Comparison Of respiratory protection during exercising tasks between different wearing methods of replaceable particulate respirators and powered air-purifying respirators BackgroundThis study evaluated the differences in respiratory protection between replaceable particulate respirators (RPRs) and powered air-purifying respirators (PAPRs), with different wearing methods, during exercising tasks.

MethodsTen participants wore either RPR or PAPR according to the recommended method, with a knit cover placed between the facepiece cushion and the face, or with the headband on a helmet. We measured the number of particles inside and outside the respiratory protective equipment (RPE) during exercising tasks for each wearing variation. The exercise state was set to exercise with an ergometer set at 80W load. While exercising tasks, the participants performed five actions adopted from JIS T8150 in 2018 (1. Normal breathing, 2. Deep breathing, 3. Turning head side to side, 4. Moving head up and down, 5. Talking). Each action was performed for 1 min. For measurements of exercise state, after 10 minutes of exercise tasks, we measured while the exercise was continued. The fit factor was calculated by dividing the concentration within the RPE by the concentration outside of it. Data were analyzed after they were log-transformed with a linear mixed model, with fit factor as the dependent variable.

ResultsWe compared the results with experimental data of resting state reported in our previous studies. Fit factor of RPRs in the exercise state was significantly lower (p<0.001) than that in the resting state, indicating inadequate respiratory protection. In contrast, the fit factor of PAPRs during exercising tasks was significantly lower (p<0.001) than that at rest; however, respiratory protection was maintained. PAPR did not show a significant decrease (p=1.000) in fit factor owing to the wearing variations during exercising tasks.

ConclusionsPAPRs were found to be superior to RPRs in terms of respiratory protection. PAPRs are better than RPRs for workers who have to wear RPE inappropriately due to health problems.
Aerosol Persistence in ICUs: Utilization of Low-cost Sensor Network The COVID-19 pandemic heightened public awareness about airborne particulate matter (PM) due to the spread of infectious diseases via aerosols. The persistence of potentially infectious aerosol in public spaces, particularly medical settings, deserves close investigation; however, approaches for rapidly parameterizing the temporospatial distribution of particles released by an infected individual have not been reported in literature. This paper presents a methodology for mapping the movement of aerosol plumes using a network of low-cost PM sensors in ICUs. Mimicking aerosol generation by a patient, we tracked aerosolized NaCl particles functioning as tracers for potentially infectious aerosols. In positive (closed door) and neutral-pressure (open door) ICUs, an aerosol spike was detected outside the room, with up to 6% or 19% of all PM escaping through the door gaps, respectively. The outside sensors registered no aerosol spike in negative-pressure ICUs. The K-means clustering analysis of temporospatial data suggests three distinct zones: (1) near the aerosol source, (2) room periphery, and (3) immediately outside the room. These zones inform two-phase aerosol plume behavior: dispersion of the original aerosol spike throughout the room, and evacuation phase where "well-mixed" PM decayed uniformly. Decay rates were calculated for 4 ICUs in positive, neutral, and negative mode, with negative modes decaying the fastest. This research demonstrates the methodology for aerosol persistence monitoring in medical settings; however, it is limited by a relatively small data set. Future studies need to evaluate medical settings with high risks of infectious disease, assess risks of airborne disease transmission, and optimize hospital infrastructure.

Significance StatementAirborne infectious diseases, including COVID-19, are a major concern for patients and hospital staff. Here, we develop a systematic methodology for mapping the temporospatial distribution of aerosols in ICUs using a network of low-cost particulate matter (PM) sensors. Our method of analysis provides a perspective on the exfiltration efficiency of ICUs as well as the benefits of rooms that have a negative-pressure mode. Our methods could be extended to other public spaces with a high risk of infectious disease to optimize infrastructure and assess the risk of airborne disease.
Short Practical Regimen of Acupuncture for Melasma: A Prospective Cohort Study in a Tertiary Hospital in Thailand BackgroundMelasma is a common skin pigmentation disorder. Acupuncture shows benefits for patients with melasma, although no standardized method or optimal number of sessions have been determined.

ObjectiveTo comparatively assess clinical outcomes of melasma between five vs ten standard acupuncture sessions.

MethodsWe performed a prospective observational cohort study in all melasma patients at the Acupuncture Clinic, King Chulalongkorn Memorial Hospital, Bangkok, Thailand. All patients were treated with standard acupuncture procedure twice a week and were evaluated after the fifth and the tenth sessions of acupuncture, with a follow-up one week after the last session. Participants were divided into two treatment groups: Groups A and B received five and ten acupuncture sessions respectively. Melasma outcomes were assessed by using the Melanin Index (MI), Melasma Area and Severity Index (MASI), patient-reported improvement scores and acupuncture-related adverse events.

ResultsOf 113 participants, 67 received five sessions of acupuncture treatment while 39 received ten sessions. 7 participants did not finish treatment. After five sessions of acupuncture in Group A, the mean MI decreased by 28.7 (95%CI -38.5 to -18.8), whereas the median MASI decreased by 3.4 (-6.9, -1.2) points. After ten sessions of acupuncture in Group B, the mean MI decreased by 31.3 (95%CI -45.0 to -17.6), whereas the median MASI decreased by 5.4 (-9.9, - 3.0) points. The first five sessions of acupuncture had a higher effect on the change in magnitude than the last five sessions, although there was no statistically significant difference. However, ten-session of acupuncture, had not reached the peak benefit on melasma yet. Further studies should be done with a higher number of sessions to determine the optimal rounds of treatment. Twenty-nine participants reported minor side effects, mostly consisting of persistent pain and small hematoma. Group B had RR of having adverse events 1.8 times (95% CI 1.0-3.4) compared to group A.

ConclusionAcupuncture has a potential dose-response effect on clinical and patient-reported melasma outcomes with minor side effects. Problems with Evidence Assessment in COVID-19 Health Policy Impact Evaluation (PEACHPIE): A systematic review of evidence strength IntroductionAssessing the impact of COVID-19 policy is critical for informing future policies. However, there are concerns about the overall strength of COVID-19 impact evaluation studies given the circumstances for evaluation and concerns about the publication environment. This study systematically reviewed the strength of evidence in the published COVID-19 policy impact evaluation literature.

MethodsWe included studies that were primarily designed to estimate the quantitative impact of one or more implemented COVID-19 policies on direct SARS-CoV-2 and COVID-19 outcomes. After searching PubMed for peer-reviewed articles published on November 26, 2020 or earlier and screening, all studies were reviewed by three reviewers first independently and then to consensus. The review tool was based on previously developed and released review guidance for COVID-19 policy impact evaluation, assessing what impact evaluation method was used, graphical display of outcomes data, functional form for the outcomes, timing between policy and impact, concurrent changes to the outcomes, and an overall rating.

ResultsAfter 102 articles were identified as potentially meeting inclusion criteria, we identified 36 published articles that evaluated the quantitative impact of COVID-19 policies on direct COVID-19 outcomes. The majority (n=23/36) of studies in our sample examined the impact of stay-at-home requirements. Nine studies were set aside because the study design was considered inappropriate for COVID-19 policy impact evaluation (n=8 pre/post; n=1 cross-section), and 27 articles were given a full consensus assessment. 20/27 met criteria for graphical display of data, 5/27 for functional form, 19/27 for timing between policy implementation and impact, and only 3/27 for concurrent changes to the outcomes. Only 1/27 studies passed all of the above checks, and 4/27 were rated as overall appropriate. Including the 9 studies set aside, reviewers found that only four of the 36 identified published and peer-reviewed health policy impact evaluation studies passed a set of key design checks for identifying the causal impact of policies on COVID-19 outcomes.

DiscussionThe reviewed literature directly evaluating the impact of COVID-19 policies largely failed to meet key design criteria for inference of sufficient rigor to be actionable by policy-makers. This was largely driven by the circumstances under which policies were passed making it difficult to attribute changes in COVID-19 outcomes to particular policies. More reliable evidence review is needed to both identify and produce policy-actionable evidence, alongside the recognition that actionable evidence is often unlikely to be feasible. 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. Culture and understanding the role of feedback for health professions students: Realist synthesis protocol. IntroductionClinical education has moved to a "competency-based" model with an emphasis on workplace-based learning and assessment which, in turn, depends on feedback to be effective. Further, the understanding of feedback has changed from information about a performance directed to the learner performing the task, to a dialogue, which enables the learner to act and develop.

In health professional education, feedback is a complex interaction between trainee, supervisor, and the healthcare system. Most published research on feedback in health professional education originates in Europe and North America. Our interest is on the impact of Culture on this process, particularly in the context of Asian cultures.

The (scientific) realist approach of Pawson and Tilley provides a means to examine complex interventions in social situations, and thus is an appropriate lens to use for this study. This is a protocol for a realist synthesis which asks how, why and in what circumstances do Asian Cultures influence health professional trainees to seek, respond to and use feedback given in the clinical environment, if at all.

Methods and analysisAn initial search was performed to help define the scope of the review question and develop our initial program theory. The formal electronic search was carried out in February 2020 and included: CINAHL, ERIC, MEDLINE, and PsycInfo, and repeated in October 2020.

Retrieved articles were imported into Covidence for screening and data extraction, after which components of the Context - Mechanisms - Outcomes configurations will be sought to refine the initial program theory.

Ethics and DisseminationAs this study is a literature review, ethics approval is not required.

The findings will be documented in line with the RAMESES publications standards for Realist syntheses,[41] and we plan to disseminate the findings by means of a peer-reviewed journal article and conference presentation(s).

Strengths and limitations of this studyO_LIThe synthesis aims to identify the how and why Asian Cultures may influence feedback seeking and provision to health professional trainees, if at all.
C_LIO_LITo our knowledge, there are few studies of feedback seeking and provision to health professional trainees in Asia.
C_LIO_LIA Realist approach has the potential to help explain the complex nature of Cultures impact on feedback.
C_LIO_LIOnly studies published in the English language will be included, so transferability of our findings to non-English speaking environments may be lacking.
C_LIO_LIIn addition to formal literature database searches, we will need to conduct citation mining to locate other relevant resources.
C_LI Investigating trends in those who experience menstrual bleeding changes after SARS-CoV-2 vaccination Early in 2021, many people began sharing that they experienced unexpected menstrual bleeding after SARS-CoV-2 inoculation. We investigated this emerging phenomenon of changed menstrual bleeding patterns among a convenience sample of currently and formerly menstruating people using a web-based survey. In this sample, 42% of people with regular menstrual cycles bled more heavily than usual while 44% reported no change after being vaccinated. Among respondents who typically do not menstruate, 71% of people on long-acting reversible contraceptives, 39% of people on gender-affirming hormones, and 66% of post-menopausal people reported breakthrough bleeding. We found increased/breakthrough bleeding was significantly associated with age, systemic vaccine side effects (fever, fatigue), history of pregnancy or birth, and ethnicity. Generally, changes to menstrual bleeding are not uncommon nor dangerous, yet attention to these experiences is necessary to build trust in medicine.

TeaserIncreased bleeding can occur post SARS-CoV-2 vaccines; this study investigates patterns in who experiences these changes. Critically ill COVID-19 status associated trait genetics reveals CDK6 inhibitors as potential treatment Despite the recent development of vaccines and monoclonal antibodies preventing SARS-CoV-2 infection, treating critically ill COVID-19 patients still remains a top goal. In principle, drug repurposing - the use of an already existing drug for a new indication - could provide a shortcut to a treatment. However, drug repurposing is often very speculative due to lack of clinical evidence. We report here on a methodology to find and test drug target candidates for drug repurposing. Using UK Biobank data, we screened for significant differences in 33 blood cell types, 30 blood biochemistries, and body mass index between an infectious disease phenotype and healthy controls. We then matched critically ill COVID-19 cases with controls that exhibited mild or no symptoms after SARS-CoV-2 infection. Using data from the UK Biobank, we describe a workflow to find evidence for high neutrophil cell count and high concentrations of blood triglycerides as predictors of the immune overreaction in critical illness due to COVID-19. Based on these findings, we identified the enzyme CDK6 as a potential drug target to prevent in high risk individuals with high neutrophil cell count the immune overreaction in critical illness due to COVID-19. Three existing CDK4/6 inhibitors -- abemaciclib, ribociclib, and palbociclib -- have been approved for the treatment of breast cancer. Clinical evidence for CDK4/6 inhibitors in treating critically ill COVID-19 patients has been reported. Further clinical investigations are ongoing. Psychological factors associated with instrumental activities of daily living disability in older adults with knee osteoarthritis PurposeThe population of older adults with knee osteoarthritis (OA)-related disabilities is increasing globally. This study aimed to investigate the psychological factors associated with instrumental activities of daily living (IADL) disability in older adults with knee OA.

Materials and MethodsA cross-sectional study was conducted on 179 patients with knee OA aged [&ge;] 65 years. The six-item short form of the Pain Catastrophizing Scale (PCS-6), the four-item short form of the Pain Self-Efficacy Questionnaire (PSEQ-4), and the fifteen-item Geriatric Depression Scale (GDS-15) were used to assess psychological factors. IADL status was assessed using eight activity items. Participants were divided into IADL-disabled and non-disabled groups. Binary logistic regression analyses were performed with the IADL disability status as the dependent variable. The PCS-6, PSEQ-4, and GDS-15 tools were included as independent variables in the logistic regression model. Demographics, motor functions, and pain intensity were also included as confounders.

ResultsOf the total participants, 88 (49.1%) showed disability in conducting IADL. PSEQ-4 (odds ratio =0.90, 95%; confidence interval=0.82-0.99, p=0.02) was a significant independent variable among all psychological factors.

ConclusionOur study showed the importance of assessing self-efficacy using the PSEQ-4 in relation to IADL disability in older adults with knee OA. 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. An observational study of the association between COVID-19 vaccination rates and entry into the "Million Dollar Vax" competition ObjectivesAre financial incentives from entry in a vaccine lottery associated with a higher probability of vaccination for COVID-19?

DesignA cross-sectional study with adjustment for covariates using logistic regression

SettingOctober and November 2021, Australia.

Participants2,375 respondents of the Taking the Pulse of the Nation Survey

InterventionsParticipation in the Million Dollar Vaccination Lottery

Primary and secondary outcome measuresThe proportion of respondents who had any vaccination, a first dose only, or second dose compared to all other respondents

ResultsThose who participated in the lottery were 2.27 times more likely to be vaccinated after the lottery opened on October 1st than those who did not. This was driven by those receiving second doses. Lottery participants were 1.38 times more likely to receive their first dose after October 1st and 2.31 times more likely to receive their second dose after October 1st.

ConclusionsLottery participation is associated with a higher vaccination rate, with this effect dominated by a higher rate of second doses. There is a smaller insignificant difference for those receiving a first dose, suggesting lotteries may not be as effective at reducing vaccine hesitancy, compared to  nudging people to get their second dose more quickly.

Strengths and limitations of this studyO_LIWe use a nationally representative sample of individuals.
C_LIO_LIWe distinguish between the association between lottery participation and first and second doses.
C_LIO_LIWe adjust for a rich set of individual characteristics associated with vaccination status
C_LIO_LIThe strong association for second dose vaccinations may reflect some individuals who had already had scheduled their second dose after the lottery opened, potentially leading to an overestimate of the association.
C_LI

Ethics statementThis study was approved by the University of Melbourne Faculty of Business and Economics & Melbourne Business School Human Ethics Advisory Group (Ref: 2056754.1). 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. Empirical networks for localized COVID-19 interventions using WiFi infrastructure at university campuses Infectious diseases, like COVID-19, pose serious challenges to university campuses, which typically adopt closure as a non-pharmaceutical intervention to control spread and ensure a gradual return to normalcy. Intervention policies, such as remote instruction (RI) where large classes are offered online, reduce potential contact but also have broad side-effects on campus by hampering the local economy, students learning outcomes, and community wellbeing. In this paper, we demonstrate that university policymakers can mitigate these tradeoffs by leveraging anonymized data from their WiFi infrastructure to learn community mobility --- a methodology we refer to as WiFi mobility models (WO_SCPLOWIC_SCPLOWMO_SCPLOWOBC_SCPLOW). This approach enables policymakers to explore more granular policies like localized closures (LC). WO_SCPLOWIC_SCPLOWMO_SCPLOWOBC_SCPLOW can construct contact networks that capture behavior in various spaces, highlighting new potential transmission pathways and temporal variation in contact behavior. Additionally, WO_SCPLOWIC_SCPLOWMO_SCPLOWOBC_SCPLOW enables us to design LC policies that close super-spreader locations on campus. By simulating disease spread with contact networks from WO_SCPLOWIC_SCPLOWMO_SCPLOWOBC_SCPLOW, we find that LC maintains the same reduction in cumulative infections as RI while showing greater reduction in peak infections and internal transmission. Moreover, LC reduces campus burden by closing fewer locations, forcing fewer students into completely online schedules, and requiring no additional isolation. WO_SCPLOWIC_SCPLOWMO_SCPLOWOBC_SCPLOW can empower universities to conceive and assess a variety of closure policies to prevent future outbreaks. Hyperreflective foci, OCT progression indicators in age-related macular degeneration, include transdifferentiated retinal pigment epithelium PurposeBy optical coherence tomography (OCT) imaging, hyperreflective foci (HRF) indicate progression risk for advanced age-related macular degeneration (AMD) and are in part attributable to ectopic retinal pigment epithelium (RPE). We hypothesized that ectopic RPE are molecularly distinct from in-layer cells and that their cross-retinal course follows Muller glia.

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

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

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

PrecisHyperreflective foci (HRF) are OCT progression risk indicators in age-related macular degeneration. Abnormal RPE cells including some that correspond to HRF lose immunoreactivity for retinoid markers and gain immunoreactivity for immune markers, indicating molecular transdifferentiation. Population Pharmacokinetic Analysis of Dexmedetomidine in Children using Real World Data from Electronic Health Records and Remnant Specimens AimOur objectives were to perform a population pharmacokinetic analysis of dexmedetomidine in children using remnant specimens and data from electronic health records (EHRs) and explore the impact of patients characteristics and pharmacogenetics on dexmedetomidine clearance.

MethodsDexmedetomidine dosing and patient data were gathered from EHRs and combined with opportunistically sampled remnant specimens. Population pharmacokinetic models were developed using nonlinear mixed-effects modeling. The first stage developed a model without genotype variables; the second stage added pharmacogenetic effects.

ResultsOur final study population included 354 post-cardiac surgery patients age 0 to 22 years (median 16 months). The final two-compartment model included allometric weight scaling and age maturation. Population parameter estimates and 95% confidence intervals were 27.3 L/hr (24.0 - 31.1 L/hr) for total clearance (CL), 161 L (139 - 187 L) for central compartment volume of distribution (V1), 26.0 L/hr (22.5 - 30.0 L/hr) for intercompartmental clearance (Q), and 7903 L (5617 - 11119 L) for peripheral compartment volume of distribution (V2). The estimate for postmenstrual age when 50% of adult clearance is achieved was 42.0 weeks (41.5 - 42.5 weeks) and the Hill coefficient estimate was 7.04 (6.99 - 7.08). Genotype was not statistically or clinically significant.

ConclusionOur study demonstrates the use of real-world EHR data and remnant specimens to perform a population PK analysis and investigate covariate effects in a large pediatric population. Weight and age were important predictors of clearance. We did not find evidence for pharmacogenetic effects of UGT1A4 or UGT2B10 genotype or CYP2A6 risk score.

What is already known about this subject{circ} Previous dexmedetomidine pharmacokinetic (PK) studies in pediatric populations have limited sample size.
{circ}Smaller studies present a challenge for identifying covariates that may impact individual PK profiles.


What this study adds{circ} We performed a dexmedetomidine population PK study with a large pediatric cohort using data obtained from electronic health records and remnant plasma specimens to enable increased sample size.
{circ}xsDifferences in PK due to UGT1A4 or UGT2B10 variants or CYP2A6 risk score are not clinically impactful for this population. An Accurate Model for SARS-CoV-2 Pooled RT-PCR Test Errors PCR testing is an important tool to mitigate outbreaks of infectious diseases. One way of increasing testing throughput is by simultaneously testing multiple samples for the presence of a pathogen, a technique known as pooling. During the current COVID-19 pandemic, rapidly testing individuals for the presence of SARS-CoV-2 is conducted in large amounts. Since testing is often a bottleneck in mitigating the spread of SARS-CoV-2, pooling is increasing in popularity. Most analyses of the error rates of pooling schemes assume that including more than a single infected sample in a pooled test does not increase the probability of a positive outcome. We challenge this assumption with experimental data and suggest a novel probabilistic model for the outcomes of pooled tests. As an application, we analyze the false-negative rates of one common pooling scheme known as Dorfman pooling. We show that the false-negative rates of Dorfman pooling increase when the prevalence of infection decreases. However, low infection prevalence is exactly the condition under which Dorfman pooling achieves highest throughput. We therefore implore the cautious use of pooling and development of pooling schemes that consider correctly accounting for tests error rates. Quantification of T- and B-cell immune receptor distribution diversity characterizes immune cell infiltration and lymphocyte heterogeneity in clear cell renal cell carcinoma Immune-modulating systemic therapies are often used to treat advanced cancer such as metastatic clear cell renal cell carcinoma (ccRCC). Used alone, sequence-based biomarkers neither accurately capture patient dynamics nor the tumor immune microenvironment. To better understand the tumor ecology of this immune microenvironment, we quantified tumor infiltration across two distinct ccRCC patient tumor cohorts using complementarity determining region-3 (CDR3) sequence recovery counts in tumor-infiltrating lymphocytes and a generalized diversity index (GDI) for CDR3 sequence distributions. GDI can be understood as a curve over a continuum of diversity scales which allows sensitive characterization of distributions to capture sample richness, evenness, and subsampling uncertainty, along with other important metrics that characterize tumor heterogeneity. For example, richness quantified the total unique sequence count, while evenness quantified similarities across sequence frequencies. Significant differences in receptor sequence diversity across gender and race revealed that patients with larger and more clinically aggressive tumors had increased richness of recovered tumoral CDR3 sequences, specifically in those from T-cell receptor alpha and B-cell immunoglobulin lambda light chain. The GDI inflection point (IP) allowed for a novel and robust measure of distribution evenness. High IP values associated with improved overall survival, suggesting that normal-like sequence distributions lead to better outcomes. These results propose a new quantitative tool that can be used to better characterize patient-specific differences related to immune cell infiltration, and to identify unique characteristics of tumor-infiltrating lymphocyte heterogeneity in ccRCC and other malignancies. Impact of COVID 19 on the quality of life (QoL) of patients living with Sickle Cell Disorder (SCD) in Lagos Nigeria The study aimed to assess the impact of the COVID-19 pandemic on Quality of Life (QoL) in persons living with Sickle Cell Disorder (SCD) in Lagos, Nigeria and to determine how they coped during the pandemic, particularly during the period of total lockdown with the additional "SHIELDING" measures to which they had to adhere. Data was collected using a standardized protocol PedsQL, Sickle Cell Disease Module version.3.0 designed for youth within the ages of (13-18) years, (19-35) years and their parents/Guardian if underage. The survey captured data on patients pain impact, hurts, management, treatments, communication with their caregivers and their Guardians perception. The survey was performed online, or Face-to-Face/telephone interview if online was not possible. Contacts of patients and parents were obtained from the database of Sickle Cell Foundation Nigeria. A total of 105 (80 patients and 25 parents) participants responded to the survey. The age distribution of respondents was highest at 56 % in the age bracket of 13 - 18 years old. Pain crisis were very common amongst patients. The survey revealed that the type of treatment or care received at these times determined whether or not the patients visited the hospital when they had pain crises. In addition, as patients reports an increase in ill-treatment they experienced in the hands of health care givers, so did the fear of accessing treatment during the COVID pandemic. It was observed that the frequency of pain crises experienced by SCD patients was proportional to the patients quality of life (the higher the frequency of pains, the worse the QoL). As a follow-up, a more detailed study would be required, as this study was limited in the capturing of the demographics, sex and number of participants; Considering the number of persons living with SCD that visit the Sickle Cell Foundation Nigeria, (about 3,000 patients), the number of responses in this study was low (105). It is believed that a higher number of responses would have given more information about the Sickle Cell burden and the QoL of persons living with SCD in Lagos during the COVID-19 pandemic. Lagos was the epicentre of the COVID-19 pandemic in Nigeria. 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. SEPRES: Sepsis prediction via a clinical data integration system and real-world studies in the intensive care unit BackgroundSepsis is vital in critical care medicine, and early detection and intervention are key to survival. We aimed to establish an early warning system for sepsis based on a data integration system that can be implemented in the intensive care unit (ICU).

MethodsWe trained the LightGBM and multilayer perceptron on the open-source database Medical Information Mart for Intensive Care for sepsis prediction. An ensemble sepsis prediction model was established based on the transfer learning and ensemble learning technique on the private dataset of Ruijin Hospital. The Shapley Additive Explanations analysis was applied to present feature importance on the prediction inference. With the development of data-integrating hub to collect and transmit data from different brands of ICU medical devices, the data integration system was established to receive, integrate, standardize, and store the real-time clinical data. In this way, the sepsis prediction model developed in the ICU of the Ruijin Hospital for the real-world study of sepsis early warning on ICU management. The trial was registered with ClinicalTrials.gov (NCT05088850).

FindingsOur best early warning model achieved an area under the receiver operating characteristic curve (AUC) of 0{middle dot}9833 in the task of detecting sepsis in 4-h preceding on the open-source database, while our ensemble model achieved an AUC of 0{middle dot}9065-0{middle dot}9436 in the retrospective research from 1-5-h preceding on the private database, and 0{middle dot}8636-0{middle dot}8992 in real-time real-world studies using the data integration system in the ICU of the Ruijin Hospital. In the continuous early warning process of patients admitted to the ICU, 22 patients who met the diagnostic criteria for sepsis during hospitalization were predicted as positive cases; 29 patients without sepsis were predicted as negative cases. Additionally, 17 patients were predicted as false-positive cases; in six patients with sepsis during ICU stay, the predicted probabilities at different time nodes were all less than the warning threshold 0{middle dot}7 and predicted as false-negative cases.

InterpretationMachine learning models could allow accurate and real-time inference to detect sepsis onset within 5-h preceding at most with the help of the data integration system. We identified the features such as age, antibiotics, ventilation, and net balance to be important for the sepsis prediction inference. We argue that this system has promising potential to improve ICU management by helping medical practitioners identify at-sepsis-risk patients and prepare for timely diagnosis and intervention.

FundingShanghai Municipal Science and Technology Major Project, the ZHANGJIANG LAB, and the Science and Technology Commission of Shanghai Municipality. 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. Evidence of increasing recorded diagnosis of autism spectrum disorders in Wales, UK - an e-cohort study Estimates place the prevalence of autism spectrum disorders (autism) at around 1% in the population. New services for adult diagnosis have been set up in Wales, UK, at a time of rising awareness of the spectrum of autism experiences, however no studies have examined adult autism prevalence in Wales. In this study we use an anonymised e-cohort comprised of healthcare record data to produce all-age estimates of prevalence and incidence of recorded autism for the years 2001-2016. We found the overall prevalence rate of autism in healthcare records was 0.51%. The number of new-recorded cases of autism increased from 0.188 per 1000 person-years in 2001 to 0.644 per 1000 person-years in 2016. The estimate of 0.51% prevalence in the population is lower than suggested by population survey and cohort studies study methodologies, but comparable to other administrative record study estimates. Rates of new incident diagnoses of autism saw a >150% increase in the years 2008-2016, with a trend towards more diagnoses in those over 35 and an eightfold increase in diagnoses in women from 2000-2016. Our study suggests that while the number of people being diagnosed with autism is increasing, many are still unrecognised by healthcare services.

Lay AbstractAutism spectrum disorders (autism) are thought to be relatively common, with analyses estimating 1% in the population could meet diagnostic criteria. New services for adult diagnosis have been set up in Wales, UK, however no studies have examined for the proportion of adults with autism in Wales. In this study we take anonymised healthcare record data from more than 3.6 million people to produce a national estimate of recorded autism diagnoses. We found the overall prevalence rate of autism in healthcare records was 0.51%. The number of new-recorded cases of autism increased from 0.188 per 1000 person-years in 2001 to 0.644 per 1000 person-years in 2016. The estimate of 0.51% prevalence in the population is lower than suggested by population survey and cohort studies, but comparable to other administrative records. From 2001-2016 the number of autism services for adults has increased, and autism is more widely known in society, while concurrently in healthcare records there was a >150% increase autism diagnoses in the years 2008-2016. An increasing number of diagnoses were amongst women and those aged over 35. Our study suggests that while the number of people being diagnosed with autism is increasing, many are still unrecognised by healthcare 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
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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
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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
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