Capturing Global, Predicting Local for ControllingAntimicrobial Resistance: a retrospective multivariable analysis BackgroundAntimicrobial resistance (AMR) is a complex multifactorial outcome of health, socio-economic and geopolitical factors. Therefore, tailored solutions for mitigation strategies could be more effective in dealing with this challenge. Knowledge-synthesis and actionable models learned upon large datasets are critical in order to diffuse the risk of entering into a post-antimicrobial era.

ObjectiveThis work is focused on learning Global determinants of AMR and predicting the susceptibility of antibiotics at the isolate level (Local) for WHO (world health organization) declared critically important pathogens Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, Enterobacter cloacae, Staphylococcus aureus.

MethodsIn this study, we used longitudinal data (2004-2017) of AMR having 633820 isolates from 70 Middle and High-income countries. We integrated AMR data with the Global burden of disease (GBD), Governance (WGI), and Finance data sets in order to find the unbiased and actionable determinants of AMR. We chose a Bayesian Decision Network (BDN) approach within the causal modeling framework to quantify determinants of AMR. Finally Integrating Bayesian networks with classical machine learning approaches lead to effective modeling of the level of AMR.

ResultsFrom MAR (Multiple Antibiotic Resistance) scores, we found that developing countries are at higher risk of AMR compared to developed countries, for all the critically important pathogens. Also, Principal Components Analysis(PCA) revealed that governance, finance, and disease burden variables have a strong association with AMR. We further quantified the impact of determinants in a probabilistic way and observed that health system access and government effectiveness are strong actionable factors in reducing AMR, which was in turn confirmed by what-if analysis. Finally, our supervised machine learning models have shown decent performance, with the highest on Staphylococcus aureus. For Staphylococcus aureus, our model predicted susceptibility to Ceftaroline and Oxacillin with the highest AUROC, 0.94(with SE of 0.01%) and 0.89(with SE of 0.002%) respectively.
The Ophthalmic Surgical Backlog caused by the COVID-19 Pandemic: A population-based and microsimulation modelling study BackgroundJurisdictions worldwide ramped down ophthalmic surgeries to mitigate the effects of coronavirus disease 2019 (COVID-19), creating a global surgical backlog. We sought to predict the long-term impact of COVID-19 on ophthalmology surgical care delivery.

MethodsThis is a population-based and a microsimulation modelling study. Provincial administrative data from January 2019 to May 2021 was used to estimate the backlog size and wait-times following the COVID-19 pandemic. For the post-pandemic recovery phase, we estimated the resources required to clear the backlog of patients accumulated on the waitlist during the pandemic.

ResultsA total of 56,923 patients were on the waitlist in the province of Ontario awaiting non-emergency ophthalmic surgery as of March 15, 2020. The number of non-emergency surgeries performed in the province decreased by 45-98% from March to May 2020, and 48-80% from April to May 2021 compared to the same months in 2019. By 2 years and 3 years, the overall estimated number of patients awaiting surgery grew by 129% and 150%, respectively. The estimated mean wait-time for patients for all subspecialty surgeries increased to 282 (SD 91) in March 2023 compared to 94 days (SD 97) in 2019. The provincial monthly additional resources required to clear the backlog by March 2023 was estimated to be a 34% escalation from the pre-pandemic volumes (4,626 additional surgeries).

InterpretationThe magnitude of the ophthalmic surgical backlog from COVID-19 has important implications for the recovery phase. The estimates from this microsimulation modelling can be adapted to other jurisdictions to assist with recovery planning for vision saving surgeries.
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 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. Exploration of interethnic variation in the ibuprofen metabolizing enzyme CYP2C9: a genetic-based cautionary guide for treatment of COVID-19 symptoms Coronavirus disease 2019 (COVID-19), is a rapidly spreading infectious illness that causes a debilitating respiratory syndrome. While non-steroidal anti-inflammatory drugs (NSAIDs), may be prescribed for the management of pain and fever, there was early controversy on the use of ibuprofen for symptomatic treatment of COVID-19. P450 enzyme CYP2C9 are known to be involved in the metabolism of NSAIDs. Although no study has been conducted in the setting of population genetics in patients with COVID-19 yet, there are plausible mechanisms by which genetic determinants may play a role in adverse drug reactions (ADRs). In this work, we adjusted expected phenotype frequencies based on racial demographic models dependent on population ancestry in drug responses and toxicity events associated with ibuprofen treatment. A cohort of 101 Jordanian Arab samples retrospectively were selected and genotyped using Affymetrix DMET Plus Premier Package, within the context of over 100,000 global subjects in 417 published reports. European populations are 7.2x more likely to show impaired ibuprofen metabolism than Sub-Saharan populations, and 4.5x more likely than East Asian ancestry populations. Hence, a proactive assessment of the most likely gene-drug candidates will lead to more effective treatments and a better understanding of the role of pharmacogenetics for COVID-19. 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. Integrating genome-wide polygenic risk scores and non-genetic risk to predict colorectal cancer diagnosis: a cohort study in UK Biobank ObjectivesTo evaluate the benefit of combining polygenic risk scores (PRS) with the QCancer-10 (colorectal cancer) non-genetic risk prediction model to identify those at highest risk of colorectal cancer (CRC).

DesignPopulation based cohort study. Six different PRS for CRC were developed (using LDpred2 PRS software, clumping and thresholding approaches, and genome-wide significant models). The top-performing genome-wide and GWAS-significant PRS were then combined with QCancer-10 and performance compared to QCancer-10 alone. Case-control (logistic regression) and time-to-event (Cox proportional hazards) analyses were used to evaluate risk model performance in men and women.

Setting and participantsUK Biobank Study. A total of 434587 individuals with complete genetic and QCancer-10 predictor data were included in the QCancer-10+PRS modelling cohorts.

Main outcome measuresPrediction of colorectal cancer diagnosis by genetic, non-genetic and combined risk models.

FindingsPRS derived using the LDpred2 program performed best, with an odds-ratio per standard deviation of 1.58, and top age- and sex-adjusted C-statistic of 0.733 (95% confidence interval 0.710 to 0.753) in logistic regression models in the validation cohort. Integrated QCancer-10+PRS models out-performed QCancer-10 alone. In men, the integrated LDpred2 (QCancer-10+LDP) model produced a C-statistic of 0.730 (0.720 to 0.741) and explained variation of 28.1% (26.3% to 30.0%), compared with 0.693 (0.682 to 0.704) and 21.0% (18.9% to 23.1%) for QCancer-10 alone. Performance improvements in women were similar. In the top 20% of individuals at highest absolute risk, the sensitivity of QCancer-10+LDP models for predicting CRC diagnosis within 5 years was 47.6% in men and 42.5% in women, with respective 3.49-fold and 2.75-fold absolute increases in the top 5% of risk compared to average. Decision curve analysis showed that adding PRS to QCancer-10 improved net-benefit and interventions avoided, across most probability thresholds.

ConclusionsIntegrating PRS with QCancer-10 significantly improves risk prediction over QCancer-10 alone. Evaluation of risk stratified population screening using this approach is warranted.

Summary BoxO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIRisk stratification based on genetic or environmental risk factors could improve cancer screening outcomes
C_LIO_LINo previously published study has examined integrated models combining genome-wide PRS and non-genetic risk factors beyond age
C_LIO_LIQCancer-10 (colorectal cancer) is the top-performing non-genetic risk prediction model for CRC
C_LI

What this study addsO_LIAdding PRS to the QCancer-10 (colorectal cancer) risk prediction model improves performance and clinical benefit, with greatest gain from the LDpred2 genome-wide PRS, to a level that suggests utility in stratifying CRC screening and prevention
C_LI Prognostic implications of structural heart disease and premature ventricular contractions in recovery of exercise BackgroundPremature ventricular contractions (PVCs) during recovery of exercise stress testing are associated with increased cardiovascular mortality, but the cause remains unknown. We aimed to evaluate the association of PVCs during recovery with echocardiographic abnormalities, and their combined prognostic performance.

MethodsEchocardiographic abnormalities (reduced left ventricular (LV) ejection fraction, valvular heart disease, LV dilatation, LV hypertrophy, or increased filling pressures) and PVCs during recovery ([&ge;]1/min) were identified among patients having undergone echocardiography within median [interquartile range] 0 [0-2] days of an exercise stress test. The association between such changes and cardiovascular mortality was analyzed using Cox regression adjusted for age, sex, clinical and exercise variables.

ResultsAmong included patients (n=3,106), PVCs during recovery were found in 1,327 (43%) patients, among which the prevalence of echocardiographic abnormalities was increased (58% vs. 44%, p<0.001). Overall, PVCs during recovery were associated with increased cardiovascular mortality (219 total events, 7.9 [5.4-11.1] years follow-up; adjusted hazard ratio (HR [95% confidence interval]) 1.6 [1.2-2.1], p<0.001). When combined with echocardiographic abnormalities, PVCs during recovery were associated with increased risk when such were present (HR 3.3 [1.9-5.5], p<0.001) but not when absent (HR 1.5 [0.8-2.8], p=0.22), in reference to those with neither.

ConclusionPVCs during recovery were associated with increased prevalence of echocardiographic abnormalities. Increased risk of cardiovascular mortality was observed only for subjects with PVCs if concomitant echocardiographic abnormalities were present. Our findings provide mechanistic insights to the increased CV risk reported in patients with PVCs during recovery. 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. The Influence of Coronavirus Disease-2019 (COVID-19) On Parkinsons Disease: An Updated Systematic Review BackgroundCOVID-19 has affected global communities with multiple neurological complications in addition to other critical medical issues. COVID-19 binds to the hosts angiotensin-converting enzyme2 (ACE2) receptors, which are expressed in the neurons and glial cells, acting as an entry port to the central nervous system (CNS). ACE2 receptors are abundantly expressed on dopamine neurons, which may worsen the prognosis of motor symptoms in Parkinsons disease (PD). SARS-CoV-2 may lead to an indirect response via immune-mediated cytokine storms and propagate through the CNS leading to damage. PD is also been associated with certain post-viral infections apart from COVID-19, such as HSV, Influenzavirus A, Measles virus, Cytomegalovirus, and Mumps.

ObjectiveIn this systematic review, we aim to provide a thorough analysis of associations between COVID-19 and neurological outcomes for patients with PD.

MethodsUsing PRISMA statement 2020, a systematic review was conducted to isolate confirmed COVID-19 patients and analyze the PD-associated neurological outcomes. A systematic literature search was conducted using the following databases: PubMed, Science Direct, Google Scholar, and Cochrane databases. The following keywords were used "COVID19, SARS-CoV-2, Parkinsons disease, Pandemic, Mortality." A modified Delphi process was employed to include the studies and ensure that the clinical outcome measures were addressed.

ResultsOf the 355 records located during the initial round of screening, 16 were included in the final synthesis. Of PD patients who tested positive for SARS-CoV-2, worsening motor symptoms and other viral-associated symptoms were reported. These symptoms included bradykinesia, tremors, gait disturbances, delirium and dementia, and severe spasms of arms and legs. Encephalopathy was presented in two of the included studies. Increased mortality rates were identified for hospitalized patients due to COVID-19 and PD as compared to other patient groups, albeit with limited generalizability due to high bias of included studies.

ConclusionPatients with PD may experience substantial worsening of motor and non-motor symptoms due to COVID 19. Given the novelty of neurological-viral associations, clinical studies in the future ought to explore the disease severity and neurological outcomes in COVID-19 positive patients with PD as compared to non-PD patients, in addition to understanding the role of ACE2 in increased vulnerability to contracting the infection and as a treatment modality. 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.) Variability in proteoglycan biosynthetic genes reveals new facets of heparan sulfates diversity. A systematic review and analysis Proteoglycans are complex macromolecules formed of glycosaminoglycan chains covalently linked to core proteins through a linker tetrasaccharide common to heparan sulfate proteoglycans (HSPG) and chondroitin sulfate proteoglycans (CSPG). Biosynthesis of a single proteoglycan requires the expression of dozens of genes, which together create the large structural and functional diversity reflected by the numerous diseases or syndromes associated to their genetic variability. Among proteoglycans, HSPG are the most structurally and functionally complex. To decrease this complexity, we retrieved and linked information on pathogenic variants, polymorphism, expression, and literature databases for 50 genes involved in the biosynthesis of HSPG core proteins, heparan sulfate (HS) chains, and their linker tetrasaccharide. This resulted in a new gene organization and biosynthetic pathway representation in which the phenotypic continuum of disorders as linkeropathies and other pathologies could be predictable. Moreover, ubiquitous NDST1, GLCE, HS2ST1, and HS6ST1 appeared to generate ubiquitous heparan sulfate (HS) sequences essential for normal development and homeostasis, whereas the tissue restricted NDST2-4, HS6ST2-3, and HS3ST1-6 appeared to generate specialized HS sequences mainly involved in responsiveness to stimuli. Supported by data on genetic polymorphism and clinical variants, we afford a new vision of HSPG involvement in homeostasis, disease, vulnerability to disease, and behavioral disorders. A collaborative maternity and newborn dashboard (CoMaND) for the COVID-19 pandemic: a protocol for timely, adaptive monitoring of perinatal outcomes in Melbourne, Australia BackgroundThe COVID-19 pandemic has resulted in a range of unprecedented disruptions to the delivery of maternity care globally and has been associated with regional changes in perinatal outcomes such as stillbirth and preterm birth. Metropolitan Melbourne endured one of the longest and most stringent lockdowns in 2020. This paper presents the protocol for a collaborative maternity dashboard project to monitor perinatal outcomes in Melbourne, Australia, during the COVID-19 pandemic.

MethodsDe-identified maternal and newborn outcomes will be collected monthly from all public maternity services in Melbourne, allowing rapid analysis of a multitude of perinatal indicators. Weekly outcomes will be displayed as run charts according to established methods for detecting non-random  signals in health care. A pre-pandemic median for all indicators will be calculated for the period of January 2018 to March 2020. A significant shift is defined as [&le;] six consecutive weeks, all above or below the pre-pandemic median. Additional statistical analyses such as regression, time-series, and survival analyses will be performed for an in-depth examination of maternal and perinatal outcomes of interests.

Ethics and DisseminationThis study has been registered as an observational study with the Australian and New Zealand Clinical Trials Registry (ACTRN12620000878976).

Strengths and weaknesses of this study This project is the first clinician-led, multi-centre perinatal data collection system for metropolitan Melbourne.
 It complements the state government data collection, with the significant benefits of more timely and flexible reporting of outcomes, and granular detail on emerging areas of concern.
 The study relies on primary source coding of exposure and outcomes from each hospital that have not been internally validated during the study period.
 Data from private maternity hospitals, containing 25% of Melbourne births, are not available.
 This resource will support data-informed hospital pandemic responses through to the end of 2022. Social support & sustained physical activity during the COVID-19 pandemic COVID-19 lockdown introduced substantial barriers to physical activity, providing a unique  natural experiment to understand the social factors associated with sustained physical activity.

ObjectivesThe objectives of this study were to identify the proportion of people who successfully sustained physical activity during lockdown and to explore whether social support, loneliness and social isolation were associated with maintenance of physical activity during COVID-19 lockdown

MethodLongitudinal data from the COVID-19 Social Study was used to identify a sample of participants who maintained their physical activity despite lockdown.

Results16% were consistently active while 44% were completely inactive. After adjustment for multiple confounders high social support was associated with a 39% (95% CI, 12-74%) increased odds of sustaining physical activity. Associations between physical activity and loneliness and social isolation were not found.

ConclusionThis study supports previous research showing the importance of social support for the long-term maintenance of physical activity behaviour but shows that such effects extend to contexts of social restrictions. Characteristic and Sex Differences in Auditory Function and Cochlear Pathophysiology in a Noise-exposed Cohort: A Cross-sectional Study BackgroundTo determine the characteristics and sex differences of auditory perception and cochlear function in individuals with long-term occupational noise exposure.

MethodsYoung workers with long-term occupational noise exposure from a shipyard were recruited in the current study as the hidden hearing loss (HHL) risk group. Age-matched office workers in the same shipyard who had no occupational noise-exposure history were enrolled in the control group. The auditory processing ability of speech-in-noise (SIN) score and gap detection threshold (GDT) were further examined by sex. The cochlear function of action potential (AP) and summating potential (SP)/AP values were tested and compared by sex and side. The correlation between the SIN score and cochlear function was studied by sex. The correlation between either auditory processing ability or cochlear function and occupational-noise working length (OWL) was also analysed in the HHL risk group.

ResultsSignificantly decreased SIN scores and a higher GDT of the 4 kHz gap marker were only found in men in the HHL risk group. Although the hearing thresholds of the women in the HHL risk group were slightly but significantly worse than those of the women in the control group, no significant defects in auditory processing or temporal resolution were found between the two groups. Significantly decreased cochlear function and increased SP/AP values in the left ear were only found in men in the HHL risk group. Neither the AP amplitude nor the AP latency differed significantly between the two groups by sex. A correlation study indicated that only the correlation between the SIN score and the AP amplitude of the right ear in men was significant. No significant difference was found between the SIN score and cochlear function in women. The AP latency of the right ear was only significantly correlated with OWL in men.

ConclusionIn long-term occupational working exposure individuals with normal hearing, defects in auditory processing, temporal resolution and cochlear function showed sex differences, none of which were significant in women. In men, a weak correlation between the SIN score and the AP amplitude of the right ear was found. There was only a weak correlation between OWL and the AP latency of the right ear in men. Our findings indicate men are more vulnerable to occupational noise than women. Considering the noise-exposure dose differences between the control and HHL risk groups, our measures are insensitive to cochlear synaptopathy in humans. Cognitive impairment and functional change in COVID-19 patients undergoing inpatient rehabilitation Cognitive impairment is increasingly recognized as a sequela of COVID-19. It is unknown how cognition changes and relates to functional gain during inpatient rehabilitation. We administered the Montreal Cognitive Assessment (MoCA) at admission to 77 patients undergoing inpatient rehabilitation for COVID-19 in a large U.S. academic medical center. 45 patients were administered the MoCA at discharge. Functional gain was assessed by change in the Quality Indicator for Self-Care (QI-SC). In the full sample, 80.5% of patients exhibited cognitive impairment on admission, which was associated with prior delirium. Among 45 patients with retest data, there were significant improvements in MoCA and QI-SC. QI-SC score gain was higher in patients who made clinically meaningful changes on the MoCA, an association that persisted after accounting for age and delirium history. Cognitive impairment is frequent among COVID-19 patients, but improves over time and is associated with functional gain during inpatient rehabilitation. "What do you mean I can't have a doctor? This is Canada!" - A Qualitative Study of the Myriad Consequences for Unattached Patients Awaiting Primary Care Attachment BackgroundPatient access to primary healthcare (PHC) is the foundation of a strong healthcare system and healthy populations. Attachment to a regular PHC provider, a key to healthcare access, has seen a decline in some jurisdictions. This study explored the consequences of unattachment from a patient perspective, an under-studied phenomenon to date.

MethodsA realist-informed qualitative study was conducted with unattached patients in Nova Scotia, Canada. Semi-structured interviews with nine participants were conducted and transcribed for analysis. The framework method was used to carry out analysis, which was guided by Donabedians model of assessing healthcare access and quality.

ResultsFive key findings were noted in this study: 1) Participants experienced a range of consequences from not having a regular PHC provider. Participants used creative strategies to 2) attempt to gain attachment to a regular PHC provider, and, to 3) address their health needs in the absence of a regular PHC provider. 4) Participants experienced negative feelings about themselves and the healthcare system, and 5) stress related to the consequences and added work of being unattached and lost care.

ConclusionsUnattached patients experienced a burden of care related to lost care and managing their own health and related information, due to the download of medical record management and system navigation to them. These findings may underestimate the consequences for further at-risk populations who would not have been included in our recruitment. This may result in poorer health outcomes, which could be mitigated by interventions at the structural level, such as enhanced centralized waitlists to promote attachment. Such waitlists may benefit from a triage approach to appropriately attach patients based on need. Detection of Somatic Copy Number Deletion of CDKN2A Gene for Clinical Practices Based on Discovery of A Base-Resolution Common Deletion Region BackgroundCDKN2A is most frequently inactivated by somatic copy number deletion (SCND) in human cancers. An accurate method to detect CDKN2A SCND is absent.

MethodsTo look for the pattern of CDKN2A SCND in cancer cells, interstitial base-resolution deletion/fusion coordinates for CDKN2A were extracted from published articles and our whole genome sequencing (WGS) datasets. A multiplex PCR assay was setup to quantify CDKN2A copy number and confirmed with WGS and loss of heterozygosity (LOH) assays using gastric carcinoma (GC) samples from two sets of patients (n=156 and 140), respectively.

ResultsWe characterized a 5.1-kb common deletion region (CDR) from the CDKN2A/P16INK4A promoter to intron-2 in >90% (83/92) of cancer cell lines and 100% (18/18) of GC samples by WGS. The CDR includes exon-2 that is shared by P16INK4A and P14ARF genes. Then, a highly reproducible and quantitative assay, P16-Light, targeted to the CDR was setup with a lower limit of detection at 20%. P16-Light was further compared with WGS (gold standard) and LOH assay by denaturing high performance liquid chromatography. The positive rate of CDKN2A SCND by P16-Light was more than two times of that by WGS in GCs from a patients cohort (25.6% vs. 10.9%), and was significantly correlated with each other (p<0.028). While CDKN2A SCND was significantly associated with GC distant metastasis (p=0.023), such association was not observed for CDKN2A LOH.

ConclusionBased on our finding that there is a 5.1-kb CDR within the CDKN2A gene, a vary convenient P16-Light assay was setup to detect CDKN2A SCND for routine clinical applications. Characterization of small fiber neuropathy in hypermobile Ehlers Danlos Syndrome Ehlers Danlos syndromes (EDS) are heritable connective tissue disorders. The hypermobile form (hEDS) is the most frequent, yet the only one without an identified genetic mutation. Patients suffering from symptomatic joint hypermobility, yet not fulfilling the hEDS criteria, enter the Hypermobility Spectrum Disorder (HSD) category. In addition to musculoskeletal pain affecting joints, hEDS/HSD patients often describe painful sensations, hypoesthesia, and autonomic symptoms suggesting a neuropathic component. Small fiber neuropathy (SFN) refers to the dysfunction or damage of A-{delta} and C-fibers, which relay thermal and nociceptive information as well as mediating autonomic function. SFN has been suggested by prior studies in hEDS but these early findings (case series N[&le;]20) with sole reliance on intraepidermal nerve fiber density (IENFD) called for a larger sample combined with functional testing.

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

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

These results add strong evidence for a peripheral neuropathic contribution to pain symptoms in hEDS/HSD, in addition to the known nociceptive and central sensitization components. Such neuropathic contribution could raise the hypothesis of a neurological cause of hEDS, the only EDS syndrome still without a known genetic cause. Hence, our data is leading the way to a better stratification of this very heterogeneous population, which could improve symptommanagement and expand pathophysiological research. The CT Scan Lung Severity Score and Vaccination Status in COVID-19 patients in India: Perspective of an Independent Radiology Practice BackgroundThe COVID-19 patients often undergo a high-resolution CT scan to determine extent of their lung involvement. The aim of this study was to determine lung involvement in confirmed/suspected COVID-19 patients (encountered at an independent radiology practice) and its correlation to vaccination status amidst the second COVID-19 wave in India.

MethodsWe retrospectively queried our data since April 2021 to identify adult patients (>17 years) who had confirmed (positive RT-PCR or antigen test) or suspected COVID-19 (classic symptoms but negative RT-PCR) and received a high-resolution CT scan to determine the extent of their lung involvement using the CT severity (CT-SS) score. Patients were classified in 3 groups based on their vaccination status to determine its correlation with the CT-SS score: fully vaccinated, partially vaccinated, and unvaccinated. Basic descriptive statistics, univariate tests and multivariate linear regression analysis were used.

ResultsWe identified 229 patients (median age 45 years, 60% male) of which 205 (89%) had confirmed COVID-19 (positive RT-PCR) and 24 had suspected disease (negative RT-PCT but classic symptoms). Of the 229 patients 29 (13%) had complete vaccination, 38 (17%) had partial vaccination and 162 (70%) had no vaccination. The CT score of the completely vaccinated patients was significantly lower compared to partially or unvaccinated patients (median 0 v. 3.5 v. 10, respectively p<.01). A multivariate linear regression model showed that partial or fully vaccinated patients had lower CT severity score compared to unvaccinated patients (adjusted R squared = 0.47).

ConclusionWe present here the real-world findings from an independent radiology practice (a unique and common practice model), in India amid the second COVID-19 wave showing significantly lower CT severity score in fully or partially vaccinated patients compared to unvaccinated patients. Complete vaccination in patients could be critical in preventing severe lung disease. 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. 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. Deceased donor kidney degradomics indicates cytoskeletal proteolytic alterations impacting post-transplant function. BackgroundIn brain death, cerebral injury contributes to systemic biological dysregulation, causing significant cellular stress in donor kidneys that adversely impacts the quality of grafts. Here, we hypothesized that DBD kidneys may undergo proteolytic processes that renders grafts susceptible to post-transplant dysfunction.

Material & MethodsUsing mass spectrometry and immunoblotting analyses, we profiled degradation patterns of cytoskeletal proteins in deceased (n=55) and living (n=10) donor kidneys.

ResultsWe found that in DBD kidneys, key podocyte cytoskeletal proteins had been proteolytically cleaved. Generated degradation profiles were not associated to donor related demographic and clinical factors but were associated to suboptimal post-transplant function. Strikingly, -actinin -4 and Talin-1 degradation profiles were not observed in circulatory-death or living-donor kidneys. As Talin-1 is a specific proteolytic target of Calpain-1, we investigated a potential trigger of Calpain activation and Talin-1 degradation using ex-vivo precision-cut human kidney slices and in-vitro immortalised human podocytes. Notably, we found that Transforming-Growth Factor-{beta} (TGF-{beta}) activated Calpain-1 and proteolytically cleaved Talin-1 to generate distinct peptide fragments. These peptide fragments were of similar size and matched the degradation patterns observed in DBD kidneys. Talin-1 degradation was prevented in vitro by Calpain-1 inhibition.

ConclusionsHere, we provide initial evidence that DBD kidneys are susceptible to cytoskeletal protein degradation that impacts posttransplant kidney function. Subsequent studies should aim to further investigate the link between brain death and activation of proteolytic pathways exploring new therapeutic opportunities.