Repurposing mebendazole against triple-negative breast cancer CNS metastasis.

PURPOSE: Triple-negative breast cancer (TNBC) often metastasizes to the central nervous system (CNS) and has the highest propensity among breast cancer subtypes to develop leptomeningeal disease (LMD). LMD is a spread of cancer into leptomeningeal space that speeds up the disease progression and severely aggravates the prognosis. LMD has limited treatment options. We sought to test whether the common anti-helminthic drug mebendazole (MBZ) may be effective against murine TNBC LMD. METHODS: A small-molecule screen involving TNBC cell lines identified benzimidazoles as potential therapeutic agents for further study. In vitro migration assays were used to evaluate cell migration capacity and the effect of MBZ. For in vivo testing, CNS metastasis was introduced into BALB/c athymic nude mice through internal carotid artery injections of brain-tropic MDA-MB-231-BR or MCF7-BR cells. Tumor growth and spread was monitored by bioluminescence imaging and immunohistochemistry. MBZ was given orally at 50 and 100 mg/kg doses. MBZ bioavailability was assayed by mass spectrometry. RESULTS: Bioinformatic analysis and migration assays revealed higher migratory capacity of TNBC compared to other breast cancer subtypes. MBZ effectively slowed down migration of TNBC cell line MDA-MB-231 and its brain tropic derivative MDA-MB-231-BR. In animal studies, MBZ reduced leptomeningeal spread, and extended survival in brain metastasis model produced by MDA-MB-231-BR cells. MBZ did not have an effect in the non-migratory MCF7-BR model. CONCLUSIONS: We demonstrated that MBZ is a safe and effective oral agent in an animal model of TNBC CNS metastasis. Our findings are concordant with previous efforts involving MBZ and CNS pathology and support the drug's potential utility to slow down leptomeningeal spread.

Patient and pharmacist perspectives on opioid misuse screening and brief interventions in community pharmacies.

BACKGROUND: Pharmacy-based screening and brief interventions (SBI) offer opportunities to identify opioid misuse and opioid safety risks and provide brief interventions that do not overly burden pharmacists. Currently, such interventions are being developed without patient input and in-depth contextual data and insufficient translation into practice. The purpose of this study is to qualitatively explore and compare patient and pharmacist perceptions and needs regarding a pharmacy-based opioid misuse SBI and to identify relevant SBI features and future implementation strategies. METHODS: Using the Consolidated Framework for Implementation Research, we conducted semi-structured interviews with 8 patients and 11 pharmacists, to explore needs and barriers to participating in a pharmacy-based SBI. We recruited a purposive sample of English-speaking patients prescribed opioids for chronic or acute pain and pharmacists practicing in varied pharmacies (small independent, large-chain, specialty retail) settings. We used an inductive content analysis approach to analyze patient interview data. Then through a template analysis approach involving comparison of pharmacist and patient themes, we developed strategies for SBI implementation. RESULTS: Most patient participants were white, older, described living in suburban areas, and were long-term opioid users. We identified template themes related to individual, interpersonal, intervention, and implementation factors and inferred applications for SBI design or potential SBI implementation strategies. We found that patients needed education on opioid safety and general opioid use, regardless of opioid use behaviors. Pharmacists described needing patient-centered training, protocols, and scripts to provide SBI. A short-self-reported screening and brief interventions including counseling, naloxone, and involving prescribers were discussed by both groups. CONCLUSIONS: Through this implementation-focused qualitative study, we identified patient needs such as opioid safety education delivered in a private and convenient format and pharmacist needs including training, workflow integration, protocols, and a time-efficient intervention for effective pharmacy-based SBI. Alternate formats of SBI using digital health technologies may be needed for effective implementation. Our findings can be used to develop patient-centered pharmacy-based SBI that can be implemented within actual pharmacy practice.

Repurposing mebendazole against triple-negative breast cancer leptomeningeal disease.

Purpose: Triple-negative breast cancer (TNBC) is an aggressive subtype that often metastasizes to the brain. Leptomeningeal disease (LMD), a devastating brain metastasis common in TNBC, has limited treatment options. We sought to test whether the common anti-helminthic drug mebendazole (MBZ) may be effective against murine TNBC LMD. Methods: A small-molecule screen involving TNBC cell lines identified benzimidazoles as potential therapeutic agents for further study. In vitro migration assays were used to evaluate cell migration capacity and the effect of MBZ. For in vivo testing, LMD was introduced into BALB/c athymic nude mice through internal carotid artery injections of brain-tropic MDA-MB-231-BR or MCF7-BR cells. Tumor growth and spread was monitored by bioluminescence imaging. MBZ was given orally at 50 and 100 mg/kg doses. MBZ bioavailability was assayed by mass spectrometry. Results: Bioinformatic analysis and migration assays revealed higher migratory capacity of TNBC compared to other breast cancer subtypes. MBZ effectively slowed down migration of TNBC cell line MDA-MB-231 and its brain tropic derivative MDA-MB-231-BR. In animal studies, MBZ reduced tumor growth and extended survival in the LMD model produced by MDA-MB-231-BR cells. MBZ did not have an effect in the non-migratory MCF7-BR model. Conclusions: We demonstrated that MBZ is a safe and effective oral agent in an animal model of TNBC LMD. Our findings are concordant with previous efforts involving MBZ and central nervous system pathology and further support the drug's potential utility as an alternative therapeutic for TNBC LMD.

Chemotherapeutic metabolism presenting as a recalcitrant case of hand-foot syndrome and mucositis.

INTRODUCTION: Mercaptopurine (6MP) and methotrexate (MTX) are commonly used for maintenance chemotherapy for acute lymphoblastic leukemia (ALL). These medications have been associated with various side effects such as myelosuppression, colitis, and thyroiditis in addition to numerous cutaneous adverse events. Cutaneous side-effects most reported include mucositis, alopecia, xerosis, and pruritus. We report an interesting case of hand-foot syndrome to 6MP in a child on maintenance therapy for B-cell ALL from an alteration in medication metabolism. CASE: We report a 10-year-old male on maintenance chemotherapy for pre-Bcell ALL who presented to the hospital with worsening oral lesions and erythematous, fissured plaques on the palms and soles. Maintenance therapy consisted of IV vincristine and 5-day pulse of steroids every 12 weeks, daily 6MP, and weekly MTX, which were increased to ≥ 150% of standard dosing due to persistent absolute neutrophil counts > 1500. Metabolites obtained on admission demonstrated elevated 6MMP metabolites at 35,761 (normal < 5700). TPMT and NUDT15 enzyme activity were normal and no alterations in genotyping were discovered. OUTCOME: Patient's oral chemotherapy, including both 6MP and MTX, were stopped and allopurinol 100 mg daily was initiated, which lead to overall improvement. DISCUSSION: Clinical findings of acute mucositis and worsening of hand-foot syndrome, in the setting of inadequate myelosuppression in a child on maintenance therapy for ALL should raise concerns to consider altered metabolism pathway leading to toxic metabolite buildup. Allopurinol can play in improving cutaneous manifestation and chemotherapeutic dosing in patients with altered metabolism.

Combined Hepatitis B Virus and Hepatocellular Carcinoma Screening Using Point-of-Care Testing and Ultrasound in a Tanzanian Emergency Department.

The WHO aims to detect 90% of global cases of hepatitis B virus (HBV) by 2030. Sub-Saharan Africa carries a disproportionate burden of HBV and hepatocellular carcinoma (HCC). In this study, we sought to assess the utility of a combined HBV and HCC screening program in Tanzania. We conducted a prospective, serial cross-sectional study of patients who participated in a combined HBV and HCC screening program at a regional referral hospital emergency department (ED) in Arusha, Tanzania, between April 19, 2022 and June 3, 2022. All patients completed a study questionnaire and were tested for HBV surface antigen. Patients who were HBV positive were screened for HCC via point-of-care ultrasound (POCUS). The primary outcome was the number of new HBV diagnoses. Data were analyzed with descriptive statistics. A total of 846 patients were tested for HBV (primary ED: 761, clinic referral: 85). The median age of patients was 44 ± 15 years, and 66% were female. Only 15% of patients reported having a primary care doctor. Thirteen percent of patients had been previously vaccinated for HBV. There were 17 new HBV diagnoses (primary ED: 16, clinic referral: 1), which corresponds to a seroprevalence of 2.0% (95% CI: 1.2%, 3.2%). No patients had liver masses detected on POCUS. An ED-based, combined HBV and HCC screening protocol can be feasibly implemented. This study could serve as a model for HBV/HCC screening in regions with high HBV endemicity and low rates of community screening.

An Implementation-Focused Qualitative Exploration of Pharmacist Needs Regarding an Opioid Use Disorder Screening and Brief Intervention.

BACKGROUND: Screening and brief interventions (SBI) can help identify opioid safety risks and healthcare professionals can accordingly intervene without a significant increase in workload. Pharmacists, one of the most accessible healthcare professionals, are uniquely positioned to offer SBI. To design an effective intervention with high potential for implementation, we explored pharmacist needs and barriers regarding SBI for opioid use disorders. METHODS: Using the Consolidated Framework for Implementation Research (CFIR), we conducted 11 semi-structured 60-minute interviews with community pharmacists. We used a purposeful sample of English-speaking pharmacists practicing in varied pharmacies (small independent, large-chain, specialty-retail) and positions (managers, owners, full-time/part-time pharmacists). Transcriptions were analyzed using deductive content analysis based on CFIR constructs, followed by inductive open coding. Utilizing a theoretical framework for data collection and analysis, a diverse sample of pharmacist roles, peer debriefing, and 2 independent coders for each transcript, altogether increased the credibility and transferability of our research. Data collection and analysis continued until data saturation was achieved. RESULTS: Pharmacists described good working relationships with colleagues, organization cultures that were open to new initiatives, and believed the SBI to be compatible with their organization goals and pharmacy structure, which are facilitators for future SBI implementation. Pharmacists were motivated by improved patient outcomes, more patient interaction and clinical roles, representing facilitators at the individual level. They also described stigma toward patients, mixed need for change, and lack of knowledge regarding SBI, which are potential barriers to be addressed. Pharmacists believed that the SBI model was adaptable, not complicated, and benefits outweighed implementation costs. CONCLUSIONS: We addressed current SBI literature gaps-mainly lack of focus on implementation and contextual data, through rigorous implementation-focused qualitative research. Our exploratory findings have direct implications on future pharmacy-based SBI implementation.

Investigation of the activity of a novel tropolone in osteosarcoma.

Osteosarcoma (OS) is a primary malignant bone tumor characterized by frequent metastasis, rapid disease progression, and a high rate of mortality. Treatment options for OS have remained largely unchanged for decades, consisting primarily of cytotoxic chemotherapy and surgery, thus necessitating the urgent need for novel therapies. Tropolones are naturally occurring seven-membered non-benzenoid aromatic compounds that possess antiproliferative effects in a wide array of cancer cell types. MO-OH-Nap is an α-substituted tropolone that has activity as an iron chelator. Here, we demonstrate that MO-OH-Nap activates all three arms of the unfolded protein response (UPR) pathway and induces apoptosis in a panel of human OS cell lines. Co-incubation with ferric chloride or ammonium ferrous sulfate completely prevents the induction of apoptotic and UPR markers in MO-OH-Nap-treated OS cells. MO-OH-Nap upregulates transferrin receptor 1 (TFR1) protein levels, as well as TFR1, divalent metal transporter 1 (DMT1), iron-regulatory proteins (IRP1, IRP2), ferroportin (FPN), and zinc transporter 14 (ZIP14) transcript levels, demonstrating the impact of MO-OH-Nap on iron-homeostasis pathways in OS cells. Furthermore, MO-OH-Nap treatment restricts the migration and invasion of OS cells in vitro. Lastly, metabolomic profiling of MO-OH-Nap-treated OS cells revealed distinct changes in purine and pyrimidine metabolism. Collectively, we demonstrate that MO-OH-Nap-induced cytotoxic effects in OS cells are dependent on the tropolone's ability to alter cellular iron availability and that this agent exploits key metabolic pathways. These studies support further evaluation of MO-OH-Nap as a novel treatment for OS.

Indigenous Peoples' rights in national climate governance: An analysis of Nationally Determined Contributions (NDCs).

Although the recognition of Indigenous Peoples' contributions to climate governance by the international community has gradually increased, a rights-based approach in national climate action is still largely absent. This article analyses the recognition of Indigenous Peoples' rights in Nationally Determined Contributions (NDCs) under the Paris Agreement. We conducted a content analysis of all NDCs submitted between 2016 and May 2022. Through a five-pronged framework of sustainable self-determination, we assessed how the NDCs recognise: i. Indigenous Peoples as rights-holders; ii. Indigenous jurisdiction over land; iii. Indigenous knowledge systems; iv. Indigenous Peoples' right to full and effective participation in climate governance; and v. the legacy of colonialism. NDCs with references related to Indigenous Peoples are increasing. However, questions remain regarding their sincerity and commitment to implementation. States must therefore make more significant efforts to ensure that the NDCs take a rights-based approach and contribute to strengthening Indigenous Peoples' role and say in climate governance.

Moving behavioral interventions in nursing homes from planning to action: a work system evaluation of a urinary tract infection toolkit implementation.

BACKGROUND: Implementation evaluations based on a hybrid deductive-inductive approach provide a detailed understanding of organizational choices to introduce and implement complex interventions and may help explain implementation success or failure. However, such evaluations may not be feasible due to resource constraints. Qualitative analyses of artifacts collected for other purposes during implementation may represent a cost-effective method to understand program implementation when robust evaluations are not feasible. This study used a work systems evaluation of how nursing homes (NHs) implemented a urinary tract infection (UTI) recognition and management improvement toolkit. METHODS: Thirty NHs participated in a randomized control trial in which intervention NHs (n = 12) were assigned a clinical coach who employed a standard template to structure coach calls with the NH champion. A hybrid inductive-deductive approach, using the Systems Engineering Initiative for Patient Safety (SEIPS) model, characterized three action domains related to (1) engagement of staff and providers, (2) distribution of toolkit elements, and (3) toolkit use. RESULTS: A total of 369 coded segments from 148 coach notes generated by three coaches working with 18 NH champions were examined. Planned changes (n = 203) were more frequent compared to actual changes (n = 169). While most NHs quickly engaged staff and providers, which leadership appeared to support, engagement actions were hindered in some NHs due to champion instability or extended champion or medical director absences. Dissemination of materials to family and providers and distribution of tools to staff occurred quickly in 75% of NHs, although delays were encountered in some NHs, usually because of champion instability. CONCLUSIONS: Implementing NH practice change is challenging, and studies examining actions to support planned versus actual change in this setting are limited. The application of the SEIPS model to coach notes collected during the implementation of a structured behavioral intervention to improve the recognition and management of UTI in NHs generated unique insights into the work system and how staff attempted to implement changes. This study identified several factors that interfered with progression from planning to actual change. Future studies are needed to better understand how to best support change interventions in NHs. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03520010 , Registered May 9, 2018.

Defining the Role of Metastasis-Initiating Cells in Promoting Carcinogenesis in Ovarian Cancer.

Ovarian cancer is the deadliest gynecological malignancy with a high prevalence of transcoelomic metastasis. Metastasis is a multi-step process and only a small percentage of cancer cells, metastasis-initiating cells (MICs), have the capacity to finally establish metastatic lesions. These MICs maintain a certain level of stemness that allows them to differentiate into other cell types with distinct transcriptomic profiles and swiftly adapt to external stresses. Furthermore, they can coordinate with the microenvironment, through reciprocal interactions, to invade and establish metastases. Therefore, identifying, characterizing, and targeting MICs is a promising strategy to counter the spread of ovarian cancer. In this review, we provided an overview of OC MICs in the context of characterization, identification through cell surface markers, and their interactions with the metastatic niche to promote metastatic colonization.

Justice implications of health and food security policies for Indigenous peoples facing COVID-19: a qualitative study and policy analysis in Peru.

The spread of COVID-19 in Peru resulted in the declaration of a national health emergency, in which Indigenous peoples were identified as being particularly vulnerable due to their pre-existing poor health indicators and disadvantaged social conditions. The aim of this paper is to examine how the Peruvian government responded to the health and food needs of the Shawi and Ashaninka Indigenous peoples of Peru during the first 18 months of the pandemic (March 2020-August 2021). This study uses both official policy documents and real-world experiences to evaluate policy responses in terms of their immediate impact and their longer-term sustainability and contribution to the improvement of health, well-being and justice for Indigenous communities. Four health and food security responses were evaluated: the Amazon Health Plan and Indigenous Command; food aid; cash aid; and COVID-19 vaccination. We employed the Multidimensional Injustice Framework to analyse the justice implications of the design and implementation of responses. Data collection included 71 interviews with government officials (n = 7), Indigenous leaders (n = 31) and community members (n = 33). The results show how national and regional governments released policies to address the health and food needs of Indigenous peoples directly or indirectly, as part of a broader focus on vulnerable people. However, justice implications were not sufficiently addressed in the design or implementation of the responses. On the distributive dimension, Indigenous communities were prioritized to receive health goods and services, nevertheless, the distribution had shortcomings that impeded their collection and Indigenous food systems and livelihoods were largely overlooked. On the procedural dimension, Indigenous representatives were included to provide culturally sensitive feedback on health interventions, but without funding, and furthermore, the community members had only passive participation. This paper points out the importance of considering and addressing justice implications for more effective and fairer health and food policy responses to current and future health crises.

High throughput method for detecting murine brain atrophy using a clinical 3T MRI.

BACKGROUND: There is a lack of understanding of the mechanisms by which the CNS is injured in multiple sclerosis (MS). Since Theiler's murine encephalomyelitis virus (TMEV) infection in SJL/J mice is an established model of progressive disability in MS, and CNS atrophy correlates with progressive disability in MS, we used in vivo MRI to quantify total ventricular volume in TMEV infection. We then sought to identify immunological and virological biomarkers that correlated with increased ventricular size. METHODS: Mice, both infected and control, were followed for 6 months. Cerebral ventricular volumes were determined by MRI, and disability was assessed by Rotarod. A range of immunological and virological measures was obtained using standard techniques. RESULTS: Disability was present in infected mice with enlarged ventricles, while infected mice without enlarged ventricles had Rotarod performance similar to sham mice. Ventricular enlargement was detected as soon as 1 month after infection. None of the immunological and virological measures correlated with the development of ventricular enlargement. CONCLUSIONS: These results support TMEV infection with brain MRI monitoring as a useful model for exploring the biology of disability progression in MS, but they did not identify an immunological or virological correlate with ventricular enlargement.

Six month incidence of major adverse cardiovascular events among adults with HIV in northern Tanzania: a prospective observational study.

OBJECTIVES: We aimed to prospectively describe incident cardiovascular events among people living with HIV (PLWH) in northern Tanzania. Secondary aims of this study were to understand non-communicable disease care-seeking behaviour and patient preferences for cardiovascular care and education. DESIGN: A prospective observational study. SETTING: This study was conducted at the Majengo HIV Care and Treatment Clinic, an outpatient government-funded clinic in Moshi, Tanzania PARTICIPANTS: Adult patients presenting to an HIV clinic for routine care in northern Tanzania were enrolled from 1 September 2020 to 1 March 2021. INTERVENTIONS: At enrolment, participants completed a survey and a resting 12-lead ECG was obtained. At 6 month follow-up, a repeat survey regarding interim health events and repeat ECG was obtained. PRIMARY AND SECONDARY OUTCOME MEASURES: Interim major adverse cardiovascular events (MACE) were defined by: self-reported interim stroke, self-reported hospitalisation for heart failure, self-reported interim myocardial infarction, interim myocardial infarction by ECG criteria (new pathologic Q waves in two contiguous leads) or death due to cardiovascular disease (CVD). RESULTS: Of 500 enrolled participants, 477 (95.4%) completed 6 month follow-up and 3 (0.6%) died. Over the 6 month follow-up period, 11 MACE occurred (3 strokes, 6 myocardial infarctions, 1 heart failure hospitalisation and 1 cardiovascular death), resulting in an incidence rate of 4.58 MACE per 100 person-years. Of participants completing 6 month follow-up, 31 (6.5%) reported a new non-communicable disease diagnosis, including 23 (4.8%) with a new hypertension diagnosis. CONCLUSIONS: The incidence of MACE among PLWH in Tanzania is high. These findings are an important preliminary step in understanding the landscape of CVD among PLWH in Tanzania and highlight the need for interventions to reduce cardiovascular risk in this population.

Adapting the stages of implementation completion to an evidence-based implementation strategy: The development of the NIATx stages of implementation completion.

Background: Dissemination and implementation frameworks provide the scaffolding to explore the effectiveness of evidence-based practices (EBPs) targeting process of care and organizational outcomes. Few instruments, like the stages of implementation completion (SIC) examine implementation fidelity to EBP adoption and how organizations differ in their approach to implementation. Instruments to measure organizational competency in the utilization of implementation strategies are lacking. Method: An iterative process was utilized to adapt the SIC to the NIATx implementation strategies. The new instrument, NIATx-SIC, was applied in a randomized controlled trial involving 53 addiction treatment agencies in Washington state to improve agency co-occurring capacity. NIATx-SIC data were reported by state staff and external facilitators and through participating agency documentation. Proportion and duration scores for each stage and phase of the NIATx-SIC were calculated for each agency. Competency was assessed using the NIATx fidelity tool. Comparisons of proportion, duration, and NIATx activities completed were determined using independent sample t-tests by agency competency level. Results: The NIATx-SIC distinguished between agencies achieving competency (n = 23) and those not achieving competency (n = 26). Agencies achieving competency completed a greater proportion of implementation phase activities and had a significantly longer Stage 7 duration. These agencies participated in significantly more individual and group coaching calls, attended more in-person meetings, implemented more change projects, and spent approximately 64 more days, on average, engaging in all NIATx activities. Conclusions: Organizational participation in dissemination and implementation research requires a significant investment of staff resources. The inability of an organization to achieve competency when utilizing a set of implementation strategies waste an opportunity to institutionalize knowledge of how to apply implementation strategies to future change efforts. The NIATx-SIC provides evidence that competency is not an attribute of the organization but rather a result of the application of the NIATx implementation strategies to improve agency co-occurring capacity. Trial Registration: ClinicalTrials.gov, NCT03007940. Registered January 2, 2017, https://clinicaltrials.gov/ct2/show/NCT03007940.

Access to integrated services for persons with co-occurring substance use and mental health disorders is a long-standing behavioral health problem. Evidence-based practices (EBPs) that focus on patient needs are effective in improving care for persons with co-occurring disorders. The stages of implementation completion (SIC) is a measure that assesses the process that organizations go through when implementing a new EBP and can be used to compare differences between organizations in their fidelity to recommended processes. To implement, organizations use specified strategies to integrate EBP into the care process. These strategies require a significant investment of staff resources. When organizations struggle to achieve competency with a set of implementation strategies, resources are wasted impacting the ability to use the strategies in future change efforts. As such, it is critical to measure organizational efforts to achieve competency, but instruments to do so are lacking. The SIC was adapted for a proven implementation strategy, NIATx, to address this gap. The NIATx strategy provides outside support and coaching to facilitate the implementation of a new EBP. Results from this study indicated that the NIATx-SIC could distinguish between addiction treatment agencies that applied NIATx implementation strategies with competency, versus those that did not, in the context of a multilevel randomized control trial. Study results provide evidence for the utility of adapting the SIC to specific implementation strategies and the benefit that the NIATx-SIC could provide for similar studies involving the use of NIATx to implement EBPs.

Longitudinal ECG changes among adults with HIV in Tanzania: A prospective cohort study.

The prevalence of cardiovascular disease (CVD) is rising among people with HIV (PWH) in sub-Saharan Africa (SSA). Despite the utility of the electrocardiogram (ECG) in screening for CVD, there is limited data regarding longitudinal ECG changes among PWH in SSA. In this study, we aimed to describe ECG changes over a 6-month period in a cohort of PWH in northern Tanzania. Between September 2020 and March 2021, adult PWH were recruited from Majengo HIV Care and Treatment Clinic (MCTC) in Moshi, Tanzania. Trained research assistants surveyed participants and obtained a baseline ECG. Participants then returned to MCTC for a 6-month follow-up, where another ECG was obtained. Two independent physician adjudicators interpreted baseline and follow-up ECGs for rhythm, left ventricular hypertrophy (LVH), bundle branch blocks, ST-segment changes, and T-wave inversion, using standardized criteria. New ECG abnormalities were defined as those that were absent in a patient's baseline ECG but present in their 6-month follow-up ECG. Of 500 enrolled participants, 476 (95.2%) completed follow-up. The mean (± SD) age of participants was 45.7 (± 11.0) years, 351 (73.7%) were female, and 495 (99.8%) were taking antiretroviral therapy. At baseline, 248 (52.1%) participants had one or more ECG abnormalities, the most common of which were LVH (n = 108, 22.7%) and T-wave inversion (n = 89, 18.7%). At six months, 112 (23.5%) participants developed new ECG abnormalities, including 40 (8.0%) cases of new T-wave inversion, 22 (4.6%) cases of new LVH, 12 (2.5%) cases of new ST elevation, and 11 (2.3%) cases of new prolonged QTc. Therefore, new ECG changes were common over a relatively short 6-month period, which suggests that subclinical CVD may develop rapidly in PWH in Tanzania. These data highlight the need for additional studies on CVD in PWH in SSA and the importance of routine CVD screening in this high-risk population.

Diarrheal disease and associations with water access and sanitation in Indigenous Shawi children along the Armanayacu River basin in Peru.

INTRODUCTION: Diarrheal disease, particularly in children under 5 years old, remains a global health challenge due to its high prevalence and chronic health consequences. Public health interventions that reduce diarrheal disease risk include improving access to water, sanitation, and hygiene. Although Peru achieved the 2015 Millennium Development Goal (MDG) indicators for water access, less progress was achieved on sanitation. Furthermore, many Indigenous Peoples were overlooked in the MDG indicators, resulting in a prioritization of Indigenous Peoples in the 2030 Sustainable Development Goals (SDGs). This study aimed to estimate the prevalence of childhood diarrhea, characterize access to water and sanitation, and determine the association of childhood diarrhea with water access and sanitation indicators in 10 Shawi Indigenous communities along the Armanayacu River in the Peruvian Amazon. METHODS: A cross-sectional survey (n=82) that captured data on diarrheal disease, sociodemographic variables, and water and sanitation exposures was conducted in 10 Shawi communities. Nutritional status of children under 5 was also assessed via physical examination. Descriptive and comparative statistics were conducted. RESULTS: A small proportion (n=7; 8.54%) of participating children reported an episode of diarrhea in the previous month. Almost half (46.30%) of participating children had stunting, wasting, or both. Although not statistically significant, children living in households that used latrines were 4.29 times (95% confidence interval (CI) 1.01-18.19) more likely to report an episode of diarrhea than children living in households that practiced open defecation. Although not statistically significant, children living in households that used water treatment methods were 4.25 times (95%CI 0.54-33.71) more likely to report an episode of diarrhea than children living in households that did not. CONCLUSION: The prevalence of childhood diarrhea was lower for Shawi than for other Amazon areas. The higher prevalence of childhood diarrhea in households that used latrines and water treatments warrants further investigation into local risk and protective factors. These Shawi communities scored low for the WHO/UNICEF Joint Monitoring Programme indicators for water and sanitation, indicating that they should be prioritized in future water, sanitation, and hygiene initiatives. Research will be required to understand and incorporate local Indigenous values and cultural practices into water, sanitation, and hygiene initiatives to maximize intervention uptake and effectiveness.

Identifying homologous recombination deficiency in breast cancer: genomic instability score distributions differ among breast cancer subtypes.

PURPOSE: A 3-biomarker homologous recombination deficiency (HRD) score is a key component of a currently FDA-approved companion diagnostic assay to identify HRD in patients with ovarian cancer using a threshold score of ≥ 42, though recent studies have explored the utility of a lower threshold (GIS ≥ 33). The present study evaluated whether the ovarian cancer thresholds may also be appropriate for major breast cancer subtypes by comparing the genomic instability score (GIS) distributions of BRCA1/2-deficient estrogen receptor-positive breast cancer (ER + BC) and triple-negative breast cancer (TNBC) to the GIS distribution of BRCA1/2-deficient ovarian cancer. METHODS: Ovarian cancer and breast cancer (ER + BC and TNBC) tumors from ten study cohorts were sequenced to identify pathogenic BRCA1/2 mutations, and GIS was calculated using a previously described algorithm. Pathologic complete response (pCR) to platinum therapy was evaluated in a subset of TNBC samples. For TNBC, a threshold was set and threshold validity was assessed relative to clinical outcomes. RESULTS: A total of 560 ovarian cancer, 805 ER + BC, and 443 TNBC tumors were included. Compared to ovarian cancer, the GIS distribution of BRCA1/2-deficient samples was shifted lower for ER + BC (p = 0.015), but not TNBC (p = 0.35). In the subset of TNBC samples, univariable logistic regression models revealed that GIS status using thresholds of ≥ 42 and ≥ 33 were significant predictors of response to platinum therapy. CONCLUSIONS: This study demonstrated that the GIS thresholds used for ovarian cancer may also be appropriate for TNBC, but not ER + BC. GIS thresholds in TNBC were validated using clinical response data to platinum therapy.

The New NCI Precision Medicine Trials.

Basket, umbrella, and platform trial designs (master protocols) have emerged over the last decade to study precision medicine approaches in oncology. First-generation trials like NCI-MATCH (Molecular Analysis for Therapy Choice) have proven the principle that studying targeted therapies on a large scale is feasible both from the laboratory and clinical perspectives. However, single-agent targeted therapies have shown limited ability to control metastatic disease, despite careful matching of drug to target. As such, newer approaches employing combinations of targeted therapy, or targeted therapy with standard therapies, need to be considered. The NCI has recently embarked on three second-generation precision medicine trials to address this need: ComboMATCH, iMATCH, and myeloMATCH. The design of these trials and necessary infrastructure are discussed in the following perspective.

Prevalence of Symptoms ≤12 Months After Acute Illness, by COVID-19 Testing Status Among Adults - United States, December 2020-March 2023.

To further the understanding of post-COVID conditions, and provide a more nuanced description of symptom progression, resolution, emergence, and reemergence after SARS-CoV-2 infection or COVID-like illness, analysts examined data from the Innovative Support for Patients with SARS-CoV-2 Infections Registry (INSPIRE), a prospective multicenter cohort study. This report includes analysis of data on self-reported symptoms collected from 1,296 adults with COVID-like illness who were tested for SARS-CoV-2 using a Food and Drug Administration-approved polymerase chain reaction or antigen test at the time of enrollment and reported symptoms at 3-month intervals for 12 months. Prevalence of any symptom decreased substantially between baseline and the 3-month follow-up, from 98.4% to 48.2% for persons who received a positive SARS-CoV-2 test results (COVID test-positive participants) and from 88.2% to 36.6% for persons who received negative SARS-CoV-2 test results (COVID test-negative participants). Persistent symptoms decreased through 12 months; no difference between the groups was observed at 12 months (prevalence among COVID test-positive and COVID test-negative participants = 18.3% and 16.1%, respectively; p>0.05). Both groups reported symptoms that emerged or reemerged at 6, 9, and 12 months. Thus, these symptoms are not unique to COVID-19 or to post-COVID conditions. Awareness that symptoms might persist for up to 12 months, and that many symptoms might emerge or reemerge in the year after COVID-like illness, can assist health care providers in understanding the clinical signs and symptoms associated with post-COVID-like conditions.