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BackgroundMore than a year after recovering from COVID-19, a large proportion of individuals, many of whom work in the healthcare sector, still report olfactory dysfunctions. However, olfactory dysfunction was common already before the COVID-19 pandemic, making it necessary to also consider the existing baseline prevalence of olfactory dysfunction. To establish the adjusted prevalence of COVID-19 related olfactory dysfunction, we assessed smell function in healthcare workers who had contracted COVID-19 during the first wave of the pandemic using psychophysical testing.MethodsParticipants were continuously tested for SARS-CoV-2 IgG antibodies since the beginning of the pandemic. To assess the baseline rate of olfactory dysfunction in the population and to control for the possibility of skewed recruitment of individuals with prior olfactory dysfunction, consistent SARS-CoV-2 IgG naïve individuals were tested as a control group.ResultsFifteen months after contracting COVID-19, 37% of healthcare workers demonstrated a quantitative reduction in their sense of smell, compared to only 20% of the individuals in the control group. Fifty-one percent of COVID-19-recovered individuals reported qualitative symptoms, compared to only 5% in the control group. In a follow-up study 2.6 years after COVID-19 diagnosis, 24% of all tested recovered individuals still experienced parosmia.ConclusionsIn summary, 65% of healthcare workers experienced parosmia/hyposmia 15 months after contracting COVID-19. When compared to a control group, the prevalence of olfactory dysfunction in the population increased by 41 percentage points. Parosmia symptoms were still lingering two-and-a half years later in 24% of SARS-CoV-2 infected individuals. Given the amount of time between infection and testing, it is possible that the olfactory problems may not be fully reversible in a plurality of individuals.

ObjectiveAt some point in their career, many healthcare workers will experience psychological distress associated with being unable to take morally or ethically correct action, as it aligns with their own values; a phenomenon known as moral distress. Similarly, there are increasing reports of healthcare workers experiencing long-term mental and psychological pain, alongside internal dissonance, known as moral injury. This review examined the triggers and factors associated with moral distress and injury in Health and Social Care Workers (HSCW) employed across a range of clinical settings with the aim of understanding how to mitigate the effects of moral distress and identify potential preventative interventions.MethodsA systematic review was conducted and reported according to recommendations from Cochrane and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Searches were conducted and updated regularly until January 2024 on 2 main databases (CENTRAL, PubMed) and three specialist databases (Scopus, CINAHL, PsycArticles), alongside hand searches of study registration databases and other systematic reviews reference lists. Eligible studies included a HSCW sample, explored moral distress/injury as a main aim, and were written in English or Italian. Verbatim quotes were extracted, and article quality was assessed via the CASP toolkit. Thematic analysis was conducted to identify patterns and arrange codes into themes. Specific factors like culture and diversity were explored, and the effects of exceptional circumstances like the pandemic.ResultsFifty-one reports of 49 studies were included in the review. Causes and triggers were categorised under three domains: individual, social, and organisational. At the individual level, patients' care options, professionals' beliefs, locus of control, task planning, and the ability to make decisions based on experience, were indicated as elements that can cause or trigger moral distress. In addition, and relevant to the CoVID-19 pandemic, was use/access to personal protection resources. The social or relational factors were linked to the responsibility for advocating for and communication with patients and families, and professionals own support network. At organisational levels, hierarchy, regulations, support, workload, culture, and resources (staff and equipment) were identified as elements that can affect professionals' moral comfort. Patients' care, morals/beliefs/standards, advocacy role and culture of context were the most referenced elements. Data on cultural differences and diversity were not sufficient to make assumptions. Lack of resources and rapid policy changes have emerged as key triggers related to the pandemic. This suggests that those responsible for policy decisions should be mindful of the potential impact on staff of sudden and top-down change.ConclusionThis review indicates that causes and triggers of moral injury are multifactorial and largely influenced by the context and constraints within which professionals work. Moral distress is linked to the duty and responsibility of care, and professionals' disposition to prioritise the wellbeing of patients. If the organisational values and regulations are in contrast with individuals' beliefs, repercussions on professionals' wellbeing and retention are to be expected. Organisational strategies to mitigate against moral distress, or the longer-term sequalae of moral injury, should address the individual, social, and organisational elements identified in this review.

Urine osmolality is used throughout research to determine hydration levels. Prior studies have found black individuals to have elevated urine creatinine and osmolality, but it remains unclear which factors explain these findings. This cross-sectional, observational study sought to understand the relationship of self-reported race to urine creatinine and urine osmolality after accounting for age, socioeconomic status, and fluid intake. Data from 1,386 participants of the 2009-2012 National Health and Nutrition Examination Survey were utilized. Age, poverty-to-income ratio (PIR), urine flow rate (UFR), fluid intake, estimated lean body mass (LBM), urine creatinine, and urine osmolality were measured. In a sex-specific manner, black and white participants were matched on age, dietary moisture, UFR, and PIR. Urine creatinine was greater in black men (171 mg/dL) than white men (150 mg/dL) and greater in black women (147 mg/dL) than white women (108 mg/dL) (p < .001). Similarly, urine osmolality was greater in black women than white women (723 vs. 656 mOsm/kg, p = .001), but no difference was observed between white and black men (737 vs. 731 mOsm/kg, p = .417). Estimated LBM was greater in black men (61.8 kg) and women (45.5 kg) than in white men (58.9 kg) and women (42.2 kg) (p≤.001). The strongest correlate of urine osmolality in all race-sex groups was urine creatinine (Spearman ρ = .68-.75). These results affirm that individuals identifying as black produce higher urine creatinine concentrations and, in women, higher urine osmolality after matching for age, fluid intake, and socioeconomic status. The findings suggest caution when comparing urine hydration markers between racial groups.

BackgroundNeonatal jaundice (NNJ) is a major contributor to childhood morbidity and mortality. As many infants are discharged by 24 hours of age, mothers are key in detecting severe forms of jaundice. Mothers with limited knowledge of NNJ have a hard time identifying these infants who could go on to have the worst outcomes. This study aimed to determine the effect of a jaundice education package delivered to mothers prior to hospital discharge on maternal knowledge after discharge.MethodsThis was a before and after interventional study involving an education package delivered through a video message and informational voucher. At 10-14 days after discharge, participants were followed up via telephone to assess their post-intervention knowledge. A paired t-test was used to determine the effectiveness of the intervention on knowledge improvement. Linear regression was used to determine predictors of baseline knowledge and of change in knowledge score.ResultsOf the 250 mothers recruited, 188 were fit for analysis. The mean knowledge score was 10.02 before and 14.61 after the intervention, a significant difference (pConclusionMaternal knowledge of jaundice can be increased using a simple educational intervention, especially in settings where the burden of detection often falls on the mother. Further study is needed to determine the impact of this intervention on care seeking and infant outcomes.

BackgroundIn alignment with the Measles and Rubella (MR) Strategic Elimination plan, India conducted a mass measles and rubella vaccination campaign across the country between 2017 and 2020 to provide a dose of MR containing vaccine to all children aged 9 months to 15 years. We estimated campaign vaccination coverage in five districts in India and assessed campaign awareness and factors associated with vaccination during the campaign to better understand reasons for not receiving the dose.Methods and findingsCommunity-based cross-sectional serosurveys were conducted in five districts of India among children aged 9 months to 15 years after the vaccination campaign. Campaign coverage was estimated based on home-based immunization record or caregiver recall. Campaign coverage was stratified by child- and household-level risk factors and descriptive analyses were performed to assess reasons for not receiving the campaign dose. Three thousand three hundred and fifty-seven children aged 9 months to 15 years at the time of the campaign were enrolled. Campaign coverage among children aged 9 months to 5 years documented or by recall ranged from 74.2% in Kanpur Nagar District to 90.4% in Dibrugarh District, Assam. Similar coverage was observed for older children. Caregiver awareness of the campaign varied from 88.3% in Hoshiarpur District, Punjab to 97.6% in Dibrugarh District, Assam, although 8% of children whose caregivers were aware of the campaign were not vaccinated during the campaign. Failure to receive the campaign dose was associated with urban settings, low maternal education, and lack of school attendance although the associations varied by district.ConclusionAwareness of the MR vaccination campaign was high; however, campaign coverage varied by district and did not reach the elimination target of 95% coverage in any of the districts studied. Areas with lower coverage among younger children must be prioritized by strengthening the routine immunization programme and implementing strategies to identify and reach under-vaccinated children.

BackgroundTo estimate the effects on pain of two medications (low-dose naltrexone and gabapentin) compared to placebo among people with HIV (PWH) with heavy alcohol use and chronic pain.MethodsWe conducted a pilot, randomized, double-blinded, 3-arm study of PWH with chronic pain and past-year heavy alcohol use in 2021. Participants were recruited in St. Petersburg, Russia, and randomized to receive daily low-dose naltrexone (4.5mg), gabapentin (up to 1800mg), or placebo. The two primary outcomes were change in self-reported pain severity and pain interference measured with the Brief Pain Inventory from baseline to 8 weeks.ResultsParticipants (N = 45, 15 in each arm) had the following baseline characteristics: 64% male; age 41 years (SD±7); mean 2 (SD±4) heavy drinking days in the past month and mean pain severity and interference were 3.2 (SD±1) and 3.0 (SD±2), respectively. Pain severity decreased for all three arms. Mean differences in change in pain severity for gabapentin vs. placebo, and naltrexone vs. placebo were -0.27 (95% confidence interval [CI] -1.76, 1.23; p = 0.73) and 0.88 (95% CI -0.7, 2.46; p = 0.55), respectively. Pain interference decreased for all three arms. Mean differences in change in pain interference for gabapentin vs. placebo, and naltrexone vs. placebo was 0.16 (95% CI -1.38, 1.71; p = 0.83) and 0.40 (95% CI -1.18, 1.99; p = 0.83), respectively.ConclusionNeither gabapentin nor low-dose naltrexone appeared to improve pain more than placebo among PWH with chronic pain and past-year heavy alcohol use.Clinical trial registrationClinicalTrials.gov (NCT4052139).

BackgroundInterventions to improve physical activity (PA) among adolescents continue to be a public health priority. To promote PA more effectively, we need to identify the main factors contributing to (not) engagement in PA in the perspective of adolescents themselves. Thus, we explored the barriers and enablers for sufficient moderate-to-vigorous physical activity (MVPA) in adolescents from their point of view.MethodsWe used qualitative data collected as part of the international Health Behaviour in School-Aged Children study. We obtained data from 14-17 years old adolescents from the first year of Slovak high school. We conducted 11 online, semi-structured individual and group interviews with 24 participants in total (7 boys; mean age = 15.17, SD = 0.87) in Slovakia. We analysed the data using consensual qualitative research and thematic analysis.ResultsIn the statements of adolescents, four main themes were identified regarding factors contributing to (not) engagement in PA among adolescents. 'Myself as a source' represents the importance of adolescents' own efforts, knowledge, physical predispositions and PA experience. 'How PA can be done' represents school as an opportunity for PA, and PA teachers and sports coaches as specialists who can create an enabling environment for sports. 'Others as a source' represents the social circle that can set a positive sports example and can encourage adolescent's efforts in PA. 'Factors outside' represents other factors that can inspire adolescents, e.g. by giving them a comfortable space and time to exercise, or can be a barrier to PA.ConclusionThe potential factors that include adolescents' perspectives can be more leveraged in designing supportive, inclusive, enjoyable, and skills-appropriate PA programmes.

Mycobacterium tuberculosis (M.tb) causes tuberculosis (TB) and remains one of the leading causes of mortality due to an infectious pathogen. Host immune responses have been implicated in driving the progression from infection to severe lung disease. We analyzed longitudinal RNA sequencing (RNAseq) data from the whole blood of 74 TB progressors whose samples were grouped into four six-month intervals preceding diagnosis (the GC6-74 study). We additionally analyzed RNAseq data from an independent cohort of 90 TB patients with positron emission tomography-computed tomography (PET-CT) scan results which were used to categorize them into groups with high and low levels of lung damage (the Catalysis TB Biomarker study). These groups were compared to non-TB controls to obtain a complete whole blood transcriptional profile for individuals spanning from early stages of M.tb infection to TB diagnosis. The results revealed a steady increase in the number of genes that were differentially expressed in progressors at time points closer to diagnosis with 278 genes at 13-18 months, 742 at 7-12 months and 5,131 detected 1-6 months before diagnosis and 9,205 detected in TB patients. A total of 2,144 differentially expressed genes were detected when comparing TB patients with high and low levels of lung damage. There was a large overlap in the genes upregulated in progressors 1-6 months before diagnosis (86%) with those in TB patients. A comprehensive pathway analysis revealed a potent activation of neutrophil and platelet mediated defenses including neutrophil and platelet degranulation, and NET formation at both time points. These pathways were also enriched in TB patients with high levels of lung damage compared to those with low. These findings suggest that neutrophils and platelets play a critical role in TB pathogenesis, and provide details of the timing of specific effector mechanisms that may contribute to TB lung pathology.

BackgroundPrevious research indicates clinical outcomes among HIV-infected men in sub-Saharan Africa are sub-optimal. The SEARCH test and treat trial (NCT01864603) intervention included antiretroviral care delivery designed to address known barriers to HIV-care among men by decreasing clinic visit frequency and providing flexible, patient-centered care with retention support. We sought to understand facilitators and barriers to retention in care in this universal treatment setting through quantitative and qualitative data analysis.MethodsWe used a convergent mixed methods study design to evaluate retention in HIV care among adults (age > = 15) during the first year of the SEARCH (NCT01864603) test and treat trial. Cox proportional hazards regression was used to evaluate predictors of retention in care. Longitudinal qualitative data from n = 190 in-depth interviews with HIV-positive individuals and health care providers were analyzed to identify facilitators and barriers to HIV care engagement.ResultsThere were 1,863 men and 3,820 women who linked to care following baseline testing. Retention in care was 89.7% (95% CI 87.0-91.8%) among men and 89.0% (86.8-90.9%) among women at one year. In both men and women older age was associated with higher rates of retention in care at one year. Additionally, among men higher CD4+ at ART initiation and decreased time between testing and ART initiation was associated with higher rates of retention. Maintaining physical health, a patient-centered treatment environment, supportive partnerships, few negative consequences to disclosure, and the ability to seek care in facilities outside of their community of residence were found to promote retention in care.ConclusionsFeatures of the ART delivery system in the SEARCH intervention and social and structural advantages emerged as facilitators to retention in HIV care among men. Messaging around the health benefits of early ART start, decreasing logistical barriers to HIV care, support of flexible treatment environments, and accelerated linkage to care, are important to men's success in ART treatment programs. Men already benefit from increased social support following disclosure of their HIV-status. Future efforts to shift gender norms towards greater equity are a potential strategy to support high levels of engagement in care for both men and women.

BackgroundCaring for someone with cancer during end of life care can be a challenging and complex experience. Those living in rural and regional areas are less likely to have local healthcare services and may be physically isolated. Even where support services such as respite do exist, they may be less likely to be accessed due to the time burden in travelling to services. This was compounded by the COVID-19 pandemic.AimTo understand the potential benefits of peer support for bereaved carers of people with cancer from rural and regional locations during the COVID-19 period.MethodsPhone interviews were conducted with bereaved cancer carers living in rural and regional areas in Victoria. Semi-structured interviews were used, and participants were asked about their experience as a carer, bereavement and the potential for peer support. Interviews were audio recorded and transcribed verbatim; transcripts were coded and a thematic analysis was conducted.Findings12 interviews were conducted. Carers were mostly female (85%) and were on average 58 years of age (range 42-71). Interviews lasted an average of 58 minutes (range 53-91 minutes). Three themes were derived from the data; 1) Supportive care needs while caring and the impact of COVID-19; 2) Isolation during bereavement compounded by the COVID-19 pandemic; and 3) Peer support requires flexibility to meet diverse needs.ConclusionPeer support has potential to assist bereaved carers of people with cancer. A co-design approach may be beneficial for developing a flexible model for supporting and linking carers together.

BackgroundCryptosporidium is a gastrointestinal pathogen that presents a serious opportunistic infection in immunocompromised individuals including those living with human immunodeficiency syndrome. The CRYPTOFAZ trial, previously published, was conducted in Malawi to evaluate the efficacy of clofazimine in response to an unmet need for drugs to treat cryptosporidiosis in HIV populations. A combination of rapid diagnostic tests, ELISA, qPCR, and conventional sequencing were employed to detect Cryptosporidium in 586 individuals during pre-screening and monitor oocyst shedding and identify enteric co-pathogens in 22 enrolled/randomized participants during the in-patient period and follow-up visits.MethodologyOocyst shedding as measured by qPCR was used to determine primary trial outcomes, however pathogen was detected even at trial days 41-55 in individuals randomized to either clofazimine or placebo arms of the study. Therefore, in this work we re-examine the trial outcomes and conclusions in light of data from the other diagnostics, particularly ELISA. ELISA data was normalized between experiments prior to comparison to qPCR. The amount of all identified enteric pathogens was examined to determine if co-pathogens other than Cryptosporidium were major causative agents to a participant's diarrhea.ConclusionELISA had higher sample-to-sample variability and proved to be equally or less sensitive than qPCR in detecting Cryptosporidium positive samples. Compared to qPCR, ELISA had equal or greater specificity in detecting Cryptosporidium negative samples. Sequencing identified several Cryptosporidium species including viatorum which has never been identified in Malawi and Southern Africa. In addition to Cryptosporidium, enterotoxigenic E. coli was also identified as a pathogen in diarrheagenic amounts in 4 out of 22 participants.

Non-physical barriers for migrating fish, such as effluent plumes discharged by sewage treatment plants (WWTPs), are hardly considered, and field studies on this topic are very scarce. The encounter with these plumes however may evoke behavioural responses in fish and could delay or (partially) block the migration. In this study, the behavioural responses of 40 acoustically-tagged silver eel (Anguilla anguilla) were monitored in situ, when confronting a WWTP effluent plume during their downstream migration in the canal Eems, the Netherlands. Their behavioural responses and the potential blocking effect of the plume were assessed using a 2D and 3D telemetry design displayed in the waterway, and matched to a modelled and calibrated WWTP effluent plume. When confronted with the WWTP effluent plume during their downstream migration, 22 of the silver eels (59%) showed an avoidance response, varying from lateral diverting to multiple turning in the vicinity of the effluent plume. Nineteen out of these 22 (86%) eventually passed the study site. No silver eel showed attraction to the plume. Delays in migration were from several hours up to several days. Due to the strong variation in discharged volumes and flow velocity of the receiving canal, the WWTP plume did not always flow over the full width of the canal. As a result, numerous migratory windows, where silver eels could pass the WWTP while avoiding direct contact with the plume, remained available in time. When discharge points cannot be avoided, reduced or restricted to areas that are not preferred as fish migration routes, discharge points should be designed such, that the chance is limited that a waterway is (temporarily) impacted over its full width.

BackgroundThe COVID-19 pandemic led to accepting a lot of various protective pandemic management-related measures (PanMan), which may have had a large impact on health care workers (HCWs) but evidence is scarce. We therefore explored the impact of measures during the second wave. We assessed the associations of PanMan with the Quality of Life (QoL) of hospital HCWs.MethodsWe collected data from 215 HCWs (77.7% females, mean age 44.4), who were working at the COVID-related departments of one large hospital in eastern Slovakia via a questionnaire, specifically developed in direct collaboration with them. We assessed PanMan related factors, such as COVID-19 experience, information overload, non-adherence of the public, work stress, barriers and facilitators of health care provision, and QoL related factors, such as impact on family life and activities, housekeeping, relationships with relatives and mental well-being. To analyse the data, we used logistic regression models adjusted for age and gender.ResultsPanMan greatly impacted the QoL of HCWs, in particular family life, housekeeping and mental well-being (odds ratio, 6.8-2.2). The most influential PanMan factors were COVID-19 experience (3.6-2.3), work stress (4.1-2.4) and barriers in health care provision (6.8-2.2). Perceiving work stress had a negative impact on all QoL domains, even on relationships with the greatest impact. Conversely, the PanMan factors reducing the negative impact on QoL were training and colleagues' support (0.4-0.1).ConclusionPanMan had a strong negative impact on the QoL of hospital HCWs during the second wave of the COVID-19 pandemic.

An increased blood pressure is a known comorbidity of both type 1 diabetes (T1DM) and obesity in children. Increasing evidence suggests a subtle interplay between epidermal growth factor (EGF) and renin along the juxtaglomerular system, regulating the impact of blood pressure on kidney health and the cardiovascular system. In this study, we investigated the relation between urinary EGF, serum renin and blood pressure in children with obesity or T1DM. 147 non-obese children with T1DM and 126 children with obesity, were included. Blood pressure was measured and mean arterial pressure (MAP) and the pulse pressure (PP) were calculated. Serum renin and urinary EGF levels were determined with a commercial ELISA kit. Partial Spearman rank correlation coefficients and multiple linear regression models were used to study the association between renin, the urinary EGF/urinary creatinine ratio and blood pressure parameters. The urinary EGF/urinary creatinine ratio is correlated with the SBP and the MAP in boys with obesity as well as in boys with T1DM. Multiple regression analysis showed that sex and pulse pressure in male subjects were found to be independently associated with renin. Sex, the presence of diabetes, age, the glomerular filtration rate and both pulse pressure and mean arterial pressure in male subjects were independently associated with urinary EGF/urinary creatinine. In conclusion, in boys with either obesity or diabetes, pulse pressure and mean arterial pressure are negatively associated with the functional integrity of the nephron, which is reflected by a decreased expression of urinary EGF.

Characterization of gene lists obtained from high-throughput genomic experiments is an essential task to uncover the underlying biological insights. A common strategy is to perform enrichment analyses that utilize standardized biological annotations, such as GO and KEGG pathways, which attempt to encompass all domains of biology. However, this approach provides generalized, static results that may fail to capture subtleties associated with research questions within a specific domain. Thus, there is a need for an application that can provide precise, relevant results by leveraging the latest research. We have therefore developed an interactive web application, Macrophage Annotation of Gene Network Enrichment Tool (MAGNET), for performing enrichment analyses on gene sets that are specifically relevant to macrophages. Using the hypergeometric distribution, MAGNET assesses the significance of overlapping genes with annotations that were curated from published manuscripts and data repositories. We implemented numerous features that enhance utility and user-friendliness, such as the simultaneous testing of multiple gene sets, different visualization options, option to upload custom datasets, and downloadable outputs. Here, we use three example studies compared against our current database of ten publications on mouse macrophages to demonstrate that MAGNET provides relevant and unique results that complement conventional enrichment analysis tools. Although specific to macrophage datasets, we envision MAGNET will catalyze developments of similar applications in other domains of interest. MAGNET can be freely accessed at the URL https://magnet-winterlab.herokuapp.com. Website implemented in Python and PostgreSQL, with all major browsers supported. The source code is available at https://github.com/sychen9584/MAGNET.

Hidradenitis suppurativa (HS) is a chronic relapsing inflammatory skin disease manifested as painful inflamed lesions including deep-seated nodules, abscesses and sinus tracts. The exact aetiology of HS is unclear. Recent evidence suggests that immune dysregulation plays a crucial role in pathogenesis and disease progression. Innate lymphoid cells (ILC) are a recently identified immune cell subset involved in mediating immunity, however their role in HS has not yet been investigated. Three distinct subsets of ILC- ILC1, ILC2 and ILC3 have been described, and these are involved in skin tissue homeostasis and pathologic inflammation associated with autoimmunity and allergic diseases. In this study, we analysed by multiparameter flow cytometry the frequencies of ILC subsets in skin and peripheral blood mononuclear cells (PBMC) of HS patients and compared these to healthy control subjects and psoriasis patients. The absolute numbers of total ILC and subsets thereof were significantly reduced in the blood of HS patients relative to healthy controls. However, when patients were stratified according to treatment, this reduction was no longer observed in patients undergoing anti-TNF treatment. In HS lesional skin the absolute numbers of ILC were significantly increased relative to control skin. Furthermore, the frequencies of total ILC as well as ILC2 and ILC3 were significantly higher in non-lesional than lesional HS skin. This study analysed for the first time the presence of ILC subsets in the blood and skin of HS patients. Our findings suggest that ILC may participate in HS pathogenesis.

Background: More than a year after recovering from COVID-19, a large proportion of individuals, many of whom work in the healthcare sector, still report olfactory dysfunctions. However, olfactory dysfunction was common already before the COVID-19 pandemic, making it necessary to also consider the existing baseline prevalence of olfactory dysfunction. To establish the adjusted prevalence of COVID-19 related olfactory dysfunction, we assessed smell function in healthcare workers who had contracted COVID‐19 during the first wave of the pandemic using psychophysical testing. Methods: Participants were continuously tested for SARS‐CoV‐2 IgG antibodies since the beginning of the pandemic. To assess the baseline rate of olfactory dysfunction in the population and to control for the possibility of skewed recruitment of individuals with prior olfactory dysfunction, consistent SARS-CoV‐2 IgG naïve individuals were tested as a control group. Results: Fifteen months after contracting COVID‐19, 37% of healthcare workers demonstrated a quantitative reduction in their sense of smell, compared to only 20% of the individuals in the control group. Fifty-one percent of COVID‐19‐recovered individuals reported qualitative symptoms, compared to only 5% in the control group. In a follow-up study 2.6 years after COVID-19 diagnosis, 24% of all tested recovered individuals still experienced parosmia. Conclusions: In summary, 65% of healthcare workers experienced parosmia/hyposmia 15 months after contracting COVID-19. When compared to a control group, the prevalence of olfactory dysfunction in the population increased by 41 percentage points. Parosmia symptoms were still lingering two-and-a half years later in 24% of SARS-CoV-2 infected individuals. Given the amount of time between infection and testing, it is possible that the olfactory problems may not be fully reversible in a plurality of individuals. [ABSTRACT FROM AUTHOR]

Objective: At some point in their career, many healthcare workers will experience psychological distress associated with being unable to take morally or ethically correct action, as it aligns with their own values; a phenomenon known as moral distress. Similarly, there are increasing reports of healthcare workers experiencing long-term mental and psychological pain, alongside internal dissonance, known as moral injury. This review examined the triggers and factors associated with moral distress and injury in Health and Social Care Workers (HSCW) employed across a range of clinical settings with the aim of understanding how to mitigate the effects of moral distress and identify potential preventative interventions. Methods: A systematic review was conducted and reported according to recommendations from Cochrane and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Searches were conducted and updated regularly until January 2024 on 2 main databases (CENTRAL, PubMed) and three specialist databases (Scopus, CINAHL, PsycArticles), alongside hand searches of study registration databases and other systematic reviews reference lists. Eligible studies included a HSCW sample, explored moral distress/injury as a main aim, and were written in English or Italian. Verbatim quotes were extracted, and article quality was assessed via the CASP toolkit. Thematic analysis was conducted to identify patterns and arrange codes into themes. Specific factors like culture and diversity were explored, and the effects of exceptional circumstances like the pandemic. Results: Fifty-one reports of 49 studies were included in the review. Causes and triggers were categorised under three domains: individual, social, and organisational. At the individual level, patients' care options, professionals' beliefs, locus of control, task planning, and the ability to make decisions based on experience, were indicated as elements that can cause or trigger moral distress. In addition, and relevant to the CoVID-19 pandemic, was use/access to personal protection resources. The social or relational factors were linked to the responsibility for advocating for and communication with patients and families, and professionals own support network. At organisational levels, hierarchy, regulations, support, workload, culture, and resources (staff and equipment) were identified as elements that can affect professionals' moral comfort. Patients' care, morals/beliefs/standards, advocacy role and culture of context were the most referenced elements. Data on cultural differences and diversity were not sufficient to make assumptions. Lack of resources and rapid policy changes have emerged as key triggers related to the pandemic. This suggests that those responsible for policy decisions should be mindful of the potential impact on staff of sudden and top-down change. Conclusion: This review indicates that causes and triggers of moral injury are multifactorial and largely influenced by the context and constraints within which professionals work. Moral distress is linked to the duty and responsibility of care, and professionals' disposition to prioritise the wellbeing of patients. If the organisational values and regulations are in contrast with individuals' beliefs, repercussions on professionals' wellbeing and retention are to be expected. Organisational strategies to mitigate against moral distress, or the longer-term sequalae of moral injury, should address the individual, social, and organisational elements identified in this review. [ABSTRACT FROM AUTHOR]

Urine osmolality is used throughout research to determine hydration levels. Prior studies have found black individuals to have elevated urine creatinine and osmolality, but it remains unclear which factors explain these findings. This cross-sectional, observational study sought to understand the relationship of self-reported race to urine creatinine and urine osmolality after accounting for age, socioeconomic status, and fluid intake. Data from 1,386 participants of the 2009–2012 National Health and Nutrition Examination Survey were utilized. Age, poverty-to-income ratio (PIR), urine flow rate (UFR), fluid intake, estimated lean body mass (LBM), urine creatinine, and urine osmolality were measured. In a sex-specific manner, black and white participants were matched on age, dietary moisture, UFR, and PIR. Urine creatinine was greater in black men (171 mg/dL) than white men (150 mg/dL) and greater in black women (147 mg/dL) than white women (108 mg/dL) (p <.001). Similarly, urine osmolality was greater in black women than white women (723 vs. 656 mOsm/kg, p =.001), but no difference was observed between white and black men (737 vs. 731 mOsm/kg, p =.417). Estimated LBM was greater in black men (61.8 kg) and women (45.5 kg) than in white men (58.9 kg) and women (42.2 kg) (p≤.001). The strongest correlate of urine osmolality in all race-sex groups was urine creatinine (Spearman ρ =.68-.75). These results affirm that individuals identifying as black produce higher urine creatinine concentrations and, in women, higher urine osmolality after matching for age, fluid intake, and socioeconomic status. The findings suggest caution when comparing urine hydration markers between racial groups. [ABSTRACT FROM AUTHOR]

Violent acts on university campuses are becoming more frequent. Enrollment rates of Latinos at universities is increasing. Research has indicated that youths are more susceptible to trauma, particularly Latinos. Thus, it is imperative to evaluate the validity of commonly used posttraumatic stress measures among Latino college students. The Impact of Event Scale-Revised (IES-R) is one of the most commonly used metrics of posttraumatic stress disorder symptomatology. However, it is largely unknown if the IES-R is measuring the same construct across different sub-samples (e.g. Latino versus non-Latino). The current study aimed to assess measurement invariance for the IES-R between Latino and non-Latino participants. A total of 545 participants completed the IES-R. One- and three-factor scoring solutions were compared using confirmatory factor analyses. Measurement invariance was then evaluated by estimating several multiple-group confirmatory factor analytic models. Four models with an increasing degree of invariance across groups were compared. A significant χ2 difference test was used to indicate a significant change in model fit between nested models within the measurement invariance testing process. The three-factor scoring solution could not be used for the measurement invariance process because the subscale correlations were too high for estimation (rs 0.92-1.00). Therefore, the one-factor model was used for the invariance testing process. Invariance was met for each level of invariance: configural, metric, scalar, and strict. All measurement invariance testing results indicated that the one-factor solution for the IES-R was equivalent for the Latino and non-Latino participants.

Accurate predictions of T-cell epitopes would be useful for designing vaccines, immunotherapies for cancer and autoimmune diseases, and improved protein therapies. The humoral immune response involves uptake of antigens by antigen presenting cells (APCs), APC processing and presentation of peptides on MHC class II (pMHCII), and T-cell receptor (TCR) recognition of pMHCII complexes. Most in silico methods predict only peptide-MHCII binding, resulting in significant over-prediction of CD4 T-cell epitopes. We present a method, ITCell, for prediction of T-cell epitopes within an input protein antigen sequence for given MHCII and TCR sequences. The method integrates information about three stages of the immune response pathway: antigen cleavage, MHCII presentation, and TCR recognition. First, antigen cleavage sites are predicted based on the cleavage profiles of cathepsins S, B, and H. Second, for each 12-mer peptide in the antigen sequence we predict whether it will bind to a given MHCII, based on the scores of modeled peptide-MHCII complexes. Third, we predict whether or not any of the top scoring peptide-MHCII complexes can bind to a given TCR, based on the scores of modeled ternary peptide-MHCII-TCR complexes and the distribution of predicted cleavage sites. Our benchmarks consist of epitope predictions generated by this algorithm, checked against 20 peptide-MHCII-TCR crystal structures, as well as epitope predictions for four peptide-MHCII-TCR complexes with known epitopes and TCR sequences but without crystal structures. ITCell successfully identified the correct epitopes as one of the 20 top scoring peptides for 22 of 24 benchmark cases. To validate the method using a clinically relevant application, we utilized five factor VIII-specific TCR sequences from hemophilia A subjects who developed an immune response to factor VIII replacement therapy. The known HLA-DR1-restricted factor VIII epitope was among the six top-scoring factor VIII peptides predicted by ITCall to bind HLA-DR1 and all five TCRs. Our integrative approach is more accurate than current single-stage epitope prediction algorithms applied to the same benchmarks. It is freely available as a web server (http://salilab.org/itcell).

Domestication research has largely focused on identification of morphological and genetic differences between extant populations of crops and their wild relatives. Little attention has been paid to the potential effects of environment despite substantial known changes in climate from the time of domestication to modern day. In recent research, the exposure of teosinte (i.e., wild maize) to environments similar to the time of domestication, resulted in a plastic induction of domesticated phenotypes in teosinte. These results suggest that early agriculturalists may have selected for genetic mechanisms that cemented domestication phenotypes initially induced by a plastic response of teosinte to environment, a process known as genetic assimilation. To better understand this phenomenon and the potential role of environment in maize domestication, we examined differential gene expression in maize (Zea mays ssp. mays) and teosinte (Zea mays ssp. parviglumis) between past and present conditions. We identified a gene set of over 2000 loci showing a change in expression across environmental conditions in teosinte and invariance in maize. In fact, overall we observed both greater plasticity in gene expression and more substantial changes in co-expressionnal networks in teosinte across environments when compared to maize. While these results suggest genetic assimilation played at least some role in domestication, genes showing expression patterns consistent with assimilation are not significantly enriched for previously identified domestication candidates, indicating assimilation did not have a genome-wide effect.

Background: Neonatal jaundice (NNJ) is a major contributor to childhood morbidity and mortality. As many infants are discharged by 24 hours of age, mothers are key in detecting severe forms of jaundice. Mothers with limited knowledge of NNJ have a hard time identifying these infants who could go on to have the worst outcomes. This study aimed to determine the effect of a jaundice education package delivered to mothers prior to hospital discharge on maternal knowledge after discharge. Methods: This was a before and after interventional study involving an education package delivered through a video message and informational voucher. At 10–14 days after discharge, participants were followed up via telephone to assess their post-intervention knowledge. A paired t-test was used to determine the effectiveness of the intervention on knowledge improvement. Linear regression was used to determine predictors of baseline knowledge and of change in knowledge score. Results: Of the 250 mothers recruited, 188 were fit for analysis. The mean knowledge score was 10.02 before and 14.61 after the intervention, a significant difference (p<0.001). Factors determining higher baseline knowledge included attendance of 4 or more antenatal visits (p < 0.001), having heard about NNJ previously (p < 0.001), having experienced an antepartum illness (p = 0.019) and higher maternal age (p = 0.015). Participants with poor baseline knowledge (β = 7.523) and moderate baseline knowledge (β = 3.114) had much more to gain from the intervention relative to those with high baseline knowledge (p < 0.001). Conclusion: Maternal knowledge of jaundice can be increased using a simple educational intervention, especially in settings where the burden of detection often falls on the mother. Further study is needed to determine the impact of this intervention on care seeking and infant outcomes. [ABSTRACT FROM AUTHOR]

Background: To estimate the effects on pain of two medications (low-dose naltrexone and gabapentin) compared to placebo among people with HIV (PWH) with heavy alcohol use and chronic pain. Methods: We conducted a pilot, randomized, double-blinded, 3-arm study of PWH with chronic pain and past-year heavy alcohol use in 2021. Participants were recruited in St. Petersburg, Russia, and randomized to receive daily low-dose naltrexone (4.5mg), gabapentin (up to 1800mg), or placebo. The two primary outcomes were change in self-reported pain severity and pain interference measured with the Brief Pain Inventory from baseline to 8 weeks. Results: Participants (N = 45, 15 in each arm) had the following baseline characteristics: 64% male; age 41 years (SD±7); mean 2 (SD±4) heavy drinking days in the past month and mean pain severity and interference were 3.2 (SD±1) and 3.0 (SD±2), respectively. Pain severity decreased for all three arms. Mean differences in change in pain severity for gabapentin vs. placebo, and naltrexone vs. placebo were -0.27 (95% confidence interval [CI] -1.76, 1.23; p = 0.73) and 0.88 (95% CI -0.7, 2.46; p = 0.55), respectively. Pain interference decreased for all three arms. Mean differences in change in pain interference for gabapentin vs. placebo, and naltrexone vs. placebo was 0.16 (95% CI -1.38, 1.71; p = 0.83) and 0.40 (95% CI -1.18, 1.99; p = 0.83), respectively. Conclusion: Neither gabapentin nor low-dose naltrexone appeared to improve pain more than placebo among PWH with chronic pain and past-year heavy alcohol use. Clinical trial registration: ClinicalTrials.gov (NCT4052139). [ABSTRACT FROM AUTHOR]

Mycobacterium tuberculosis (M.tb) causes tuberculosis (TB) and remains one of the leading causes of mortality due to an infectious pathogen. Host immune responses have been implicated in driving the progression from infection to severe lung disease. We analyzed longitudinal RNA sequencing (RNAseq) data from the whole blood of 74 TB progressors whose samples were grouped into four six-month intervals preceding diagnosis (the GC6-74 study). We additionally analyzed RNAseq data from an independent cohort of 90 TB patients with positron emission tomography-computed tomography (PET-CT) scan results which were used to categorize them into groups with high and low levels of lung damage (the Catalysis TB Biomarker study). These groups were compared to non-TB controls to obtain a complete whole blood transcriptional profile for individuals spanning from early stages of M.tb infection to TB diagnosis. The results revealed a steady increase in the number of genes that were differentially expressed in progressors at time points closer to diagnosis with 278 genes at 13-18 months, 742 at 7-12 months and 5,131 detected 1-6 months before diagnosis and 9,205 detected in TB patients. A total of 2,144 differentially expressed genes were detected when comparing TB patients with high and low levels of lung damage. There was a large overlap in the genes upregulated in progressors 1-6 months before diagnosis (86%) with those in TB patients. A comprehensive pathway analysis revealed a potent activation of neutrophil and platelet mediated defenses including neutrophil and platelet degranulation, and NET formation at both time points. These pathways were also enriched in TB patients with high levels of lung damage compared to those with low. These findings suggest that neutrophils and platelets play a critical role in TB pathogenesis, and provide details of the timing of specific effector mechanisms that may contribute to TB lung pathology.

ObjectivesThis systematic review assesses the scientific evidence regarding the effectiveness of organisational-level workplace mental health interventions on stress, burnout, non-clinical depressive and anxiety symptoms, and wellbeing in construction workers.MethodsEligibility criteria were randomized controlled trials (RCTs), cluster randomized controlled trials (cRCTs), controlled or uncontrolled before- and after studies published in peer-reviewed journals between 2010 and May 2022 in five databases (Academic Search Complete, PsycInfo, PubMed, Scopus and Web of Science). Outcomes were stress, burnout and non-clinical depression and anxiety symptoms, and wellbeing (primary) and workplace changes and sickness absenteeism (secondary). Quality appraisal was conducted using the QATQS scale, a narrative synthesis was applied. The protocol was published in PROSPERO CRD42020183640 https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020183640.Main resultsWe identified five articles (four studies) with a total sample size of 260, one cRCT, one controlled before- and after study, and two uncontrolled before- and after studies. The methodological quality of one study was rated as moderate, while for three studies it was weak. One study showed significant effects of a work redesign programme in short-term physiological stress parameters, one study showed a significant employee perceived improvement of information flow after supervisor training and one study showed a substantial non-significant decline in sick leave. There was no significant effect on general mental health (SF12) nor on emotional exhaustion. The focus of all studies was on physical health, while detailed mental health and wellbeing measures were not applied.Main conclusionsThe evidence for the effectiveness of organisational-level workplace mental health interventions in construction workers is limited with opportunities for methodological and conceptual improvement. Recommendations include the use of a wider range of mental health and wellbeing outcomes, interventions tailored to the specific workplace and culture in construction and the application of the principles of complex interventions in design and evaluation.

New Zealand’s Prime Minister, Jacinda Ardern, adopted a “go hard, go early” approach to eliminate COVID-19. Although Ardern and her Labour party are considered left-leaning, the policies implemented during the pandemic (e.g., police roadblocks) have the hallmarks of Right-Wing Authoritarianism (RWA). RWA is characterized by three attitudinal clusters (authoritarian aggression, submission, and conventionalism). The uniqueness of the clusters, and whether they react to environmental change, has been debated. Here, in the context of the pandemic, we investigate the relationship between political orientation and RWA. Specifically, we measured political orientation, support for New Zealand’s major political parties, and RWA among 1,430 adult community members. A multivariate Bayesian model demonstrated that, in the middle of a pandemic, both left-leaning and right-leaning individuals endorsed items tapping authoritarian submission. In contrast to authoritarian submission, and demonstrating the multidimensional nature of RWA, we observed the typical relationships between political orientation and authoritarian aggression and conventionalism was observed.

Background COVID-19 has so far affected more than 250 million individuals worldwide, causing more than 5 million deaths. Several risk factors for severe disease have been identified, most of which coincide with advanced age. In younger individuals, severe COVID-19 often occurs in the absence of obvious comorbidities. Guided by the finding of cytomegalovirus (CMV)-specific T cells with some cross-reactivity to SARS-CoV-2 in a COVID-19 intensive care unit (ICU) patient, we decided to investigate whether CMV seropositivity is associated with severe or critical COVID-19. Herpes simplex virus (HSV) serostatus was investigated as control. Methods National German COVID-19 bio-sample and data banks were used to retrospectively analyze the CMV and HSV serostatus of patients who experienced mild (n = 101), moderate (n = 130) or severe to critical (n = 80) disease by IgG serology. We then investigated the relationship between disease severity and herpesvirus serostatus via statistical models. Results Non-geriatric patients (< 60 years) with severe COVID-19 were found to have a very high prevalence of CMV-seropositivity, while CMV status distribution in individuals with mild disease was similar to the prevalence in the German population; interestingly, this was not detectable in older patients. Prediction models support the hypothesis that the CMV serostatus, unlike HSV, might be a strong biomarker in identifying younger individuals with a higher risk of developing severe COVID-19, in particular in absence of other co-morbidities. Conclusions We identified ‘CMV-seropositivity’ as a potential novel risk factor for severe COVID-19 in non-geriatric individuals in the studied cohorts. More mechanistic analyses as well as confirmation of similar findings in cohorts representing the currently most relevant SARS-CoV-2 variants should be performed shortly.

Background Social functioning is often impaired in schizophrenia (SZ) and Alzheimer’s disease (AD). However, commonalities and differences in social dysfunction among these patient groups remain elusive. Materials and methods Using data from the PRISM study, behavioral (all subscales and total score of the Social Functioning Scale) and affective (perceived social disability and loneliness) indicators of social functioning were measured in patients with SZ (N = 56), probable AD (N = 50) and age-matched healthy controls groups (HC, N = 29 and N = 28). We examined to what extent social functioning differed between disease and age-matched HC groups, as well as between patient groups. Furthermore, we examined how severity of disease and mood were correlated with social functioning, irrespective of diagnosis. Results As compared to HC, both behavioral and affective social functioning seemed impaired in SZ patients (Cohen’s d’s 0.81–1.69), whereas AD patients mainly showed impaired behavioral social function (Cohen’s d’s 0.65–1.14). While behavioral indices of social functioning were similar across patient groups, SZ patients reported more perceived social disability than AD patients (Cohen’s d’s 0.65). Across patient groups, positive mood, lower depression and anxiety levels were strong determinants of better social functioning (p’s Conclusions AD and SZ patients both exhibit poor social functioning in comparison to age- and sex matched HC participants. Social dysfunction in SZ patients may be more severe than in AD patients, though this may be due to underreporting by AD patients. Across patients, social functioning appeared as more influenced by mood states than by severity of disease.

BackgroundThe ability to accurately distinguish bacterial from viral infection would help clinicians better target antimicrobial therapy during suspected lower respiratory tract infections (LRTI). Although technological developments make it feasible to rapidly generate patient-specific microbiota profiles, evidence is required to show the clinical value of using microbiota data for infection diagnosis. In this study, we investigated whether adding nasal cavity microbiota profiles to readily available clinical information could improve machine learning classifiers to distinguish bacterial from viral infection in patients with LRTI.ResultsVarious multi-parametric Random Forests classifiers were evaluated on the clinical and microbiota data of 293 LRTI patients for their prediction accuracies to differentiate bacterial from viral infection. The most predictive variable was C-reactive protein (CRP). We observed a marginal prediction improvement when 7 most prevalent nasal microbiota genera were added to the CRP model. In contrast, adding three clinical variables, absolute neutrophil count, consolidation on X-ray, and age group to the CRP model significantly improved the prediction. The best model correctly predicted 85% of the 'bacterial' patients and 82% of the 'viral' patients using 13 clinical and 3 nasal cavity microbiota genera (Staphylococcus, Moraxella, and Streptococcus).ConclusionsWe developed high-accuracy multi-parametric machine learning classifiers to differentiate bacterial from viral infections in LRTI patients of various ages. We demonstrated the predictive value of four easy-to-collect clinical variables which facilitate personalized and accurate clinical decision-making. We observed that nasal cavity microbiota correlate with the clinical variables and thus may not add significant value to diagnostic algorithms that aim to differentiate bacterial from viral infections.

Fibrolamellar carcinoma (FLC) is a primary liver cancer that most commonly arises in adolescents and young adults in a background of normal liver tissue and has a poor prognosis due to lack of effective chemotherapeutic agents. The DNAJB1-PRKACA gene fusion (DP) has been reported in the majority of FLC tumors; however, its oncogenic mechanisms remain unclear. Given the paucity of cellular models, in particular FLC tumor cell lines, we hypothesized that engineering the DP fusion gene in HEK293T cells would provide insight into the cellular effects of the fusion gene. We used CRISPR/Cas9 to engineer HEK293T clones expressing DP fusion gene (HEK-DP) and performed transcriptomic, proteomic, and mitochondrial studies to characterize this cellular model. Proteomic analysis of DP interacting partners identified mitochondrial proteins as well as proteins in other subcellular compartments. HEK-DP cells demonstrated significantly elevated mitochondrial fission, which suggests a role for DP in altering mitochondrial dynamics. Transcriptomic analysis of HEK-DP cells revealed a significant increase in LINC00473 expression, similar to what has been observed in primary FLC samples. LINC00473 overexpression was reversible with siRNA targeting of PRKACA as well as pharmacologic targeting of PKA and Hsp40 in HEK-DP cells. Therefore, our model suggests that LINC00473 is a candidate marker for DP activity.

Q fever is a zoonosis caused by Coxiella burnetii. In Germany, the common sources of human infections include small ruminants that excrete the pathogen. Q fever in humans can be asymptomatic or nonspecific. However, severe disease progression is also possible, which can lead to death. Q fever in small ruminants is usually asymptomatic, although reproductive disorders may occur. To protect humans from Q fever, it is important that human and veterinary health professionals (practitioners/health authority employees) have comprehensive knowledge of the diagnosis, control and prevention of Q fever, and its zoonotic potential. To ensure and enhance this understanding, this stakeholder analysis assessed Q fever expertise in human and veterinary health professionals in Germany and investigated how these knowledge gaps can best be resolved. For this purpose, an online survey and two focus group discussions were conducted with 836 and 18 participants, respectively. Knowledge gaps are due to a lack of awareness of Q fever, especially among human health practitioners. Moreover, colleagues who have heard about Q fever still lack the necessary cross-species knowledge to successfully diagnose, control and prevent this zoonosis. Additionally, differences exist between stakeholders regarding their work context and the region in which they work. In this study, stakeholders in southwestern Germany had slightly better Q fever knowledge than their colleagues in northeastern Germany. In addition, information sources aimed at resolving knowledge gaps involve direct conversations between the stakeholders, as well as reading materials and seminars. Each of these information sources should focus on interdisciplinary resources to strengthen the cooperation between human and veterinary health professionals and to raise awareness of the strengths of each stakeholder group. These results have already been implemented by the Q-GAPS project, with goals of raising awareness of Q fever and filling knowledge gaps.

Chronic pelvic pain conditions such as interstitial cystitis/bladder pain syndrome (IC/BPS) remain clinical and mechanistic enigmas. Microglia are resident immune cells of the central nervous system (CNS) that respond to changes in the gut microbiome, and studies have linked microglial activation to acute and chronic pain in a variety of models, including pelvic pain. We have previously reported that mice deficient for the lipase acyloxyacyl hydrolase (AOAH) develop pelvic allodynia and exhibit symptoms, comorbidities, and gut dysbiosis mimicking IC/BPS. Here, we assessed the role of AOAH in microglial activation and pelvic pain. RNAseq analyses using the ARCHS4 database and confocal microscopy revealed that AOAH is highly expressed in wild type microglia but at low levels in astrocytes, suggesting a functional role for AOAH in microglia. Pharmacologic ablation of CNS microglia with PLX5622 resulted in decreased pelvic allodynia in AOAH-deficient mice and resurgence of pelvic pain upon drug washout. Skeletal analyses revealed that AOAH-deficient mice have an activated microglia morphology in the medial prefrontal cortex and paraventricular nucleus, brain regions associated with pain modulation. Because microglia express Toll-like receptors and respond to microbial components, we also examine the potential role of dysbiosis in microglial activation. Consistent with our hypothesis of microglia activation by leakage of gut microbes, we observed increased serum endotoxins in AOAH-deficient mice and increased activation of cultured BV2 microglial cells by stool of AOAH-deficient mice. Together, these findings demonstrate a role for AOAH in microglial modulation of pelvic pain and thus identify a novel therapeutic target for IC/BPS.

PurposeThe recent developments of tau-positron emission tomography (tau-PET) enable in vivo assessment of neuropathological tau aggregates. Among the tau-specific tracers, the application of 11C-pyridinyl-butadienyl-benzothiazole 3 (11C-PBB3) in PET shows high sensitivity to Alzheimer disease (AD)-related tau deposition. The current study investigates the regional tau load in patients within the AD continuum, biomarker-negative individuals (BN) and patients with suspected non-AD pathophysiology (SNAP) using 11C-PBB3-PET.Materials and methodsA total of 23 memory clinic outpatients with recent decline of episodic memory were examined using 11C-PBB3-PET. Pittsburg compound B (11C-PIB) PET was available for 17, 18F-flurodeoxyglucose (18F-FDG) PET for 16, and cerebrospinal fluid (CSF) protein levels for 11 patients. CSF biomarkers were considered abnormal based on Aβ42 (< 600 ng/L) and t-tau (> 450 ng/L). The PET biomarkers were classified as positive or negative using statistical parametric mapping (SPM) analysis and visual assessment. Using the amyloid/tau/neurodegeneration (A/T/N) scheme, patients were grouped as within the AD continuum, SNAP, and BN based on amyloid and neurodegeneration status. The 11C-PBB3 load detected by PET was compared among the groups using both atlas-based and voxel-wise analyses.ResultsSeven patients were identified as within the AD continuum, 10 SNAP and 6 BN. In voxel-wise analysis, significantly higher 11C-PBB3 binding was observed in the AD continuum group compared to the BN patients in the cingulate gyrus, tempo-parieto-occipital junction and frontal lobe. Compared to the SNAP group, patients within the AD continuum had a considerably increased 11C-PBB3 uptake in the posterior cingulate cortex. There was no significant difference between SNAP and BN groups. The atlas-based analysis supported the outcome of the voxel-wise quantification analysis.ConclusionOur results suggest that 11C-PBB3-PET can effectively analyze regional tau load and has the potential to differentiate patients in the AD continuum group from the BN and SNAP group.

ObjectiveTo explore the association of a functional germline variant in the 3'-UTR of KRAS with endometrial cancer risk, as well as the association of microRNA (miRNA) signatures and the KRAS-variant with clinical characteristics and survival outcomes in two prospective RTOG endometrial cancer trials.Methods/materialsThe association of the KRAS-variant with endometrial cancer risk was evaluated by case-control analysis of 467 women with type 1 or 2 endometrial cancer and 582 age-matched controls. miRNA and DNA were isolated for expression profiling and genotyping from tumor specimens of 46 women with type 1 endometrial cancer enrolled in RTOG trials 9708 and 9905. miRNA expression levels and KRAS-variant genotype were correlated with patient and tumor characteristics, and survival outcomes were evaluated by variant allele type.ResultsThe KRAS-variant was not significantly associated with overall endometrial cancer risk (14% controls and 17% type 1 cancers), although was enriched in type 2 endometrial cancers (24%, p = 0.2). In the combined analysis of RTOG 9708/9905, miRNA expression differed by age, presence of lymphovascular invasion and KRAS-variant status. Overall survival rates at 3 years for patients with the variant and wild-type alleles were 100% and 77% (HR 0.3, p = 0.24), respectively, favoring the variant.ConclusionsThe KRAS-variant may be a genetic marker of risk for type 2 endometrial cancers. In addition, tumor miRNA expression appears to be associated with patient age, lymphovascular invasion and the KRAS-variant, supporting the hypothesis that altered tumor biology can be measured by miRNA expression, and that the KRAS-variant likely impacts endometrial tumor biology.

Brucella ovis is a major cause of reproductive failure in rams and it is one of the few well-described Brucella species that is not zoonotic. Previous work showed that a B. ovis mutant lacking a species-specific ABC transporter (ΔabcBA) was attenuated in mice and was unable to survive in macrophages. The aim of this study was to evaluate the role of this ABC transporter during intracellular survival of B. ovis. In HeLa cells, B. ovis WT was able to survive and replicate at later time point (48 hpi), whereas an ΔabcBA mutant was attenuated at 24 hpi. The reduced survival of the ΔabcBA mutant was associated with a decreased ability to exclude the lysosomal marker LAMP1 from its vacuolar membrane, suggesting a failure to establish a replicative niche. The ΔabcBA mutant showed a reduced abundance of the Type IV secretion system (T4SS) proteins VirB8 and VirB11 in both rich and acid media, when compared to WT B. ovis. However, mRNA levels of virB1, virB8, hutC, and vjbR were similar in both strains. These results support the notion that the ABC transporter encoded by abcEDCBA or its transported substrate acts at a post-transcriptional level to promote the optimal expression of the B. ovis T4SS within infected host cells.

Since the appearance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the question regarding the efficacy of various hygiene measures and the use of personal protective equipment (PPE) has become the focus of scientific and above all public discussion. To compare respirators, medical face masks, and cloth masks and determine if it is recommendable to wear face masks to protect the individual wearer of the mask from inhaling airborne particles, we challenged 29 different masks with aerosols and tested the pressure drop as a surrogate for breathing resistance owing to the mask material. We found that Type II medical face masks showed the lowest pressure drop (12.9±6.8 Pa/cm2) and therefore additional breathing resistance, whereas respirators such as the KN95 (32.3±7.0 Pa/cm2) and FFP2 (26.8±7.4 Pa/cm2) showed the highest pressure drops among the tested masks. The filtration efficacy of the mask material was the lowest for cloth masks (28±25%) followed by non-certified face masks (63±19%) and certified medical face masks (70±10%). The materials of the different respirators showed very high aerosol retentions (KN95 [94±4%] and FFP2 [98±1%]). For evaluating the as-worn filtration performance simulating real live conditions each mask type was also tested on a standardized dummy head. Cloth masks and non-EN-certified face masks had the worst as-worn filtration efficacies among the tested masks, filtering less than 20% of the test aerosol. Remarkably, certified type II medical face masks showed similar (p>0.5) as-worn filtration results (47±20%) than KN95 masks (41±4%) and FFP2 masks (65±27%), despite having a lower pressure drop. Face shields did not show any significant retention function against aerosols in our experiment. Our results indicate that it seems recommendable to wear face masks for providing base protection and risk reduction against inhaling airborne particles, in low-risk situations. In our study, especially EN 14683 type II certified medical face masks showed protective effectiveness against aerosols accompanied by minimal additional breathing resistance. FFP2 Respirators, on the other hand, could be useful in high-risk situations but require greater breathing effort and therefore physical stress for users.