Canadian Armed Forces Veterans' Perspectives on the Effects of Exposure to Children in Armed Conflict During Military Service: Protocol for a Qualitative Study.

BACKGROUND: The mental health of military personnel has garnered increased attention over the last few decades; however, the impacts of perpetuating, observing, or failing to prevent acts that transgress deeply held moral standards, referred to as moral injuries, are less understood, particularly in relation to encounters with children during deployment. This paper describes a multiphased research protocol that centers around the lived experiences of Canadian Armed Forces (CAF) Veterans to understand how encounters with children during military deployments impact the well-being and mental health of military personnel. OBJECTIVE: This study has four objectives: (1) highlight the lived experiences of CAF Veterans who encountered children during military deployments; (2) improve understanding of the nature of experiences that military personnel faced that related to observing or engaging with children during military service; (3) improve understanding of the mental health impacts of encountering children during military service; and (4) use participatory action research (PAR) to develop recommendations for improving preparation, training, and support for military personnel deployed to contexts where encounters with children are likely. METHODS: The research project has 2 main phases where phase 1 includes qualitative interviews with CAF Veterans who encountered children during military deployments and phase 2 uses PAR to actively engage Canadian Veterans with lived experiences of encountering children during military deployments, as well as health professionals and researchers to identify recommendations to better address the mental health effects of these encounters. RESULTS: As of January 26, 2024, a total of 55 participants and research partners have participated in the 2 phases of the research project. A total of 16 CAF Veterans participated in phase 1 (qualitative interviews), and 39 CAF Veterans, health professionals, and researchers participated in phase 2 (PAR). The results for phase 1 have been finalized and are accepted for publication. Data collection and analysis are ongoing for phase 2. CONCLUSIONS: Prioritizing and valuing the experiences of CAF Veterans has deepened our understanding of the intricate nature and impacts of potentially morally injurious events involving children during military deployments. Together with health professionals and researchers, the PAR approach empowers CAF Veterans to articulate important recommendations for developing and improving training and mental health support. This support is crucial not only during the deployment cycle but also throughout the military career, helping lessen the effects of moral injury among military personnel. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/57146.

The nature and impacts of deployment-related encounters with children among Canadian military Veterans: a qualitative analysis.

Background: As armed conflict grows increasingly complex, the involvement of children in armed violence across diverse roles is rising. Consequently, military personnel are more likely to encounter children during deployment. However, little is known about deployment-related encounters with children and their impact on the mental health of military personnel and Veterans.Objective: This study qualitatively examines the nature and impacts of deployment-related encounters with children.Methods: We conducted semi-structured interviews with 16 Canadian Armed Forces Veterans, eliciting rich information on the nature of child encounters on deployment, the psycho-social-spiritual impacts of these encounters, and perceptions of support. Interview transcripts were analysed using thematic analysis.Results: Six primary themes were identified: types of encounters (i.e. factual aspects of deployment-related encounters with children), contextual factors (i.e. aspects of the mission, environment, and personal context relevant to one's experience of the encounter), appraisals of encounters (i.e. sensory or sense-making experiences relevant to the encounter), impacts of encounters (i.e. psycho-social, existential, and occupational impacts), coping strategies engaged in both during and after deployment, and support experiences, describing both formal and informal sources of support.Conclusions: Encounters with children are diverse and highly stressful, resulting in impacts pertinent to mental health, including psychological and moral distress, and difficulties with identity, spirituality, and relationships. These impacts are prompted by complex interactions among appraisals, expectations of morality, cultural norms, and professional duties and are amplified by various personal factors (e.g. childhood maltreatment history, parenthood), feelings of unpreparedness, and lack of post-deployment support. Implications for prevention, intervention, and policy are discussed with the aim of informing future efforts to safeguard and support military personnel facing a high likelihood of encounters with children.

Deployment-related encounters with children result in diverse impacts, including psychological and moral distress, along with disruptions in identity, spirituality, and interpersonal relationships.Encounters with children during military deployments are diverse and highly stressful, characterized by complex interactions among appraisals and expectations of morality, cultural norms, and professional duties.Emphasis on feeling unprepared for encounters with children highlights the need for future efforts to safeguard and support military personnel facing such situations.

Measuring moral distress and moral injury: A systematic review and content analysis of existing scales.

BACKGROUND: Moral distress (MD) and moral injury (MI) are related constructs describing the negative consequences of morally challenging stressors. Despite growing support for the clinical relevance of these constructs, ongoing challenges regarding measurement quality risk limiting research and clinical advances. This study summarizes the nature, quality, and utility of existing MD and MI scales, and provides recommendations for future use. METHOD: We identified psychometric studies describing the development or validation of MD or MI scales and extracted information on methodological and psychometric qualities. Content analyses identified specific outcomes measured by each scale. RESULTS: We reviewed 77 studies representing 42 unique scales. The quality of psychometric approaches varied greatly across studies, and most failed to examine convergent and divergent validity. Content analyses indicated most scales measure exposures to potential moral stressors and outcomes together, with relatively few measuring only exposures (n = 3) or outcomes (n = 7). Scales using the term MD typically assess general distress. Scales using the term MI typically assess several specific outcomes. CONCLUSIONS: Results show how the terms MD and MI are applied in research. Several scales were identified as appropriate for research and clinical use. Recommendations for the application, development, and validation of MD and MI scales are provided.

Moral Distress, Mental Health, and Risk and Resilience Factors Among Military Personnel Deployed to Long-Term Care Facilities During the COVID-19 Pandemic: Research Protocol and Participation Metrics.

BACKGROUND: The earliest days of the COVID-19 pandemic in Canada were marked by a significant surge in COVID-19 cases and COVID-19-related deaths among residents of long-term care facilities (LTCFs). As part of Canada's response to the COVID-19 pandemic, Canadian Armed Forces (CAF) personnel were mobilized for an initial emergency domestic deployment to the hardest-hit LTCFs (Operation LASER LTCF) to support the remaining civilian staff in ensuring the continued delivery of care to residents. Akin to what was observed following past CAF international humanitarian missions, there was an expected increased risk of exposure to multiple stressors that may be psychologically traumatic and potentially morally injurious in nature (ie, related to core values, eg, witnessing human suffering). Emerging data from health care workers exposed to the unprecedented medical challenges and dilemmas of the early pandemic stages also indicated that such experiences were associated with increased risk of adverse mental health outcomes. OBJECTIVE: This study aims to identify and quantify the individual-, group-, and organizational-level risk and resilience factors associated with moral distress, moral injury, and traditional mental health and well-being outcomes of Operation LASER LTCF CAF personnel. This paper aimed to document the methodology, implementation procedures, and participation metrics. METHODS: A multimethod research initiative was conducted consisting of 2 primary data collection studies (a quantitative survey and qualitative interviews). The quantitative arm was a complete enumeration survey with web-based, self-report questionnaires administered at 3 time points (3, 6, and 12 mo after deployment). The qualitative arm consisted of individual, web-based interviews with a focus on understanding the nuanced lived experiences of individuals participating in the Operation LASER LTCF deployment. RESULTS: CAF personnel deployed to Operation LASER LTCF (N=2595) were invited to participate in the study. Data collection is now complete. Overall, of the 2595 deployed personnel, 1088 (41.93%), 582 (22.43%), and 497 (19.15%) responded to the survey at time point 1 (3 mo), time point 2 (6 mo), and time point 3 (12 mo) after deployment, respectively. The target sample size for the qualitative interviews was set at approximately 50 considering resourcing and data saturation. Interest in participating in qualitative interviews surpassed expectations, with >200 individuals expressing interest; this allowed for purposive sampling across key characteristics, including gender, rank, Operation LASER LTCF role, and province. In total, 53 interviews were conducted. CONCLUSIONS: The data generated through this research have the potential to inform and promote better understanding of the well-being and mental health of Operation LASER LTCF personnel over time; identify general and Operation LASER LTCF-specific risk and protective factors; provide necessary support to the military personnel who served in this mission; and inform preparation and interventions for future missions, especially those more domestic and humanitarian in nature. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/44299.

Plasmid-mediated quinolone resistance genes detected in Ciprofloxacin non-susceptible Escherichia coli and Klebsiella isolated from children under five years at hospital discharge, Kenya.

BACKGROUND: The increasing spread of fluoroquinolone resistant enteric bacteria is a global public health concern. Children recently discharged from the hospital are at high risk of carriage of antimicrobial resistance (AMR) due to frequent exposure to antimicrobials during inpatient stays. This study aimed to determine the prevalence, correlates of ciprofloxacin (CIP) non-susceptibility, and distribution of plasmid-mediated quinolone resistance (PMQR) genes in Escherichia coli (E. coli) and Klebsiella spp isolated from children under five years being discharged from two Kenyan Hospitals. METHODS: E. coli and Klebsiella spp were isolated from fecal samples from children discharged from hospital and subjected to antimicrobial susceptibility testing (AST) by disc diffusion and E-test. CIP non-susceptible isolates were screened for seven PMQR genes using multiplex polymerase chain reaction (PCR). Poisson regression was used to determine the association between the carriage of CIP non-susceptible isolates and patient characteristics. RESULTS: Of the 280 CIP non-susceptible isolates: 188 E. coli and 92 Klebsiella spp isolates identified among 266 discharged children, 195 (68%) were CIP-non-susceptible with minimum inhibitory concentrations (MICs) of ≥ 1 µg/mL. Among these 195 isolates, 130 (67%) had high-level CIP MIC = ≥ 32 µg/mL). Over 80% of the isolates had at least one PMQR gene identified: aac(6')lb-cr (60%), qnrB (24%), oqxAB (22%), qnrS (16%), and qepA (6%), however, qnrA was not identified in any isolates tested. Co-carriage of qnrB with acc(6')-lb-cr was the most predominant accounting for 20% of all the isolates. Ceftriaxone use during hospital admission and the presence of extended spectrum beta-lactamase (ESBL) production were significantly associated with the carriage of CIP non-susceptible E. coli and Klebsiella spp. CONCLUSION: CIP non-susceptibility is common among E. coli and Klebsiella spp isolated from hospital discharged children in Kenya. Carriage and co-carriage of PMQR, including the newly identified qepA gene, were frequently observed. These findings suggest that children leaving the hospital may serve as an important reservoir for transmission of resistant E. coli and Klebsiella spp to the community. Enhanced surveillance for AMR determinants is critical to inform interventions to control antimicrobial-resistant bacteria.

Understanding the Relationship Between Social Stressors, Trauma, and Somatic Symptoms Among Latina Immigrant Women.

BACKGROUND: Latina immigrant women are at increased risk for poor mental health. Little is known about factors associated with somatic symptoms, the physical manifestation of distress, in this population. This study examined associations between social stressors, trauma, and somatic symptoms. METHODS: This study used survey data from a community-based sample of Latina immigrant women (n = 154). We determined the frequency of somatic symptoms and used linear regressions to estimate associations of stressors and trauma with physical symptoms. RESULTS: Most participants reported mild or moderate levels of somatic symptom severity. In univariate models, all social stressors and trauma types were significantly associated with higher levels of somatic symptoms. A multivariate model suggested perceived stress was associated with increased somatic symptoms after accounting for other stressors and trauma. DISCUSSION: Future research should examine whether stress and trauma lead to higher levels of somatic symptoms among Latina immigrants.

Conducting research during the COVID-19 pandemic: the Op LASER study. / Mener des recherches au cours de la pandémie de COVID-19 : l'étude sur l'Opération LASER.

The Canadian Armed Forces (CAF) deployed 2595 regular and reserve force personnel on Operation (Op) LASER, the CAF's mission to provide support to civilian staff at longterm care facilities in Ontario and in the Centres d'hébergement de soins de longue durée in Quebec. An online longitudinal survey and in-depth virtual discussions were conducted by a multidisciplinary team of researchers with complementary expertise. This paper highlights the challenges encountered in conducting this research and their impact on the design and implementation of the study, and provides lessons learned that may be useful to researchers responding to similar public health crises in the future.

There are a number of challenges involved in conducting longitudinal research in an applied military setting during a global public health crisis such as the COVID-19 pandemic. These challenges include but are not limited to a sudden transition to a distributed remote work environment, tight timelines, the need to obtain approvals from different agencies and departments, having to prioritize multiple study objectives, and survey fatigue. To overcome these challenges in future public health crises, it is important to (1) develop and maintain collaborative networks across government, academia and industry; (2) develop a standard set of pre-deployment demographic and health indicators to establish a baseline; and (3) use mixed methods approaches for a richer understanding of mental health trajectories following stressful events.

La réalisation d'une enquête longitudinale dans un contexte militaire concret pendant une crise mondiale de santé publique, comme la pandémie de COVID-19, vient avec son lot de défis. Parmi ces défis, on peut relever une transition subite vers un environnement de travail à distance, des délais serrés, la nécessité d'obtenir des approbations de différents organismes et ministères, la nécessité de prioriser plusieurs objectifs d'étude et la lassitude à l'égard des enquêtes. Pour relever ces défis au cours des futures crises de santé publique, il sera essentiel : 1) de créer et d'entretenir des réseaux de collaboration qui relieront le gouvernement, le milieu universitaire et les divers secteurs d'activité, 2) de créer un ensemble normalisé d'indicateurs démographiques et sanitaires avant le déploiement, en vue de l'obtention de données de référence et 3) de recourir à des méthodes mixtes pour mieux comprendre les trajectoires en matière de santé mentale à la suite d'événements stressants.

Antimicrobial resistance including Extended Spectrum Beta Lactamases (ESBL) among E. coli isolated from kenyan children at hospital discharge.

BACKGROUND: Children who have been discharged from hospital in sub-Saharan Africa remain at substantial risk of mortality in the post-discharge period. Antimicrobial resistance (AMR) may be an important factor. We sought to determine the prevalence and risk factors associated with AMR in commensal Escherichia coli (E. coli) from Kenyan children at the time of discharge. METHODOLOGY/PRINCIPLE FINDINGS: Fecal samples were collected from 406 children aged 1-59 months in western Kenya at the time of discharge from hospital and cultured for E. coli. Susceptibility to ampicillin, ceftriaxone, cefotaxime, ceftazidime, cefoxitin, imipenem, ciprofloxacin, gentamicin, combined amoxicillin/clavulanic acid, trimethoprim-sulfamethoxazole, azithromycin, and chloramphenicol was determined by disc diffusion according to guidelines from the Clinical and Laboratory Standards Institute (CLSI). Poisson regression was used to determine associations between participant characteristics and the presence of extended-spectrum beta-lactamases (ESBL) producing E. coli. Non-susceptibility to ampicillin (95%), gentamicin (44%), ceftriaxone (46%), and the presence of ESBL (44%) was high. Receipt of antibiotics during the hospitalization was associated with the presence of ESBL (aPR = 2.23; 95% CI: 1.29-3.83) as was being hospitalized within the prior year (aPR = 1.32 [1.07-1.69]). Open defecation (aPR = 2.02; 95% CI: 1.39-2.94), having a toilet shared with other households (aPR = 1.49; 95% CI: 1.17-1.89), and being female (aPR = 1.42; 95% CI: 1.15-1.76) were associated with carriage of ESBL E. coli. CONCLUSIONS/SIGNIFICANCE: AMR is common among isolates of E. coli from children at hospital discharge in Kenya, including nearly half having detectable ESBL.

Pathways to mental health care in active military populations across the Five-Eyes nations: An integrated perspective.

Military service is associated with increased risk of mental health problems. Previous reviews have pointed to under-utilization of mental health services in military populations. Building on the most recent systematic review, our narrative, critical review takes a complementary approach and considers research across the Five-Eyes nations from the past six years to update and broaden the discussion on pathways to mental healthcare in military populations. We find that at a broad population level, there is improvement in several indicators of mental health care access, with greater gains in initial engagement, time to first treatment contact, and subjective satisfaction with care, and smaller gains in objective indicators of adequacy of care. Among individual-level barriers to care-seeking, there is progress in improving recognition of need for care and reducing stigma concerns. Among organizational-level barriers, there are advances in availability of services and cultural acceptance of care-seeking. Other barriers, such as concerns around confidentiality, career impact, and deployability persist, however, and may account for some remaining unmet need. To address these barriers, new initiatives that are more evidence-based, theoretically-driven, and culturally-sensitive, are therefore needed, and must be rigorously evaluated to ensure they bring about additional improvements in pathways to care.

Effect of 3 Days of Oral Azithromycin on Young Children With Acute Diarrhea in Low-Resource Settings: A Randomized Clinical Trial.

Importance: World Health Organization (WHO) guidelines do not recommend routine antibiotic use for children with acute watery diarrhea. However, recent studies suggest that a significant proportion of such episodes have a bacterial cause and are associated with mortality and growth impairment, especially among children at high risk of diarrhea-associated mortality. Expanding antibiotic use among dehydrated or undernourished children may reduce diarrhea-associated mortality and improve growth. Objective: To determine whether the addition of azithromycin to standard case management of acute nonbloody watery diarrhea for children aged 2 to 23 months who are dehydrated or undernourished could reduce mortality and improve linear growth. Design, Setting, and Participants: The Antibiotics for Children with Diarrhea (ABCD) trial was a multicountry, randomized, double-blind, clinical trial among 8266 high-risk children aged 2 to 23 months presenting with acute nonbloody diarrhea. Participants were recruited between July 1, 2017, and July 10, 2019, from 36 outpatient hospital departments or community health centers in a mixture of urban and rural settings in Bangladesh, India, Kenya, Malawi, Mali, Pakistan, and Tanzania. Each participant was followed up for 180 days. Primary analysis included all randomized participants by intention to treat. Interventions: Enrolled children were randomly assigned to receive either oral azithromycin, 10 mg/kg, or placebo once daily for 3 days in addition to standard WHO case management protocols for the management of acute watery diarrhea. Main Outcomes and Measures: Primary outcomes included all-cause mortality up to 180 days after enrollment and linear growth faltering 90 days after enrollment. Results: A total of 8266 children (4463 boys [54.0%]; mean [SD] age, 11.6 [5.3] months) were randomized. A total of 20 of 4133 children in the azithromycin group (0.5%) and 28 of 4135 children in the placebo group (0.7%) died (relative risk, 0.72; 95% CI, 0.40-1.27). The mean (SD) change in length-for-age z scores 90 days after enrollment was -0.16 (0.59) in the azithromycin group and -0.19 (0.60) in the placebo group (risk difference, 0.03; 95% CI, 0.01-0.06). Overall mortality was much lower than anticipated, and the trial was stopped for futility at the prespecified interim analysis. Conclusions and Relevance: The study did not detect a survival benefit for children from the addition of azithromycin to standard WHO case management of acute watery diarrhea in low-resource settings. There was a small reduction in linear growth faltering in the azithromycin group, although the magnitude of this effect was not likely to be clinically significant. In low-resource settings, expansion of antibiotic use is not warranted. Adherence to current WHO case management protocols for watery diarrhea remains appropriate and should be encouraged. Trial Registration: ClinicalTrials.gov Identifier: NCT03130114.

Coping With COVID-19: The Impact of the Pandemic on Latina Immigrant Women's Mental Health and Well-being.

INTRODUCTION: We sought to describe how Latina immigrants living in King County coped with the pandemic, including their attitudes and behaviors related to COVID-19, and the impact of the pandemic on their mental health and wellbeing. METHOD: We conducted surveys by phone with adult Spanish-speaking Latina immigrants (n = 137) in the summer of 2020. RESULTS: Very few women had been infected with COVID-19, and 23% reported having been tested. Most frequent reasons for not being tested were not knowing where to go (14%), concerns over the cost (15%), and not wanting to know if they were infected (12%). Most participants had concerns about paying for housing (76%) and food (73%). Depression and anxiety symptoms were in the moderate range. Almost all participants were practicing recommended preventive behaviors. CONCLUSION: Although few participants had COVID-19 infection, the pandemic had significant impacts on their mental health and ability to meet basic needs.

Azithromycin for the prevention of rehospitalisation and death among Kenyan children being discharged from hospital: a double-blind, placebo-controlled, randomised controlled trial.

BACKGROUND: Mass drug administration of azithromycin to children in sub-Saharan Africa has been shown to improve survival in high-mortality settings. The period after hospital discharge is a time of elevated risk unaddressed by current interventions and might provide an opportunity for targeting empirical azithromycin administration. We aimed to assess the efficacy of azithromycin administered at hospital discharge on risk of death and rehospitalisation in Kenyan children younger than 5 years. METHODS: In this double-blind, placebo-controlled randomised trial, children were randomly assigned (1:1) to receive a 5-day course of azithromycin (oral suspension 10 mg/kg on day 1, followed by 5mg/kg per day on days 2-5) or identically appearing and tasting placebo at discharge from four hospitals in western Kenya. Children were eligible if they were aged 1-59 months at hospital discharge, weighed at least 2 kg, and had been admitted to hospital for any medical reason other than trauma, poisoning, or congenital anomaly. The primary outcome was death or rehospitalisation in the subsequent 6-month period in a modified intention-to-treat population, compared by randomisation group with Cox proportional hazards regression and Kaplan-Meier. Azithromycin resistance in Escherichia coli isolates from a random subset of children was compared by randomisation group with generalised estimating equations. This trial is registered with ClinicalTrials.gov, NCT02414399. FINDINGS: Between June 28, 2016, and Nov 4, 2019, 1400 children were enrolled in the trial at discharge from hospital, with 703 (50·2%) randomly assigned to azithromycin and 697 (49·8%) to placebo. Among the 1398 children included in the modified intention-to-treat analysis (702 in the azithromycin group and 696 in the placebo group), the incidence of death or rehospitalisation was 20·4 per 100 child-years in the azithromycin group and 22·5 per 100 child-years in the placebo group (adjusted hazard ratio 0·91, 95·5% CI 0·64-1·29, p=0·58). Azithromycin resistance was common in commensal E coli isolates from enrolled children before randomisation (37·7% of 406 isolates) despite only 3·7% of children having received a macrolide antibiotic during the hospitalisation. Azithromycin resistance was slightly higher at 3 months after randomisation in the azithromycin group (26·9%) than in the placebo group (19·1%; adjusted prevalence ratio 1·41, 95% CI 0·95-2·09, p=0·088), with no difference observed at 6 months (1·17, 0·78-1·76, p=0·44). INTERPRETATION: We did not observe a significant benefit of a 5-day course of azithromycin delivered to children younger than 5 years at hospital discharge despite the overall high risk of mortality and rehospitalisation. These findings highlight the need for more research into mechanisms and interventions for prevention of morbidity and mortality in the post-discharge period. FUNDING: Eunice Kennedy Shriver National Institute of Child Health & Human Development.

Stress, social support and their relationship to depression and anxiety among Latina immigrant women.

OBJECTIVE: Latina immigrant women in the United States are at increased risk of adverse mental health outcomes due to economic, political, cultural and social stressors related to migration and resettlement. However, few studies have described how stress and social supports are related to depression and anxiety symptoms among Latina immigrant women. METHOD: This cross-sectional study used survey data collected from a community-based sample as part of the Amigas Latinas Motivando el Alma (ALMA) study to describe levels of stress, social support, depression and anxiety among Latina immigrant women (N=153). We also estimated associations between stressors, social supports and mental health. RESULTS: At baseline, 29% of participants reported moderate to severe depressive symptoms and 32% of participants reported moderate to severe anxiety symptoms. In adjusted regression models, stressors including social isolation (ß=0.2, p<0.001), perceived stress (ß=0.6, p<.0001), and law/immigration enforcement stress (ß=0.3, p=0.04) were associated with higher levels of depression symptoms. Perceived stress (ß=0.6, p<0.001) and stress associated with meeting basic needs (ß=0.6, p<0.001) were associated with higher levels of anxiety symptoms, while social support received through positive social interactions was associated with fewer anxiety symptoms (ß=-0.8, p=0.03). CONCLUSIONS: Latina immigrant women experience a number of stressors associated with immigration and their social position, which in turn are associated with increased symptoms of depression and anxiety. Future research should examine how social support, along with programs and policies that reduce stress, can improve mental health outcomes in this population.

Phase I Study of Docetaxel and Temsirolimus in Refractory Solid Tumors.

INTRODUCTION: The mammalian target of rapamycin (mTOR) is a downstream mediator in the phosphatidylinositol 3-kinase/Akt signaling pathway, and plays a central role in cell proliferation, growth, differentiation, migration, and survival. Temsirolimus (CCI-779), a selective inhibitor of the mTOR, is an ester analog of rapamycin (sirolimus) with improved aqueous solubility and pharmacokinetic (PK) properties. Preclinical studies have confirmed additive and synergistic antitumor activity in cancer cell lines (breast, prostate cancer) with combinations of taxanes and mTOR inhibitors. We conducted a phase I open-label, dose-escalation study to determine the maximal tolerated dose (MTD) of docetaxel in combination with temsirolimus in patients with refractory solid tumors. PATIENTS AND METHODS: Eligible patients had a diagnosis of a refractory solid malignancy, measurable disease, and adequate organ function. Patients were sequentially enrolled in 4 dose level intravenous combinations of docetaxel and temsirolimus. Temsirolimus was administered weekly with docetaxel administered every 3 weeks. Laboratory data for tumor markers and radiologic imaging were conducted prestudy and then after every 2 cycles of the treatment. Radiologic response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Blood samples for PK and pharmacodynamic analysis were planned to be drawn at MTD. Apart from the traditional 3+3 design, we also implemented Bayesian Optimal Interval design which uses isotonic regression method to select MTD. We proceeded with isotonic regression analysis by using 20% dose-limiting toxicity (DLT) rate as target. RESULTS: Twenty-six patients were treated in this study in 4 cohorts and dose levels. Fourteen males and 12 females were enrolled with a median age of 50 years (range of 27 to 72 y) and median Eastern Cooperative Oncology Group performance score of 1. Tumor histologies included pancreas (6), colon (5), rectum (3), gallbladder (2), non-small cell lung (2), endometrium (1), neuroendocrine (1), esophagus (1), stomach (1), pharynx (1), small intestine (1), and duodenum (1). Stable disease was observed in 2/4 (50%), 3/7 (43%), 4/10 (40%), and 3/5 (60%) patients in cohorts 1, 2, 3, and 4, respectively. Dose escalation in cohorts 2, 3, and 4 was complicated by DLTs such as grade 4 neutropenia and grade 3 diarrhea and an inability for patients to tolerate treatments during and beyond cycle 1 without dose reductions. Therefore, we could not determine an MTD or recommended phase II dose using the traditional 3+3 study analysis. Blood samples for PK and pharmacodynamic analysis were not collected since MTD was not determined. By using 20% DLT rate closest to the target, isotonic regression analysis showed identical estimated DLT rates in dose -1 (docetaxel 50 mg/m2 and temsirolimus 15 mg/m2) and dose level 1 (docetaxel 60mg/m2 and temsirolimus 15 mg/m2). CONCLUSIONS: Dose escalation of docetaxel and temsirolimus was limited by severe myelosuppressive toxicity in this phase I study. Most of the DLTs occurred after cycle 1 of therapy hence, we were unable to determine MTD or collect blood samples for PK and pharmacodynamic analysis. Our trial did not meet its objectives due to significant DLTs with this chemotherapy combination. Although our novel use of Bayesian Optimal Interval design using isotonic regression method to select MTD showed identical estimated DLT rates in dose levels 1 and -1, clinically our patients were not able to complete 2 cycles of this regimen without dose reductions due to myelosuppressive toxicity in either of these dose levels, and hence, escaped clinical validity. This combination regimen should not be studied further at the dose levels and schedules tested in our study.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) in Alzheimer's disease: A genetic and proteomic multi-cohort study.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a hepatic enzyme that regulates circulating low-density lipoprotein (LDL) cholesterol levels by binding to LDL receptors (LDLR) and promoting their degradation. Although PCSK9 inhibitors were shown to reduce the risk of cardiovascular disease, a warning was issued concerning their possible impact on cognitive functions. In Alzheimer's disease (AD), it is believed that cognitive impairment is associated with cholesterol metabolism alterations, which could involve PCSK9. The main objective of this study is to determine if PCSK9 plays a significant role in the pre-symptomatic phase of the disease when the pathophysiological markers of AD unfolds and, later, when cognitive symptoms emerge. METHODS AND FINDINGS: To test if PCSK9 is associated with AD pathology, we measured its expression levels in 65 autopsy confirmed AD brains and 45 age and gender matched controls. Messenger ribonucleic acid (mRNA) were quantified using real-time polymerase chain reaction (RT-PCR) and protein levels were quantified using enzyme-linked immunosorbent assay (ELISA). PCSK9 was elevated in frontal cortices of AD subjects compared to controls, both at the mRNA and protein levels. LDLR protein levels were unchanged in AD frontal cortices, despite and upregulation at the mRNA level. To verify if PCSK9 dysregulation was observable before the onset of AD, we measured its expression in the cerebrospinal fluid (CSF) of 104 "at-risk" subjects and contrasted it with known apolipoproteins levels and specific AD biomarkers using ELISAs. Positive correlations were found between CSF PCSK9 and apolipoprotein E (APOE), apolipoprotein J (APOJ or CLU), apolipoprotein B (APOB), phospho Tau (pTau) and total Tau. To investigate if PCSK9 levels were driven by genetic variants, we conducted an expression quantitative trait loci (eQTL) study using bioinformatic tools and found two polymorphisms in strong association. Further investigation of these variants in two independent cohorts showed a female specific association with AD risk and with CSF Tau levels in cognitively impaired individuals. CONCLUSIONS: PCSK9 levels differ between control and AD brains and its protein levels correlate with those of other lipoproteins and AD biomarkers even before the onset of the disease. PCSK9 regulation seems to be under tight genetic control in females only, with specific variants that could predispose to increased AD risk.

A mixed method multi-country assessment of barriers to implementing pediatric inpatient care guidelines.

INTRODUCTION: Accelerating progress in reducing child deaths is needed in order to achieve the Sustainable Development Goal child mortality target. This will require a focus on vulnerable children-including young children, those who are undernourished or with acute illnesses requiring hospitalization. Improving adherence to inpatient guidelines may be an important strategy to reduce child mortality, including among the most vulnerable. The aim of our assessment of nine sub-Saharan African and South Asian hospitals was to determine adherence to pediatric inpatient care recommendations, in addition to capacity for and barriers to implementation of guideline-adherent care prior to commencing the Childhood Acute Illness and Nutrition (CHAIN) Cohort study. The CHAIN Cohort study aims to identify modifiable risk factors for poor inpatient and post discharge outcomes above and beyond implementation of guidelines. METHODS: Hospital infrastructure, staffing, durable equipment, and consumable supplies such as medicines and laboratory reagents, were evaluated through observation and key informant interviews. Inpatient medical records of 2-23 month old children were assessed for adherence to national and international guidelines. The records of children with severe acute malnutrition (SAM) were oversampled to reflect the CHAIN study population. Seven core adherence indicators were examined: oximetry and oxygen therapy, fluids, anemia diagnosis and transfusion, antibiotics, malaria testing and antimalarials, nutritional assessment and management, and HIV testing. RESULTS: All sites had facilities and equipment necessary to implement care consistent with World Health Organization and national guidelines. However, stockouts of essential medicines and laboratory reagents were reported to be common at some sites, even though they were mostly present during the assessment visits. Doctor and nurse to patient ratios varied widely. We reviewed the notes of 261 children with admission diagnoses of sepsis (17), malaria (47), pneumonia (70), diarrhea (106), and SAM (119); 115 had multiple diagnoses. Adherence to oxygen therapy, antimalarial, and malnutrition refeeding guidelines was >75%. Appropriate antimicrobials were prescribed for 75% of antibiotic-indicative conditions. However, 20/23 (87%) diarrhea and 20/27 (74%) malaria cases without a documented indication were prescribed antibiotics. Only 23/122 (19%) with hemoglobin levels meeting anemia criteria had recorded anemia diagnoses. HIV test results were infrequently documented even at hospitals with universal screening policies (66/173, 38%). Informants at all sites attributed inconsistent guideline implementation to inadequate staffing. CONCLUSION: Assessed hospitals had the infrastructure and equipment to implement guideline-consistent care. While fluids, appropriate antimalarials and antibiotics, and malnutrition refeeding adherence was comparable to published estimates from low- and high-resource settings, there were inconsistencies in implementation of some other recommendations. Stockouts of essential therapeutics and laboratory reagents were a noted barrier, but facility staff perceived inadequate human resources as the primary constraint to consistent guideline implementation.

Manipulation of Host Diet To Reduce Gastrointestinal Colonization by the Opportunistic Pathogen Candida albicans.

Candida albicans, the most common human fungal pathogen, can cause systemic infections with a mortality rate of ~40%. Infections arise from colonization of the gastrointestinal (GI) tract, where C. albicans is part of the normal microflora. Reducing colonization in at-risk patients using antifungal drugs prevents C. albicans-associated mortalities. C. albicans provides a clinically relevant system for studying the relationship between diet and the microbiota as it relates to commensalism and pathogenicity. As a first step toward a dietary intervention to reduce C. albicans GI colonization, we investigated the impact of dietary lipids on murine colonization by C. albicans. Coconut oil and its constituent fatty acids have antifungal activity in vitro; we hypothesized that dietary coconut oil would reduce GI colonization by C. albicans. Colonization was lower in mice fed a coconut oil-rich diet than in mice fed diets rich in beef tallow or soybean oil. Switching beef tallow-fed mice to a coconut oil diet reduced preexisting colonization. Coconut oil reduced colonization even when the diet also contained beef tallow. Dietary coconut oil also altered the metabolic program of colonizing C. albicans cells. Long-chain fatty acids were less abundant in the cecal contents of coconut oil-fed mice than in the cecal contents of beef tallow-fed mice; the expression of genes involved in fatty acid utilization was lower in C. albicans from coconut oil-fed mice than in C. albicans from beef tallow-fed mice. Extrapolating to humans, these findings suggest that coconut oil could become the first dietary intervention to reduce C. albicans GI colonization. IMPORTANCE Candida albicans, the most common human fungal pathogen, can cause infections with a mortality rate of ~40%. C. albicans is part of the normal gut flora, but when a patient's immune system is compromised, it can leave the gut and cause infections. By reducing the amount of C. albicans in the gut of susceptible patients, infections (and the resulting fatalities) can be prevented. Currently, this is done using antimicrobial drugs; to "preserve" drugs for treating infections, we looked for a dietary change to reduce the amount of C. albicans in the gut. Using a mouse model, we showed that adding coconut oil to the diet could become the first drug-free way to reduce C. albicans in the gut. More broadly, this model lets us study the interactions between our diet and the microbes in our body and the reasons why some of those microbes, under certain conditions, cause disease. Podcast: A podcast concerning this article is available.

APOE and cholesterol homeostasis in Alzheimer's disease.

Converging evidence from clinical and pathological studies indicate the presence of important relationships between the ongoing deterioration of brain lipid homeostasis, vascular changes and the pathophysiology of sporadic Alzheimer's disease (AD). These associations include the recognition of cholesterol transporters apolipoprotein E (APOE), APOC1 and APOJ as major genetic risk factors for common AD and observations associating risk factors for cardiovascular disease such as high midlife plasma cholesterol, diabetes, stroke, obesity and hypertension to dementia. Moreover, recent clinical findings lend support to the notion that progressive deterioration of cholesterol homeostasis in AD is a central player in the disease pathophysiology and is, therefore, a potential therapeutic target for disease prevention.