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The number of households experiencing fuel poverty is thought to have risen by at least 600,000 in the UK because of the ongoing Covid-19 pandemic. The concentration of fuel poor households in poor quality, energy inefficient accommodation that they have little power to improve means they are particularly negatively affected by the retreat into the home brought about by successive lockdowns and restrictions. For many such households, the home is not the place of sanctuary that it needs to be at a time like this. However, our empirical research into the lived experiences of fuel poverty reveals additional consequences for fuel poor households, chiefly associated with restricted access to third spaces and other disruptions to their usual coping strategies. Based on our evidence, we highlight three key considerations for policy on fuel poverty in the era of Covid-19: the need to rapidly upgrade the energy performance of the existing housing stock; the need to address the additional financial hardship faced by fuel poor households; and the need to prioritise access to third spaces and high-quality public spaces while restrictions last. This paper develops the concept of energy poverty by considering the role of spaces outside the home as part of the overall experience of energy poverty and the range of ways in which policy makers can mitigate its impacts.

Exercise can reduce the incidence of stress-related mental diseases, such as depression and anxiety. Control group was neither exposed to CVMS nor TRE (noCVMS/noTRE). Females were tested and levels of serum17-beta-oestradiol (E2), estrogen receptors α immunoreactive neurons (ERα-IRs), estrogen receptors β immunoreactive neurons (ERβ-IRs) and oxytocin immunoreactive neurons (OT-IRs) were measured. The results showed there’s increased anxiety-like behaviors for mice from CVMS/noTRE, CVMS/higher speed TRE (CVMS/HTRE) and noCVMS/HTRE groups when they were put in open field and elevated maze tests. They had lower serum E2 levels than mice from CVMS/low-moderate speed TRE (CVMS/LMTRE), noCVMS/LMTRE and noCVMS/noTRE groups. The three groups of CVMS/noTRE, CVMS/HTRE and noCVMS/HTRE mice had more ERα-IRs and less ERβ-IRs in the medial preoptic area (mPOA), bed nucleus of the stria terminalis (BNST) and medial amygdala (MeA), hypothalamic paraventricular nucleus (PVN) and supraoptic nucleus (SON). The number of OT-IRs in PVN and SON of CVMS/noTRE, CVMS/HTRE and noCVMS/HTRE mice was also lower than that of mice from CVMS/LMTRE, noCVMS/LMTRE and noCVMS/noTRE groups. Interestingly, CVMS/LMTRE and noCVMS/LMTRE mice were similar to noCVMS/noTRE mice in that they did not show anxiety, while CVMS/HTRE and noCVMS/HTRE mice did not, which were similar to the mice in CVMS/noTRE. We propose that LMTRE instead of HTRE changes the serum concentration of E2. ERβ/ERα ratio and OT level in the brain may be responsible for the decrease in anxiety-like behavior in female mice exposed to anxiety-inducing stress conditions., Highlights • CVMS/LMTRE did not show anxiety. • noCVMS/LMTRE did not show anxiety. • ERβ/ERα ratio decreas anxiety. • OT decreas anxiety.

Probiotics that regulate the microbiome-gut-brain axis and provide mental health benefits to the host are referred to as psychobiotics. Preclinical studies have demonstrated psychobiotic effects on early life stress-induced anxiety- and depression-related behavior in rodents; however, the specific mechanisms remain ill-defined. In the current study, we investigated the effects of probiotic supplementation on neurobiological responses to chronic stress in adult male Long-Evans rats. Twenty-four rats were randomly assigned to probiotic (PB) or vehicle control (VEH) groups, then to either chronic unpredictable stress (CUS) or no-stress control (CON) conditions within each group (n = 6/subgroup). We hypothesized that PB supplementation would reduce markers of anxiety and enhance emotional resilience, especially in the CUS animals. In the cognitive uncertainty task, a nonsignificant trend was observed indicating that the PB-supplemented animals spent more time oriented toward the food reward than VEH animals. In the open-field task, CUS-PB animals spent more time in the center of the arena than CUS-VEH animals, an effect not observed between the two CON groups. In the swim task, the PB animals, regardless of stress assignment, exhibited increased floating, suggesting a conserved response in a challenging context. Focusing on the endocrine measures, higher dehydroepiandrosterone (DHEA)-to-corticosterone fecal metabolite ratios, a correlate of emotional resilience, were observed in PB animals. Further, PB animals exhibited reduced microglia immunoreactivity in the basolateral amygdala, possibly indicating a neuroprotective effect of PB supplements in this rodent model. These results provide evidence that PB supplementation interacts with stress exposure to influence adaptive responses associated with endocrine, neural, and behavioral indices of anxiety.

Purpose The purpose of this study is to examine the effects of fatigue on muscular performance, oxygenation saturation, and cognition following acute hypoxic exposure at Normoxia, Moderate Hypoxia (MH), and Severe Hypoxia (SH). Methods Twelve males performed 3 sets of leg extensions to failure under Normoxia (FiO2: 21%), MH (Fi02: 15.4%), and SH (Fi02: 12.9%). Heart rate, peripheral oxygenation saturation, total saturation index, psychomotor vigilance testing reaction time, psychomotor vigilance error rate, maximum strength, and repetitions to failure were measured throughout each visit. Results The primary findings indicated that MH and SH resulted in significant decreases in psychomotor vigilance test performance (MH: 388.25–427.17 ms, 0.41–0.33 error rate; SH: 398.17–445.42 ms reaction time, 0.25–1.00 error rate), absolute muscle tissue oxygen saturation (Abs-StO2) (MH:67.22% compared to SH:57.56%), but similar muscular strength, heart rate, and patterns of muscle tissue oxygen saturation responses (StO2%) during fatigue when compared to Normoxia. There was an acute decrease in the ability to remain vigilant and/or respond correctly to visual stimuli as indicated by the worsened reaction time (PVTRT) during MH (FiO2: 15.4%) and increased PVTRT and error rate (PVTE) during SH (FiO2: 12.9%) conditions. Conclusions Acute hypoxic exposure in the current study was not a sufficient stimuli to elicit hypoxic-related changes in HR, muscular strength (1-RM), or repetitions to failure. The SpO2 responses were hypoxic-level dependent with increasing levels of hypoxia resulting in greater and more sustained reductions in SpO2. The combined SpO2 and StO2 responses at MH and SH suggested a balance between the muscles metabolic demand remaining lower than the muscle oxygen diffusion capacity. During the SH condition, Abs-StO2 suggested greater metabolic stress than Normoxia and MH conditions during the fatiguing leg extensions. The patterns of responses for StO2% during the three sets of leg press to failure indicated that exercise is a more potent influencer to muscle oxygenation status than hypoxic conditions (FiO2: 15.4 and 12.9%)., Graphical abstract Image 1, Highlights • Moderate Hypoxia (FiO2: 15.4%) coupled with fatigue resulted in a decrease in reaction time. • Severe Hypoxia (FiO2: 12.9%) coupled with fatigue resulted in increased error rate and a decrease in reaction time. • Fatigue was the primary influencer on heart rate, muscular strength, and muscular endurance and not hypoxic exposure. • Severe Hypoxia (FiO2: 12.9%) resulted in greatly reduced muscle tissue oxygenation saturation before and after fatigue.

In the current study, we aimed to investigate the network structure of COVID-19 symptoms and its related psychiatric symptoms, using a network approach. Specifically, we examined how COVID-19 symptoms relate to psychiatric symptoms and highlighted potential pathways between COVID-19 severity and psychiatric symptoms. With a sample of six hundred seventy-five recovered COVID-19 patients recruited 1 month after hospital discharge, we respectively integrated COVID-19 symptoms with PTSD, depression, and anxiety symptoms and analyzed the three network structures. In all three networks, COVID-19 severity and ICU admission are not linked directly to COVID-19 symptoms after hospitalization, while COVID-19 severity (but not ICU admission) is linked directly to one or more psychiatric symptoms. Specific pathways between COVID-19 symptoms and psychiatric symptoms were discussed. Finally, we used directed acyclic graph estimation to show potential causal effects between COVID-19 related variables and demographic characteristics.

Familial Adenomatous Polyposis (FAP) is an autosomal dominant disorder caused by mutation of the APC gene presenting with numerous colorectal adenomatous polyps and a near 100% risk of colon cancer. Preliminary research findings from our group indicate that FAP patients experience significant deficits across many cognitive domains. In the current study, fMRI brain metrics in a FAP population and matched controls were used to further the mechanistic understanding of reported cognitive deficits. This research identified and characterized any possible differences in resting brain networks and associations between neural network changes and cognition from 34 participants (18 FAP patients, 16 healthy controls). Functional connectivity analysis was performed using FSL with independent component analysis (ICA) to identify functional networks. Significant differences between cases and controls were observed in 8 well-established resting state networks. With the addition of an aggregate cognitive measure as a covariate, these differences were virtually non-existent, indicating a strong correlation between cognition and brain activity at the network level. The data indicate robust and pervasive effects on functional neural network activity among FAP patients and these effects are likely involved in cognitive deficits associated with this disease.

Background Analysis of fluid metabolites has the potential to provide insight into the neuropathophysiology of injury in patients with traumatic brain injury (TBI). Objective Using a 1H nuclear magnetic resonance (NMR)-based quantitative metabolic profiling approach, this study determined (1) if urinary metabolites change during recovery in patients with mild to severe TBI; (2) whether changes in urinary metabolites correlate to injury severity; (3) whether biological pathway analysis reflects mechanisms that mediate neural damage/repair throughout TBI recovery. Methods Urine samples were collected within 7 days and at 6-months post-injury in male participants (n = 8) with mild-severe TBI. Samples were analyzed with NMR-based quantitative spectroscopy for metabolomic profiles and analyzed with multivariate statistical and machine learning-based analyses. Results Lower levels of homovanillate (R = −0.74, p ≤ 0.001), L-methionine (R = −0.78, p, Highlights • NMR-based metabolomics of urine can identify metabolic fingerprints associated with functional recovery following TBI. • Metabolic profiles in urine correlate to injury severity. • Biological pathway analysis reflects mechanisms that mediate neural damage and repair processes throughout recovery. • Metabolomics provides insight into the neuropathophysiology of injury in TBI patients.

Objective Sprint-interval training (SIT) and intermittent fasting are effective independent methods in achieving clinical health outcomes. However, the impact of both modalities when performed concurrently is unclear. The aim of this study was to compare the effects of 6 weeks of SIT performed in the fasted versus fed state on physiological and clinical health markers in healthy adults. Methods. Thirty recreationally-active participants were equally randomised into either the fasted (FAS; 4 males, 11 females) or the fed (FED; 6 males, 9 females) group. For all exercise sessions, FAS participants had to fast ≥10 h prior to exercising while FED participants had to consume food within 3 h to exercise. All participants underwent three sessions of SIT per week for 6 weeks. Each session consists of repeated bouts of 30-s Wingate Anaerobic cycle exercise. Pre- and post-training peak oxygen uptake (VO2peak), isokinetic leg strength, insulin sensitivity, blood pressure and serum lipid levels were assessed. Results. There were no differences in baseline physiological and clinical measures between both groups (all p > 0.05). VO2peak improved by 6.0 ± 8.8% in the FAS group and 5.3 ± 10.6% in the FED group (both p 0.05). A similar pattern of results was seen for knee flexion maximum voluntary contraction at 300°·s−1. SIT training in either fasted or fed state had no impact on insulin sensitivity (both p > 0.05). There was significant reduction in diastolic blood pressure (8.2 ± 4.2%) and mean arterial pressure (7.0 ± 3.2%) in the FAS group (both p 0.05). Conclusion. VO2peak and leg strength improved with SIT regardless of whether participants trained in the fasted or fed state. Chronic SIT in the fasted state may potentially reduce blood pressure to a greater extent than the same chronic SIT in the fed state., Highlights • SIT in the fasted state leads to a significant decrease in blood pressure. • VO2peak and leg strength improves with SIT, regardless of nutrition status. • SIT, performed in fasted or fed state, does not improve insulin sensitivity, body fat percentage or lipid profile.

Purpose The present study examined acute normobaric hypoxic exposure on the number of repetitions to failure, electromyographic (EMG) repetition duration (Time), EMG root mean square (RMS) and EMG mean power frequency (MPF) during biceps brachii (BB) dynamic constant external resistance (DCER) exercise. Methods Thirteen subjects performed two sets of fatiguing DCER arm curl repetitions to failure at 70% of their one repetition maximum under normoxic (NH), moderate hypoxia FiO2 = 15% (MH) and severe hypoxia FiO2 = 13% (SH). Electromyography of the BB was analyzed for EMG Time, EMG RMS, and EMG MPF. Repetitions were selected as 25%, 50%, 75%, and 100% of total repetitions (%Fail) completed. Pulse oximetry (SpO2) was measured pre-and post-fatigue. Results There was no significant three-way (Condition x Set x %Fail) or two-way (Condition x Set) interaction for any variable. The number of repetitions to failure significantly decreased from (mean ± SEM) 18.2 ± 1.4 to 9.5 ± 1.0 with each Set. In addition, EMG Time increased (25% 75%>100%), and EMG MPF decreased (75% > 100%) as a result of fatiguing exercise. SpO2 was lower during MH (Δ5.3%) and SH (Δ9.2%) compared to NH and as a result of fatiguing exercise increased only in MH (Δ2.1%) and SH (Δ5.7%). Conclusion The changes in BB EMG variables indicated exercise caused myoelectric manifestations of fatigue, however, acute moderate or severe hypoxia had no additional influence on the rate of fatigue development or neuromuscular parameters., Highlights • Acute MH (FiO2 15%) and SH (FiO2 14%) did not alter the muscle contractile process. • Arm curl repetitions to failure decreased MU recruitment and conduction velocity. • EMG fatigue analysis, hypoxia and arm curls to failure, EMG RMS, EMG MPF and Time. • SpO2 was lower at MH and SH which increased following fatiguing exercise.

This paper compares the relative frequency of zoonotic disease emergence associated with food animals versus emergence from other animal sources and explores differences in disease characteristics and drivers of emergence between the two sources. It draws on a published compilation of 202 Emerging Infectious Zoonotic Disease (EIZD) events for the period 1940–2004. Of the 202 zoonotic EID events in the dataset, 74 (36.6%) were associated with animals kept for food production, which acted as reservoir for the zoonotic pathogen in 64 events and as intermediate / amplifying host in 8 events. Significant differences exist both in the characteristics of the causal agents and the drivers of emergence of zoonotic diseases from food animals and non-food animals. However, the prevailing policy debate on prevention, detection and control of EIZDs largely focuses on diseases of non-food animal origin (wildlife), neglecting the role of food animals. Policies and investments that ensure appropriate veterinary public health measures along and within food animal value chains are essential to mitigate the global risk of EIZDs, particularly in developing regions where the livestock sector is experiencing rapid growth and structural transformation., Highlights • Over 36% of emerging infectious zoonotic diseases (EIZDs) are associated with animals kept for food production. • The prevailing policy debate on managing EIZDs largely focuses on diseases of non-food animal origin (wildlife) • The causal agents and drivers of emergence of zoonotic diseases from food animals and non-food animals are significantly different. • Policies that ensure appropriate veterinary public health measures are essential to mitigate the global risk of EIZDs.

Highlights • Contact with stigmatized groups is a promising mechanism for reducing bias. • The nature of contact with patients who misuse opioids matters significantly. • Contact with patients who misuse opioids can have negative consequences for physicians. • Consequences occur in physicians who are experiencing stress, burnout, and bias. • Interventions need to consider factors that may reduce the effectiveness of contact., Introduction Prior research suggests that some physicians hold negative attitudes toward patients who misuse opioids and that this serves as a barrier which limits the availability and effectiveness of health care services. Interventions which improve physicians’ attitudes have thus garnered attention, many of which have focused on increasing contact between physicians and patients who misuse opioids. However, drawing on recent literature on intergroup contact, the current paper argues that contact may not have uniformly positive effects on prejudice. Methods We surveyed 408 board-certified physicians in the state of Ohio where many opioid overdose deaths have been concentrated. We used regression to test for interactions between contact and three focal variables, bias, burnout, and stress, on physician willingness to work with patients who misuse opioids. Results The negative relationships between bias, physician burnout, and stress induced by working with patients who misuse opioids and physicians’ willingness to work with this patient population are each exacerbated when contact with patients who misuse opioids is high. Conclusions Although intervention studies have shown promise for the role that increased contact may have in reducing stigma toward patients who misuse opioids, these interventions may not be appropriate for physicians who are experiencing strain or who hold preexisting negative attitudes toward this patient population. Future interventions may need to target bias, burnout, and stress, in addition to facilitating contact, to increase physician willingness to work with these patients.

Psychosis is a chronic neuropsychiatric disorder that affects millions of individuals worldwide and impairs the quality of life and productivity of the patients. Terminalia macroptera Guill & Perr. (Combrataceae) is a plant that is used in the management of anxiety related disorders. The present study investigates the antipsychotic effects of ethyl acetate fraction of T. macroptera (EFTM) leaf in ketamine-induced psychosis in mice. Acute toxicity of EFTM was determine using Lorke’s method. Ketamine (25 mg/kg) was injected once daily for 7 consecutive days in Swiss albino mice to induce psychosis. The effect of the extracts (100, 200 and 400 mg/kg) was evaluated against psychotic-like behaviors induced by ketamine including locomotor activity and stereotypy in the open field test, immobility duration in the forced swim test, and memory impairment using the Y- maze test. The acute antipsychotic effect of EFTM was evaluated on apomorphine climbing test, while woodblock test was performed to assess its extrapyramidal side effects. The LD50 was found to be 3807 mg/kg p.o. which is considered safe. EFTM (100, 200 and 400 mg/kg) exhibited significant antipsychotic effect by reducing ketamine-induced hyperactivity, immobility, and memory deficit in mice, EFTM also suppressed stereotypic climbing behavior due to apomorphine. Accordingly, the antipsychotic activity of EFTM was not associated with extrapyramidal side effects as evidenced by lack of catalepsy. The study revealed that EFTM ameliorated psychotic-like symptoms and is devoid of extrapyramidal side effects in mice, underscoring its antipsychotic-like effect.

It has been demonstrated that adult born granule cells are generated after traumatic brain injury (TBI). There is evidence that these newly generated neurons are aberrant and are poised to contribute to poor cognitive function after TBI. Yet, there is also evidence that these newly generated neurons are important for cognitive recovery. Pattern separation is a cognitive task known to be dependent on the function of adult generated granule cells. Performance on this task and the relation to dentate gyrus dysfunction after TBI has not been previously studied. Here we subjected Sprague Dawley rats to lateral fluid percussion injury or sham and tested them on the dentate gyrus dependent task pattern separation. At 2 weeks after injury, we examined common markers of dentate gyrus function such as GSK3ß phosphorylation, Ki-67 immunohistochemistry, and generation of adult born granule cells. We found that injured animals have deficits in pattern separation. We additionally found a decrease in proliferative capacity at 2 weeks indicated by decreased phosphorylation of GSK3ß and Ki-67 immunopositivity as compared to sham animals. Lastly we found an increase in numbers of new neurons generated during the pattern separation task. These findings provide evidence that dentate gyrus dysfunction may be an important contributor to TBI pathology.

Most studies examining sleep in mammals are done under controlled conditions in laboratory/zoological facilities with few studies being conducted in their natural environment. It is not always possible to record sleep polysomnographically (PSG) from animals in their natural environments, as PSG is invasive, requiring the surgical implantation of electrodes on the surface of the brain. In contrast, actigraphy (ACT) has been shown to be a minimally-invasive method to objectively measure overall sleep times in some mammals, although not revealing specific sleep states. The aim of this study is two-fold, first, to measure sleep polysomnographically in free-roaming blue wildebeest (Connochaetes taurinus) under the most natural conditions possible, and second, to establish the degree of concordance between ACT and PSG recordings undertaken simultaneously in the same individuals. Here we examined sleep in the blue wildebeest, in a naturalistic setting, using both polysomnography (PSG) and actigraphy (ACT). PSG showed that total sleep time (TST) in the blue wildebeest for a 24-h period was 4.53 h (±0.12 h), 4.26 h (±0.11 h) spent in slow wave (non-REM) sleep and 0.28 h (±0.01 h) spent in rapid eye movement (REM) sleep, with 19.47 h (±0.12 h) spent in Wake. ACT showed that the blue wildebeest spent 19.23 h (±0.18 h) Active and 4.77 h (±0.18 h) Inactive. For both animals studied, a fair agreement between the two techniques for sleep scoring was observed, with approximately 45% of corresponding epochs analyzed being scored as both sleep (using PSG) and inactive (using ACT)., Graphical Abstract Flow diagram illustrating the occurrence of state transitions (represented as a percentage) between Wake, non-REM sleep and REM sleep states with the pooled data from both blue wildebeest studied over a 72 h recording period.ga1, Highlights • We recorded sleep in two free-roaming adult blue wildebeest using two techniques. • On average these wildebeest spend around 4.5 h sleeping each day. • This sleep is comprised of both non-REM (4.2 h) and REM (0.28 h). • Actigraphy recordings show fair agreement with polysomnography. • This data contributes towards our understanding of sleep evolution.

Porpose The aim of this study was to evaluate, through a meta-analysis, the predictability of Regenerative Endodontic therapies with antibiotic pastes and calcium hydroxide [Ca(OH)2], related to four variables as follows: root dentin wall thickening, apical closure, apical repair and root lengthening. Methods Literature electronic searches were performed in Pubmed - MEDLINE, Scopus and Lilacs-BVS platforms using appropriate search terms, Mesh (Medical Subject Headings), DeCS (Health Sciences Descriptors) and Boolean operators comprising articles published between 2009 and 2020. Thirty-two original indexed papers were included making a total of 758 regenerative endodontic procedures. A descriptive meta-analysis was performed. Results Dentin wall thickening was present in 66% (CI95: 58%–73%) of the cases treated with antibiotic paste, while when Ca(OH)2 was used, a percentage of 53% (CI95: 26%–78%), was obtained. When antibiotic paste was used, apical closure was found in the 66% (CI95: 58%–73%) of the regenerative endodontic procedures, while when Ca(OH)2 was used, 88% (CI95: 80%–93%) of the cases were found to reach apical closure. Root lengthening and apical repair were found satisfactory for both disinfection protocols. Conclusions There could be differences between the two treatments since a higher percentage of root dentin wall thickening was found when using antibiotic pastes, while a higher percentage of apical closure was found when calcium hydroxide was used. Development of more clinical studies would be necessary in order to confirm the observed differences. The proposed approach could provide a useful contribution for endodontists when planning regenerative endodontic procedures, so as to guide decision-making to the best elective treatment and to select the appropriate disinfection method in accordance with preoperative radiographic diagnosis of root development stage, then increasing the predictability of regenerative endodontic treatment and reducing potential risk of root fractures.

Background Arterial stiffness is important because it is associated with adverse cardiovascular events including stroke. Methods that are based on pulse wave velocity have significant limitations in estimating arterial stiffness. The purpose of this paper is to present a novel easy to apply non-invasive method to estimate arterial stiffness that is based on pulse pressure. Methods Two indices to estimate arterial stiffness, (1) arterial stiffness 1 (AS1) and (2) arterial stiffness 2 (AS2) were developed and applied in two National Institutes of Health funded clinical trials, the Systolic Hypertension in the Elderly Program and the Systolic Blood Pressure Intervention Trial. These indices were developed by fitting individual survival models for selected predictor variables to the response, i.e. time to stroke, by selecting the coefficients that were statistically significant at the 0.05 α level after adjusting the variable weights. The indices were derived as the weighted linear combination of the coefficients. Results AS1 and AS2 performed well in two goodness of fit criteria i.e. overall model p-value and concordance correlation. Comparison of Cox models using indices AS1 and AS2 and chronological age indicated that AS1 and AS2 independently predicted the occurrence of stroke at five years better than chronological age. Nearly identical effects were observed when the analyses were limited to Black participants in SPRINT with a concordance correlation of 0.80 and log rank test p-value of 0.007. Conclusion These indices that are derived from pulse pressure predict the occurrence of stroke better than either pulse pressure or chronological age alone and may be used in designing new randomized clinical trials, and possibly incorporated in hypertension and stroke guidelines.

ObjectivesTo estimate the absolute risk of cerebral venous thrombosis (CVT) and portal vein thrombosis (PVT) in the two weeks following a diagnosis of COVID-19, and to assess the relative risks (RR) compared to influenza or the administration of an mRNA vaccine against COVID-19.DesignRetrospective cohort study based on an electronic health records networkSettingLinked records between primary and secondary care centres within 59 healthcare organisations, primarily in the USAParticipantsAll patients with a confirmed diagnosis of COVID-19 between January 20, 2020 and March 25, 2021 were included (N=537,913, mean [SD] age: 46.2 [21.4] years; 54.9% females). Cohorts (matched for age, sex, and race) of participants diagnosed with influenza (N=392,424) or receiving the BNT162b2 or mRNA-1273 vaccine (N=366,869) were used for comparison.Main outcome measuresDiagnosis of CVT (ICD-10 code I67.6) or PVT (ICD-10 code I81) within 2 weeks after a diagnosis of COVID-19.ResultsThe incidence of CVT after COVID-19 diagnosis was 42.8 per million people (95% CI 28.5–64.2) including 35.3 per million (95% CI 22.6–55.2) first diagnoses. This was significantly higher than the CVT incidence in a matched cohort of patients with influenza (RR=3.83, 95% CI 1.56–9.41, PConclusionsThe incidence of CVT and PVT is significantly increased after COVID-19. The data highlight the risk of serious thrombotic events in COVID-19 and can help contextualize the risks and benefits of vaccination in this regard.What is known‐A systematic review of cohort studies suggested an incidence of CVT among hospitalised patients with COVID-19 to be about 800 per million patients. There was evidence of selection, ascertainment, and reporting bias in all included studies.‐The incidence of CVT and PVT among both hospitalised and non-hospitalised patients with COVID-19 is unknown.‐It is unknown if COVID-19 increases the risk of CVT and PVT.What this study addsOur study estimates that the absolute risk of CVT and PVT are respectively 42.8 and 392.3 per million patients (both hospitalised and non-hospitalised) in the 2 weeks after a diagnosis of COVID-19. COVID-19 increases the risk of CVT and PVT compared to patients diagnosed with influenza, and to people who have received a COVID-19 mRNA vaccine.

Background The longitudinal trajectories of cardiopulmonary abnormalities and symptoms following infection with coronavirus disease (COVID-19) are unclear. We sought to describe their natural history in previously hospitalised patients, compare this with controls, and assess the relationship between symptoms and cardiopulmonary impairment at 6 months post-COVID-19. Methods Fifty-eight patients and thirty matched controls (single visit), recruited between 14th March - 25th May 2020, underwent symptom-questionnaires, cardiac and lung magnetic resonance imaging (CMR), cardiopulmonary exercise test (CPET), and spirometry at 3 months following COVID-19. Of them, forty-six patients returned for follow-up assessments at 6 months. • View related content for this article Findings At 2-3 months, 83% of patients had at least one cardiopulmonary symptom versus 33% of controls. Patients and controls had comparable biventricular volumes and function. Native cardiac T1 (marker of fibroinflammation) and late gadolinium enhancement (LGE, marker of focal fibrosis) were increased in patients at 2-3 months. Sixty percent of patients had lung parenchymal abnormalities on CMR and 55% had reduced peak oxygen consumption (pV̇O2) on CPET. By 6 months, 52% of patients remained symptomatic. On CMR, indexed right ventricular (RV) end-diastolic volume (-4·3 mls/m2, P=0·005) decreased and RV ejection fraction (+3·2%, P=0·0003) increased. Native T1 and LGE improved and was comparable to controls. Lung parenchymal abnormalities and peak V̇O2, although better, were abnormal in patients versus controls. 31% had reduced pV̇O2 secondary to symptomatic limitation and muscular impairment. Cardiopulmonary symptoms in patients did not associate with CMR, lung function, or CPET measures. Interpretation In patients, cardiopulmonary abnormalities improve over time, though some measures remain abnormal relative to controls. Persistent symptoms at 6 months post-COVID-19 did not associate with objective measures of cardiopulmonary health. Funding The authors’ work was supported by the NIHR Oxford Biomedical Research Centre, Oxford British Heart Foundation (BHF) Centre of Research Excellence (RE/18/3/34214), United Kingdom Research Innovation and Wellcome Trust. This project is part of a tier 3 study (C-MORE) within the collaborative research programme entitled PHOSP-COVID Post-hospitalization COVID-19 study: a national consortium to understand and improve long-term health outcomes, funded by the Medical Research Council and Department of Health and Social Care/National Institute for Health Research Grant (MR/V027859/1) ISRCTN number 10980107.

Background Since 2020 SARS-CoV-2 spreads pandemically, infecting more than 119 million people, causing >2·6 million fatalities. Symptoms of SARS-CoV-2 infection vary greatly, ranging from asymptomatic to fatal. Different populations react differently to the disease, making it very hard to track the spread of the infection in a population. Measuring specific anti-SARS-CoV-2 antibodies is an important tool to assess the spread of the infection or successful vaccinations. To achieve sufficient sample numbers, alternatives to venous blood sampling are needed not requiring medical personnel or cold-chains. Dried-blood-spots (DBS) on filter-cards have been used for different studies, but not routinely for serology. Methods We developed a semi-automated protocol using self-sampled DBS for SARS-CoV-2 serology. It was validated in a cohort of matched DBS and venous-blood samples (n = 1710). Feasibility is demonstrated with two large serosurveys with 10247 company employees and a population cohort of 4465 participants. Findings Sensitivity and specificity reached 99·20% and 98·65%, respectively. Providing written instructions and video tutorials, 99·87% (4465/4471) of the unsupervised home sampling DBS cards could be analysed. Interpretation DBS-sampling is a valid and highly reliable tool for large scale serosurveys. We demonstrate feasibility and accuracy with a large validation cohort including unsupervised home sampling. This protocol might be of big importance for surveillance in resource-limited settings, providing low-cost highly accurate serology data. Funding Provided by Bavarian State Ministry of Science and the Arts, LMU University-Hospital; Helmholtz-Centre-Munich, German Ministry for Education and Research (project01KI20271); University of Bonn; University of Bielefeld; the Medical Biodefense Research Program of Bundeswehr-Medical-Service; Euroimmun, RocheDiagnostics provided discounted kits and machines

Public transport has been identified as high risk as the corona-virus carrying droplets generated by the infected passengers could be distributed to other passengers. Therefore, predicting the patterns of droplet spreading in public transport environment is of primary importance. This paper puts forward a novel computational and artificial intelligence (AI) framework for fast prediction of the spread of droplets produced by a sneezing passenger in a bus. The formation of droplets of salvia is numerically modelled using a volume of fluid methodology applied to the mouth and lips of an infected person during the sneezing process. This is followed by a large eddy simulation of the resultant two phase flow in the vicinity of the person while the effects of droplet evaporation and ventilation in the bus are considered. The results are subsequently fed to an AI tool that employs deep learning to predict the distribution of droplets in the entire volume of the bus. This combined framework is two orders of magnitude faster than the pure computational approach. It is shown that the droplets with diameters less than 250 micrometers are most responsible for the transmission of the virus, as they can travel the entire length of the bus., Graphical Abstract ga1

Background: COVID-19 prevention and control policies have entailed lockdowns and confinement. This study aimed to summarize the global research evidence describing the effect of COVID-19 isolation measures on the health of people living with dementia. Methods: We searched Pubmed, PsycINFO and CINAHL up to 27th of February 2021 for peer-reviewed quantitative studies about the effects of isolation during COVID-19 on the cognitive, psychological and functional symptoms of people with dementia or mild cognitive impairment. The Joanna Briggs Institute critical appraisal tool was used to conduct the quality assessment. PROSPERO registration: CRD42021229259. Findings: 15 eligible papers were identified, examining a total of 6442 people with dementia. 13/15 studies investigated people living in the community and 2 in care homes. Out of 15 studies, 9 (60%) reported changes in cognition and 14 (93%) worsening or new onset of behavioral and psychological symptoms. Six studies (46%) reported a functional decline in daily activities in a variable proportion of the population analyzed. Interpretation: COVID-19 isolation measures have damaged the cognitive and mental health of people with dementia across the world. It is urgent to issue guidance that balances infection control measures against the principles of non-maleficence to guarantee fair and appropriate care during pandemic times for this population. Funding: ASG receives funding from a grant jointly funded by the Economic and Social Research Council (UK) and the National Institute for Health Research (UK) (ES/S010467/1). GL is supported by UCLH National Institute for Health Research (NIHR) Biomedical Research Centre, and by NIHR North Thames ARC as a NIHR senior investigator. JR is supported by a UK Research and Innovation's Global Challenges Research Fund (UKRI GCRF) (ES/P0109381).

Background The discipline of anaesthesiology in China has undergone historical changes and development during the past century. However, nationwide comprehensive data on the current status of each hospital department providing anaesthesia care has been lacking since the discipline was first established in China. This information is essential for effective regulation of healthcare policies by both the professional associations and the government health ministry. Therefore, a nationwide survey was set up in 2018 to investigate the current status of Chinese anaesthesiology. This paper reports the findings of the survey. Methods We performed a cross-sectional nationwide census survey of the current status of each hospital department providing anaesthesia care in 31 provinces across the Chinese mainland. The content of the survey included general information of the department, the hospital level and scale, the volume of the anaesthesiology department, the characteristics of anaesthesiologists, and the caseload of the anaesthesiology departments. Face-to-face interviews were performed by trained interviewers. The Chinese Anaesthesiology Department Tracking Database (CADTD) was established during the survey. Data quality control was undertaken by the investigation committee throughout the survey process. Findings The nationwide census survey was completed by 11,432 hospital departments providing anaesthesia care throughout mainland China from June 1, 2018 to June 30, 2019. Among the 11,432 departments, 4591 (40•16%) belonged to specialised hospitals, while 6841 (59•84%) were affiliated to general hospitals. The proportion of independent anaesthesiology departments was 45•15% in mainland China. There was a total of 92,726 anaesthesiologists, or 6•7 per 100,000 of the population. Regions with better economic conditions had more anaesthesiologists per 100,000 of the population. From 2015 to 2017, the workload of anaesthesiologists has increased by 10%. Interpretation The discipline of anaesthesiology in China has entered a rapid development phase. However, the current status of anaesthesiology is not well defined, which makes it difficult to meet the needs of the increasing Chinese healthcare demand. The evidence from this survey offers valuable information for policy makers and anaesthesiology associations to monitor the development of the discipline and regulate healthcare policies effectively. Funding National Key Research and Development Program of China (Grant No. 2018YFC2001900).

Background Guillain-Barre syndrome (GBS) is the most prevalent acute autoimmune polyneuropathy, however, the incidence of GBS across China remains undetermined. We conducted the first nationwide study to extrapolate the incidence and mortality rates of GBS across all age groups at a national scale. Methods This study analyzed patient metrics from the National Hospital Quality Monitoring System, a comprehensive administrative database of which incorporate all 1665 tertiary hospitals in mainland China. For all study patients the "Medical Record Homepage" encompasses 346 distinct variables such as demographic characteristics, diagnoses, procedures, expenses, etc., that are systematically recorded from these hospitals by standard protocol. All GBS diagnoses adhered to the National Institute of Neurologic and Communicative Disorders and Stroke (NINCDS) diagnostic criteria and were identified with ICD-10 code (G61•0). Findings From 2016 to 2019, 75,548 hospital admissions for 38,861 GBS patients were identified. The age- and sex-adjusted incidence per 100,000 person-years is 0•698 (95% confidence interval [CI], 0•691-0•705), 0•233(0•225-0•242) in children and 0•829(0•820-0•837) in adults. The male-to-female ratio is 1•49. Peak disease onset was detected in the 70–74 years age group with an incidence of 1•806/100, 000 (95% CI, 1•741-1•870). Recognizable GBS distribution patterns were recognized in the southeastern coastal areas, where the cases of GBS were concentrated in the summer and autumn seasons. Prevalent comorbidities include hypertension (28•8%) and stroke (14•3%). The median length of hospitalization was 13•0 (8•0–18•0) days with a median hospitalization cost of $2371•60 ($1281•80–5463•60). Covering 69•9% of study patients, the Basic Medical Insurance was the most common payment mechanism. From 2016-2019, 426 adults and 13 children died in this study pool, with a hospital mortality rate of 11•2 per 1,000 person-years. Interpretation For the first time, we obtained a national incidence for GBS at 0•233 in children and 0•829 in adults per 100,000 in China. A differential spatiotemporal incidence is presented most southeast coastal areas in the summer and autumn seasons. Funding National Science Foundation of China (91949208, 91642205, and 81830038); Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing.

Summary: Background: The high rate of infections among patients admitted to critical care units (CCUs) is associated with high rate of antibiotic consumption, especially broad-spectrum antibiotics. This study is to describe the antibiotics use in CCUs in primary and secondary hospitals in Vietnam, a setting with high burden of antibiotic resistance. Methods: This was a 7-day observational study in 51 CCUs in hospitals from 5 provinces in Vietnam from March to July 2019. Patients aged ≥ 18 years admitted to the participating CCUs was enrolled consecutively. We collected data on patient's demographics, initial diagnosis and antibiotic therapy within the first 24 hours. Antibiotic therapy was classified by the Anatomical Therapeutic Chemical (ATC) Index and the 2019 WHO Access, Watch, Reserve (AWaRe) groups. Findings: Out of 1747 enrolled patients, empirical antibiotic treatments were initiated in 1112 (63.6%) patients. The most frequently prescribed antibiotics were cefotaxime (22.3%), levofloxacin (19%) and ceftazidime (10.8%). Antibiotics were given in 31.5% of patients without diagnosis of infection. Watch and/or Reserve group antibiotic were given in 87.3% of patients and associated with patient's age (aOR 1.01 per 1-year increment, 95%CI 1.00-1.02) and the presence of SIRS on admission (aOR 2.1, 95%CI 1.38-3.2). Interpretation: We observed a high frequency use and a substantial variation in patterns of empirical antibiotic use in the CCUs in Vietnam. It highlights the importance of continuous monitoring antibiotic consumption in CCUs. Funding: None.

Background: A childhood cancer diagnosis and late effects of treatment may affect survivors' possibilities of employment or highly skilled occupations later in life. In this study, we compared the employment and occupational status of childhood cancer survivors with population comparisons and siblings.Methods: In a cohort study based on Nordic registers, we identified 10 461 survivors of childhood cancer diagnosed before age 20 years in Denmark, Finland and Sweden since 1971. Survivors were compared with 48 928 population comparisons matched to survivors by age, sex and geographical region and 12 605 siblings of survivors. Annual outcome information on employment, unemployment, health-related unemployment and occupational position was obtained from the statistical institutes between 1980-2017 and assessed in multivariate logistic regression analyses from age 30 onwards.Findings: By 30 years of age, 9.2% (95% CI, 8.6-9.9%) of survivors were unemployed for health reasons. Childhood cancer survivors had considerably higher odds of health-related unemployment at ages 30, 40 and 50 than population comparisons (ORage30, 2.57; 95% CI, 2.35-2.81) and siblings (ORage30, 2.50; 95% CI, 2.15-2.90). We observed no large difference in unemployment unrelated to health or in occupational position. Health-related unemployment was particularly pronounced among survivors of central nervous system tumours and survivors diagnosed below 15 years of age.Interpretation: Survivors at risk of health-related unemployment should be offered comprehensive survivorship care and interventions for obtaining and maintaining suitable employment.Funding: NordForsk [76111], the Danish Childhood Cancer Foundation [2016-0293], Aarhus University [43239402], the Swedish Childhood Cancer Foundation [PR2020-0130] and [OB2019-0003], Tømrermester Jørgen Holm og Hustru Elisa F. Hansens Mindelegat [20088] and the Swiss National Science Foundation to LM [P2LUP3_175288].

Highlights • Among PWH, cocaine use vs no-use was associated with worse HIV treatment outcomes. • Powder cocaine only users were more likely to be younger, Hispanic, and employed. • Users of powder + crack cocaine had lower viral suppression than users of either alone. • Harm reduction efforts addressing substance use should be a key component of HIV care., Introduction Cocaine (including powder and crack) use is common among people with HIV (PWH). We identified socio-demographic and behavioral factors associated with cocaine use (overall and various forms) among PWH; we also examined differences in HIV treatment outcomes across cocaine exposure groups. Methods The study sample (N = 1166) was derived from two cohorts of PWH in Florida between 2014 and 2020. Baseline data were linked to the Enhanced HIV/AIDS Reporting System (eHARS) which tracks HIV viral load. Socio-demographics and polysubstance use were compared by cocaine use and the three cocaine use groups (powder only n = 101, crack only n = 91, or both n = 65). The association between the three cocaine use groups, ART adherence, and HIV viral suppression (

Background The heterogeneity in symptomatology and phenotypic profile attributable to COVID-19 is widely unknown. The objective of this manuscript is to conduct a trans-ancestry genome wide association study (GWAS) meta-analysis of COVID-19 severity to improve the understanding of potentially causal targets for SARS-CoV-2. Methods This cross-sectional study recruited 646 participants in the UAE that were divided into two phenotypic groups based on the severity of COVID-19 phenotypes, hospitalized (n=482) and non-hospitalized (n=164) participants. Hospitalized participants were COVID-19 patients that developed acute respiratory distress syndrome (ARDS), pneumonia or progression to respiratory failure that required supplemental oxygen therapy or mechanical ventilation support or had severe complications such as septic shock or multi-organ failure. We conducted a trans-ancestry meta-analysis GWAS of European (n=302), American (n=102), South Asian (n=99), and East Asian (n=107) ancestry populations. We also carried out comprehensive post-GWAS analysis, including enrichment of SNP associations in tissues and cell-types, expression quantitative trait loci and differential expression analysis. Findings Eight genes demonstrated a strong association signal: VWA8 gene in locus 13p14·11 (SNP rs10507497; p=9·54 x10-7), PDE8B gene in locus 5q13·3 (SNP rs7715119; p=2·19 x10-6), CTSC gene in locus 11q14·2 (rs72953026; p=2·38 x10-6), THSD7B gene in locus 2q22·1 (rs7605851; p=3·07x10-6), STK39 gene in locus 2q24·3 (rs7595310; p=4·55 x10-6), FBXO34 gene in locus 14q22·3 (rs10140801; p=8·26 x10-6), RPL6P27 gene in locus 18p11·31 (rs11659676; p=8·88 x10-6), and METTL21C gene in locus 13q33·1 (rs599976; p=8·95 x10-6). The genes are expressed in the lung, associated to tumour progression, emphysema, airway obstruction, and surface tension within the lung, as well as an association to T-cell-mediated inflammation and the production of inflammatory cytokines. Interpretation We have discovered eight highly plausible genetic association with hospitalized cases in COVID-19. Further studies must be conducted on worldwide population genetics to facilitate the development of population specific therapeutics to mitigate this worldwide challenge. Funding This review was commissioned as part of a project to study the host cell receptors of coronaviruses funded by Khalifa University's CPRA grant (Reference number 2020-004).

Background On 23 July 2018, the German Constitutional Court decided that mechanical restraint in psychiatric patients lasting longer than 30 minutes requires a judge's immediate decision. On the same day, the German Association for Psychiatry and Psychotherapy published its guideline on the prevention of coercion and violence. The registry for coercive measures in the federal state of Baden-Wuerttemberg, available since 2015 and comprising all 32 hospitals licensed to admit involuntary patients, has made it possible to evaluate the effect of the legal change, considered the strongest intervention ever in Germany to reduce coercion. Methods We analysed the mean percentage of patients subjected to coercive measures and the mean cumulative duration of these interventions in ICD-10 diagnostic groups in psychiatric hospitals from 2017 compared to 2019 among a total of 233,0273 admissions. Findings The percentage of patients subjected to any kind of freedom-restricting coercion decreased from 6·6% in 2017 to 5·8% in 2019 (p = 0·000). Accordingly, the percentage of patients subjected to mechanical restraint decreased from 4·8% to 3·6% in 2019 (p = 0·000). At the same time, the percentage of patients subjected to seclusion increased from 2·9% to 3·3% (p = 0·000). The median cumulated duration of restraint and seclusion per affected case decreased from 12·5 to 11·9 hrs (p = 0·001). Interpretation There is clear evidence that a strong legal intervention was effective in reducing the use of coercive measures under routine conditions. Funding The registry is funded by the Ministry of Social Welfare and Integration.

Non-governmental organizations (NGOs) often implement overseas development aid through intensive small-scale animal agriculture to alleviate food insecurity in low- and middle-income countries. Intensive animal farming can pose unclear outcomes to households engaged in the practice because of the reliance on industrial animal breeds that are reared with antibiotics and raised in higher densities compared to traditional scavenging husbandry systems. As a result, intensive small-scale farming operations that lack proper infrastructure, training, and financial resources could facilitate the spread of antimicrobial resistance and infectious diseases. We applied a mixed-methods framework towards analyzing the effectiveness of small-scale broiler chicken farming in northern Ecuador. First, from May 2016 – May 2017, our observational surveys indicated that intensive small-scale poultry farming follows a boom-and-bust cycle that is extremely vulnerable to environmental stressors. Second, in May 2016, we followed a cohort of households enrolled in a poultry development project led by an NGO. We observed a substantial decline in chicken survivorship from Survey period 1 to 2 (mean chicken count decrease from 50 to 35 corresponding to a 70% survivorship) and from Survey period 2 to 3 (mean chicken count decrease from 35 to 20.3 corresponding to a 58% survivorship). Heads of households were self-reporting broiler chicken survivorship substantially higher than our recorded observations during survey period two (46 compared to 35 respectively) and three (44.3 compared to 20.3 respectively). We speculate that if households continue to inaccurately report poultry demographics, then it could perpetuate a negative feedback loop where NGOs continue to conduct the same intervention practices without receiving accurate outcome metrics. Third, we used semi-structured questionnaires to determine that access to financial resources was the major motivation for determining when to farm broiler chickens. Intensive small-scale poultry farming can be unreliable and disease-enhancing, yet also associated with dubious self-reports of success.

Background: Country-specific evidence is needed to guide decisions regarding whether and how to implement lung cancer screening in different settings. For this study, we estimated the potential numbers of individuals screened and lung cancer deaths prevented in Brazil after applying different strategies to define screening eligibility. Methods: We applied the Lung Cancer Death Risk Assessment Tool (LCDRAT) to survey data on current and former smokers (ever-smokers) in 15 Brazilian state capital cities that comprise 18% of the Brazilian population. We evaluated three strategies to define eligibility for screening: (1) pack-years and cessation time (≥30 pack-years and

Background Reducing the alcohol-attributable cancer burden in the WHO European Region is a public health priority. This study aims to estimate the number of potentially avoidable cancers in countries of the WHO European Region in 2019 for three scenarios in which current excise duties on alcoholic beverages were increased by 20%, 50%, or 100%. Methods Mean prices and excise duties for beer, wine, and spirits in the Member States of the WHO European Region in 2020 were used as the baseline scenario. We assumed that increases in excise duties (20%, 50%, and 100%) were fully incorporated into the consumer price. Beverage-specific price elasticities of demand, with lower elasticities for heavy drinkers, were obtained from a meta-analysis. Model estimates were applied to alcohol exposure data for 2009 and cancer incidence and mortality rates for 2019, assuming a 10-year lag time between alcohol intake and cancer development and mortality. Findings Of 180,887 (95% Confidence interval [CI]: 160,595-201,705) new alcohol-attributable cancer cases and 85,130 (95% CI: 74,920-95,523) deaths in the WHO European Region in 2019, 5·9% (95% CI: 5·6-6·4) and 5·7% (95% CI: 5·4-6·1), respectively, could have been avoided by increasing excise duties by 100%. According to our model, alcohol-attributable female breast cancer and colorectal cancer contributed most to the avoidable cases and deaths. Interpretation Doubling current alcohol excise duties could avoid just under 6% (or 10,700 cases and 4,850 deaths) of new alcohol-attributable cancers within the WHO European Region, particularly in Member States of the European Union where excise duties are in many cases very low. Funding None.

Graphical abstract, Highlights • Concurrent capecitabine with radiotherapy in painful bone metastases was safe. • It was effective in palliation of pain from bone metastases in breast cancer patients. • It associated with higher overall response rates regarding pain control. • This decreased analgesic consumption and improved the quality of life., Background In breast cancer, painful bone metastases are common. Local radiotherapy is the standard treatment of painful bone metastases. Pain control and overall response rateswere low in radiotherapy alone. The objectives of this study were to compare the safety and efficacy of external beam radiotherapy with concurrent capecitabine vs. external beam radiotherapy alone in pain control of painful bone metastases in breast cancer patients. Materials and methods Eighty-four patients with painful bone metastases from breast cancer participated in this prospective study. We randomized the patients into two groups: group A treated with radiotherapy 30 Gy in 10 fractions and group B treated with capecitabine 825 mg/m2 every 12 hrs. concurrently with the same radiotherapy dose. Results There was no statistically significant difference between the two groups regarding early treatment toxicity. Most of the toxicity was gastrointestinal (diarrhea and nausea) and mild (grade I or II). The median pain score decreased from week one, and there was a marked response at week4. The difference in median pain score between both groups was statistically significant with p-value = 0.045. The median analgesic score in both groups was statistically significant with a p-value = 0.032 at week 12. A complete response to pain at week 4 was 19% and 42.9% in groups A and B, respectively. Conclusion Concurrent chemoradiation in painful bone metastases from breast cancer origin was tolerable and safe; it had a higher overall response rate and pain palliation than radiotherapy alone.

Background Metabolic syndrome (MetS) is a cluster of multiple cardiometabolic risk factors that increase the risk of type 2 diabetes and cardiovascular diseases. Identifying novel biomarkers of MetS and their genetic associations could provide insights into the mechanisms of cardiometabolic diseases. Methods Potential MetS-associated metabolites were screened and internally validated by untargeted metabolomics analyses among 693 patients with MetS and 705 controls. External validation was conducted using two well-established targeted metabolomic methods among 149 patients with MetS and 253 controls. The genetic associations of metabolites were determined by linear regression using our previous genome-wide SNP data. Causal relationships were assessed using a one-sample Mendelian Randomization (MR) approach. Findings Nine metabolites were ultimately found to be associated with MetS or its components. Five metabolites, including LysoPC(14:0), LysoPC(15:0), propionyl carnitine, phenylalanine, and docosapentaenoic acid (DPA) were selected to construct a metabolite risk score (MRS), which was found to have a dose-response relationship with MetS and metabolic abnormalities. Moreover, MRS displayed a good ability to differentiate MetS and metabolic abnormalities. Three SNPs (rs11635491, rs7067822, and rs1952458) were associated with LysoPC(15:0). Two SNPs, rs1952458 and rs11635491 were found to be marginally correlated with several MetS components. MR analyses showed that a higher LysoPC(15:0) level was causally associated with the risk of overweight/obesity, dyslipidaemia, high uric acid, high insulin and high HOMA-IR. Interpretation We identified five metabolite biomarkers of MetS and three SNPs associated with LysoPC(15:0). MR analyses revealed that abnormal LysoPC metabolism may be causally linked the metabolic risk. Funding This work was supported by grants from the National Key Research and Development Program of China (2017YFC0907004).

Background Little is known about chronic cannabis smoking-associated oral microbiome and its effects on central nervous system (CNS) functions. Methods In the current study, we have analyzed the saliva microbiome in individuals who chronically smoked cannabis with cannabis use disorder (n = 16) and in non-smoking controls (n = 27). The saliva microbiome was analyzed using microbial 16S rRNA sequencing. To investigate the function of cannabis use-associated oral microbiome, mice were orally inoculated with live Actinomyces meyeri, Actinomyces odontolyticus, or Neisseria elongata twice per week for six months, which mimicked human conditions. Findings We found that cannabis smoking in humans was associated with oral microbial dysbiosis. The most increased oral bacteria were Streptococcus and Actinomyces genus and the most decreased bacteria were Neisseria genus in chronic cannabis smokers compared to those in non-smokers. Among the distinct species bacteria in cannabis smokers, the enrichment of Actinomyces meyeri was inversely associated with the age of first cannabis smoking. Strikingly, oral exposure of Actinomyces meyeri, an oral pathobiont, but not the other two control bacteria, decreased global activity, increased macrophage infiltration, and increased β-amyloid 42 protein production in the mouse brains. Interpretation This is the first study to reveal that long-term oral cannabis exposure is associated oral enrichment of Actinomyces meyeri and its contributions to CNS abnormalities.

Background The dynamic monitoring of perioperative carcinoembryonic antigen (CEA) is recommended by current colorectal cancer (CRC) guidelines, while the benefits of additional measurements of carbohydrate antigen 19-9 (CA19-9) and carbohydrate antigen 125 (CA125) have remained controversial. Methods This retrospective longitudinal cohort included 3539 CRC patients who underwent curative resection. Distinct trajectory groups were identified by the latent class growth mixed model. Patients were grouped into subgroups jointly by CEA, CA19-9, and CA125 according to preoperative levels and longitudinal trajectories, respectively. The end points were overall survival (OS) and recurrence-free survival (RFS). Findings Three distinct trajectory groups were characterized for serum CEA, CA19-9, and CA125: low-stable, early-rising, and later-rising. Jointly, patients were grouped into six preoperative (trajectory) joint groups. Compared with the three-low group, the adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) associated with death were 1.87 (1.29-2.70), 3.82 (2.37-6.17), 1.87 (0.97-3.61), 2.81 (1.93-4.11), and 4.99 (2.80-8.86) for the CEA-high, CA19-9-high, CA125-high, two-high, and three-high group, respectively. And compared with the three-stable trajectory group, the corresponding HRs (95% CIs) were 1.59 (1.10-2.30), 1.55 (0.77-3.10), 6.25 (4.02-9.70), 4.05 (2.73-6.02), and 12.40 (5.77-26.70) for the five rising trajectory groups, respectively. Similar associations between joint groups and RFS were observed. Notably, the trajectory joint group still had prognostic significance after adjusting for preoperative levels. The CA19-9-high group (HR: 3.82, 95% CI: 2.37-6.17) was associated with higher risk of death than the two-high group (HR: 2.81, 95% CI: 1.93-4.11). Likewise, for the CA125-rising trajectory group and two-rising trajectory group, the HRs (95% CIs) were 6.13 (3.75-10.00) and 3.99 (2.63-6.05) for death, and 3.08 (2.07-4.58) and 2.10 (1.52-2.90) for recurrence. Interpretation In addition to CEA, the dynamic measurements of CA19-9 and CA125 are recommended to monitor the prognosis of CRC patients. Funding National Natural Science Foundation of China [81973147, 82001986, 81960592, 82073569, 81660545].

Background: Preoperative determination of breast cancer molecular subtypes facilitates individualized treatment plan-making and improves patient prognosis. We aimed to develop an assembled convolutional neural network (ACNN) model for the preoperative prediction of molecular subtypes using multimodal ultrasound (US) images. Methods: This multicentre study prospectively evaluated a dataset of greyscale US, colour Doppler flow imaging (CDFI), and shear-wave elastography (SWE) images in 807 patients with 818 breast cancers from November 2016 to February 2021. The St. Gallen molecular subtypes of breast cancer were confirmed by postoperative immunohistochemical examination. The monomodal ACNN model based on greyscale US images, the dual-modal ACNN model based on greyscale US and CDFI images, and the multimodal ACNN model based on greyscale US and CDFI as well as SWE images were constructed in the training cohort. The performances of three ACNN models in predicting four- and five-classification molecular subtypes and identifying triple negative from non-triple negative subtypes were assessed and compared. The performance of the multimodal ACNN was also compared with preoperative core needle biopsy (CNB). Finding: The performance of the multimodal ACNN model (macroaverage area under the curve [AUC]: 0.89–0.96) was superior to that of the dual-modal ACNN model (macroaverage AUC: 0.81–0.84) and the monomodal ACNN model (macroaverage AUC: 0.73–0.75) in predicting four-classification breast cancer molecular subtypes, which was also better than that of preoperative CNB (AUC: 0.89–0.99 vs. 0.67–0.82, p

Highlights • Adoption of adjuvant bisphosphonates for early breast cancer into standard clinical practice. • UK and Australian experience of adjuvant bisphosphonates in early breast cancer. • Pathway taken for adjuvant bisphosphonates implementation in the UK. • Steps to increase update of adjuvant bisphosphonates in early breast cancer. • Improve the care of women with early breast cancer., International guidelines recommend adjuvant bisphosphonates (BPs) for post-menopausal women with early breast cancer to reduce recurrence and mortality. However, globally, wide variation exists in their adoption. In the UK, adjuvant BPs were a recommendation in the breast cancer Clinical Reference Group service specification and were included as a priority for implementation by the national oncologists group UK Breast Cancer Group in November 2015, promoting national uptake, guidance and funding arrangements. In 2018, adjuvant BPs were recommended by the UKs National Institute for Health and Care Excellence. In Australia, adjuvant BPs are still ‘off-label’ and do not receive national reimbursement or endorsement. To date there has been no research into the prescribing habits of these agents in Australia. With the aim to gather data on adjuvant BPs prescribing practices, online surveys were developed and disseminated to breast oncologists in both countries between December 2018 and June 2019. Almost all of the UK oncologists prescribed adjuvant BPs, demonstrating that education, endorsement from professional bodies, presence of national guidelines and funding decisions have been critical to implementation. In contrast, only 48% of the Australian responders prescribed adjuvant BPs, while 83% reported that they would prescribe them if funding was available. Lack of local protocol guidance was also seen as a major barrier. This study was intended to assess the pathway taken for adjuvant BP implementation in the UK and how it might inform changes in Australian practice and also guide other countries with similar issues with the ultimate aim of improving the care of women with early breast cancer globally.

Background Dihydrolipoamide dehydrogenase deficiency (DLDD) is a rare metabolic disorder inherited in an autosomal recessive manner. This heterogeneous disease has a variable clinical presentation, onset, and biochemical markers. Materials and methods We retrospectively reviewed the clinical and molecular diagnosis of eight cases with DLDD from four referral centers in Saudi Arabia. Results Remarkably, we found hepatic involvement ranging from acute hepatic failure to chronic hepatitis in five patients. In addition, neurological disorders in the form of seizures, developmental delay, ataxia, hypotonia and psychomotor symptoms were found in five patients, two of them with a combination of hepatic and neurological symptoms. In addition, only one patient had recurrent episodes of hypoglycemia. While most patients had the hepatic form of homozygous variant c.685G > T in the DLD gene, one patient was found to have a novel variant c.623C > T that had neurological and hepatic symptoms. Conclusions We describe the largest reported DLDD cohort in the Saudi population. Clinical, biochemical, radiological, and molecular characterization was reviewed and no clear genotype-phenotype correlation was found in this cohort.

Despite significant advances in the research domain of continuous twin screw granulation, limited information is currently available on the impact of raw material properties, especially considering batch-to-batch variability. The importance of raw material variability and subsequent mitigation of the impact of this variability on the manufacturing process and drug product was recently stressed in the Draft Guidance for Industry on Quality Considerations for Continuous Manufacturing by the U.S. Food and Drug Administration (FDA). Therefore, this study assessed the impact of microcrystalline cellulose (MCC) batch-to-batch variability and process settings in a continuous twin screw wet granulation and semi-continuous drying line. Based on extensive raw material characterization and subsequent principal component analysis, raw material variability was quantitatively introduced in the design of experiments approach by means of t1 and t2 scores. L/S ratio had a larger effect on critical granule attributes and processability than screw speed and drying time. A large impact of the t1 and t2 scores was found, indicating the importance of raw material attributes. For the studied formulation, it was concluded that MCC batches with a low water binding capacity, low moisture content and high bulk density generated granules with the most desirable quality attributes. Additionally, an innovative and quantitative approach towards mitigating batch-to-batch variability of raw materials was proposed, which is also applicable for additional excipients and APIs., Graphical abstract Unlabelled Image

Background Water, Sanitation, and Hygiene (WASH) systems aim to reduce the spread of enteric pathogens, particularly amongst children under five years old. The most common primary outcome of WASH trials is carer-reported diarrhoea. We evaluate different diarrhoea survey instruments as proxy markers of enteric pathogen presence in stool. Methods We recruited 800 community-based participants from the Cox's Bazar Displaced Person's Camp in Bangladesh, split evenly between the rainy (July/August 2020) and dry (November/December 2020) periods. Participants were randomized evenly into either a standard survey asking carers if their child under five years old has had diarrhoea in the past fortnight, or a pictorial survey asking carers to pick from a pictorial chart which stools their child under five years old has had in the past fortnight. We collected stools from a random sub-sample of 120. Stools were examined visually, and tested for proteins associated with enteric infection and 16 enteric pathogens. We calculated sensitivities and specificities for each survey type, visual examination, and proteins with respect to enteric pathogen presence. Findings The sensitivity of the standard survey for enteric pathogen presence was 0.49[95%CI:0.32,0.66] and the specificity was 0.65[0.41,0.85]. Similar sensitivities and specificities were observed for pictorial survey, visual inspection, and proteins. Interpretation While diarrhoea is an important sign in clinical practice it appears that it is a poor proxy for enteric pathogen presence in stool in epidemiological surveys. When enteric infection is of interest, this should be measured directly. Funding The project was funded by the National Institutes for Health Research Global Health Research Unit on Improving Health in Slums (16/136/87) and by the University of Warwick.

Background: Comparative effectiveness of 7 glucagon-like peptide 1 (GLP-1) agents on weight loss (WL) in obesity is unknown. Methods: Study Design: Systematic review, network meta-analysis (NMA) Data Sources: MEDLINE, EMBASE, Scopus, Cochrane Central and clinical trial registries, from inception to March 2, 2021 Prespecified Criteria for Study Inclusion: Randomized clinical trials (RCTs) of >12 weeks’ duration. Data Appraisal and Extraction: Two investigators independently, using published reports. Main Outcomes and Statistical Methods: WL over placebo (WLOP) and adverse events (AEs) among GLP-1 agents using random-effects NMA (frequentist approach); relative ranking using surface under the cumulative ranking (SUCRA) method and certainty of evidence using GRADE. Registration: None Findings: Data Synthesis: 64 RCTs (2004-2021) had 27018 patients (medians of age, 55.1y; 57.4% women; baseline weight 94.8kg and BMI 33.0kg/m2; trial duration 26 weeks). Direct meta-analysis showed significant WLOP with: -1.44kg (95% CI, -2.14 to ‑0.74) with dulaglutide ≥1.5 mg; -1.82kg (‑2.42 to ‑1.23) with exenatide IR; -2.20kg (-4.31 to -0.08) with exenatide ER; -3.20kg (-6.53 to 0.15) with efpeglenatide; -2.72kg (‑3.35 to -2.09) with liraglutide ≤1.8mg; -4.49kg (-5.26 to -3.72) with liraglutide >1.8mg; ‑0.62kg (-1.22 to -0.02) with lixisenatide; ‑4.33kg (-5.71 to -3.00) with semaglutide SQ 1.8mg (SUCRAs 100, 86.1, 82.8 respectively). Highest SUCRAs for discontinuation due to AEs were with taspoglutide and liraglutide >1.8mg.Risk of bias was high or unclear for random sequence generation (29.7%), allocation concealment (26.6%), and incomplete outcome data (26.6%). Heterogeneity (I 2 >50%) in WL and AEs reflected magnitude, not direction of effect. Interpretation: Semaglutide (SQ, oral) and liraglutide (SQ) were the most efficacious GLP-1 agents to induce WL during > 12 weeks’ treatment. Funding: NIH R01-DK67071 (Camilleri) Declaration of Interest: Dr. Michael Camilleri serves on an advisory board for Phenomix Sciences regarding the company’s development of a test to predict weight loss response to obesity therapy, and he is a stockholder in the company. Phenomix Sciences has obtained an exclusive license to Dr. Michael Camilleri’s and Dr. Andres Acosta’s biomarker technology, submitted patent, and know-how to develop a biomarker to predict response to obesity pharmacotherapy. Dr. Camilleri also serves as a consultant to Kallyope for the company’s development program regarding obesity (the consulting fee is paid to his employer, Mayo Clinic). All other authors have nothing to declare.

Elevated serum chitotriosidase (CHITO) is an indication of macrophage activation, and its capacity have been explored as a marker of inflammation in a number of disease states. For over a decade, CHITO plasma levels have been used by clinicians as a biomarker of inflammation in the lysosomal disease, Gaucher disease, including monitoring response to therapies in patients with Gaucher disease type I. Although it is becoming increasingly recognized that inflammation is a prominent component of many lysosomal diseases, the relation of CHITO levels to disease burden has not been well-characterized in the large majority of lysosomal diseases. Moreover, the role of CHITO in lysosomal diseases that affect the central nervous system (CNS) has not been systematically studied. In this study, one hundred and thirty-four specimens of CSF and serum were collected from 34 patients with lysosomal diseases affecting the CNS. This study included patients with GM1-gangliosidosis, GM2-gangliosidosis, mucopolysaccharidoses (MPS), multiple sulfatase deficiency and Gaucher disease. CHITO levels in the CSF were significantly higher in patients with more rapidly progressing severe neurological impairment: GM1-gangliosidosis vs MPS (p

The prevention and control of infectious diseases in livestock is of great significance for maintaining the food and health of people. The main bottleneck in preventing and controlling the epidemic is asymmetrical information between farmers and the livestock department regarding dead livestock. In this pursuit, China has levied the contract commitment system to ensure farmers to cooperate with livestock departments, cooperative organizations, and other farmers by proper contract in order to combat the livestock epidemic by reporting the status of dead livestock on time. Based on the data of 514 pig farmers in Hebei, Henan, and Hubei, this research employed the Heckprobit model to explore the contract commitment system's effect on pig farmers' behavior in reporting the status of dead livestock. The outcome showed that the contract commitment system encouraged the farmers to report dead pig information promptly. Moreover, modern information channels such as mobile phones or the Internet further enhanced the contract commitment system's effectiveness. Besides, the impacts of the contract commitment system on different scale farmers are found substantially heterogeneous. Based on the empirical findings, it is confirmed that the contract commitment system should not exclude government regulatory measures and economic incentive policies. It is a useful remedy to encourage farmers to report dead livestock information on time and supports in preventing and controlling livestock epidemics. Additionally, the government should enhance and strengthen the contract commitment system, establish the channels and platforms required to deliver necessary information about epidemics, and implement differentiated policy programs for different scale farmers. More importantly, these countermeasures can also provide important guidelines for other developing countries, facing livestock epidemics.

The burden of anemia in Senegal is high, particularly in children and women in rural households. The main objectives of the study reported here were (i) to measure and compare the prevalence of anemia and intestinal parasitic infections in farmers and family members and sheep in two agro-ecological zones in Senegal and (ii) to examine the association between anemia and age or sex in farmers and family members. The study was conducted in Mpal (250 km from Dakar, the capital city) and Diawara (700 km from Dakar, a remote location near the Malian border). In humans, the prevalence of anemia was higher in Diawara (64/86 = 74%), compared to Mpal (13/29 = 45%) (p

International audience; Mitochondrial malate dehydrogenase (MDH2) deficiency (MDH2D) is an ultra-rare disease with only three patients described in literature to date. MDH2D leads to an interruption of the tricarboxylic acid (TCA) cycle and malate-aspartate shuttle (MAS) and results in severe early onset encephalopathy. Affected infants suffer from psychomotor delay, muscular hypotonia and frequent seizures. Laboratory findings are unspecific, including elevated lactate in blood and cerebrospinal fluid. Brain magnetic resonance imaging reveals delayed myelination and brain atrophy. Currently there is no curative therapy to treat this devastating disease.Here, we present a female patient diagnosed with MDH2D after a stroke-like episode at 18 months. Trio-whole exome sequencing revealed compound heterozygous missense variants in the MDH2 gene: c.398C>T, p.(Pro133Leu) and c.445delinsACA, p.(Pro149Hisfs*22). MDH2 activity assay and oxygraphic analysis in patient's fibroblasts confirmed the variants were pathogenic. At the age of 36 months, a drug trial with triheptanoin was initiated and well tolerated. The patient's neurologic and biochemical phenotype improved and she had no further metabolic decompensations during the treatment period suggesting a beneficial effect of triheptanoin on MDH2D.Further preclinical and clinical studies are required to evaluate triheptanoin treatment for MDH2D and other TCA cycle and MAS defects.

Background The emergence and spread of multidrug-resistant organisms (MDROs) represent a threat to human and animal health. Objectives To assess duration of carriage of MDROs in dogs and cats presented to veterinary clinics/hospitals in Switzerland. To estimate prevalence, duration of and risk factors for MDRO carriage in their owners and the occurrence of co-carriage in owner-pet pairs. Methods Prospective, longitudinal, observational study. Nasal swabs and fecal samples were collected from 50 owners of dogs and cats presented to 3 large veterinary hospitals, 1 medium-sized clinic and 1 practice. If pet or owner tested positive for a MDRO, follow-up samples were collected for up to 8��months. Methicillin-resistant (MR) Staphylococcus aureus, MR S. pseudintermedius, MR coagulase-negative staphylococci (MRCoNS), MR Macrococcus spp., cephalosporinase- and carbapenemase-producing (CP) Enterobacterales were isolated and further characterized by MALDI-TOF MS, microdilution, ��-lactam resistance gene detection, REP/ERIC-PCR, multilocus sequence typing or whole-genome sequencing. Risk factors for MDRO carriage in owners were explored based on questionnaire-derived data. Results Five out of 50 owners carried 3rd generation cephalosporin-resistant Enterobacterales (3GC-R-Ent.), and 5/50 MRCoNS. In 3 dogs and 4 cats carriage of 3GC-R-Ent. persisted for up to 136��days after discharge (median 99��days, IQR 83��days, range 36-136��days), in two cats isolates were carbapenem-resistant. Owner-pet co-carriage was not observed. No specific risk factors for MDRO carriage in owners were identified. Conclusions After discharge from veterinary care, dogs and cats may carry 3GC-R-Ent. for prolonged time periods. Carriage of MDROs was common in owners, but pet-owner co-carriage of the same MDRO was not observed.

Background: Growing concerns about the impact of coronavirus disease 2019 (COVID-19) will likely lead to increased mental health diagnoses and treatment. To provide a pre-COVID-19 baseline, we have examined antidepressant prescribing trends for 5 years preceding COVID-19. Methods: A retrospective analysis of anonymised data on medicines prescribed by GPs in England from the Open-Prescribing Database (January 2015 to December 2019) identified the 10 most prescribed antidepressant and, for comparison, cardiovascular medicines. Results: Prescription items for the 10 most prescribed antidepressants rose 25% from 58 million (2015) to 72 million (2019). Citalopram was the most prescribed antidepressant; prescriptions for sertraline rose fastest at 2 million items year on year. Over the same period, costs for antidepressant prescribing fell 27.8%. Across all Clinical Commissioning Groups (CCGs) in England, antidepressant prescribing levels, adjusted for population were positively correlated with the index of multiple deprivation (IMD) score. In comparison, prescribing for the top 10 most prescribed cardiovascular medicines increased by 2.75% from 207 million (2015) to 213 million (2019) items. Limitations: Anonymised data in the Open-Prescribing Database means no patient diagnoses or treatment plans are linked to this data. Conclusion: Antidepressant prescribing, particularly sertraline, is increasing. Prescribing is higher in more deprived regions, but costs are falling to

COVID-19; Mortality comparison; Pneumonia COVID-19; Comparación de la mortalidad; Neumonía COVID-19; Comparació de la mortalitat; Pneumònia Background It is unclear whether the changes in critical care throughout the pandemic have improved the outcomes in coronavirus disease 2019 (COVID-19) patients admitted to the intensive care units (ICUs). Methods We conducted a retrospective cohort study in adults with COVID-19 pneumonia admitted to 73 ICUs from Spain, Andorra and Ireland between February 2020 and March 2021. The first wave corresponded with the period from February 2020 to June 2020, whereas the second/third waves occurred from July 2020 to March 2021. The primary outcome was ICU mortality between study periods. Mortality predictors and differences in mortality between COVID-19 waves were identified using logistic regression. Findings As of March 2021, the participating ICUs had included 3795 COVID-19 pneumonia patients, 2479 (65·3%) and 1316 (34·7%) belonging to the first and second/third waves, respectively. Illness severity scores predicting mortality were lower in the second/third waves compared with the first wave according with the Acute Physiology and Chronic Health Evaluation system (median APACHE II score 12 [IQR 9–16] vs 14 [IQR 10–19]) and the organ failure assessment score (median SOFA 4 [3–6] vs 5 [3–7], p

Objective: To determine point prevalence of postpartum depression (PPD) and whether quarantine policies required in postpartum COVID-19 suspects increased the risk of depressive symptoms when compared COVID -19 non suspects in early postpartum period. Methods: A cross-sectional study conducted in the postnatal ward of Lady Hardinge Medical College and Smt. Sucheta Kriplani Hospital, New Delhi from August 2020 to February 2021 using Edinburgh Postnatal Depression Scale (EPDS) to estimate point prevalence of postpartum depression (PPD) in the stratified zones (suspect and nonsuspect) of the hospital. Results: Total of 408 postpartum women,204 each (COVID-19 suspects, and nonsuspects zone) were enrolled. Prevalence of Postpartum depression using an EDPS score of >9 was 11.9%. Prevalence of depression (17.9%; vs 4.85%, p

Background: Previous studies showed that caregivers of children with autism spectrum disorder (ASD) and other developmental disorders had higher levels of parenting stress, anxiety and depression. In the present study, the author examined the caregivers' mental health and investigated the mediating role of social support between symptoms severity and parenting stress during COVID-19. Methods: During 20 March to 8 April 2020, 1932 caregivers of children and adolescents with ASD and other developmental disorders from China were enrolled to fill in a sociodemographic questionnaire, Depression, Anxiety and Stress Scale and Social Support Rating Scale. The author also collected children's disability severity symptoms and behavioral problems. Results: The results showed that 46.01% of the caregivers reported symptoms of depression, 44.67% showed anxiety and 44.62% showed stress during COVID-19 pandemic. Fathers were found to get more subjective support than mothers (P