Distinct temporal characteristics of circulating alveolar epithelial and endothelial injury markers in ARDS with COVID-19: a preliminary retrospective report The time course and specific contributions of alveolar epithelial and endothelial injury to the pathogenesis of acute respiratory distress syndrome (ARDS) with coronavirus disease (COVID-19) remain unclear. Here, we evaluated the characteristics of circulating markers of alveolar epithelial and endothelial injury in serum samples from eleven ARDS patients and ten non-ARDS patients, all with COVID-19. Our results indicates that the alveolar epithelial injury at the very early disease stage and the endothelial injury which continues to exacerbate during the later disease stage seem to be the hallmarks of ARDS with COVID-19.
Observational study of changes in utilization and outcomes in non-invasive ventilation in COVID-19 RationaleThe role of non-invasive ventilation (NIV) in severe COVID-19 remains a matter of debate.

ObjectivesTo determine the utilization and outcome of NIV in COVID-19 in an unbiased cohort.

MethodsObservational study of confirmed COVID-19 cases of claims data of the Local Health Care Funds comparing patients with non-invasive and invasive mechanical ventilation (IMV) between spring versus autumn period 2020.

Measurements and Main ResultsNationwide cohort of 7490 cases (median/IQR age 70/60-79 years, 66% male) 3851 (51%) patients primarily received IMV without NIV, 1614 (22%) patients received NIV without subsequent intubation, and 1247 (17%) patients had NIV failure (NIV-F), defined by subsequent endotracheal intubation. The proportion of patients who received invasive MV decreased from 74% to 39% during the second period. Accordingly, the proportion of patients with NIV exclusively increased from 10% to 28%, and those failing NIV increased from 9% to 21%. Median length of hospital stay decreased from 26 to 22 days, and duration of MV decreased from 11.6 to 7.6 days. The NIV failure rate decreased from 49% to 42%. Overall mortality remained unchanged (51% versus 53%). Mortality was 39% with NIV-only, 52% with IMV and 66% with NIV-F with mortality rates steadily increasing from 58% in early NIV-F (day 1) to 75% in late NIV-F (>4 days).

ConclusionUtilization of NIV rapidly increased during the autumn period, which was associated with a reduced duration of MV, but not with overall mortality. High NIV-F rates are associated with increased mortality, particularly in late NIV-F.

FundingInstitutional support and physical resources were provided by the University Witten/Herdecke and Kliniken der Stadt Koln and the Federal Association of the Local Health Care Funds.

At a Glance CommentaryO_ST_ABSScientific Knowledge on the SubjectC_ST_ABSCurrent management of ventilatory support in COVID-19 patients with respiratory failure is heterogeneous. Despite increasing use of non-invasive ventilation (NIV), defining intubation criteria still remains a matter of uncertainty and discussion, especially with regard to the balance between the NIV benefits and the risk of NIV failure. In addition, robust data concerning the influence of the duration and failure of NIV on intubation and mortality rates are still missing, although the time span between initiation of NIV and subsequent intubation in case of respiratory failure progression is suggested to influence patient outcome.

What This Study Adds to the FieldThis is the first large observational study describing differences of ventilatory strategies between the spring and autumn period of the SARS-CoV-2 pandemic in Germany and provides the in-hospital mortality rate of 7,490 patients who received mechanical ventilation. The increased utilization of NIV from 10% (first period) to 29% (second period) was associated with overall reduced durations of mechanical ventilation and length of hospital stay, but overall mortality remained comparably high and reached 51%, 53% respectively. Patients succeeding with NIV had lower mortality rates than those getting intubated without preceding NIV attempts, but those failing NIV had higher mortality rates, respectively, and this became even more predominant in late NIV failure. The present observational study shows the increasing role of NIV in the concert of ICU medicine related to COVID-19, but also clearly addresses its risks in addition to its benefits, both impacting on mortality.
COVID-19 Acceleration and Vaccine Status in France - Summer 2021 ObjectivesThis note provides an assessment of COVID-19 acceleration among groups with different vaccine status in France.

MethodsWe assess viral acceleration using a novel indicator introduced in Baunez et al. (2021). The acceleration index relates the percentage change of tests that have been performed on a given day to the percentage change in the associated positive cases that same day. We compare viral acceleration among vaccinated and unvaccinated individuals in France over the period May 31st - August 29, 2021.

ResultsOnce the state of the epidemic within each groups is accounted for, it turns out that viral acceleration has since mid-July converged to similar levels among vaccinated and unvaccinated individuals in France, even though viral speed is larger for the latter group compared to the former.

ConclusionOur results call for an increasing testing effort for both vaccinated and unvaccinated individuals, in view of the fact that viral circulation is currently accelerating at similar levels for both groups in France. Hyperactive immature state and differential CXCR2 expression of neutrophils in severe COVID-19 Neutrophils are vital in defence against pathogens but excessive neutrophil activity can lead to tissue damage and promote acute respiratory distress syndrome (ARDS). COVID-19 is associated with systemic expansion of immature neutrophils but the functional consequences of this shift to immaturity are not understood. We used flow cytometry to investigate activity and phenotypic diversity of circulating neutrophils in COVID-19. First, we demonstrate hyperactivation of immature CD10- subpopulations in severe disease, with elevated degranulation of secondary granule markers. Partially activated immature neutrophils are detectable three months post symptom onset, indication long term myeloid dysregulation in convalescent COVID-19 patients. Second, we demonstrate that neutrophils from moderately ill patients downregulate the chemokine receptor CXCR2, while neutrophils from severely ill individuals failed to do so, suggesting altered ability for organ trafficking. CD10- and CXCR2hi neutrophil subpopulations were enriched in severe disease and may represent biomarkers for early identification of individuals at high risk of progressing to severe COVID-19. Detection of COVID-19 and age-dependent dysosmia with paired crushable odorant ampules BackgroundSigns of anosmia can help detect COVID-19 infection when testing for viral positivity is not available. Inexpensive mass-produced disposable olfactory sensitivity tests suitable for worldwide use might serve not only as a screening tool for potential infection but also to identify cases at elevated risk of severe disease as anosmic COVID-19 patients have a better prognosis.

Methods and FindingsWe adopted paired crushable ampules with two concentrations of a standard test odorant (n-butanol) as standard of care in several clinics as community prevalence of COVID-19 infection waxed and waned. This was not a clinical trial; a chart review was undertaken to evaluate the operating characteristics and potential utility of the test device as RT-PCR testing became routine. The risk of anosmia was greater in COVID-19 patients. Olfactory sensitivity was concentration-dependent and decreased with aging. Hyposmia was detected across a wider age range than expected from the literature, and tests can be optimized to characterize different age groups.

Conclusionsn-Butanol at 0.32 and 3.2% in crushable ampules can be used to characterize olfactory function quickly and inexpensively and thus has potential benefits in pandemic screening, epidemiology, and clinical decision-making. The effect of hypersensitivity pneumonitis guideline on pathologic diagnosis of interstitial pneumonia Hypersensitivity pneumonitis (HP) and interstitial pneumonia (IP) have several overlapping characteristics, and a high diagnostic concordance rate of HP is rarely obtained. New guideline, highly influenced by pathology, were devised for its diagnosis. We recently reported that the 2020 HP guideline may result in a possible overdiagnosis of fibrotic HP (fHP) through multidisciplinary discussion. Here, we attempted to investigate the impact of the 2020 HP guideline on the pathological diagnosis of cases previously diagnosed as IP. We classified 247 cases with fibrotic IP diagnoses sourced from 2014-2019 into three categories according to the 2020 HP guideline: typical, probable, and indeterminate HP. The original pathological diagnosis and categorization based on the 2020 HP guideline were compared. The clinical data including serum data and pulmonary function tests were compared among groups. The number of cases that changed to HP from an original diagnosis other than HP based on the guideline was 56 (23%). The clinical data of these cases bore a greater resemblance to cases diagnosed as indeterminate for HP than those diagnosed as typical or probable. The ratio of typical and probable HP to the total cases was significantly lower when using a transbronchial lung cryobiopsy (TBLC). Based on the new guideline, the pathological diagnosis of HP efficiently excluded HP cases but increased the rate of HP diagnosis for cases with fibrotic IP that may not suit an HP diagnosis. Thus, a TBLC may not be useful when imparting findings for fibrotic HP diagnosis using the new criteria.

Key messagesO_LIWhat is the key question? >
Does the 2020 HP Guideline improve pathological diagnosis?
C_LIO_LIWhat is the bottom line? >
By applying the new guideline, about 1/4 of the pathological diagnoses were changed from not chronic HP to probable or typical fHP, but most of the changed cases showed a clinical picture closer to not chronic HP.
C_LIO_LIWhy read on? >
To understand that simple application of the pathological criteria of the HP guideline may cause a misleading diagnosis.
C_LI Longitudinal intronic RNA-Seq analysis of Parkinson Disease patients reveals disease-specific nascent transcription Transcriptomic studies usually focus on either gene or exon-based annotations, and only limited experiments have reported changes in reads mapping to introns. The analysis of intronic reads allows the detection of nascent transcription that is not influenced by steady - state RNA levels and provides information on actively transcribed genes. Here we describe substantial intronic transcriptional changes in Parkinsons Disease (PD) patients compared to healthy controls (CO) at two different timepoints; at the time of diagnosis (BL) and three years later (V08). We used blood RNA-Seq data from the Parkinsons Progression Markers Initiative (PPMI) cohort and identified significantly changed transcription of intronic reads only in PD patients during this follow up period. In CO subjects, only nine transcripts demonstrated differentially expressed introns between visits. However, in PD patients 4,873 transcripts had differentially expressed introns at visit V08 compared to BL, many of them in genes previously associated with neurodegenerative diseases, such as LRRK2, C9orf72, LGALS3, KANSL1AS1 and ALS2. In addition, at the time of diagnosis (BL visit) we identified 836 transcripts (e.g. SNCA, DNAJC19, PRRG4) and at visit V08 2,184 transcripts (e.g. PINK1, GBA, ALS2, PLEKHM1) with differential intronic expression specific to PD patients. In contrast, reads mapping to exonic regions demonstrated little variation indicating highly specific changes only in intronic transcription. Our study demonstrated that Parkinsons disease is characterized by substantial changes in the nascent transcription and description of these changes could help to understand the molecular pathology underpinning this disease.

Impact statementTranscriptomic studies in most cases describe the steady state changes of the cellular RNA combined with signals from newly synthesised RNA or nascent RNA. Nascent RNA reflects dynamic alterations in the cellular transcriptome and improves the resolution of RNA-Seq analysis. In the present study, we describe the changes in nascent RNA transcription in Parkinsons disease by using intronic RNA-Seq analysis. We compared transcriptome changes at the time of diagnosis and 3 years after the initial diagnosis. As a result, we were able to describe disease-specific time-dependent alterations in the nascent transcription in the blood of Parkinsons patients illustrating another layer of the blood-based biomarkers that could be diagnostic of both risk and progression of Parkinsons disease. Using controlled interrupted time series to estimate the population-level effects of Ontario's recently implemented overdose prevention sites and consumption and treatment services BackgroundOntario recently implemented overdose prevention sites and consumption and treatment services (OPS/CTS) to stem the harms of the opioid epidemic. We tested whether operating any site improved local opioid-related health service use and mortality rates.

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

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

ConclusionAlthough OPS/CTS are not sufficient to stem the harms of the opioid overdose epidemic on their own, they play a critical role in local harm reduction strategies. Effectiveness of a short term induction regimen of a biosimilar Adalimumab in the long term management of symptomatic Ankylosing Spondylitis Symptomatic Ankylosing Spondylitis: A Community Based Proof of Concept Observational Study IntroductionCost and drug toxicity often deter prolonged therapeutic use of anti-TNF agents in ankylosing spondylitis (AS). A planned study was completed to endorse our clinic based observation of long term relief following short-term administration of anti-TNF agent.

Methods50 consenting patients with symptomatic active chronic AS under rheumatology care in a community clinic were enrolled. They had no past history of anti-TNF use. 40 mg standard biosimilar adalimumab (BS-ADA, Exemptia trade name)was injected subcutaneously every fortnight for six injections (10 weeks). Patients were monitored at several time points. Improvement was assessed at regular interval as per protocol which included standard indices (Bath and Assessment Spondyloarthritis International Society /ASAS). An intention to treat analysis with significant p<0.05 was carried out.

ResultsPatients showed early and substantial significant improvement in pain, NSAID requirement, function and in several indices (ASAS 20 & 40, ASAS partial remission, BASDAI, BASFI, ASDAS) which persisted after stopping injections. 84% and 52 % of patients respectively showed ASAS 20 improvement at week 12 and 48: corresponding ASAS partial remission 34% and 24%. Over 50% patients maintained prolonged improvement and provided proof of concept (defined a-priori). Serum Interleukin-6 assay showed a sharp reduction at 24 weeks. None developed TB or serious drug toxicity. 11 patients withdrew (mostly inadequate response). Absence of control was a limitation.

ConclusionA ten-week administration of biosimilar adalimumab in difficult to treat AS showed early substantial improvement which often persisted for 24 weeks. This unconventional strategy was socioeconomically appealing. It merits further validation and acceptance especially in resource strained settings. Survey of Contaminated Percutaneous Injuries in Anesthesia Practitioners BackgroundAnesthesia practitioners are at inherent risk for percutaneous injuries by blood-contaminated needles and sharp objects. These exposures may result in transmission of HIV and hepatitis viruses. Data about this occupational hazard from contaminated needles and sharp devices is limited and decades old. We conducted a web-based survey to assess the occurrence, reporting, characteristics, and outcome of contaminated percutaneous injuries (CPI) in anesthesia residents, fellows, and attendings.

MethodsAfter institutional research board approval, an email was sent to 217 anesthesia practitioners requesting their participation in an online survey about contaminated percutaneous injuries. Responses were collected from February through March 2020. Results are reported as absolute numbers and proportions with 95% confidence interval (CI).

ResultsThe overall survey response rate was 51% (110/217). 59% (65/110) (95% CI, 50-68) of participants reported having one or more contaminated percutaneous injury during their years of anesthesia practice (42% (21/50) of residents, 50% (4/8) of fellows, 77% (40/52) of anesthesia attendings). Prevalence of injuries related to attendings years of anesthesia practice was 69% (95% CI, 44-94) for 5-10 years, 62.5% (95% CI, 29-96) for 10-15 years, and 79% (95% CI, 63- 95) for greater than 15 years of practice.

35% (95% CI, 26-44) of participants reported having one or more CPI within the last 5 years (40% of residents, 50% of fellows, 29% of attendings). Occurrence of CPI within the last 5 years based on attending anesthesiologist years of practice was 57% for less than 5 years, 37.5% for 10-15 years, and 20% for 15-20 years of practice. 75% (95% CI, 65-85) reported the incident at the time of injury. 59% (95% CI, 48-70) of injuries were due to hollow bore needles. 50% (95% CI, 39-61) of total injuries were high risk. 26% of injured anesthesia practitioners received post-exposure prophylaxis and there were zero seroconversions.

ConclusionMost anesthesiologists will sustain a contaminated percutaneous injury during their careers. Incidence of these injuries decreases with years of practice. Occurrence of these injuries is high among anesthesia residents, with the majority reporting their injuries. Half of the injuries are high risk with a quarter requiring postexposure prophylaxis. More education and interventions are needed to reduce percutaneous injuries and improve reporting. Can cheap, rapid air filtration control the pandemic? Public health departments such as CDC and California Department of Public Health (CA-DPH) advise HEPA-purifiers to limit transmission of SARS-CoV-2 in classrooms and community spaces. CA-DPH recommends 4-6 air exchanges per hour often necessitating multiple HEPA-purifiers per room, unaffordable in under-resourced community settings. Pressure to seek cheap, rapid air filtration resulted in proliferation of lower-cost, Do-It-Yourself (DIY) air purifiers whose performance is not well characterized compared to HEPA-purifiers. Primary metrics are clean air delivery rate (CADR), noise generated (dBA), and affordability ($$). CADR measurement often requires hard-to-replicate laboratory experiments with generated aerosols. In this study, we use simplified, low-cost measurement tools of ambient aerosols enabling scalable evaluation of aerosol filtration efficiencies (0.3 to 10 microns), estimated CADR, and noise generation to compare a dozen HEPA-purifiers and DIY purifier designs. DIY purifiers consist of one or two box fans coupled to single MERV 13-16 filters (1"-5" thick) or quad filters in a cube. Accounting for reduced filtration efficiency (%) of MERV 13-16 filters (versus HEPA) at the most penetrating particle size of 0.3 microns, estimated CADR of DIY purifiers using 2" (67%), 4" (66%), and 5" (85%) filters at lowest fan speed was 293 cfm ($35), 322 cfm ($58), and 405 cfm ($120) comparable to best-in-class, low-noise generating HEPA-purifier running at maximum speed with at 282 cfm ($549). Quad filter designs, popularly known as Corsi-Rosenthal box, achieved gains in estimated CADR less than 80% over single filter designs, less than the 100% gain by adding a second DIY purifier. Replacing one of the four filters with a second fan resulted in gains of 125%-150% in estimated CADR. DIY alternatives using lower-efficiency, single filters compare favorably to HEPA-purifiers in estimated CADR, noise generated at five to ten times lower cost, enabling cheap, rapid aerosol removal around the world. Clinical impact of the rapid molecular detection of RSV and influenza A and B viruses in the emergency department IntroductionUsing respiratory viruses rapid diagnostic tests in the emergency room (ER) could allow a better and faster clinical management. Point-of-care PCR instruments provide now results in less than 30 minutes. The objective of this study was to assess the impact of the use of the cobas(R) Influenza A/B & RSV Assay for use on Roches cobas(R) Liat(R) instrument on the clinical management of ER patients.

MethodsPatients (adults and children) requiring admission or suffering from an underlying condition at risk of respiratory complication were prospectively recruited in the ER of four hospitals in the Brussels region. Physicians intentions regarding admission, isolation, antibiotic and antiviral use were collected before and after performing a cobas(R) Influenza A/B & RSV molecular test. Additionally, a comparison of the analytical performance of this test against antigen rapid tests and viral culture was performed as well as a time-to-result evaluation.

ResultsPCR yielded twice more positive results than antigen rapid diagnostic tests. It allowed a decrease in the overall need for isolation and treatment by limiting the isolation of negative patients and the antibiotic use for positive patients. Meanwhile, antiviral treatments better targeted patients with a positive influenza PCR.

ConclusionThe use of a rapid influenza and RSV molecular test improves the clinical management of patients admitted to the ER by providing a fast and reliable result. Their additional cost compared to antigen tests should be balanced with the benefit of their analytical performance, leading to efficient reductions in the need of isolation and antibiotic use. Macronutrient mass intake explains deferential weight and fat loss in isocaloric diets Differential weight and fat losses under isocaloric diets of distinct macronutrient composition are well-documented findings in obesity research.1-6 Such data are considered a result of inadequate methodology as it disagree with the energy balance theory.7 A recent mathematical analysis of this paradigm has found, however, serious analytical contradictions in its foundations.8 As an alternative, a mass balance model was proposed to explain the aforesaid body composition alterations. Here, we expand on this observation by contrasting both models. We show that mass balance explains a wide range of fending experiments including those concurring with the energy balance principle. The latter, however, is less flexible and results in poor forecasts in settings consistent with mass balance. The energy balance theory is thus an unsatisfactory model of body composition changes. Consequently, by shifting to a mass balance paradigm of obesity a much deeper understanding of this disease may follow in the near future. Relationship Between Patient Sex and Serum Tumor Necrosis Factor Antagonist Drug and Anti-Drug Antibody Concentrations in Inflammatory Bowel Disease; A Nationwide Cohort Study BackgroundAnti-drug antibodies to infliximab (ATI) and adalimumab (ATA) are associated with loss of response to tumor necrosis factor antagonist (anti-TNF) therapy in inflammatory bowel disease (IBD). We evaluated the relationship between patient sex and serum TNF antagonist drug and antibody concentrations in inflammatory bowel disease

MethodsA nationwide multicenter retrospective cohort study was conducted by evaluating patients charts from July 2018 until September 2021. The effect of patient sex on anti-drug antibodies and serum drug concentration in patients with IBD across 7 hospitals was investigated. A subgroup analysis also investigated the effect of anti-TNF combination therapy. Geometric means were calculated, and multiple linear regression was used to estimate the adjusted ratio of geometric means (RoGM) and their 95% confidence intervals (CI).

ResultsIn the total study sample (n = 1093), males receiving infliximab had higher anti-drug antibody concentrations (38.3 vs. 22.3 AU/ml; aRoGM = 1.72, 95% CI: 1.30-2.27, p-value <0.001) compared to females. Additionally, infliximab serum drug concentrations among males were lower compared to females (2.6 vs. 4.1 ug/ml; aRoGM = 0.62, 95% CI: 0.44-0.88, p-value = 0.007). In the subgroup analysis (n = 359), male compared to female patients on combination therapy with infliximab and immunomodulators had similar anti-drug antibody concentrations (30.2 vs. 21.9 AU/ml; aRoGM = 1.38, 95% CI: 0.79-2.40, p-value = 0.254). There was no difference in the anti-drug antibody and serum drug concentrations among males and females on adalimumab.

ConclusionIn patients receiving infliximab, anti-drug antibodies were higher in males than females. Consistent with this, serum drug concentrations were lower in males than females on infliximab. There was no difference in anti-drug antibody and serum drug concentrations among males and females on adalimumab. In addition, no difference in anti-drug antibodies between males and females receiving anti-TNF combination therapy was observed. Knee-extensor strength, symptoms, and need for surgery after two, four, or six exercise sessions/week using a home-based one-exercise program: A randomized dose-response trial of knee-extensor resistance exercise in patients eligible for knee replacement (the QUADX-1 trial). ObjectiveTo investigate firstly the efficacy of three different dosages of one home-based, knee-extensor resistance exercise on knee-extensor strength in patients eligible for knee replacement, and secondly, the influence of exercise on symptoms, physical function and decision on surgery.

MethodOne-hundred and forty patients eligible for knee replacement were randomized to three groups: 2, 4 or 6 home-based knee-extensor resistance exercise-sessions per week (group 2, 4 and 6 respectively) for 12 weeks. Primary outcome: isometric knee-extensor strength. Secondary outcomes: Oxford Knee Score, Knee injury and Osteoarthritis Outcome Score, average knee pain last week (0-10 numeric rating scale), 6-minute walk test, stair climbing test, exercise adherence and "need for surgery".

ResultsPrimary analysis: Intention-to-treat analysis of 140 patients did not find statistically significant differences between the groups from baseline to after 12 weeks of exercise in isometric knee-extensor strength: Group 2 vs. 4 (0.003 Nm/kg (0.2%) [95% CI -0.15 to 0.15], P=0.965) and group 4 vs. 6 (-0.04 Nm/kg (-2.7%) [95% CI -0.15 to 0.12], P=0.628). Secondary analysis: Intention-to-treat analyses showed statistically significant differences between the two and six sessions/week groups in favor of the two sessions/week group for Oxford Knee Score: 4.8 OKS points (15.2%) [1.3 to 8.3], P=0.008) and avg. knee pain last week (NRS 0-10): - 1.3 NRS points (-19.5%) [-2.3 to -0.2], P=0.018. After the 12-week exercise intervention, data were available for 117 patients (N=39/group): 38 (32.5%) patients wanted surgery and 79 (67.5%) postponed surgery. This was independent of exercise dosage.

ConclusionIn patients eligible for knee-replacement we found no between-group differences in isometric knee extensor strength after 2, 4 and 6 knee-extensor resistance exercise sessions per week. We saw no indication of an exercise dose-response relationship for isometric knee-extensor strength and only clinically irrelevant within group changes. For some secondary outcome (e.g. KOOS subscales) we found clinically relevant within group changes, which could help explain why only one in three patients decided to have surgery after the simple home-based exercise intervention.

Trial registrationClinicalTrials.gov identifier: NCT02931058. Preprint: https://doi.org/10.1101/2021.04.07.21254965. Macular vascular complexity analysis of diabetes mellitus by swept-source optical coherence tomographic angiography PurposeTo evaluate the associations of retinal vascular complexity features, including fractal dimension (FD) and blood vessel tortuosity (BVT), with the severity of diabetic retinopathy (DR) by using noninvasive optical coherence tomographic angiography (OCTA).

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

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

ConclusionFD and BVT determined using OCTA might be useful parameters for objectively distinguishing DR from non-DR and indicating DR progression. Knowledge, attitude, and practices regarding COVID-19: A study on food handlers in a joint venture food industry in Dhaka, Bangladesh. While people around the world are terrified of the global pandemic coronavirus disease 2019 (COVID-19) and are dying for a permanent solution, undertaking preventive safety measures are said to be the most effective way to stay away from it. Peoples adherences to these measures are broadly dependent on their knowledge, attitude, and practices (KAP). People working in the food industries must be extra cautious during this time because they are in close proximity to consumable items. The present study was designed to evaluate food handlers knowledge, attitude, and practices regarding COVID-19 in different food industries in Bangladesh. A number of 400 food handlers from 15 food industries took part in this online-based study. The information was collected from the participants through a questionnaire prepared in Google form. With a correct response rate of about 90% on average (knowledge 89.7%, attitude 93%, practices 88.2%), the participants showed an acceptable of KAP regarding COVID-19. Education and working experiences had a significant association with the total KAP scores (p < 0.05). The findings may assist public health professionals and practitioners in developing targeted strategies for implementing such studies in other industrial sectors and taking appropriate measures based on the KAP studies. Surgical interventions targeting the nucleus caudalis for craniofacial pain: a systematic and historical review. IntroductionChronic facial pain is a prevalent group of conditions and when refractory to common treatments poses a social and economic burden. The last decade has seen a multitude of advancements in the multimodal management of pain. Ablative or neuromodulatory interventions targeting the nucleus caudalis (NC) of the trigeminocervical complex is one such treatment that has remained underutilized.

MethodsHere we present a systematic review of the literature and historical perspective regarding interventions targeting the NC. We examine the various intervention techniques, clinical indications, and procedural efficacy. A novel outcome reporting scheme was devised to allow comparison between studies using differing outcome reporting methods.

ResultsA review of the literature revealed 49 retrospective studies published over the last 80 years, reporting on 858 patients. The most common technique was the open NC dorsal root entry zone nucleotomy/tractotomy (n=515, 60.0%); however, there has been an emergence of novel approaches such as endoscopic (n=6, 0.7%) and spinal cord stimulation (n=20, 2.3%) in the last 10 years. Regardless of intervention technique or preoperative diagnosis, 90.4% of patients demonstrated some improvement from treatment.

ConclusionThis systematic review highlights recent advancements in NC intervention technique and the wide range of facial pain syndromes for which these interventions show promising efficacy. New and less invasive techniques continue to emerge, however prospective studies remain absent in the literature. Future work should address efficacy comparisons between intervention type and preoperative diagnosis. Transdiagnostic Profiles of Behaviour and Communication Relate to Academic and Socioemotional Functioning and Neural White Matter Organisation BackgroundBehavioural and language difficulties co-occur in multiple neurodevelopmental conditions. Our understanding of these problems has arguably been slowed by an overreliance on study designs that compare deficit/diagnostic groups and fail to capture the overlap across different neurodevelopmental disorders and the heterogeneity within them.

MethodsWe recruited a large transdiagnostic cohort of children with complex needs (N = 805) to identify distinct subgroups of children with common profiles of behavioural and language strengths and difficulties. We then investigated whether and how these data-driven groupings could be distinguished from a comparison sample (N = 158) on measures of academic and socioemotional functioning and patterns of global and local white matter connectome organisation. Academic skills were assessed via standardised measures of reading and maths. Socioemotional functioning was captured by the parent-rated version of the Strengths and Difficulties Questionnaire.

ResultsWe identified three distinct subgroups of children, each with different levels of difficulties in structural language, pragmatic communication, and hot and cool executive functions. All three subgroups struggled with academic and socioemotional skills relative to the comparison sample, potentially representing three alternative but related developmental pathways to difficulties in these areas. The children with the weakest language skills had the most widespread difficulties with learning, whereas those with more pronounced difficulties with hot executive skills experienced the most severe difficulties in the socioemotional domain. Each data-driven subgroup could be distinguished from the comparison sample based on both shared and subgroup-unique patterns of neural white matter organisation. Children with the most pronounced deficits in language, cool executive, or hot executive function were differentiated from the comparison sample by altered connectivity in predominately thalamocortical, temporal-parietal-occipital, and frontostriatal circuits, respectively.

ConclusionThese findings advance our understanding of commonly co-morbid behavioural and language problems and their relationship to behavioural outcomes and neurobiological substrates. Transdiagnostic Profiles of Behaviour and Communication Relate to Academic and Socioemotional Functioning and Neural White Matter Organisation A novel echo-parameter supersedes the Society of Thoracic Surgeons risk score in predicting post transcatheter aortic valve replacement mortality ObjectiveTo accurately predict post-TAVR mortality, we proposed a family of new echo-parameters (augmented blood pressure) derived from blood pressure and aortic valve gradient measurements and examined them in this study.

Patients and MethodsPatients in the Mayo Clinic National Cardiovascular Diseases Registry-TAVR database who underwent TAVR between January 1, 2012, and June 30, 2017, were identified to retrieve baseline demographics, echocardiographic and mortality data. Augmented blood pressure parameters and valvulo-arterial impedance were evaluated by univariate and multivariate Cox regression. Receiver operating characteristic curve analysis was used to assess the model performance against the Society of Thoracic Surgeons (STS) risk score.

ResultsThe final cohort contained 974 patients with a mean age of 81.4{+/-}8.3 years old, and 56.6% were male. The mean STS risk score was 8.2{+/-}5.2. The median follow-up duration was 354 days, and the one-year all-cause mortality rate was 14.2%. Both univariate and multivariate Cox regression showed that augmented systolic blood pressure and augmented mean arterial pressure (AugMAP) parameters were independent predictors for 1-year post-TAVR mortality (all p<0.0001). A univariate model of AugMAP1 supersedes the STS score model in predicting 1-year post-TAVR mortality (area under curve: 0.700 vs. 0.587, p=0.0051).

ConclusionAugmented mean arterial pressure provides a simple but effective approach for clinicians to quickly estimate the clinical outcome of TAVR patients. It can be incorporated in the assessment of TAVR candidacy. 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.) Substance Use Onset in High-Risk 9-13 Year-Olds in the ABCD Study AimA key aim of the Adolescent Brain Cognitive DevelopmentSM (ABCD) Study is to document substance use onset, patterns, and sequelae across adolescent development. However, substance use misreporting obscures accurate drug use characterization. Hair toxicology tests provide objective historical substance use data, but are rarely investigated in youth. Here, we compare objective hair toxicology results with self-reported substance use in youth.

MethodsA literature-based substance use risk algorithm identified 696 ABCD Study(R) participants for hair sample collections between baseline and 2-year follow-up (spanning ages 9-13) for laboratory analysis. Chi-square and t-tests assessed differences between participants demographics, positive and negative hair tests, risk algorithm scores, and self-reported substance use.

ResultsHair testing confirmed that 17% of at-risk 9-13 year-olds had evidence of past 3-month use of one (n=99), two (n=17), three (n=3), or four (n=2) drug classes. After considering prescribed medication use, 11% had a positive test incongruent with self- or parent-report. No participant with a positive result self-reported substance use consistent with their toxicology results. Participants with positive tests under-reported use (p<.001), reported less sipping of alcohol (p<.001), and scored higher on the risk algorithm (p<.001) than those with negative hair toxicology.

ConclusionsAn alarming 11% of tested samples in at-risk 9-13 year-olds were positive for at least one unreported substance, suggesting underreporting in this population when participating in a national healthy development study. The degree of underreporting cannot yet be calculated, as at-risk samples were prioritized for assays. Expanded toxicology testing is key to characterize substance use in youth. Diagnostic Value of Genetic Mutation Analysis and Mutation Profiling of cfDNA in Intraocular Fluid for Vitreoretinal Lymphoma ObjectiveVitreoretinal lymphoma (VRL) is a rare but aggressive masquerade syndrome, with challenging diagnosis. Since the tumor-related genetic mutation analysis based on cell-free DNA (cfDNA) are underutilized in ocular oncology, we aimed to test the VRL diagnostic value of cfDNA genetic mutation analysis using intraocular fluid (IOF) samples and to identify its mutation profile.

SubjectsSeventeen VRL and 6 uveitis patients from Zhongshan Ophthalmic Centre were selected as training group, and 5 VRL and 5 uveitis patients from Beijing Chaoyang Hospital were selected as validation group.

MethodsThe medical records and genetic mutation analysis using a panel containing 446 tumor-related genes of included patients were retrospectively reviewed. We analyzed the mutation profile, and identified the molecular subtypes and subdivisions of B-cell differentiation pathways of our VRL patients.

Main outcomesThe cfDNA genetic mutations detected in IOF.

ResultsThe VRL patients from the training group exhibited abundant cfDNA mutations in IOF (sensitivity 100%), while only 2 out of 6 uveitis patients were positive (specificity 67%). However, the number of cfDNA mutations observed in VRL patients was higher than that of uveitis patients. The mutation-positive patients from the validation group were diagnosed with VRL while the mutation-negative patients were diagnosed with uveitis (sensitivity and specificity 100%). VRL patients were characterized by the high mutation frequencies of PIM1, MYD88, CD79B, ETV6, and IRF4.

ConclusionsThe genetic mutation analysis of IOF samples represents a feasible diagnosis method for VRL with 100% sensitivity; it could track genetic profiles; thus, revealing genetic heterogeneity of VRL.

Statement of translational relevanceThe anterior chamber paracentesis and diagnostic vitrectomy have been widely used in ophthalmic clinics, as they are less invasive sampling techniques for liquid biopsies. Genetic mutation analysis of cell-free DNA (cfDNA) of intraocular fluid using a panel containing 446 targeted genes represents a feasible method with 100% sensitivity for vitreoretinal lymphoma (VRL) diagnosis. Furthermore, it can address cytological diagnostic issues including limited cellular yield, cell lysis associated with the fragile nature of lymphoma cells, and high risks associated with retinal tissue biopsies. Furthermore, it allows for genetic profile tracking, having the potential to reveal genetic heterogeneity and molecular characteristics of VRL in the future