COVID-19 has been declared a pandemic by the world health organization. Patients with cancer, and particularly hematologic malignancies may be at higher risk for severe complications due to their malignancy, immune dysregulation, therapy, and associated comorbidities. The oncology community has been proactive in issuing practice guidelines to help optimize management, and limit infection risk and complications from SARS-COV-2. Although hematologic malignancies account for only 10% of all cancers, their management is particularly complex, especially in the time of COVID-19. Screening or early detection of COVID-19 are central for preventative/mitigation strategy, which is the best current strategy in our battle against COVID-19. Herein, we provide an overview of COVID-19 screening strategies and highlight the unique aspects of treating patients with hematologic malignancies. In December 2019, infection with a novel betacoronavirus, subsequently named SARS-CoV-2, has been reported in a cluster of pneumonia cases in the Wuhan region of China , 4. As aHematologic malignancies encompass a wide range of neoplasms, including leukemia, lymphoma, multiple myeloma, myelodysplastic syndrome and myeloproliferative neoplasms, which all account for 10% of all malignancies –13.The triage of patients according to their COVID-19 status  has been the key measure in limiting in-hospital contaminations . The absLiterature on COVID-19 in hematologic malignancies is sparse and mainly derived from case series that are focused on patients with solid tumors. Two cases series from China showed a higher incidence (1 vs. 0.3%), and a higher case-fatality rate (5 vs. 1%) in patients with cancer compared with the overall population , 15. HowPatients with hematologic malignancies might be at higher risk of contracting and experiencing complications from COVID-19, such as hospitalization, intensive care unit (ICU)/invasive ventilation, sepsis, cytokine dysregulation, multiorgan failure and/or death . ReasonsTo our knowledge, at the time of writing this review, only 10 cases of COVID-19 have been published to date in the English literature in patients with hematologic malignancies. Details are summarized in The American Society of Hematology Research Collaborative has recently launched a COVID-19 international registry for patients with hematologic malignancies . By Aprin = 105) and without cancer (n = 536) was presented at the American Association for Cancer Research 2020 virtual meeting . One meta-analysis showed a positive predictive value reaching 90.4% for chest CT scan. Taken together, these findings support the superiority of CT over PCR for detection and screening of COVID-19 especially in endemic areas and for higher-risk patients such as those with hematologic malignancies. Nonetheless, many challenges remain before implementation to screen for asymptomatic carriers . Ar. Arp < 0carriers . Deep lecarriers , 48. AI carriers . Deep lecarriers .Despite the paucity of current available data, several medical societies have provided clinical practice guidelines for management of patients with hematologic malignancies in order to optimize therapy and limit infection risk and complications , 51. ConAccording to the European Society for Blood and Marrow Transplantation guidelines, COVID-19 should be ruled-out in all patients, including asymptomatic ones, before undergoing conditioning chemotherapy . AdditioScreening measures in the pre-CAR T cell phase should include screening for symptoms for all patients before apheresis and CAR T cell infusion. RT-PCR testing is considered within 48–72 h before apheresis and recommended within 48–72 h before lymphodepleting chemotherapy and 7 days within CAR T cell infusion. A repeat evaluation of RT-PCR within 72 h of CAR T cell infusion to detect interim COVID-19 infection and perform serologic testing for COVID-19 seroconversion once available , 64. ThaLast, blood transfusions should be carefully monitored during this outbreak. Blood donors should be screened for any suspicious signs or close exposure to COVID-19 present in at least the past 2 weeks . The WHOPatients with hematologic malignancies are thought to be particularly vulnerable for severe illness from COVID-19. The outbreak has added a large burden to the complexity of cancer care in hematologic malignancies on many aspects. Balancing the management of COVID-19 and its complications and management of cancer is particularly challenging in patients with hematologic malignancies, especially when treating with curative intent, which is often the case in many blood cancers. In the context of limited available scientific data in a such young and rapidly evolving field, physicians are left for now with their clinical judgement, educated guesses and consensual expert opinions . Until tThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.All authors contributed equally to the manuscript writing and review.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


After adjusting for sociodemographic and socioeconomic factors, public trust remained negatively associated with psychological distress  and positively associated with physical well-being . Perceived self-efficacy to practice COVID-19 protective behavior partially mediated the relationship between public trust and psychological distress (13.07%); and physical well-being (28.02%). Perceived self-efficacy to protect self against COVID-19 infection can serve as a psychological pathway through which public trust may be associated with mental and physical health.The well-being of the public during the 2019 coronavirus (COVID-19) pandemic is deeply rooted in institutional trust in the government’s risk communication effort. The objective of this study was to examine the psychological pathway through which public trust in the government is associated with mental and physical well-being. We collected cross-sectional data from 501 participants aged ≥18 years using an online panel. Public trust in the government was assessed as our exposure variable. We screened for psychological distress by combining the Patient Health Questionnaire and the General Anxiety Disorder scale. Physical well-being was examined using self-rated health. We further assessed the roles of risk perceptions. The author conducted a one-way analysis of variance (ANOVA), Pearson’s correlations, multivariable regressions, and mediation analyses (using the Preachers and Hayes’ approach). Participants were 55.29% female, 67.86% Caucasian/white with a mean age of 32.44 ± 11.94 years. Public trust in the government regarding COVID-19 was negatively correlated with psychological distress ( The 2019 Coronavirus disease (COVID-19) pandemic, caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has led to unprecedented interruptions to the normal way of life for many individuals around the world . CompareRegarding mental well-being, early works on the public’s response have established an expected increase in symptoms of anxiety, depression, and harmful behaviors such as suicide, self-harm, alcohol and substance misuse, domestic and child abuse globally . RegardiA notable antecedent of physical and mental well-being during outbreaks is risk communication. Risk communication can be defined as a purposeful exchange of information among interested parties about the nature, magnitude, significance, or control of a risk . During Regarding the COVID-19 pandemic, a plethora of information sources has arisen, which often debunk information provided by the local or national government. There have also been mixed reactions about the government’s slow response to the pandemic. This cumulative experience may spur feelings of betrayal by the official authorities and feed conspiracy theories by rival political parties, eroding the public’s trust and increasing the public’s anxious response. This lack of institutional trust may further result in poor physical and mental health . More evPsychologically, the public’s trust in the government’s risk communication and social persuasion strategies may affect their perception of the pandemic’s severity, their vulnerability to the virus and their perceived self-efficacy in practicing preventive behavior or taking care of their health . These pWe recruited participants via Prolific, an online crowdsourcing platform for researchers . This plI am confident that the government’s information is helpful. (ii) I trust what the government says about coronavirus. (iii) Government health websites are trustworthy (iv) I trust the government to do what is needed to protect our health. Response options ranged from 1 (Strongly agree) to 5 (Strongly disagree). Items were reverse coded and averaged such that higher values represented greater trust (α = 0.72).We measured public trust with four questions . ParticiCoronavirus is a serious infection for me to contract.” Response options ranged from 1 (Strongly disagree) to 5 (Strongly agree).We measured the perceived severity of COVID-19 with a single item that asked respondents, “It is possible for me to protect myself against coronavirus infection.” Response options ranged from 1 (Strongly disagree) to 5 (Strongly agree), α = 0.83.We assessed perceived self-efficacy using a 4-item measure  that ask“Over the past 2 weeks, how often have you been bothered by any of the following problems: feeling nervous, anxious, or on the edge?” Responses ranged from 1  to 4 (Nearly every day). Lower numbers indicate lower psychological distress.We combined the shortened version of the Patient Health Questionnaires- PHQ-2  which haHow good or bad has your health been over the last 3 months?” on a 5-point scale ranging from 1 (Excellent) to 5 (Terrible). Responses were reverse scored so that higher values reflect better physical well-being.We assessed subjective well-being using the Self-rated Health (SRH) item . The SRHAs public trust and well-being are likely to be influenced by key demographics , we assessed key demographic variables for participants’ descriptions and statistical control . More spz-test . Second, we conducted analyses of variances (ANOVA) and Pearson’s correlations to assess the relationship between public trust, risk perceptions (perceived severity and perceived self-efficacy), and physical and mental well-being. Third, we also conducted multivariable regression analyses, adjusting for sociodemographic covariates to assess the relationship between public trust and psychological distress and physical well-being. Fourth, we assessed whether perceived severity and perceived self-efficacy partially mediated the relationship between public trust and (i) psychological distress, (ii) physical health. To test the significance of the mediation effect, we used the Preacher and Hayes’ approach of calculating standard errors and 95% confidence intervals of the relationship of public trust with well-being through risk perceptions . We usedz-test . We recoz-test .N = 501) reported a mean age of 32.44 ± 11.94 years, being females (55.29%), White (67.86%), single/never married (68.46%), college graduate or more (53.71%), and employed (54.89%). The government’s website as shown in r = 0.19, p < 0.001), perceived severity , physical well-being , and negatively associated with psychological distress .After excluding one participant who failed the attention check , the othAfter adjusting for sociodemographic and SES , public Standardized mediation tests on perceived severity showed a non-significant indirect effect of public trust on psychological distress  and physical well-being . However, perceived self-efficacy partially mediated 13.07% of the relationship between public trust and psychological distress   and physIn this study, the relationship between public trust in the government and (i) psychosocial distress and (ii) physical well-being, was partially mediated by perceived self-efficacy to practice COVID-19 protective behavior. Our findings suggest that this perceived self-efficacy can serve as a psychological pathway through which public trust in the government may be associated with mental and physical well-being during this pandemic.Our finding is supported by the principles of Social Cognitive Theory SCT; , which rMajor life events like disease pandemics induce psychosocial stress among the population. The psychological consequence of this type of stress includes anxiety and depression . Our finAnother major implication of our study is the need for government institutions to conduct COVID-19 risk communication efforts in a way that they earn the public’s trust. Also, our results indicate considerable negative associations between perceived severity and three variables: self-efficacy and mental and physical well-being. In other words, as the perceived severity increases, individuals are reporting lower scores of self-efficacies as well as mental and physical well-being. Considering these relationships, risk communication efforts should seek to balance the communication of the seriousness of COVID-19 with information that boosts self-efficacy in practicing COVID-19 protective behavior. Based on our findings, which suggests that perceived self-efficacy may increase with mental and physical well-being, we recommend the development of a reporting guideline for risk communication during pandemics events. This guideline can correct the imbalance in the type of risk information and make sure that there is an equilibrium between severity-framed and efficacy-framed communication.Our study is not without its limitations; first, our sample selection was not random, consisting mainly of young, educated adults; hence, our results may not be generalizable across the US and should be interpreted with caution. Second, our use of a cross-sectional study design makes it challenging to establish causal ordering and warrants a careful interpretation of our result. Although recent longitudinal studies on COVID-19 suggests a validation of the zero-order relationships in our model , future The current study sought to further investigate the psychological pathway through which public trust in the government’s effort to manage the COVID-19 pandemic is associated with physical and mental well-being. Risk communication by government institutions, conducted in a way that earns trust, may improve the perceived self-efficacy to practice COVID-19 preventive behavior, which is positively associated with mental and physical well-being.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher.The studies involving human participants were reviewed and approved by the institution review board of the University of Illinois at Chicago. The patients/participants provided their written informed consent to participate in this study.AO: conceptualization, data curation, formal analysis, methodology, and writing—original draft. OO: writing—original draft and writing—review and editing. AH: methodology, supervision, and writing—review and editing. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Quality of life (QoL) is multi-dimensional concept of an individual’ general well-being status in relation to their value, environment, cultural and social context in which they live. This study aimed to quantitatively synthesise available evidence on the association between QoL and mortality in the general population.An electronic search was conducted using three bibliographic databases, MEDLINE, EMBASE and PsycINFO. Inclusion criteria were studies that assessed QoL using standardized tools and examined mortality risk in a non-patient population. Qualitative data synthesis and meta-analyses using a random-effects model were performed.Of 4184 articles identified, 47 were eligible for inclusion, involving approximately 1,200,000 participants. Studies were highly heterogeneous in terms of QoL measures, population characteristics and data analysis. In total, 43 studies (91.5%) reported that better QoL was associated with lower mortality risk. The results of four meta-analyses indicated that higher health-related QoL (HRQoL) is associated with lower mortality risk, which was consistent for overall HRQoL , physical function , physical component score , and mental component score .These findings provide evidence that better QoL/HRQoL was associated with lower mortality risk. The utility of these measures in predicting mortality risk indicates that they should be considered further as potential screening tools in general clinical practice, beyond the traditional objective measures such as body mass index and the results of laboratory tests. Quality of life (QoL) is a multi-dimensional concept of an individual’s general well-being status in relation to the value, environment, cultural and social context in which they live . Since QMoreover, QoL has increasingly been used in the wider context to monitor the efficacy of health services , to assess intervention outcomes, and as an indicator of unmet needs –15. SeveTo date, there has been only one pooled analysis of eight heterogeneous-Finnish cohorts. That study of 3153 older adults, focused exclusively on the prognostic value of the validated 15-dimentional (15D) health-related QoL (HRQoL) measures  for predThis systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement . The proArticles were included if they: (a) involved adults aged 18 years and older; (b) were general population-based samples with or without a range of health conditions; (c) assessed mortality from any cause or cause-specific mortality using a longitudinal design; and (d) included a QoL / HRQoL measure using a standard tool. QoL, the general well-being of individuals, consists of a range of contexts – health, education, employment, wealth, politics and the environment . HRQoL, The screening of articles for eligibility according to title and abstract was undertaken independently by two reviewers (AZZP and HC). All relevant full-text articles were independently reviewed by two reviewers (AZZP and HC) for eligibility against inclusion criteria. The inter-coder reliability among two reviewers (AZZP and HC) was 98%. Discrepancies and disagreements between two reviewers (AZZP and HC) were resolved through discussion with a third reviewer (JR). The screening process was undertaken using Covidence online software  and EndNA standard data extraction form was used which included the following fields – title, authors, year of publication, setting/country, name of the study and design, sample size, follow-up period, participant characteristics (age and sex), specific QoL measure, cause of death (if available), and results  which were standardized in term of 1-unit increase or 1-SD increase for continuous risk estimate, or high vs. low for categorical risk estimates. The first reviewer (AZZP) completed the data extraction form and a second reviewer (HC) verified the extracted information. All efforts were made to contact authors when there was missing information.The quality of included studies was appraised using ‘the Newcastle – Ottawa Quality Assessment Scale (NOS)’ . The NOSThe clinical and methodical heterogeneity of the studies was examined, in particular considering the measure of QoL used, and the effect estimates reported (Hazard Ratio (HR), Relative Risk (RR) or Odds Ratio (OR)). Where studies were considered too methodically heterogeneous to enable pooling, the results were summarized quantitatively in tables according to related categories with risk estimates; and 95% CIs.2 statistic, and the results were interpreted based on the Cochrane guidelines  [2 statistic showed considerable heterogeneity (≥ 75%), the influence of individual studies on the pooled risk estimate was assessed using the metaninf command of STATA. Funnel plots and Egger’s test were used to assess publication bias. Data analysis was undertaken using STATA statistical software, version 15.0 .A meta-analysis was performed when there was a sufficient number of studies (four or more) which used the same domain of QoL measure and equivalent effect estimate parameters. In the present study, four meta-analyses were conducted for a pooled risk estimate of studies using (a) physical component score (PCS) of 36-item Short Form (SF-36) and OR / RR; (b) physical function domain of SF-36 and HR; (c) mental component score (MCS) of SF-36 and OR / RR; and (d) the 15-dimensional measure (15D) and HR. A DerSimonian-Laird random-effects model was chosen given heterogeneity in the studies in terms of population characteristics and varying health status. When more than one risk estimate was reported in the study, the fully adjusted/final regression model was included. In addition, when the included studies from the same cohorts with the same follow-up were eligible for meta-analysis, only one study with larger sample size was chosen for meta-analysis. Effect estimates were standardized where possible, so all values corresponded to a 1-unit increase in SF-36 or a 1-SD increase in 15D (single index number). A pooled risk estimates of less than one indicates a decreased risk of mortality with higher QoL. Statistical heterogeneity was evaluated by using the IA total of 4175 articles were identified from the systematic database search, and six additional articles were found via searching the reference list of included articles  measured QoL using the Short Form 36 (SF-36) Tables  and 2. O4 studiesThe methodological quality of included studies based on NOS ranged between five and nine stars. Among the included studies, seven were of high methodological quality, with nine stars. Across the ten studies with less than seven stars, they were scored most poorly on the items assessing how representative the cohort was in relation to the overall population being sampled and whether they adjusted for potential confounding factors in their analysis  studies reported for at least one of the domains examined, that better QOL was associated with lower mortality risk . There was substantial heterogeneity between studies  . There was substantial heterogeneity between studies  . There was substantial heterogeneity between studies  . There was moderate heterogeneity between studies  .Visual inspection of the funnel plots which were used to assess for publication bias were presented in the Supplementary Figures S1-S4, Additional File n = 78,589) of PCS, physical function and MCS domains of the SF-36, and 15D HRQoL.This systematic review is the first to investigate the association between QoL and mortality in community-dwelling individuals with or without health conditions rather than patients in a hospital or people living in assisted living. It summarizes the findings from 47 studies including approximately 1,200,000 individuals aged predominantly 65 years and older (age range 18–101 years), with 46 studies (98%) conducted in high-income or upper-middle-income countries. Overall thirteen different instruments were used to assess the association between QoL or more specifically HRQoL and mortality risk after 9 months to 18 years of follow-up, with the SF-36 or its derivatives  most commonly used. Overall, 43 (91.5%) studies of the 47 included studies reported for at least one of the domains examined, that better QoL was associated lower mortality risk, which was also supported by the results of four meta-analyses , and the review was undertaken in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement. A reproducible and rigorous search strategy using three electronic databases was used, which helped ensure that all relevant articles were included. The literature screening was independently performed by two reviewers, who were also involved in the process of data extraction and methodological quality assessment of the included studies in accordance with NOS. Based on the NOS, all studies received greater than or equal to five out of nine stars, which indicates that there was generally a low risk of bias. Similarly, most studies provided risk estimates that controlled for important factors including current health and socio-economic status. Since our review criteria were not limited to articles with the commonly used QoL (or HRQoL) tools such as the SF-36, this has increased the generalisability of the findings. Therefore, this review has a broad and comprehensive perspective, with results that are rigorous and can be reproduced.Among included articles, large heterogeneity was observed in terms of country-of-origin, participant characteristics, and evaluation of QoL. The majority of the included articles were conducted in English speaking counties, and restriction to English language articles as part of our inclusion criteria, may impact the generalisability of these findings. Since the different QoL standard tools examine different aspects , 85 and This is the first systematic review and meta-analysis that has determined whether QoL is associated with mortality in the general non-patient population. In summary, the findings provide evidence that better QoL or HRQoL measured by different tools were associated with lower mortality risk in the general population. Therefore, our findings could be applied more generally to QoL or HRQoL assessed using different instruments. Our unique and first review indicates that QoL measures can be considered as potential screening tools beyond the existing traditional clinical assessment of mortality risk. Additionally, our result also encourages clinicians to incorporate QoL measure into routine data collection of health system which in turn could enable initiation of early primary health care for people at high risk of premature death. Furthermore, this study also adds further support to the predictive capacity of physical HRQoL for mortality risk. Additional research is needed to determine whether these associations differ across gender, and other populations in low- and lower-middle-income countries, who have suffered of a double burden of infectious and chronic diseases, with having difficulties for accessing quality health services. Ultimately these findings suggest the utility of QoL measures to help identify populations at greatest risk of mortality and who might benefit most from routine screening in general practice and possible interventions.Additional file 1: Figure S1. Funnel plot of all-cause mortality risk per one unit increase in SF-36 PCS. Figure S2. Funnel plot of all-cause mortality risk per one unit increase in SF-36 Physical-Functioning. Figure S3. Funnel plot of all-cause mortality risk per one unit increase in SF-36 MCS. Figure S4. Funnel plot of all-cause mortality risk per one-SD (0.14) increase in 15D index. Table S1. Search Strategy using Ovid MEDLINE 1946 to June 212,019. Table S2. Search Strategy using Embase Classic 1947 to June 212,019. Table S3. Search Strategy using PsycINFO 1806 to June Week 32,019. Table S4. Additional Search Strategy up to June Week 32,019. Table S5. The list of excluded articles and reasons for exclusion (n = 38). Table S6. Appraisal Standard of Newcastle/Ottawa Scale. Table S7. Quality appraisal of included studies based on the Newcastle–Ottawa Quality Assessment Scale. Table S8. One study removed analysis for all-cause mortality risk per one unit increase in SF-36 PCS. Table S9. One study removed analysis for all-cause mortality risk per one unit increase in SF-36 Physical-Functioning. Table S10. One study removed analysis for all-cause mortality risk per one unit increase in SF-36 MCS.


Heat shock protein 60 (HSP60) and survivin reside in both the cytosolic and mitochondrial compartments under physiological conditions. They can form HSP60-survivin complexes through protein–protein interactions. Their expression levels in cancer tissues are positively correlated and higher expression of either protein is associated with poor clinical prognosis. The subcellular location of HSP60-survivin complex in either the cytosol or mitochondria is cell type-dependent, while the biological significance of HSP60-survivin interaction remains elusive. Current knowledge indicates that the function of HSP60 partly rests on where HSP60-survivin interaction takes place. HSP60 has a pro-survival function when binding to survivin in the mitochondria through interacting with other factors such as CCAR2 and p53. In response to cell death signals, mitochondrial survivin functions through preventing procaspase activation. Degradation of cytosolic survivin leads to the loss of mitochondrial membrane potential and aberrant mitosis processes. On the other hand, HSP60 release from mitochondria to cytosol upon death stimuli might exert a pro-death function, either through stabilizing Bax, enhancing procaspase-3 activation, or increasing protein ubiquitination. Combining the knowledge of mitochondrial HSP60-survivin complex function, cytosolic survivin degradation effect, and pro-death function upon mitochondria release of HSP60, a hypothetical scenario for HSP60-survivin shuttling upon death stimuli is proposed. The heat shock protein 60 (HSP60 or HSPD1), a mitochondrial chaperonin, is one of the abundant proteins in mitochondria of cells. Expression of HSP60 increases in various types of cancers, such as liver cancer, prostate cancer, and colorectal cancer, and higher HSP60 levels have been associated with tumor progression ,3. CliniSurvivin (BIRC5), the smallest member of the inhibitor of apoptosis protein (IAP) family, regulates cell division and inhibits apoptosis through blocking procaspase activation ,19. AmonIn tumor cells, HSP60 and survivin are capable of forming complexes to reside in either the mitochondria or the cytosol for survivin stabilization ,12. ConsAlthough HSP60 is abundant in the mitochondria, its expression can be found in both the cytosol and mitochondria under physiological conditions ,31. The L and Bcl-2, decreasing pro-apoptotic Bax, and inhibiting the activation of procaspase-3. In which, HSP60 not only interacts with Bax and Bcl-xL but also inhibits the ubiquitination of Bcl-xL [The aforementioned anti-apoptotic or pro-apoptotic results are both obtained by altering the total amount of HSP60. However, because of the dual subcellular localization, the function of HSP60 as anti- or pro-apoptosis could be dependent on its location in cells and/or its ability to shuttle between mitochondria and cytosol. There are lines of evidence showing that mitochondrial HSP60 has a pro-survival/anti-apoptotic function because it interacts with or perturbes the functions of numerous survival regulators to participate in anti-apoptotic processes. For example, overexpressed mitochondrial HSP60/HSP10 is capable of suppressing doxorubicin-induced apoptosis in cardiomyocytes through increasing anti-apoptotic Bcl-xf Bcl-xL . In anotf Bcl-xL . Furtherf Bcl-xL . Taken tIn contrast to the pro-survival/anti-apoptotic function of mitochondrial HSP60, the cytosolic HSP60 has been found to contribute to both anti-apoptosis and pro-apoptosis processes. In HeLa cells, cytosolic HSP60 participates in IKK/NF-κB activation by directly binding to IKKα/β. Loss of cytosolic HSP60 interrupts TNF-α-mediated activation of the IKK/NF-κB signaling, whereas cytosol-targeted expression of HSP60 promotes the IKK/NF-κB survival pathway, implying that cytosolic HSP60 has a pro-survival function . In cardc and dATP in an ATP-dependent manner, suggesting a pro-apoptotic function [Lines of evidence also suggest that HSP60 can contribute to pro-apoptotic functions. In a study conducted in Jurkat T cells, procaspase-3 forms a complex with HSP60 and HSP10 in mitochondria. Upon induction of apoptosis with staurosporine, HSPs are released from the mitochondria to the cytosol. Cytosolic HSP60 promotes the activation of procaspase-3 through cytochrome function . Elevatefunction . Howeverfunction .As stated above, HSP60 in mitochondria has a pro-survival/anti-apoptosis function, while in the cytosol, a dual function. When reviewing these studies, it appears that cytosolic HSP60 can either be derived from mitochondria or generated by de novo synthesis in the cytosol. There is an argument whether the pro- or anti-apoptotic function of cytosolic HSP60 is dependent on the origin of HSP60. In the study by Samali et al., it was found that increased cytosolic HSP60 abundance is due to its release from mitochondria to cytosol in staurosporine-induced apoptotic Jurkat T cells . SimilarIn various normal tissues such as spleen and liver, survivin not only expresses at a low level but also resides exclusively in the cytosol . HoweverA study in 2004 by Dohi et al. firstly indicated the existence of mitochondrial survivin in cancer cells . In 2016In the study by Dohi et al., it has been demonstrated that mitochondrial survivin exerts cytoprotective function through inhibition of apoptosis. They found that in HeLa cells, following hypoxia stimuli, the dramatic elevation of survivin levels was found in the mitochondria but only a minimal change was noted in the cytosol. Subsequent studies discovered that mitochondrial survivin was capable of inhibiting staurosporine-induced apoptosis by preventing the activation of procaspase-3 and procaspase-9. On the other hand, the tumor cells are more sensitive to cell death stimulation in the lack of mitochondrial survivin . NotablyBesides exerting the anti-apoptosis function through inhibition of procaspase activation, mitochondrial survivin could also function via interaction with other mitochondrial proteins. For example, mitochondrial survivin can form a complex with HSP90 in mitochondria of vascular smooth muscle cells (VSMCs), stabilizing both proteins. In VSMCs suffering from shepherdin-induced apoptosis, both survivin and HSP90 were degraded. On the other hand, mitochondrial survivin levels increased in prototypic vascular growth factor (platelet-derived growth factor–BB)-induced VSMCs activation, suggesting a pro-survival function . In anotNot only the mitochondrial survivin exerts cytoprotective functions against apoptosis, but the cytosolic survivin is also capable of promoting cell survival. In a study by Fortugno et al., survivin has been found in both nucleus and cytoplasm. The cytosolic survivin is associated with interphase microtubules, centrosomes, spindle poles, and mitotic spindle microtubules during cell divisions and, therefore, possibly contributes a role in spindle assembly during mitosis . EctopicDespite most studies have demonstrated that both mitochondrial and cytosolic survivin have an anti-apoptotic function, some studies suggest that the cytosolic survivin is also involved in pro-apoptosis processes of tumor cells following death stimuli, although the latter view is arguable. In the aforementioned study by Dohi et al., INS-1 cells stably expressing mitochondrial survivin (INS-1/MT-S cells) manifested survivin release from mitochondria and accumulation in the cytosol, accompanied by cell apoptosis upon death stimuli . One couDifferent from the survivin-XIAP mediated mechanism, a later study has discovered that the XIAP is also a ubiquitin E3 ligase for survivin. Interferon-β-mediated XIAP-associated factor 1 (XAF1) induction promotes the formation of XIAP–XAF1–survivin complex to enhance survivin ubiquitination and degradation . XAF1 isThe interaction between HSP60 and survivin was first proposed in 2008 by Ghosh et al. They have demonstrated that binding of HSP60 to survivin occurs in the mitochondria but not in the cytosol of MCF-7 cells. The formation of mitochondrial HSP60–survivin complex assists the stabilization of mitochondrial survivin. Silencing HSP60 in MCF-7 cells triggers the activation of procaspase and results in cell death. This pro-apoptotic process can be prevented by overexpressing survivin simultaneously .Similarly, our recent study also revealed the formation of HSP60-survivin complex in HCC cells (Huh7 and J7). However, different from what has been found in breast cancer cells, the HSP60–survivin complex in HCC cells only exists in the cytosol but not mitochondria. Nevertheless, the molecular stabilization effect of survivin through the formation of cytosolic HSP60–survivin complex in HCC cells is the same as what has occurred in breast cancer cells . No mattBoth HSP60 and survivin in mitochondria play a pro-survival/anti-apoptotic function during cell death stimuli. The formation of HSP60-survivin complexes in mitochondria seems to be a critical event assisting cells to overcome death stimuli. For example, knockdown of mitochondrial HSP60 promotes apoptosis by disrupting HSP60–survivin interaction in tumor cells . RecentlThere is little dispute regarding the pro-survival/anti-apoptotic function of HSP60, survivin, and HSP60-survivin complexes in mitochondria. However, both HSP60 and survivin in the cytosol are involved in pro- and anti-apoptotic mechanisms, partly dependent on whether their cytosolic accumulation is due to their release from mitochondria. In tumor cells receiving death stimuli, it has been shown that HSP60 and survivin respectively accumulate in the cytosol, accompanied by decreasing amounts of them in mitochondria. The release of these proteins from mitochondria to cytosol partly contributes to death stimuli associated apoptosis ,40. In cOn the other hand, it is important to investigate the molecular roles of HSP60–survivin complexes that exist only in the cytosol of tumor cells (such as HCC cells) during apoptosis. In many cancers, the expression levels between HSP60 and survivin show a positive correlation, and the levels of survivin are partly regulated by HSP60 ,12,34. IIn the study by Kalderon et al., cytosolic HSP60 is capable of regulating proteasome activity in yeast. Elevation of cytosolic HSP60 induces the accumulation of polyubiquitinated proteins . During There are many similar biological functions between HSP60 and survivin. Both of them are overexpressed in many cancer cells or tissues, especially for survivin. Silencing the total amount of HSP60 or survivin can inhibit cell proliferation and promote apoptosis in various types of tumor cells ,59,60,61


Healthcare workers (HCW) are potentially at increased risk of infection with coronavirus disease (COVID-19) and may transmit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to vulnerable patients. We present results from staff testing at Sheffield Teaching Hospitals NHS Foundation Trust, United Kingdom. Between 16 and 29 March 2020, 1,533 symptomatic HCW were tested, of whom 282 (18%) were positive for SARS-CoV-2. Testing HCW is a crucial strategy to optimise staffing levels during this outbreak. The coronavirus disease COVID-19) pandemic has posed an unprecedented challenge for healthcare systems throughout the world. As at 6 April 2020, Public Health England (PHE) have reported 51,608 cases in the United Kingdom (UK) and 5,373 deaths [9 pandemiSheffield Teaching Hospitals NHS Foundation Trust (STH) is one of the UK’s largest foundation trusts, employing ca 17,000 individuals and providing a range of hospital and community services. On 17 March 2020, STH commenced testing of symptomatic staff for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coordinated by the Occupational Health department. Staff members presenting with an influenza-like illness  or persistent cough, were directed to self-swab in the on-site assessment pods previously used for testing of ambulatory patients in the community. Written and pictorial instructions were provided to staff to self-swab the back of the oropharynx and then insert the same swab 4–6 cm to the back of the nasopharynx. The Sigma-Virocult swabs , containing viral transport medium, were transported to the hospital laboratory at least four times daily. Nucleic acid extraction was performed using MagNA Pure 96 . Real-time RT-PCR was performed using the ABI LightCycler  with primers and probes specific for both RNA-dependent RNA polymerase (RdRP) and envelope (E) genes . SamplesThe majority of test results were communicated to staff on the same or the next day. Staff with a negative SARS-CoV-2 test were able to return to work if they felt well enough to do so. The policy was authorised by hospital management on 17 March.http://www.hra-decisiontools.org.uk/research/), it was decided that no formal ethical approval from the Institutional Review Board was required to produce this report.We present the data from the first fortnight of staff testing. Test results were obtained from electronic laboratory systems. Where available, details of staff roles and their work patterns since the onset of symptoms were obtained through their electronic clinical record. However, owing to the volume of work in the virology department, no electronic clinical records were created for positive staff from 22 March 2020. This report is a description of the standard clinical care provided to staff at Sheffield Teaching Hospitals. Following application of the NHS Health Research Authority algorithm  positive. In the following week, 1,082 additional staff were tested, and 20 staff were retested because of worsening symptoms, with 224 (20%) positive. Of the 20 staff retested, three were positive and 17 remained negative for SARS-CoV-2. Overall 282 of 1,533 (18%) staff tested positive, 1,246 of 1,533 (81%) tested negative and five of 1,533 (< 1%) had an indeterminate result. All samples contained sufficient human cellular material. Among staff positive for SARS-CoV-2 for whom data were recorded (n = 52), 25 were nursing staff, eight were doctors, nine were other patient-facing clinical staff, nine were laboratory or secretarial staff and one worked in cleaning services. Regarding symptoms, where data were recorded (n = 48), 23 had not worked with any symptoms, seven had been at work when symptoms developed and had left work on the same day, and 18 had worked at least one full shift with symptoms which were subsequently attributed to COVID-19 disease. None of the staff who tested positive for SARS-CoV-2 required hospital admission at the time of their positive result. In the week when staff testing was started, between 16 and 20 March 2020, the Occupational Health department received 4,337 phone calls, compared with 998 calls between 9 and 13 March 2020.From 12 March 2020, in the UK, community testing was discontinued and any person with a fever or a new persistent cough was advised to self-isolate for 7 days, in order to enable UK laboratories to deliver priority testing for increasing numbers of hospitalised patients . From 16Our data demonstrate that the majority of staff who reported symptoms during the first fortnight of staff testing were negative for SARS-CoV-2. In a time where healthcare systems are particularly stretched, it is important to be able to maximise the available workforce. Facilitating testing may substantially decrease absence in staff when SARS-CoV-2 can be excluded. The sensitivity, and therefore the false-negative rate, of the two-gene target RT-PCR assay has not been formally described in the early stages of illness. However, SARS-2-CoV viral load in upper respiratory secretions is highest between 1 and 5 days from symptom onset, which is the optimal time to test symptomatic HCW . If thisThe nature of work performed by healthcare professionals means that they may be at increased risk of COVID-19 infection and can also transmit infection to vulnerable patients . More thTesting of staff at our institution may also have provided a limited snapshot of SARS-CoV-2 prevalence in the community  with mild influenza-like illness or persistent cough. While it is important that the provision of testing is carefully balanced with consideration of laboratory capacity, increasing laboratory capacity to allow widespread testing of NHS staff could be a vital tool in achieving adequate staffing during the COVID-19 outbreak, and reducing the risk of transmission to vulnerable patients.


Some patients with Corona Virus Disease 2019 (COVID-19) develop a severe clinical course with acute respiratory distress syndrome (ARDS) and fatal outcome. Clinical manifestations and biomarkers in early stages of disease with relevant predictive impact for outcomes remain largely unexplored. We aimed to identify parameters which are significantly different between subgroups.125 patients with COVID-19 were analysed. Patients with ARDS (N = 59) or non-ARDS (N = 66) were compared, as well as fatal outcome versus survival in the two groups.ARDS and non-ARDS patients did not differ with respect to comorbidities or medication on developing a fatal outcome versus survival. Body mass index was higher in patients with ARDS versus non-ARDS (p = 0.01), but not different within the groups in survivors versus non-survivors. Interleukin-6 levels on admission were higher in patients with ARDS compared to non-ARDS as well as in patients with fatal outcome versus survivors, whereas lymphocyte levels were lower in the different subgroups . There was a highly significant 3.5-fold difference in fever load in non-survivors compared to survivors (p<0.0001). Extrapulmonary viral spread was detected more often in patients with fatal outcome compared to survivors (P = 0.01). Further the detection of SARS-CoV-2 in serum showed a significantly more severe course and an increased risk of death (both p<0.05).We have identified early risk markers for a severe clinical course, like ARDS or fatal outcome. This data might help develop a strategy to address new therapeutic options early in patients with COVID-19 and at high risk for fatal outcome. Recently, a new type of Coronavirus, SARS-CoV (Severe Acute Respiratory Syndrome Corona Virus)-2, led to a worldwide pandemic outbreak of an infectious disease, called COVID-19 (Corona Virus Disease 2019). The clinical manifestation of this disease is very broad and variable, ranging from asymptomatic carriers to symptoms of acute infection of the upper airways and occasionally severe acute respiratory insufficiency and death . VariousAlthough COVID-19 appears to have a lower fatality rate than infections with SARS-CoV or Middle East Respiratory Syndrome (MERS)-CoV, the absolute number of deaths is high due to the global burden of infection. Beside possible regional differences in health care, an age-related increase in mortality has consistently been observed. Recently, based on results from an observational database of 169 hospitals in Asia, Europe, and North America, cardiovascular and pulmonary comorbidities have been reported to be independently associated with increased in-hospital death . FurtherHowever, none of these studies focus on predictors of severe clinical course and fatal outcome soon after hospital admission. In addition to being clinically relevant, such predictors are crucial for early identification of high-risk individuals, as these patients may benefit from early novel treatment strategies.In a preliminary report, we presented clinical data from 50 patients hospitalized due to COVID-19 . In the th 2020, until July 30th. Observation of the first 50 patients has been described initially , but did not differ in survivors versus non-survivors . Comparing a fatal outcome and survival for the subgroups of ARDS or non ARDS patients showed no significant difference in BMI levels. The mean absolute difference in BMI between ARDS and non-ARDS patients was 1.8 kg/m2 (reflecting a difference of about 10 kg between groups) and there was no difference in median BMI between non-survivors and survivors, suggesting that BMI was associated with disease severity, but not with fatal outcome.Although there was no significant difference in the prevalence of diabetes or prediabetes between subgroups, the BMI levels as a grade of overweight  vs. 65.9 (25.1–112.8) mg/l; p<0.0001], PCT , and IL-6  were significantly higher, and lymphocytes  were significantly lower, at the time of hospital admission . CompariSince an ongoing inflammatory reaction or „storm”has been discussed as a denominator for clinical outcome , 10, we Cumulative incidence analysis suggests that 50% of all non-survivors died within the first 20 days after the onset of symptoms . In the This report of 125 patients hospitalized due to COVID-19 infection in Germany, is showing an increased inflammatory burden and SARS-CoV-2 seropositivity as early markers in patients with ARDS or for fatal outcome.In different reports of large cohorts, mainly from China, Italy, or the US, comorbidities like pulmonary and cardiovascular diseases, as well as diabetes and kidney diseases, have been proposed as risk factors, or were associated with worse outcomes , 11, 12.In order to identify discriminating early markers for severity and disease outcome at hospital admission, we observed significant differences in inflammatory markers. An increased inflammatory reaction, or so called „cytokine storm“, has been previously described , 19, andViral load dynamics in relation to disease severity has been reported recently . OverallIt didn´t escape our attention that this is the first data of a tertiary care center in Germany, which is currently able to provide sufficient intensive care to patients with COVID-19. At the same time, the rather specific cohort of patients treated in our university hospital is the major limitation of this study, the evidence and scientific contribution is rather descriptive. Furthermore, we are aware that some significant associations might be due to small numbers or lack of multiple testing, for which we didn´t adjust. However, we hope that the results and conclusions will incite further evaluation in different ongoing studies worldwide.This study has several limitations. First, the character of retrospectively collected data limited the completeness of the data and made missing data unavoidable. Second, recruitment of the patients differed in the disease stage including patients with and without ARDS concerning the onset of the disease. Some patients were transferred to our hospital from other ICUs already diagnosed with ARDS. Third, Given the comparable small number of patients and events further analyses including logistic regressions are limited in their potential to identify significant relations.In conclusion, we have identified early risk markers for a severe clinical course like ARDS or fatal outcome in patients being hospitalized for COVID-19. Simple laboratory markers in addition to SARS-CoV-2 viremia, age and time of symptom onset to hospitalization seems to be feasible in predicting survival.


Non-governmental organisations (NGOs) in Ukraine have provided HIV testing, treatment, and condom distribution for men who have sex with men (MSM). HIV prevalence among MSM in Ukraine is 5.6%. We estimated the impact and cost-effectiveness of MSM-targeted NGO activities in Ukraine.A mathematical model of HIV transmission among MSM was calibrated to data from Ukraine (2011-2018).The model, designed before the 2022 Russian invasion of Ukraine, evaluated the impact of 2018 status quo (SQ) coverage levels of 28% of MSM being NGO clients over 2016-2020 and 2021-2030 compared to no NGO activities over these time periods. Impact was measured in HIV incidence and infections averted. We compared the costs and disability adjusted life years [DALYs] for the SQ and a counterfactual scenario  until 2030 to estimate the mean incremental cost-effectiveness ratio .Without NGO activity over 2016-2020, the HIV incidence in 2021 would have been 44% (95%CrI: 36%-59%) higher than with SQ levels of NGO activity, with 25% (21-30%) more incident infections occurring over 2016-2020. Continuing with SQ NGO coverage levels will decrease HIV incidence by 41% over 2021-2030, whereas it will increase by 79% (60-120%) with no NGOs over this period and 37% (30-51%) more HIV infections will occur. Compared to if NGO activities had ceased over 2016-2020 (but continued thereafter), the SQ scenario averts 14,918 DALYs over 2016-2030 with a mean ICER of US$600.15 per DALY averted.MSM-targeted NGOs in Ukraine have prevented considerable HIV infections and are highly cost-effective compared with a willingness-to-pay threshold of 50% of Ukraine’s 2018 GDP . The Eastern Europe and Central Asia region has a fast growing HIV epidemic, with UkMost funding for HIV treatment and prevention services in Ukraine, including among MSM, goes to non-governmental organisations (NGOs). NGOs taTo help policymakers allocate their limited resources, information is needed on the benefits and costs of different health interventions. This has become particularly important in middle-income countries such as Ukraine because funding for NGO activities is transitioning from international funding agencies to governments. AlthougWe developed a dynamic, deterministic model of HIV transmission among MSM  and not accessing NGOs, with a constant proportion being high-risk and the remainder low-risk. Individuals exit due to age-related or HIV-related deaths, with only the former being replaced with new entrants. Transitions occur between the low- and high-risk groups at rates that differ for ages 18-39 and ≥40 years but balance the flows between these groups. MSM become clients of NGOs at time-varying rates from 2003 and cease contact with NGOs at a constant rate. HIV-positive MSM become NGO clients at a higher rate due to NGO efforts to link HIV-positive MSM to care; our previous analyses show a higher proportion of NGO clients are HIV-positive than for non-NGO clients.We assume all HIV transmission is within the MSM population as few MSM  have ever injected drugs and most HIV-infected women are female sex workers, 13, whiFollowing HIV infection, individuals progress through acute, latent, pre-AIDS, and AIDS stages of HIV disease. Transmissibility is heightened during acute infection and pre-AIDS HIV disease, whereasPre-exposure prophylaxis (PrEP) is not readily available in Ukraine. A full The model is primarily parameterised using four national IBBS among MSM implemented in 2011 , 2013 , 2015 , and 2018 –18. Key Age-related mortality data comes from UN databases and we uThe model is seeded so that the age distribution of MSM in 1990 matches Ukraine’s male population, with MSM then entering and aging through the model. Although the HIV epidemic probably started later in Ukraine than Western Europe, there iIncreased condom usage during their last anal intercourse ,Increased HIV testing in last year ,Increased coverage of ART .In our previous analyses of the MSM IBBS data, being an NGO client was associated with: IncreasWe therefore assumed the rate of HIV-diagnosis and ART initiation are higher among NGO clients than non-NGO clients, and that they have higher condom use. This assumption is supported by NGO activities for MSM in Ukraine being focussed on providing HIV testing and counselling services, condom distribution, and linking HIV-positive people to ART services. NGOs also offer post-diagnosis case-management to MSM that test positive for HIV, incorporating counselling and linkage to ART. A detailed description of the assumptions made around the effects of NGOs is in the supplement .NGOs targeting MSM initiated in Ukraine in 2003. Numbers from Alliance for Public Health (APH) indicate that there were 22,824 MSM registered with NGOs in 2013, 50,615 in 2018 (~28% of MSM), and stable thereafter, except for a COVID-19-related dip in 2020 . These numbers of MSM registered as NGO clients include those that receive at least the minimum package of services . They do not include other MSM that would have benefitted from NGO services such as condom distribution. The model was fit to these trends by assuming different rates of joining NGOs over time, with the rate increasing between 2003-2012 and 2013-2019 and then being constant thereafter, except in 2020 where a lower rate is assumed. Overall levels of condom use are assumed to have increased over 1990-2007, with rath-97.5th percentile range.We calibrated the model using an Approximate Bayesian computation sequential Monte Carlo (ABC SMC) scheme to summaThe baseline model fits were cross-validated against overall HIV incidence  andWe modelled the impact of existing coverage levels of NGOs (status quo) over 2016-2020, and if they were continued over 2021-2030, both compared to counterfactual scenarios where there was no effect of NGOs on condom use, HIV testing and initiating ART over these specific time periods, equivalent to NGOs ceasing activities and their effects stopping over these time periods. Although the recent invasion by Russia will have changed the status quo situation, it is too early to understand to what degree, with the counterfactual situation now also being relevant to show what could occur if services are disrupted compared to them being maintained. For the 2021-2030 scenario, we also varied the counterfactual to estimate the impact of each beneficial effect of the NGOs. We also estimated the impact over 2021-2030 of increasing the coverage of NGOs from 28% to 60% of MSM by 2025. Impact was estimated in terms of the number and percentage of HIV infections averted, percentage reduction in HIV incidence and HIV prevalence, and number and percentage of HIV deaths averted.To investigate our assumptions about the effectiveness of NGOs, we also performed a sensitivity analysis in where we assumed not all the differences in condom use, HIV testing and ART coverage between NGO and non-NGO clients were due to NGO activities. For these, the counterfactual scenario incorporated different percentages of the difference in condom use, HIV testing, and linkage to HIV care between NGO and non-NGO clients. The status quo scenario was then compared to these scenarios. This can be interpreted as different percentages of the effects we are currently prescribing to NGOs being due to other causes.Unit cost estimates for ART and NGO services for MSM  came from published reports–29 and uDue to the ongoing nature of NGO activities, we estimated the cost-effectiveness of current NGO activities by comparing the status quo scenario over 2016-2030 with a counterfactual scenario where NGO activities are stopped for 5 years (costs and effects of NGOs are removed) from 2016 and then restarted in 2021 until 2030. This allows us to capture some of the longer-term benefits of the NGO activities that occurred over 2016-2020. This waWith existing levels of NGO activity , where 2If there had been no NGO activity over 2016-2020 then HIV incidence would have been 44% (95%CrI: 36%-59%) higher in 2021, at 1.05 (95%CrI: 0.84-1.27) per 100 person-years . There wWhen we consider the effect of removing specific beneficial effects of NGOs over 2016-2020, we find the number of HIV infections increases by 3% (95%CrI: 2%-6%) compared with the status quo scenario if we remove the increase in HIV diagnosis; 9% (95%CrI: 6%-14%) if we remove the increase in ART initiation; and 12% (95%CrI: 11%-14%) if we remove the increase in condom usage.Lastly, If NGO activities were to cease over 2021-2030, then the number of incident HIV infections over this period would increase by 37% (95%CrI: 30%-51%) compared to the status quo scenario, HIV incidence in 2030 would be 79% (95%CrI: 60%-120%) higher, and 15% (95%CrI: 12%-20%) more deaths would occur . ImportaAlternatively, if NGO activities were scaled-up from 2021 such that double  the number of MSM were clients of NGOs in 2025 than the status quo scenario , then incidence decreases by half  of what it would be in 2030 with the status quo scenario, to 0.23 (95%CrI: 0.14-0.30) per 100 person-years. This is 69% lower than it is currently estimated to be in 2020. HIV prevalence also decreases further to 3.9% (95%CrI: 3.0%-4.6%) in 2030, and there would be 29% (95%CrI: 25%-37%) fewer HIV infections and 12% (95%CrI: 10%-16%) fewer HIV deaths over 2021-2030 than for the status quo scenario.Compared to the counterfactual scenario with no effects of NGOs over 2016-2020 (but with NGO activities continuing over 2021-2030), the status quo scenario with NGOs in place over 2016-2030 is estimated to avert 3,025  HIV infections, 1,895  HIV deaths and 14,918 DALYs over 2016-2030. The status quo scenario costs US$35,600,695 , whilst the counterfactual scenario costs US$26,627,922 . The status quo scenario therefore incurs additional costs of US$8,952,733 over 2016-2030, resulting in a mean ICER of US$600.15 per DALY averted . The meaThe various one-way sensitivity analyses showed the cost-effectiveness results were robust, with the greatest mean ICER per DALY averted occurring when we assume higher costs for ART : US$863.95/DALY averted, which is still lower than the 0.5xGDP threshold, and so highly cost-effective. Conversely, the intervention becomes even more cost-effective (US$114/DALY averted) when a longer time horizon to 2050 is assumed. In the additional sensitivity analysis where different percentages of the effects prescribed to NGOs are assumed to be due to other causes , NGOs arOur modelling analyses suggest that without current NGO activities among MSM in Ukraine (over 2016-2020), the HIV incidence in 2021 would have been 44% higher and 25% more HIV infections would have occurred from 2016-2020. Going forward to 2030, continuing current NGO activities will reduce incidence by 40% and prevalence by 25% compared to what they are in 2021, whereas they would be 79% and 21% higher by 2030, respectively, if NGO activities cease. Importantly, most of the increase in HIV incidence occurs in the first year highlighting the importance of maintaining NGO activities despite the war with Russia because the public health implications of not doing so are stark. Doubling coverage of NGO activities from 2021 will further halve incidence by 2030. Projections suggest much of the ongoing benefit of NGO activities is through improving condom distribution and linkage to ART, with current NGO activities estimated to have increased the coverage of ART among HIV-positive MSM from 25% to 42% in 2021. Lastly, our analyses suggest that current NGO activities are highly cost-effective, costing US$600.15 per DALY averted, with all model projections and sensitivity analyses being lower than available willingness-to-pay thresholds for Ukraine.To our knowledge, this is the first study to examine the impact and cost-effectiveness of MSM-targeted NGOs in Ukraine. Wirtz et al previously modelled the impact of HIV prevention and treatment interventions among MSM in various low- and middle-income countries (LMIC), including Ukraine, and found that little impact on HIV incidence would be achieved unless ART was expanded. UnfortuThere has been limited research on Ukraine’s HIV epidemic among MSM. Our previous study used in this analysis found that NGOs were associated with beneficial outcomes among MSM, agreeinThe ICER per DALY averted for our study compares favourably with ICERs for other health interventions in Ukraine, particularly when considering this study’s ICER over a longer time horizon to 2050 (US$114). Other interventions in Ukraine with published ICERs include treatments for pneumonia  scaling The strength of our modelling includes using four rounds of national IBBS data to parameterise and calibrate the model within a Bayesian framework. Another strength is its novelty, with there being few evaluations of MSM-targeted interventions for Eastern Europe. LimitatThe IBBS surveys are also limited because they are observational, and, so, could only be used to look at associations rather than causality in the epidemiological analyses that fed into this modelling. It is possible that some of our modelled intervention effects may result from more health-conscious people attending NGOs or from risk-behaviours differing between HIV-negative and HIV-positive MSM (HIV-positive MSM attended NGOs more than HIV-negative MSM), resulting in our projections possibly being overestimates. To counter this, we showed using stratified analyses that the beneficial associations of being an NGO client remained for both HIV-negative and HIV-positive MSM . Also, mOur analyses suggest that NGOs targeting MSM in Ukraine are highly cost-effective and have been preventing considerable HIV infections and deaths. This beneficial impact has been achieved through condom distribution, while quickly diagnosing HIV-positive MSM and linking them to ART. UnfortuSupplemental Data File


The PRS was associated with alcohol-related morbidity (4785 incident events) and the risk estimate between the highest and lowest quintiles of the PRS was 1.83 . When adjusted for self-reported alcohol consumption, education, marital status, and gamma-glutamyl transferase blood levels in 28,639 participants with comprehensive baseline data from prospective cohorts, the risk estimate between the highest and lowest quintiles of the PRS was 1.58 . The PRS was also associated with all-cause mortality with a risk estimate of 1.33 between the highest and lowest quintiles  in the adjusted model. In conclusion, the PRS for alcohol consumption independently associates for both alcohol-related morbidity and all-cause mortality. Together, these findings underline the importance of heritable factors in alcohol-related health burden while highlighting how measured genetic risk for an important behavioral risk factor can be used to predict related health outcomes.While polygenic risk scores (PRS) have been shown to predict many diseases and risk factors, the potential of genomic prediction in harm caused by alcohol use has not yet been extensively studied. Here, we built a novel polygenic risk score of 1.1 million variants for alcohol consumption and studied its predictive capacity in 96,499 participants from the FinnGen study and 39,695 participants from prospective cohorts with detailed baseline data and up to 25 years of follow-up time. A 1 SD increase in the PRS was associated with 11.2 g (=0.93 drinks) higher weekly alcohol consumption (CI = 9.85–12.58 g,  As ethanol is a psychoactive substance with addictive properties2, alcohol consumption can lead to the development of alcohol use disorders (AUDs), globally prevalent mental disorders of pathological addictive or abusive drinking patterns, which are linked to worse health outcomes, negative socioeconomic effects, and increased mortality3. There is a strong connection between the health burden and the level of alcohol consumed4, and in total, alcohol has been estimated to be the most damaging of all substances of abuse, in terms of harm caused to self and others5.Alcohol drinking is a major dose-dependent contributor to morbidity and mortality. Globally, 3 million annual deaths  result from alcohol consumption, and is also linked to more than 200 disease and injury outcomes6 and its single nucleotide polymorphism-based heritability has been estimated to be 10%7. Recent large-scale genome-wide association studies (GWAS) have identified multiple loci associated with alcohol consumption, underlining the importance of large study populations for unraveling the genetic architecture underlying alcohol-related traits8. Similarly, GWAS of alcohol dependence, AUD, and the Alcohol Use Disorders Identification Test (AUDIT) scores have shown the traits to be genetically distinct but positively correlated11.Alcohol-related behaviors are also affected by genetic factors and the estimated heritability of alcohol consumption in twin studies has ranged between 35% and 65% (weighted average 37%)12. PRSs for known risk factors have also been shown to associate with the related disease13, and recently associations between multiple risk factor PRSs and related traits were confirmed and reported15. However, the link between PRSs for behavioral traits and associated health outcomes remains poorly understood.Polygenic risk scores (PRSs) derived from GWAS summary statistics have showcased improved performance in disease predictionn = 96,499) linked to electronic health records. Furthermore, we studied whether the PRS for alcohol consumption predicts alcohol-related outcomes beyond self-reported alcohol consumption and other related risk factors, thus providing more objective information independent of individual reporting bias or temporal fluctuations.The assessment of potential health risks related to alcohol has so far relied on traditional risk factors, including family history, without explicit measurement of genetic risk. Here we developed a highly polygenic risk score for alcohol consumption and studied whether alcohol-related polygenic burden predicts alcohol-use disorders and other alcohol-related morbidity and mortality in Finnish biobank cohorts (https://www.finngen.fi/), which includes prospective epidemiological and disease-based cohorts as well as hospital biobank samples 19.Additionally, three Finnish twin cohorts, FinnTwin12, NAG-FIN, and Old Twin, were pooled and analyzed as one dataset. For these datasets, cohort baseline data were available, but the cohorts were not linked to electronical health records. For details regarding the twin datasets, see the online descriptions (Using nationwide registries for deaths (1969–2016), hospital discharges (1969–2016), outpatient specialist appointments (1998–2016), and drug purchases (1995–2016), we combined 21 somatic and psychiatric alcohol-related diagnoses into a composite disease endpoint, harmonizing the International Classification of Diseases (ICD) revisions 8, 9, and 10, and ATC-codes Table . These rFinnGen, FINRISK, Health 2000, and Finnish Twin Cohort samples were genotyped with Illumina and Affymetrix genomewide SNP arrays. Individuals with non-European ancestry or uncertain sex were excluded. Within each cohort, every genotyping batch was first imputed separately and then merged together for association analyses. The details about the genotype calling, quality controls, and imputation are provided in the n = 527,282 after exclusions). LDpred-method20 was used to account for linkage disequilibrium (LD) among loci with whole-genome sequencing data on 2690 Finns serving as the external LD reference panel. We compared the PRSs generated with LDpred-parameters and their predictive ability in FINRISK  by calculating the weighted sum of risk allele dosages for each variant. The number of variants in the final scores was 1.1 million .Summary statistics from the largest existing GWAS meta-analysis on alcohol consumption (8) were used for constructing the PRS. To avoid overfitting, a separate ad hoc meta-analysis was performed by GSCAN , and 95% confidence interval (95% CI) in the survival analyses where age was used as the time scale. R’s cox.zph function was used to test whether the proportional assumption criteria applied in our models. Linear regression in FINRISK and Health 2000 and linear mixed model in the Twin Cohort was used for estimating the relationship between the PRS and alcohol consumption. Logistic regression in the FINRISK and Health 2000 cohorts and linear mixed model in the Twin Cohort was used to estimate the relationship between alcohol abstinence and the PRS.x + 1) -transformed alcohol consumption-estimate, current smoking status, binary higher education status, binary marital/cohabitation status, and gamma-glutamyl transferase (GGT) blood levels at baseline served as covariates. The GGT levels were measured following uniform recommendations of the European Committee for Clinical Laboratory Standards (ECCLS)22 enabling comparability between the cohorts.All the cohorts  were analyzed independently as single datasets where age, sex, genotyping array, and the first ten principal components of ancestry were used as core covariates. Additionally, body mass was used as a covariate in the model estimating the PRS–alcohol consumption relationship. Self-reported weekly average alcohol consumption from the past year  was used as the estimate for alcohol consumption. In the fully adjusted survival model analyses, log and individuals with covariate missingness were excluded. The PRS was normalized and included as a continuous variable in the models. In the survival analysis, the highest and lowest genetic risk for alcohol consumption were compared using PRS quintiles.In analyses using baseline consumption data, the analyses were performed separately in the Health 2000, FINRISK Study, and Twin Cohorts and then meta-analyzed using fixed effects model.23 along with calculating the continuous reclassification improvement (NRI)24 and integrated discrimination improvement (IDI)25. The Hosmer–Lemeshow goodness-of-fit test was used to test model calibration.In risk prediction, FINRISK cohorts with at least 10 years of follow-up (from 1992 to 2002) were used to train the model, and the predictive performance was tested in the Health 2000 cohort. The maximal follow-up window was restricted to 10 years. The change in the predictive performance was assessed by comparing models with and without the PRS using the correlated C-index approachThe study was conducted in accordance with the principles of the Helsinki declaration. Written informed consent was obtained from all the study participants. For the Finnish Institute of Health and Welfare (THL)-driven FinnGen preparatory project and FinnGen project, all patients and control subjects had provided informed consent for biobank research, based on the Finnish Biobank Act. Alternatively, FINRISK and Health 2000 cohorts were based on study specific consents and later transferred to the THL Biobank after approval by Valvira, the National Supervisory Authority for Welfare and Health. Recruitment protocols followed the biobank protocols approved by Valvira. The Biobank Access Decisions for FinnGen samples and data utilized in FinnGen Data Freeze 2 include: Auria Biobank AB17-5154, THL Biobank BB2017_55, BB2017_111, BB2018_19, BB_2018_34, Finnish Red Cross Blood Service Biobank 7.12.2017, Helsinki Biobank HUS/359/2017 and Northern Finland Biobank Borealis BB_2017_1013. The Ethical Review Board of the Hospital District of Helsinki and Uusimaa approved the FinnGen study protocol Nr HUS/990/2017. The FinnGen preparatory project as well as the FinnGen project was approved by THL, approval numbers THL/2031/6.02.00/2017, amendments THL/341/6.02.00/2018, THL/2222/6.02.00/2018, THL/1101/5.05.00/2017, VRK43431/2017-3, KELA 131/522/2018, and Statistics Finland TK-53-1041-17. The Twin Cohort studies were approved by the Coordinating Ethical Committee of the Helsinki and Uusimaa Hospital District, reference numbers 246/13/03/00/15, 113/E3/2001, and HUS/1169/2016. The transfer of the FINRISK and Health 2000 sample collections to the THL biobank has been approved by the Coordinating Ethics Committee of Helsinki University Hospital on 10 October 2014 and by the Ministry of Social Affairs and Health on 9 March 2015. This study was conducted under the THL biobank permission BB2017_64 . No additional ethical approval was needed for meta-analyzing the results. All DNA samples and data in this study were pseudonymized.Our primary dataset (FinnGen) is comprised of 96,499 unrelated individuals  with a total of 55,484,114 person-years of registry-based follow-up and 4785 first-observed alcohol-related major health events. Alcohol consumption estimates were available for a total of 39,695 individuals from the prospective cohorts , the PRS for alcohol consumption was strongly associated with self-reported alcohol consumption. A 1 SD increase in the PRS was associated with an 11.2 g (=0.93 drinks á 12 g) increase in weekly pure alcohol intake  . In addition, the PRS was negatively associated with alcohol abstinence . In FINRISK and Health2000, a 1 SD increase in the PRS for alcohol consumption was associated with a 13.7% reduced likelihood of being a nondrinker  while this was not the case in the Twin Cohort where there were only 30 nondrinkers (OR = 0.999 [0.998–1.00] p = 0.31).In a meta-analysis of the three cohorts with alcohol consumption estimates available (58) Fig. . Adding n = 96,499, cases = 4785)  and a 1 SD increase in the PRS was associated with a 26% increase in risk . The association was similar in both males  and females .The PRS for alcohol consumption was strongly associated with increased risk for lifelong major alcohol-related events derived from electronic health-records in the FinnGen dataset (85) Fig. . The difn = 28,639, cases = 911). In a meta-analysis of the two cohorts, 1 PRS SD was associated with a 26% increased risk of incident alcohol-related events when the consumption-estimate was not in the model  and with a 15% increase when alcohol consumption was in the model . In a fully adjusted model, including marital status, education, smoking status, and GGT, the estimate was unchanged  (Table p = 8.2 × 10–5).In the cohorts where alcohol consumption estimates and other related baseline data were available at the cohort entry time, the PRS was associated with an increased risk of incident major alcohol-related events and the association was maintained also in the fully adjusted model (p = 2.0 × 10–11). The risk estimate between the highest and lowest 20% in the PRS was 1.27 . In our prospective cohorts, with cause-of-death information available, 4125 deaths were recorded. For all-cause mortality, there was 11% increase in the risk of death per 1 PRS SD in the basic model  and 9% in the fully adjusted model . The risk difference between the highest and lowest quintiles of the PRS was 33%  in the fully adjusted model.We observed a similar increase in the risk of alcohol-related and all-cause mortality. In FinnGen with 7249 deaths, 1 SD increase in the PRS for alcohol consumption was associated with 8% increase in the risk of death . When alcohol consumption was included in the model, the increase was 13%  and in a model with all co-variates, 11%  (Table n = 3790) when fully adjusted for all covariates .Of the 4125 deaths, 335 were known to be alcohol-related. Without alcohol consumption in the model, the increase in alcohol-related mortality was 26% per 1 PRS SD  in the unadjusted model. Adjusting for marital status, education, and smoking explained part of the effect  and further adjusting with maximal amount of drinks taken explained most of the effect .The PRS was also associated with an interview-based DSM-IV AUD diagnosis in the Nicotine Addiction Genetics Family cohort  and a subset of FinnTwin16 cohort . A meta-analysis of the two cohorts (713 cases) resulted in a combined 20% increase in the prevalence of AUD per 1 PRS SD . Both IDI  and NRI  shifts were positive and statistically significant. When the log-transformed alcohol consumption estimate was included, a minimal improvement of prediction was observed . Similarly, a minimal gain was observed when adding PRS to a model with all available covariates including also marital status, education status, smoking status, and GGT .The predictive performance of the PRS was evaluated in the Health 2000 cohort  with a follow-up-window of 10 years based on the Cox model trained in the FINRISK cohort . In a model not including the alcohol consumption estimate, adding the PRS to the model increased the C-index by 0.020, from 0.69 to 0.71 . A higher genetic predisposition for alcohol-related harms was detected both in the presence and absence of alcohol consumption data, as our PRS predicted alcohol-related harms beyond self-reported alcohol consumption. Health services are encouraged to support initiatives for screening and brief interventions for harmful drinking31 as an effective strategy for tackling alcohol-related harm32. Thus, genetic information could potentially be used to improve the arsenal of possible strategies to detect high-risk individuals for targets of brief interventions. The fact that individuals in the highest PRS quintile showed an elevated risk for alcohol-related health events even in fully adjusted models could justify the use of genetic information even in clinical settings where a detailed history of alcohol consumption estimates, AUDIT-scores, or similar information are attainable. Communicating the information of higher risk for alcohol-related harm to patients could serve as a motivator for reducing drinking or committing to abstinence. However, the true effects of informing patients about their alcohol-related genomic risk warrants further research.Our score provides a genetic basis for potentially identifying a subset of high-risk individuals even early on in life, with potential for more targeted prevention of AUDs and other alcohol-related morbidity. Prevention is a cost-effective and efficient strategy to reduce alcohol-related harms34. Also, GGT is known to be less-than-ideal biochemical measure of drinking35. Some inaccuracy derives from true measurement error, but another source is the lifelong temporal fluctuation of alcohol-drinking patterns not captured by a measure at one single timepoint. Our PRS was associated with alcohol-related harms even when adjusting for self-reported alcohol consumption estimate. One potential reason for this is that the PRS contains information from the latent genetic predisposition for alcohol consumption, thus overriding both the true measurement error and temporal fluctuations in alcohol drinking volume.Self-reported alcohol consumption is known to be biased and problematic in terms of reliability and validity for predicting alcohol-related risks36. However, we built a PRS for alcohol consumption and successfully used it to predict alcohol-related harms. Due to the robustness of a self-reported single timepoint alcohol consumption estimate and the fact that different alcohol-related traits are to some degree genetically distinct11, it is expected that a PRS developed directly for alcohol-related morbidity will outperform our PRS in predicting alcohol-related health burden. Supporting this assumption, the general pattern is that PRSs are more strongly associated with their respective diseases than with related phenotypes.15. Unfortunately, no high-quality summary statistics for alcohol-related harms including both somatic and psychiatric outcomes yet exist; the performed GWAS have only covered AUD and alcohol dependence11 and been smaller in size than our discovery sample of choice, thus making future efforts for large-scale GWAS discovery based on alcohol-related harms more than necessary.Furthermore, it has been hypothesized that alcohol consumption-based genetic discovery might inform more about low-level drinking than about problematic drinking and AUDs37.Our PRS was derived using European ancestry discovery samples and tested in the Finnish population. Its applicability in other populations therefore needs further evaluation as the alcohol-related genetic mechanisms may vary between populations. However, it has to be noted that the PRS derived from a non-Finnish sample performed well in the Finnish dataset, even though Finns are somewhat genetically different from the rest of the EuropeansOur design allowed us to study outcomes prospectively. Our registry-based follow-up captures alcohol-related outpatient and inpatient visits, withdrawal treatment prescription for alcoholism, and deaths, thus covering major alcohol-related health events over several decades. Nonetheless, some of the milder cases of alcohol-related health problems could have gone undetected.In conclusion, a PRS for alcohol consumption was associated with elevated risk for incident alcohol-related health events and all-cause mortality. These findings underline the importance of heritable factors driving alcohol-related behavior. A successful attempt to predict alcohol-related health outcomes with a PRS shows promise in possible future utilization of genetic information in risk estimation and prediction of alcohol-related harms.SI. Supplementary Information


Leishmania infantum, the causative agent of human zoonotic visceral leishmaniasis, and therefore domestic dogs play a central role in transmitting the disease to humans. Studies on the effect of insecticide-impregnated dog collars for controlling canine visceral leishmaniasis (CanL) have been increasing; however, meta-analysis has not been conducted. This study assessed the effectiveness of insecticide-impregnated dog collars for preventing CanL. We searched , and Cochrane library), from inception until 2 May 2020. Two authors independently performed articles screening and data extraction. We applied the RoB 2.0 tool to evaluate the risk of bias in randomized trials, while the ROBINS-I tool was used for non-randomized trials. I-squared statistics(I2) and funnel plot and Egger’s test, respectively, were used to assesses heterogeneity between studies and publication bias. Relative Risk (RR) and 95% Confidence Interval (CI) were calculated using the random-effects model in Stata 14 software. Out of 242 citations identified, 14 studies comprising 3786 collared dogs and 3428 uncollared dogs were eligible for meta-analysis. The use of deltamethrin-impregnated dog collars(DMC) showed an overall effectiveness of 54%  in decreasing incidence of CanL, while 10% imidacloprid and 4.5% flumethrin collars provided an overall effectiveness of 90% . DMC efficacy stratified by follow-up duration was estimated to be 58% , 54% , 53%  for follow-up periods of 5 to 6 months, 1 year and 2 years, respectively. The current evidence indicates that using insecticide-impregnated dog collars can reduce the risk of CanL caused by L. infantum. Therefore, insecticide-impregnated dog collars could be a viable alternative for inclusion as a public health measure for controlling CanL.Canines are proven reservoir hosts of  Leishmania infantum, mostly occur in the Mediterranean region, and South America ×100% where df is degrees of freedom (number of studies minus 1) [2 values of <30%, 30–75%, and <75% were deemed as low, moderate, and high heterogeneity, respectively, and the P-value was set at 0.05. We assessed publication bias qualitatively and then quantitatively confirmed using the funnel plot and Egger's test for small-study effects, respectively. Since publication bias was detected, we applied Duval and Tweedie's non-parametric/ trim and fill method to adjust the pooled estimate. We also carried out one study-leave-out sensitivity analysis to investigate the effect of each study on the pooled effect size estimate.We implemented minus 1) . I2 valuThe process of articles search, screening, selection of eligible studies for this study is presented in A summary of 14 eligible studies (with 15 comparisons) , 21–30 iP < 0.001. Since publication bias was detected, we performed Duval and Tweedie non-parametric/ trim and fill method [In this study, the presence of publication bias among studies that used DMC for controlling CanL incidence was examined by visual inspection of the funnel plot and Egger's test for small-study effects. The funnel plot appears to be asymmetrical , and thel method ; howeverA leave-one-out sensitivity analysis was performed to determine the effect of a single study on the overall efficacy estimates between studies using DMC . A leave2 = 63.2%, P = 0.002). And according to combined results of 3 studies, the use of Seresto decreases CanL incidence by 90% in collared dogs relative to uncollared control dogs  , with statistically significant moderate heterogeneity among studies (I = 0.0%) .The result of the pooled effectiveness of DMC stratified by diagnostic methods and follow-up period are presented in P = 0.893) and total sample size ; P  =  0.512) were found to be statistically non-significant predictors of effectiveness of DMC in reducing CanL incidence. Because of an insufficient number of studies, meta-regression analysis was impossible for Seresto efficacy.Univariate meta-regression was conducted based on years of publication of included studies and a total sample size of 12 selected studies assessing the effectiveness of DMC on CanL incidence. However, both years of publication , While a previous systematic review  supports the use of insecticide-impregnated dog collars can prevent CanL , this stIn the present systematic review and meta-analysis, pooled estimates of DMC effectiveness for reducing CanL incidence was 54%. This finding is in line with the findings of individual studies in Brazil, Italy, Iran that reported that DMC could reduce risk of CanL by 46–54% , 26, 27,Collar loss rate and collar replacement approaches would have led to the discrepancy in DMC and Seresto collars' effectiveness. The loss of collar rate in DMC studies was generally higher 34.5–56%) , 29, 34 .5–56% , In this systematic review and meta-analyses, meta-regression analysis did not show statistically significant association with both total sample size and year of publication, which can be interpreted as DMC efficacy in reducing the risk of incidental CanL was not influenced by total sample size newer studies.The protective effect of Seresto against CanL is relatively less extensively studied and exclusively evaluated in Italy. Based on pooled estimates of this study, Seresto showed better effectiveness in the reduction of CanL incidence (90%), compared to DMC (54%). This comparatively better protection provided by Seresto could be due to the synergistic action of insecticidal properties of imidacloprid and the acaricidal properties of flumethrin, which ensure the slow and continuous release of active ingredients from collar matrix system to over skin surface of collared dogs, thereby provide 8 months of protection against the vector, although DMC conferred 4–6 months of protection against sandflies , 35. ConThere are some limitations noted in this study. First, due to the relatively small number of included studies, assessment of publication bias and meta-regression analysis could be underpowered. Second, taking in to account the small studies included here to provide pooled estimates of Seresto effectiveness of for control of CanL incidence, there may be a lack of power in the overall effectiveness of Seresto. Therefore, the overall effectiveness of Seresto should be interpreted with caution. Third, while the loss of follow-up in a longitudinal study is inevitable, the included studies have reported high rate loss to follow-up which may induce attrition bias. Fourth, the studies included in this meta-analysis are from three countries. Fifth, this study did not include studies published other than the English language, which may lead to language bias. Despite these shortcomings, we performed an exhaustive and systematic literature search using databases and manual searches, we were able to use robust statistical techniques to combine overall effectiveness by enlarging sample size, we assessed sources of heterogeneity using both subgroup analysis and meta-regression, and we performed a sensitivity analysis to ensure that our estimate was not affected by a single study which could enable us to draw a firm conclusion.The result of the current evidence suggests that insecticide-impregnated dog collars could reduce the incidence rate of CanL. Consequently, insecticide-impregnated dog collars could be a valid alternative for inclusion in public health measures for reducing the incidence of CanL, which may in turn help to mitigate humans' zoonotic visceral leishmaniasis. Further large-scale studies that would evaluate and monitor the effectiveness of insecticide-impregnated dog collars are needed to provide a clearer picture of how much insecticide-impregnated dog collars may influence CanL incidence taking into account various socio-demographic and environmental factors.S1 Checklist(DOC)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S1 File(DOCX)Click here for additional data file.S2 File(DOCX)Click here for additional data file.


Whether the associations are due to the preterm birth insult We employed a within-sibling comparison design, using cognitive-performance and event-related potential (ERP) measures from 104 preterm-born adolescents and 104 of their term-born siblings. Analyses focused on ADHD symptoms and cognitive and ERP measures from a cued continuous performance test, an arrow flanker task and a reaction time task.β = 0.32, p = 0.01, 95% CI 0.05 to 0.58) and specific cognitive-ERP impairments, such as IQ , preparation-vigilance measures and measures of error processing . There was a negligible within-sibling association between preterm birth with executive control measures of inhibition  or verbal working memory .Within-sibling analyses showed that preterm birth was significantly associated with increased ADHD symptoms  is independent of family-level risk and consistent with a causal inference. In contrast, our results suggest that previously observed associations between preterm birth with executive control processes of inhibition and working memory are instead linked to background characteristics of families with a preterm-born child rather than preterm birth insult  Of the sibling pairs, 45% (n = 47) were same-sex siblings. In total, 55% of the preterm-born siblings were older than their term-born sibling. A 48-h ADHD medication-free period was required prior to assessments. Written informed consent was obtained following procedures approved by the National Research Ethics Service Committee London – Bromley (13/LO/0068).The present analysis only uses siblings discordant for preterm birth. Therefore, the final sample in this analysis consisted of 208 participants: 104 preterm-born participants (GA ranged from 23 weeks to 36) and their 104 term-born siblings (GA ranged from 37 to 42 weeks). On average, the siblings in a pair were discordant by 5.97  assessment with cognitive tests and clinical interviews. As part of the EEG assessment, participants completed a cued continuous performance test (CPT) with flankers (CPT-OX) , the national standard development record given to parents. Preterm birth was considered as <37 gestational weeks and term birth was considered ⩾37 weeks.The vocabulary and block design subtests of the Wechsler Abbreviated Scale of Intelligence (WASI)   were calculated for each condition.Participants performed a four-choice RT task with a baseline condition  with four empty circles  first appearing for 8000 ms, after which one of them (the target) was coloured in , with a 500 Hz sampling rate, impedances kept under 10 kΩ, and FCz as the recording reference electrode. The electrooculograms were recorded from electrodes above and below the left eye and at the outer canthi. The EEG data were analysed using a Brain Vision Analyzer (2.0) . After down-sampling the data to 256 Hz, the EEG data were re-referenced to the average (turning FCz into an active electrode) and filtered offline with digital band-pass  Butterworth filters. Ocular artefacts were identified and removed from the data using Independent Component Analysis ; lower IQ, as well as decreased CNV amplitude and decreased Go-P3 amplitude on the CPT-OX task, decreased N2 amplitude and decreased Pe and ERN on the flanker task, increased MRT and RTV in the baseline condition of fast task, and decreased CNV amplitude and P3 amplitude on the fast-incentive condition of fast task, independent of familial factors  or NoGo-P3 amplitude  on the CPT-OX, compared to their term-born siblings; these within-sibling associations were therefore largely attenuated compared to the unrelated comparisons  and NoGo-P3 amplitude , compared to the unrelated control group; the results remained similar when IQ was additionally adjusted .Within-sibling comparisons showed that those who were born preterm were more likely to have increased parent-rated total ADHD symptoms [and on both inattentiveness .et al., et al., per se.In this sibling-comparison study of adolescents, we find evidence for significant associations of preterm birth with increased ADHD symptoms, including both inattentiveness and hyperactivity-impulsivity sub-scales, and with specific cognitive-neurophysiological impairments, including IQ, preparation-vigilance processes  and error and conflict processing , which are independent of familial factors shared by siblings, indicating that preterm birth is likely in the causal pathway leading to these identified impairments. In contrast, the association of preterm birth with executive control measures of working memory (DSB) and inhibition (NoGo-P3) was not independent of familial factors, indicating that these previously obtained associations  and attenuated response inhibition (NoGo-P3) when controlling for unmeasured familial confounding factors. This suggests that familial factors shared by siblings, which include factors correlated with preterm birth , may account for these deviations with preterm birth previously observed in preterm individuals when compared to unrelated controls. The finding that working memory is not on the causal pathway from preterm birth is in line with results from a study which demonstrated that a combined measure of short-term auditory memory and verbal working memory (combining DSF and DSB) were not on the causal pathway between birth weight and ADHD symptoms in adolescents (Morgan et al., et al., The present study is, to our knowledge, the first study investigating the effects of preterm birth on cognitive-neurophysiological measures in adolescents in a quasi-experimental sibling design, which is essential for drawing stronger causal inferences. However, as is the case for all such non-randomised quasi-experimental studies, we cannot rule out all confounding factors (D'Onofrio In conclusion, our findings provide novel insight into the potential causal pathways to cognitive-neurophysiological impairments and increased ADHD symptoms in adolescents born preterm. By distinguishing impairments that are consistent with a causal inference of preterm birth from those that are instead linked to background characteristics of families with a preterm-born child, these results suggest that interventions need to target both preterm-birth specific and family-level risk factors to minimise impairments in those at risk. If replicated, clinical implications include raising the awareness about the increased risk of cognitive and brain impairments in preterm-born children; and understanding the increased risk of IQ and cognitive/brain impairments are likely causally related to preterm birth itself, whereas executive function impairments are via different causal mechanisms associated with families at risk.