 and December 2020 for our outcomes. For each public health unit (PHU) that implemented any OPS/CTS, we created a synthetic control as a weighted combination of unexposed PHU. We estimated the population-level effects of operating any site using controlled interrupted time series with segmented regression and adjusted for time varying confounders (i.e. OPS/CTS capacity, naloxone kits distributed, and persons receiving opioid agonist treatment per 100,000 population). We repeated the analysis using a multiple baseline approach to estimate province-wide effects.

ResultsBetween 2017 and 2020, nine out of 34 PHU implemented at least one OPS/CTS. ED visit (RR=0.96, 95%CI: 0.92 - 0.99) and hospitalization (RR=0.95, 95%CI: 0.92 - 0.98) trends declined faster among treated units. Improvements in local ED visit rate trends were observed for the majority of treated units. Hospitalization rates declined faster for London (RR=0.97, 95%CI: 0.95 - 0.99) and Niagara (RR=0.95, 95%CI: 0.92 - 0.98); while mortality rates declined faster for Hamilton (RR=0.93, 95%CI: 0.90 - 0.96), Niagara (RR=0.97, 95%CI: 0.94 - 0.99) and Guelph (RR=0.94, 95%CI: 0.88 - 1.00).

ConclusionAlthough OPS/CTS are not sufficient to stem the harms of the opioid overdose epidemic on their own, they play a critical role in local harm reduction strategies. 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. An ergonomic assessment tool for evaluating the effect of back exoskeletons on injury risk Low back disorders (LBDs) are a leading injury in the workplace. Back exoskeletons (exos) are wearable assist devices that complement traditional ergonomic controls and reduce LBD risks by alleviating musculoskeletal overexertion. However, there are currently no ergonomic assessment tools to evaluate risk for workers wearing back exos. Exo-LiFFT, an extension of the Lifting Fatigue Failure Tool, is introduced as a means to unify the etiology of LBDs with the biomechanical function of exos. We present multiple examples demonstrating how Exo-LiFFT can assess or predict the effect of exos on LBD risk without costly, time-consuming electromyography studies. For instance, using simulated and real-world material handling data we show an exo providing a 30 Nm lumbar moment is projected to reduce cumulative back damage by [~]70% and LBD risk by [~]20%. Exo-LiFFT provides a practical, efficient ergonomic assessment tool to assist safety professionals exploring back exos as part of a comprehensive occupational health program.

HIGHLIGHTSO_LIBack exos are wearable assist devices that complement ergonomic controls for reducing low back disorder (LBD) risks
C_LIO_LIHowever, no ergonomic assessment tools exist to evaluate LBD risks for workers wearing back exos
C_LIO_LIWe introduce Exo-LiFFT, an ergonomic assessment tool adapted from the Lifting Fatigue Failure Tool
C_LIO_LIExo-LiFFT is a practical tool that unifies the etiology of LBDs and biomechanical function of exos
C_LIO_LIExo-LiFFT can be used to assess or predict the effect of exos on LBD risk without EMG testing
C_LI What delirium detection tools are used in routine clinical practice in the United Kingdom? Survey results from 91% of acute healthcare organisations. PurposeOur aim was to collect information on delirium assessment processes and pathways in non-intensive care settings in the United Kingdom (UK).

MethodsWe sent a Freedom of Information request to 169 UK National Health Service (NHS) hospitals, trusts and health boards (units) in July 2020 to obtain data on usage of delirium assessment tools in clinical practice and delirium pathways or guidelines.

ResultsWe received responses from 154/169 units (91% response rate). Of these, 146/154 (95%) units reported use of formal delirium assessment processes and 131/154 (85%) units had guidelines or pathways in place. The 4  As Test (4AT) was the most widely used tool, with 117/146 (80%) units reporting use. The Confusion Assessment Method was used in 65/146 (45%) units, and the Single Question to identify Delirium (SQiD) in 52/146 (36%) units.

ConclusionsOur findings show that the 4AT is the most commonly used tool in the UK, with 80% of units reporting use. This study adds to our knowledge of real-world uptake of delirium detection methods at scale. Future studies should evaluate real-world implementation of delirium assessment tools further via (i) tool completion rates and (ii) rates of positive scores against the expected prevalence delirium in the clinical population concerned.

KEY SUMMARY POINTSO_ST_ABSAimC_ST_ABSTo seek information on delirium assessment processes and pathways in non-intensive clinical care settings in the United Kingdom (UK), and to assess usage of specific delirium assessment tools: the 4  As Test (4AT), Confusion Assessment Method and Single Question to identify Delirium (SQiD).

FindingsIn total, 95% of National Health Service (NHS) units (hospitals, trusts and health boards) reported use of formal delirium assessment processes and 85% of units had guidelines or pathways in place. The 4AT was the most widely used tool, with 80% of units reporting use; the Confusion Assessment Method was reportedly used in 45% of units and the SQiD in 36% of units.

MessageThis study shows real-world, large-scale uptake of delirium detection methods and delirium guidelines in UK hospitals, which contributes to ongoing efforts to improve delirium care. Hairpin structure facilitates multiplex high-fidelity DNA amplification in real-time PCR Clinically and biologically, it is essential to detect rare DNA-sequence variants for early cancer diagnosis or drug-resistance mutations identification. Some of the common quantitative PCR (qPCR)-based variant detection methods are restricted in the limit of detection (LoD) because the DNA polymerases used have a high polymerase misincorporation rate, thus the detection sensitivity is sometimes unsatisfactory. With the proofreading activity, high-fidelity (HiFi) DNA polymerases have a 50- to 250-fold higher fidelity. However, there are currently no proper probe-based designs as the fluorescence indicator allowing multiplexed HiFi qPCR reactions, thus restricting the application of HiFi DNA polymerases like the variant detection. We presented the Occlusion System, composed of a 5-overhanged primer with fluorophore modification and a probe with a short-stem hairpin and a 3 quencher modification. We demonstrated that the Occlusion System allowed multiplexing HiFi qPCR reaction, and it was compatible with the current variant-enrichment method to improve the LoD up to 10-fold. Thus, the Occlusion System satisfactorily functioned as efficient fluorescence indicator in HiFi qPCR reactions and allowed application of HiFi DNA polymerases in variant detection methods to improve detection sensitivity. RELATIONSHIP BETWEEN ADVERSE EVENTS PREVALENCE, PATIENT SAFETY CULTURE AND PATIENT SAFETY PERCEPTION IN A SINGLE SAMPLE OF PATIENTS: A CROSS-SECTIONAL AND CORRELATIONAL STUDY ObjectiveTo assess the relationship between Adverse Events Prevalence, Patient Safety Culture and Patient Safety Perception.

DesignCross-sectional, ex post facto comparative study on a single sample of patients.

SettingFour medium-high-level hospitals were included in the study -- two public and two private from Zulia State in Venezuela.

Participants556 medical records and patients were studied for the prevalence and patient safety perception study, and 397 of the healthcare providers involved in the care of these patients were surveyed for the patient safety culture study, at two public and two private hospitals.

Outcome measurementThe primary outcome of this study was the Association between Adverse Events Prevalence, Patient Safety Culture and Patient Safety Perception, and according to hospital funding type, private and public.

ResultsAn inverse association was observed between Adverse Events Prevalence and its severity and Patient Safety Culture Index (PSCI: rho=-0.8 p=0.5) (95% CI=0.26-0.10) and Patient Safety Perception Index (PSPI: rho=-0.6 p=0.18) (95% CI=0.10-0.28), which were protective factors for patient safety. No association was identified between Patient Safety Culture and Patient Safety Perception (rho=0.0001). No statistical differences were identified by hospital type (p=0.93) (95% CI=0.70-1.2).

ConclusionsThe analysis of the variable correlations studied (AEP, PSC and PSP) within the same sample offers an interesting and useful perspective. In this sample, although no correlation was observed between the three variables as an interacting set, some correlation patterns were observed between pairs of variables that could guide further studies.

Strengths and limitations of this studyO_LIThe association analysis of the three main variables (adverse events prevalence, patient safety culture and patient safety perception) in the same sample of patients and health professionals and over the same time period during which the care process and, consequently, the adverse events took place is an unprecedented and innovative approach, which contributes to the body of knowledge on this field of study.
C_LIO_LIThe relational theoretical framework produced provides a "map" that can facilitate decision-taking and which establishes the variables that should be considered a priority. As a result, it is highly likely to have an impact on the clinical efficiency and safety of healthcare institutions and services.
C_LIO_LIThe study was carried out at both private and public hospitals, enabling the behaviour of the aforementioned variables to be compared and analysed at each type of institution. The literature to date on this approach is scarce and offers little information.
C_LIO_LIAlthough the sample of hospitals selected is not representative of Venezuela, it is representative of the hospitals of one of the most productive and populated states in the country.
C_LIO_LIDuring stages 1 and 2, some resistance to collaborating with and completing the evaluation instruments was identified among the health professionals.
C_LI Molecular analysis suggests oligoclonality and metastasis of endometriosis lesions across anatomically defined subtypes. Endometriosis symptoms are heterogeneous with controversy on whether it constitutes a single disease or multiple distinct types. Our previous work found recurrent somatic cancer-driver alterations in endometriosis; however, these have not been found ubiquitously. A handful of cases spread across studies also suggest mutations might be shared (clonal) between lesions of the same type. As current classification systems correlate poorly with symptoms or outcomes, somatic genomics may improve the current system. Here, we investigate heterogeneity of somatic cancer-driver mutations within patients and across endometriosis types. We examined anatomically distinct types of endometriosis (ovarian, deep infiltrating, and superficial endometriosis) in 27 individual patients all of whom had at least two types of endometriosis. Specimens were analyzed using high-sensitivity targeted sequencing with orthogonal validation from droplet digital PCR and mutation-surrogate immunohistochemistry. Results found 13/27 patients had informative somatic driver mutation in endometriosis, 9/13 had identical mutations across distinct lesions. Endometriomas tended to have a higher mutational complexity, with functionally redundant driver mutations in same gene and within the same lesions.

Our data are consistent with clonality across endometriosis lesions regardless of subtype. Further the finding of redundancy in mutations with the same gene and lesions is also consistent with endometriosis representing an oligoclonal disease with dissemination likely to consist of multiple epithelial clones travelling together. This suggests the current anatomically defined classification of endometriosis does not fully recognize the etiology of the disease. A novel classification should take into account genomic and other molecular features. These findings could further contribute to development of a more personalized endometriosis diagnosis and care. Effects of repeated injection of 1% lidocaine vs. radial extra-corporeal shock wave therapy for treating myofascial trigger points: a randomized controlled trial Background and ObjectivesThis study tested the hypothesis that treatment of myofascial trigger points (MTrPs) in the upper trapezius muscle (UTM) with repeated injection of 1% lidocaine results in better alleviation of muscular stiffness and soreness as well as improved metabolism in the hypercontracted MTrP area than treatment with radial extracorporeal shock wave therapy (rESWT).

Materials and MethodsA single-blinded, prospective, randomized controlled trial was conducted on patients suffering from MTrPs in the UTM. Thirty patients were treated with repeated injection of 2 ml of 1% lidocaine (three injections; one injection per week). Another 30 patients were treated with rESWT (three treatment sessions; one treatment session per week; 2000 radial extracorporeal shock waves per treatment session; positive energy flux density = 0.10 mJ/mm2). The primary outcome measure was pain severity using the VAS score. The secondary outcome measures included muscle elasticity index, pressure pain threshold and neck disability index. Evaluation was performed at baseline (T1), 15-30 minutes after the first treatment in order to register immediate treatment effects (T2), before the second treatment (i.e., one week after baseline) (T3) and one week after the third treatment (i.e., four weeks after baseline) (T4).

ResultsThere were no statistically significant differences in the primary and secondary outcome measures between the patients in the lidocaine arm and the patients in the rESWT arm at T1 and T4. Within the arms, the mean differences of all outcomes were statistically significant (P < 0.001) when comparing the data obtained at T1 with the data obtained at T3 and the data obtained at T4.

ConclusionsThe results of this pilot study suggest that the use of rESWT in patients with MTrPs in the UTM is safe and leads to reduced pain and improved muscle elasticty, pressure pain threshold and neck disability index, without adverse effects. Larger trials are necessary to verify this. Clinicians should consider rESWT instead of injections of lidocaine in the treatment of MTrPs in the UTM. 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. Longitudinal determination of mRNA-vaccination induced strongly binding SARS-CoV-2 IgG antibodies in a cohort of Romanian healthcare workers Mass vaccination against the disease caused by the novel coronavirus (COVID-19) was a crucial step in slowing the spread of SARS-CoV-2 in 2021. Even in the face of new variants, it still remains extremely important for reducing hospitalizations and COVID-19 deaths. Only limited data exists about the short- and long-term dynamics of humoral immune response. We present a longitudinal analysis of post-vaccination IgG levels in a cohort of 166 healthcare workers vaccinated with BNT162b2 with weekly follow-up until 35 days past the first dose and monthly follow-up up to 6 months post-vaccination. A subset of the patients continued with follow-up after 6 months and either received a booster dose or got infected during the Delta wave in Romania. Tests were carried out on 1697 samples using a CE-marked IgG ELISA assay developed in-house, containing S1 and N antigens of the wild type virus.

Participants infected with SARS-CoV-2 before vaccination mount a quick immune response, reaching peak IgG levels two weeks after the first dose, while IgG levels of previously uninfected participants mount gradually, increasing abruptly after the second dose. Overall higher IgG levels are maintained for the previously infected group 35-70 days after vaccination. The decrease of IgG levels is gradual, with lower overall values in the infection naive cohort even 7-8 months after vaccination, compared to the previously infected cohort. Administration of a booster dose yielded higher average IgG antibody levels than post second dose in the infection naive group and comparable levels in the previously infected group. Adaptation of HL7 FHIR for the exchange of patients' gene expression profiles High-throughput technologies, especially gene expression analyses can accurately capture the molecular state in patients under different conditions. Thus, their application in clinical routine gains increasing relevance and fosters patient stratification towards individualized treatment decisions. Electronic health records already evolved to capture genomic data within clinical systems and standards like FHIR enable sharing within, and even between institutions. However, FHIR only provides profiles tailored to variations in the molecular sequence, while expression patterns are neglected although being equally important for decision making. Here we provide an exemplary implementation of gene expression profiles of a microarray analysis of patients with acute myeloid leukemia using an adaptation of the FHIR genomics extension. Our results demonstrate how FHIR resources can be facilitated in clinical systems and thereby pave the way for usage for the aggregation and exchange of transcriptomic data in multi-center studies. 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. Impact of a Multidisciplinary Nutritional Support Team on Quality Improvement in Home Parenteral Nutrition IntroductionHPN is essential for patients requiring long term nutritional support. This Quality Improvement Project for HPN Patients (QIP-PN) studied the effect of a Physician Nutrition Expert (PNE)- led multidisciplinary nutritional support team (MNST) on HPN care.

ObjectiveTo test the effect of an MNST on adherence to protocols, outcomes and QOL in HPN.

MethodsData review was conducted in phases 1a and 1b, observation in phase 2 and intervention in phase 3. In Phase 3 the MNST made recommendations to treating physicians. All long-term HPN patients were offered study participation. 75 signed consent forms. Treating physician study participation agreements were signed for 42 patients (the study group). A random sample of 30 long-term HPN patients comprised the case-matched control group (control). Data were collected on demographics, treating physicians PNE status, HPN care variables, recommended interventions, quality-of-life assessment, adverse outcomes and hospitalizations. Independent samples t-test was used for continuous data between study group and control group. Paired t-test was used for phase 2 and phase 3 patient data. Comparison between the study and control group utilized a negative binomial regression model. Statistical analysis utilized R (https://www.r-project.org/).

Results34 patients were reviewed retrospectively in phase 1a and 197 prospectively in phase 1b. 40 study patients completed phase 2 and progressed into phase 3, of whom 30 completed [&ge;]60 therapy days. Improvements in weight, BMI and QOL were seen in the study patients during intervention. Recommendations made and accepted by treating physicians differed based on PNE status. Study patients had fewer adverse outcomes and related hospitalizations than case matched controls.

ConclusionMNST recommendations improved clinical, biochemical parameters and patients self-reported overall health. It reduced adverse outcomes, hospitalization and hospital length of stay. MNST input could have a significant impact on the quality and cost of HPN care. How Informative Were Early SARS-CoV-2 Treatment and Prevention Trials? A longitudinal cohort analysis of trials registered on clinicaltrials.gov BackgroundEarly in the SARS-CoV-2 pandemic, commentators warned that some COVID trials were inadequately conceived, designed and reported. Here, we retrospectively assess the prevalence of informative COVID trials launched in the first 6 months of the pandemic.

MethodsWe created a cohort of SARS-CoV-2 treatment and prevention efficacy trials that were initiated from 2020-01-01 to 2020-06-30 using ClinicalTrials.gov registration records. We evaluated trials on 3 criteria of informativeness: potential redundancy, design quality and feasibility of patient-participant recruitment. The study protocol was prospectively registered with the Open Science Framework (https://osf.io/fp726/).

ResultsWe included 500 trials in our cohort, 58% of which were Phase 2 and 84.8% were directed towards the treatment of SARS-CoV-2. Close to one third of trials met all three criteria and were deemed informative (29.0% (95% Confidence Interval 23.7 - 36.9)). The proportion of potentially redundant trials in our cohort was 4.1%. Over half of the trials in our cohort (56.2%) did not meet our criteria for high quality trial design. The proportion of trials with infeasible patient-participant recruitment was 22.6%.

ConclusionsLess than one third of COVID-19 trials registered on ClinicalTrials.gov during the first six months met all three criteria for informativeness. Shortcomings in trial design, recruitment feasibility and redundancy reflect longstanding weaknesses in the clinical research enterprise that were likely amplified by the exceptional circumstances of a pandemic. Impact of tozinameran (BNT162b2) mRNA vaccine on kidney transplant and chronic dialysis patients: 3-5 months followup BackgroundDetermining the humoral immunogenicity of tozinameran (BNT162b2) vaccine in patients requiring chronic renal replacement therapy, and its impact on COVID-19 morbidity several months after vaccination, will guide risk assessment and subsequent changes in vaccination policy.

MethodsIn a prospective post-vaccination cohort study with up to 5 months follow-up we studied outpatient dialysis and kidney transplant patients and respective healthcare teams. Outcomes were anti S1/S2 antibody response to vaccine or infection and infection rate during followup.

Results175 dialysis patients (40% women, 65{+/-}15 years), 252 kidney transplant patients (33% women, 54{+/-}14 years) and 71 controls (65% women, 44{+/-}14 years) were followed. Three months or longer after vaccination we detected anti S1/S2 IgG antibodies in 80% of dialysis patients, 44% of transplant recipients and 100% of controls, whereas respective rates after infection were 94%, 75% and 100%. Predictors of non-response were older age, diabetes, history of cancer, lower lymphocyte count and lower vitamin-D levels. Factors associated with lower titers in dialysis patients were modality (hemodialysis vs peritoneal) and high serum ferritin levels. In transplant patients, hypertension and higher calcineurin or mTOR inhibitor drug levels were linked with diminished antibody response. Vaccination associated with fewer subsequent infections (HR=0.23, p<0.05). Moreover, higher antibody titers associated with fewer events, HR 0.41 for each unit increased in log10titer (p<0.05).

ConclusionsDialysis patients, and more so kidney transplant recipients, mounted reduced antibody response to COVID-19 mRNA vaccination, and lesser humoral response associated with more infections. Measures to identify and protect non-responsive patients are urgently required.

SignificanceReports on the humoral immunogenicity of SARS-CoV-2 mRNA vaccines in patients with end stage renal disease are scarce, and association with subsequent COVID-19 morbidity is unknown. In this cohort study that included 175 patients treated with dialysis, 252 kidney transplant recipients and 71 control volunteers, the proportion achieving an antibody response was time- and group-dependent, reaching 80%, 44% and 100% at 3 months post prime inoculation. Personal history of vaccination, positive antibody responses and antibody titers associated with significantly lower risk of COVID-19 infection. Thus, in patients with end stage renal disease, SARS-CoV-2 antibody testing may be warranted after vaccination, to identify non-responders at higher risk for disease. Preferences and patterns of response to public health advice during the COVID-19 pandemic With recurring waves of the Covid-19 pandemic, a dilemma facing public health leadership is whether to provide public advice that is medically optimal (e.g., most protective against infection if followed), but unlikely to be adhered to, or advice that is less protective but is more likely to be followed. To provide insight about this dilemma, we examined and quantified public perceptions about the tradeoff between (a) the stand-alone value of health behavior advice, and (b) the advices adherence likelihood. In a series of studies about preference for public health leadership advice, we asked 1,061 participants to choose between (1) strict advice that is medically optimal if adhered to but which is less likely to be broadly followed, and (2) relaxed advice, which is less medically effective but more likely to gain adherence - given varying infection expectancies. Participants preference was consistent with risk aversion. Offering an informed choice alternative that shifts volition to advice recipients only strengthened risk aversion, but also demonstrated that informed choice was preferred as much or more than the risk-averse strict advice. Development of machine learning models for the prediction of complications after colorectal and small intestine surgery in psychiatric and non-psychiatric patient collectives (P-Study) Psychiatric and psychosomatic diseases are an increasingly cumbersome burden for the medical system. Indeed, hospital costs associated with mental health conditions have been constantly on the rise in recent years. Moreover, psychiatric conditions are likely to have a negative effect on the treatment of other medical conditions and surgical outcomes, in addition to their direct effects on the overall quality of life. Our study aims to investigate the impact of preoperative Risk factor, psychiatric and psychosomatic diseases on the outcomes of colorectal surgery and length of hospital stay via predictive modeling techniques.

MethodPatient data will be collected from several participating national and international surgical centers The machine learning models will be calculated and coded, but also published according to the TRIPOD guidelines (transparent reporting of a multivariable prediction model for individual prognosis or diagnosis).

ResultIt is conceivable to arrive at generalizable models predicting the abovementioned endpoints through large amounts of data from several centers. The models will be subsequently deployed as a free-to-use web-based prediction tool using the Shiny environment [47]. The cost for the hosting server and digital infrastructure will be covered by Dr. Anas Taha. The sponsor will store the data for ten years. A framework for reconstructing SARS-CoV-2 transmission dynamics using excess mortality data Detailed reconstruction of the SARS-CoV-2 transmission dynamics and assessment of its burden in several parts of the world has still remained largely unknown due to the scarcity of epidemiological analyses and limited testing capacities of different countries to identify cases and deaths attributable to COVID-19 [1-4]. Understanding the true burden of the Iranian COVID-19 epidemic is subject to similar challenges with limited clinical and epidemiological studies at the subnational level [5-9]. To address this, we develop a new quantitative framework that enables us to fully reconstruct the transmission dynamics across the country and assess the level of under-reporting in infections and deaths using province-level, age-stratified all-cause mortality data. We show that excess mortality aligns with seroprevalence estimates in each province and subsequently estimate that as of 2021-10-22, only 48% (95% confidence interval: 43-55%) of COVID-19 deaths in Iran have been reported. We find that in the most affected provinces such as East Azerbaijan, Qazvin, and Qom approximately 0.4% of the population have died of COVID-19 so far. We also find significant heterogeneity in the estimated attack rates across the country with 11 provinces reaching close to or higher than 100% attack rates. Despite a relatively young age structure in Iran, our analysis reveals that the infection fatality rate in most provinces is comparable to high-income countries with a larger percentage of older adults, suggesting that limited access to medical services, coupled with undercounting of COVID-19-related deaths, can have a significant impact on accurate estimation of COVID-19 fatalities. Our estimation of high attack rates in provinces with largely unmitigated epidemics whereby, on average, between 10% to 25% individuals have been infected with COVID-19 at least twice over the course of 20 months also suggests that, despite several waves of infection, herd immunity through natural infection has not been achieved in the population. COMPARISON OF sPLA2-IIA PERFORMANCE WITH HIGH-SENSITIVE CRP, NEUTROPHIL PERCENTAGE, PCT AND LACTATE TO IDENTIFY BACTERIAL INFECTION: A PROSPECTIVE STUDY Early bacterial infection (BI) identification in resource-limiting Emergency Departments (ED) is challenging especially in low- and middle-income counties (LMIC). Misdiagnosis predisposes to antibiotic overuse and propagates antimicrobial resistance. This study evaluates new emerging biomarkers, secretory phospholipase A2 group IIA (sPLA2-IIA), and compares with other biomarkers on their performance characteristic of BI detection in Malaysia, an LMIC. A prospective cohort study was conducted involving 151 consecutive patients admitted to the ED. A single measurement was taken upon patient arrival in ED and was analysed for serum levels of sPLA2-IIA, high-sensitive C-reactive protein (CRP), procalcitonin (PCT), neutrophil percentage (N%), and lactate. All biomarkers performance was compared for the outcomes using area under the receiver operating characteristic curve (AUROC), sensitivity, and specificity. The performance of sPLA2-IIA (AUROC 0.93 [95% CI: 0.89-0.97]; Sn 80% [95% CI: 72-87] Sp 94% [95% CI: 81-89]) was the highest among all. It was comparable with high-sensitive CRP (AUROC 0.93 [95% CI: 0.88-0.97]; Sn 75% [95% CI: 66-83]; Sp 91 [95% CI: 77-98]) but had a higher Sn and Sp. The sPLA2-IIA was also found superior to N%, PCT, and lactate. This finding suggested sPLA2-IIA was recommended biomarkers for BI detection in LMIC. Complementary frailty and mortality prediction models on older patients as a tool for assessing palliative care needs BackgroundPalliative care (PC) has demonstrated benefits for life-limiting illnesses. Cancer patients have mainly accessed these services, but there is growing consensus about the importance of promoting access for patients with non-malignant disease. Bad survival prognosis and patients frailty are usual dimensions to decide PC inclusion.

ObjectivesThe main aim of this work is to design and evaluate three quantitative models based on machine learning approaches to predict frailty and mortality on older patients in the context of supporting PC decision making: one-year mortality, survival regression and one-year frailty classification.

MethodsThe dataset used in this study is composed of 39,310 hospital admissions for 19,753 older patients (age >= 65) from January 1st, 2011 to December 30th, 2018. All prediction models were based on Gradient Boosting Machines. From the initial pool of variables at hospital admission, 20 were selected by a recursive feature elimination algorithm based on the random forests GINI importance criterion. Besides, we run an independent grid search to find the best hyperparameters in each model. The evaluation was performed by 10-fold cross-validation and area under the receiver operating characteristic curve and mean absolute error were reported. The Cox proportional-hazards model was used to compare our proposed approach with classical survival methods.

ResultsThe one-year mortality model achieved an AUC ROC of 0.87 {+/-} 0.01; the mortality regression model achieved an MAE of 329.97 {+/-} 5.24 days. The one-year frailty classification reported an AUC ROC of 0.9 {+/-} 0.01. The Spearmans correlation between the admission frailty index and the survival time was -0.1, while the point-biserial correlation between one-year frailty index and survival time was -0.16.

ConclusionsOne-year mortality model performance is at a state-of-the-art level. Frailty Index used in this study behaves coherently with other works in the literature. One-year frailty classifier demonstrated that frailty status within the year could be predicted accurately. To our knowledge, this is the first study predicting one-year frailty status based on a frailty index. We found mortality and frailty as two weakly correlated and complementary PC needs assessment criteria. Predictive models are available online at http://demoiapc.upv.es. 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 Evaluating a first fully automated interview grounded in Multiple Mini Interview (MMI) methodology: results from a feasibility study ObjectivesGlobal, Covid-driven restrictions around face-to-face interviews for healthcare student selection have forced admissions staff to rapidly adopt adapted online systems before supporting evidence is available. We have developed, what we believe is, the first fully automated interview grounded in Multiple Mini-Interview (MMI) methodology. This study aimed to explore test re-test reliability, acceptability and usability of the system.

Design, setting and participantsmixed-methods feasibility study in Physician Associate (PA) programmes from two UK and one US university during 2019 - 2020.

Primary, secondary outcomesFeasibility measures (test retest reliability acceptability and usability) were assessed using intra-class correlation (ICC), descriptive statistics, thematic and content analysis.

MethodsVolunteers took (T1), then repeated (T2), the automated MMI, with a seven-day interval (+/- 2) then completed an evaluation questionnaire. Admissions staff participated in focus group discussions.

ResultsSixty-two students and seven admission staff participated; 34 students and four staff from UK and 28 students and three staff from US universities.

Good-excellent test-retest reliability was observed with T1 and T2 ICC between 0.62-0.81 (p<0.001) when assessed by individual total scores (range 80.6-119), station total scores 0.6-0.91, p<0.005, individual site (all ICC[&ge;] 0.76 p<0.001) and mean test retest across sites 0.82 p<0.001 (95% CI 0.7-0.9).

Admissions staff reported potential to reduce resource costs and bias through a more objective screening tool for pre-selection or to replace some MMI stations in a  hybrid model. Maintaining human interaction through  touch points was considered essential.

Users positively evaluated the system, stating it was intuitive with an accessible interface. Concepts chosen for dynamic probing needed to be appropriately tailored.

ConclusionThese preliminary findings suggest that the system is reliable, generating consistent scores for candidates and is acceptable to end-users provided human touchpoints are maintained. Thus, there is evidence for the potential of such an automated system to augment healthcare student selection processes. Decreased Diastolic Hydraulic Forces Incrementally Associate With Survival Beyond Conventional Measures of Diastolic Dysfunction AIMSDecreased hydraulic forces during diastole contribute to reduced left ventricular (LV) filling and heart failure with preserved ejection fraction. However, their association with diastolic function and patient outcomes are unknown. The aim of this study was to determine the association between diastolic hydraulic forces, estimated by echocardiography as the atrioventricular area difference (AVAD), and both diastolic function and survival.

METHODS AND RESULTSPatients (n=11,734, median [interquartile range] 3.9 [2.4-5.0] years follow-up, 1,213 events) were selected from the National Echo Database Australia based on the presence of relevant transthoracic echocardiographic measures, LV ejection fraction (LVEF) [&ge;]50%, heart rate 50-100 beats/minute, the absence of moderate or severe valvular disease, and no prior cardiac surgery. AVAD was calculated as the cross-sectional area difference between the LV and left atrium. LV diastolic dysfunction was graded according to 2016 guidelines. AVAD was weakly associated with E/e, left atrial volume index, and LVEF (multivariable global R2=0.15, p<0.001), and not associated with e and peak tricuspid regurgitation velocity. Decreased AVAD was independently associated with poorer survival, and demonstrated improved model discrimination after adjustment for diastolic function grading (C-statistic [95% confidence interval] 0.645 [0.629-0.662] vs 0.607 [0.592-0.623], p<0.001) and E/e (0.639 [0.623-0.655] vs 0.621 [0.604-0.637], p<0.001), respectively.

CONCLUSIONDecreased hydraulic forces, estimated by AVAD, are weakly associated with diastolic dysfunction and demonstrate an incremental prognostic association with survival beyond conventional measures used to grade diastolic dysfunction.