Tumor treating fields increases blood-brain barrier permeability and relative cerebral blood volume in patients with glioblastoma.

BACKGROUND AND OBJECTIVE: 200 kHz tumor treating fields (TTFields) is clinically approved for newly-diagnosed glioblastoma (nGBM). Because its effects on conventional surveillance MRI brain scans are equivocal, we investigated its effects on perfusion MRI (pMRI) brain scans. METHODS: Each patient underwent institutional standard pMRI: dynamic contrast-enhanced (DCE) and dynamic susceptibility contrast (DSC) pMRI at three time points: baseline, 2-, and 6-months on-adjuvant therapy. At each timepoint, the difference between T1 pre- versus post-contrast tumor volume (ΔT1) and these pMRI metrics were evaluated: normalized and standardized relative cerebral blood volume (nRCBV, sRCBV); fractional plasma volume (Vp), volume of extravascular extracellular space (EES) per volume of tissue (Ve), blood-brain barrier (BBB) permeability (Ktrans), and time constant for gadolinium reflux from EES back into the vascular system (Kep). Between-group comparisons were performed using rank-sum analysis, and bootstrapping evaluated likely reproducibility of the results. RESULTS: Among 13 pMRI datasets (11 nGBM, 2 recurrent GBM), therapies included temozolomide-only (n = 9) and temozolomide + TTFields (n = 4). No significant differences were found in patient or tumor characteristics. Compared to temozolomide-only, temozolomide + TTFields did not significantly affect the percent-change in pMRI metrics from baseline to 2 months. But during the 2- to 6-month period, temozolomide + TTFields significantly increased the percent-change in nRCBV (+26.9% [interquartile range 55.1%] vs -39.1% [37.0%], p = 0.049), sRCBV (+9.5% [39.7%] vs -30.5% [39.4%], p = 0.049), Ktrans (+54.6% [1768.4%] vs -26.9% [61.2%], p = 0.024), Ve (+111.0% [518.1%] vs -13.0% [22.5%], p = 0.048), and Vp (+98.8% [2172.4%] vs -24.6% [53.3%], p = 0.024) compared to temozolomide-only. CONCLUSION: Using pMRI, we provide initial in-human validation of pre-clinical studies regarding the effects of TTFields on tumor blood volume and BBB permeability in GBM.

Patterns of Progression in Patients With Newly Diagnosed Glioblastoma Treated With 5-mm Margins in a Phase 1/2 Trial of 5-Fraction Stereotactic Radiosurgery With Concurrent and Adjuvant Temozolomide.

PURPOSE: In patients with newly diagnosed glioblastoma (GBM), tumor margins of at least 20 mm are the standard of care. We sought to determine the pattern of tumor progression in patients treated with 5-fraction stereotactic radiosurgery with 5-mm margins. METHODS AND MATERIALS: Thirty adult patients with newly diagnosed GBM were treated with 5-fraction stereotactic radiosurgery in escalated doses from 25 to 40 Gy with a 5-mm total treatment margin. Progression was scored as "in-field" if the recurrent tumor was within or contiguous with the 5-mm margin, "marginal" if between 5 and 20 mm, and "distant" if entirely occurring greater than 20 mm. As geometric patterns of progression do not reflect the biologic dose received, we calculated the minimum equi-effective dose in 2 Gy (EQD2) per day at the site of tumor recurrence. Progression was "dosimetrically in-field" if covered by a minimum EQD2 per day of 48 Gy10. RESULTS: From 2010 to 2016, 27 patients had progressed. Progression was in-field in 17 (63%), marginal in 3 (11%), and distant in 7 (26%) patients. In the 3 patients with marginal progression, the minimum EQD2 to recurrent tumor were 48 Gy10, 56 Gy10 (both considered dosimetrically in-field), and 7 Gy10 (ie, dosimetrically out-of-field). Median overall survival was 12.1 months for in-field (95% confidence interval [CI], 8.9-17.6), 15.1 months (95% CI, 10.1 to not achieved) for marginal, and 21.4 months (95% CI, 11.2-33.5) for distant progression. Patients with radiation necrosis were less likely to have in-field progression (1 of 7; 14%) compared with those without radiation necrosis (16 of 20; 80%; P = .003); those with necrosis had a median overall survival of 27.2 months (95% CI, 11.2-48.3) compared with 11.7 months (95% CI, 8.9-17.6) for patients with no necrosis (P = .077). CONCLUSIONS: In patients with newly diagnosed GBM treated with a 5-mm clinical target volume margin, 3 patients (11%) had marginal progression within 5 to 20 mm; only 1 patient (4%) may have dosimetrically benefitted from conventional 20-mm margins. Radiation necrosis was associated with in-field tumor control.

Underprepared: influences of U.S. medical students' self-assessed confidence in immigrant and refugee health care.

BACKGROUND: United States (U.S.) census data from 2017 indicates that the percentage of persons born outside of the U.S. is increasing. However, no studies describe the amount of class time focused on immigrant and refugee health during medical school in the U.S. nor on incoming residents' confidence in providing culturally sensitive care. The objective of this study is to characterize final-year medical students' exposure to immigrant and refugee health and their confidence in caring for these populations. METHODS: A voluntary, cross-sectional survey was sent electronically to fourth-year medical students at twelve U.S. medical schools in 2020, with 707 respondents (46% response rate). Questions addressed respondents' curricular exposure to immigrant and refugee health care during medical school and their confidence in providing culturally sensitive care. Chi-square tests were used to assess relationships between categorical variables, and odds ratios were calculated for dichotomized variables. RESULTS: Most students (70.6%) described insufficient class time dedicated to culturally sensitive care, and many (64.5%) reported insufficient clinical exposure in caring for immigrants/refugees. The odds that incoming residents felt 'usually' or 'always' confident in their ability to provide culturally sensitive care to immigrants and refugees were higher in those with more class time on culturally sensitive care (OR 5.2 [3.6-7.4]), those with more clinical opportunities to care for immigrants and refugees (OR 7.2 [5.1-10.2]), and those who participated in a domestic low-resource or international elective (OR 1.4 [1.02-1.9]). More than half (55.3%) of respondents reported feeling 'not at all' or only 'sometimes' confident in their ability to provide culturally sensitive care to immigrants/refugees. CONCLUSIONS: Most fourth-year U.S. medical students entering residency feel unprepared to deliver culturally sensitive care to immigrants and refugees. This may be mediated by increased exposure to didactic curricula class time and/or experiential clinical activities, as those factors are associated with improved student confidence.

Radiation Therapy for IDH-Mutant Grade 2 and Grade 3 Diffuse Glioma: An ASTRO Clinical Practice Guideline.

PURPOSE: This guideline provides evidence-based recommendations for adults with isocitrate dehydrogenase (IDH)-mutant grade 2 and grade 3 diffuse glioma, as classified in the 2021 World Health Organization (WHO) Classification of Tumours. It includes indications for radiation therapy (RT), advanced RT techniques, and clinical management of adverse effects. METHODS: The American Society for Radiation Oncology convened a multidisciplinary task force to address 4 key questions focused on the RT management of patients with IDH-mutant grade 2 and grade 3 diffuse glioma. Recommendations were based on a systematic literature review and created using a predefined consensus-building methodology and system for grading evidence quality and recommendation strength. RESULTS: A strong recommendation for close surveillance alone was made for patients with oligodendroglioma, IDH-mutant, 1p/19q codeleted, WHO grade 2 after gross total resection without high-risk features. For oligodendroglioma, WHO grade 2 with any high-risk features, adjuvant RT was conditionally recommended. However, adjuvant RT was strongly recommended for oligodendroglioma, WHO grade 3. A conditional recommendation for close surveillance alone was made for astrocytoma, IDH-mutant, WHO grade 2 after gross total resection without high-risk features. Adjuvant RT was conditionally recommended for astrocytoma, WHO grade 2, with any high-risk features and strongly recommended for astrocytoma, WHO grade 3. Dose recommendations varied based on histology and grade. Given known adverse long-term effects of RT, consideration for advanced techniques such as intensity modulated radiation therapy/volumetric modulated arc therapy or proton therapy were given as strong and conditional recommendations, respectively. Finally, based on expert opinion, the guideline recommends assessment, surveillance, and management for toxicity management. CONCLUSIONS: Based on published data, the American Society for Radiation Oncology task force has proposed recommendations to inform the management of adults with IDH-mutant grade 2 and grade 3 diffuse glioma as defined by WHO 2021 classification, based on the highest quality published data, and best translated by our task force of subject matter experts.

Prevention and Management of High-Burden Noncommunicable Diseases in School-Age Children: A Systematic Review.

BACKGROUND AND OBJECTIVES: Noncommunicable diseases (NCDs) are chronic conditions requiring health care, education, social and community services, addressing prevention, treatment, and management. This review aimed to summarize and synthesize the available evidence on interventions from systematic reviews of high-burden NCDs and risk factors among school-aged children. METHODS: The following databases were used for this research: Medline, Embase, The Cochrane Library, and the Campbell library. The search dates were from 2000 to 2021. We included systematic reviews that synthesized studies to evaluate intervention effectiveness in children aged 5 to 19 years globally. Two reviewers independently extracted data and assessed methodological quality of included reviews using the AMSTAR 2 tool. RESULTS: Fifty studies were included. Asthma had the highest number of eligible reviews (n = 19). Of the reviews reporting the delivery platform, 27% (n = 16) reported outpatient settings, 13% (n = 8) home and community-based respectively, and 8% (n = 5) school-based platforms. Included reviews primarily (69%) reported high-income country data. This may limit the results' generalizability for school-aged children and adolescents in low- and middle- income countries. CONCLUSIONS: School-aged children and adolescents affected by NCDs require access to quality care, treatment, and support to effectively manage their diseases into adulthood. Strengthening research and the capacity of countries, especially low- and middle- income countries, for early screening, risk education and management of disease are crucial for NCD prevention and control.

Perceived roles, benefits and barriers of virtual global health partnership initiatives: a cross-sectional exploratory study.

BACKGROUND: Virtual global health partnership initiatives (VGHPIs) evolved rapidly during the COVID-19 pandemic to ensure partnership continuity. However the current landscape for VGHPI use and preference is unknown. This study aimed to increase understanding of GH partners' perspectives on VGHPIs. METHODS: From 15 October to 30 November 2020, An online, international survey was conducted using snowball sampling to document pandemic-related changes in partnership activities, preferences for VGHPIs, and perceived acceptability and barriers. The survey underwent iterative development within a diverse author group, representing academic and clinical institutions, and the non-profit sector. Participants from their professional global health networks were invited, including focal points for global health partnerships while excluding trainees and respondents from the European Economic Area. Analysis stratified responses by country income classification and partnership type. Authors used descriptive statistics to characterize responses, defining statistical significance as α = 0.05. RESULTS: A total of 128 respondents described 219 partnerships. 152/219 (69%) partnerships were transnational, 157/219 (72%) were of > 5 years duration, and 127/219 (60%) included bidirectional site visits. High-income country (HIC) partners sent significantly more learners to low- to middle-income country (LMIC) partner sites (p < 0.01). Participants commented on pandemic-related disruptions affecting 217/219 (99%) partnerships; 195/217 (90%) were disruption to activities; 122/217 (56%) to communication; 73/217 (34%) to access to professional support; and 72/217 (33%) to funding. Respondents indicated that VGHPIs would be important to 206/219 (94%) of their partnerships moving forward. There were overall differences in resource availability, technological capacity, and VGHPI preferences between LMIC and HIC respondents, with a statistically significant difference in VGHPI acceptability (p < 0.001). There was no significant difference between groups regarding VGHPIs' perceived barriers. CONCLUSIONS: The pandemic disrupted essential partnership elements, compounding differences between LMIC and HIC partners in their resources and preferences for partnership activities. VGHPIs have the potential to bridge new and existing gaps and maximize gains, bi-directionality, and equity in partnerships during and after COVID-19.

What can work and how? An overview of evidence-based interventions and delivery strategies to support health and human development from before conception to 20 years.

Progress has been made globally in improving the coverage of key maternal, newborn, and early childhood interventions in low-income and middle-income countries, which has contributed to a decrease in child mortality and morbidity. However, inequities remain, and many children and adolescents are still not covered by life-saving and nurturing care interventions, despite their relatively low costs and high cost-effectiveness. This Series paper builds on a large body of work from the past two decades on evidence-based interventions and packages of care for survival, strategies for delivery, and platforms to reach the most vulnerable. We review the current evidence base on the effectiveness of a variety of essential and emerging interventions that can be delivered from before conception until age 20 years to help children and adolescents not only survive into adulthood, but also to grow and develop optimally, support their wellbeing, and help them reach their full developmental potential. Although scaling up evidence-based interventions in children younger than 5 years might have the greatest effect on reducing child mortality rates, we highlight interventions and evidence gaps for school-age children (5-9 years) and the transition from childhood to adolescence (10-19 years), including interventions to support mental health and positive development, and address unintentional injuries, neglected tropical diseases, and non-communicable diseases.

Recurrent Status Epilepticus in the Setting of Chimeric Antigen Receptor (CAR)-T Cell Therapy.

Axicabtagene ciloleucel (AC) is an FDA-approved anti-CD19 autologous chimeric antigen receptor T-cell (CAR-T) therapy for refractory diffuse large B cell lymphoma (DLBCL). While its efficacy in DLBCL has been promising, neurotoxicity remains a significant concern. We present a case of a 22-year-old woman with chemotherapy-refractory DLBCL who exhibited Grade IV neurotoxicity in the setting of sepsis, after undergoing AC infusion. Despite prophylactic levetiracetam given per guidelines,1,2 she experienced a precipitous mental status decline on post-infusion day 8 (D8) followed by hypoxic respiratory failure in the setting of clinical status epilepticus on D11 and nonconvulsive status epilepticus (NCSE) on D18. While neuroimaging was unremarkable, EEG demonstrated diffuse slowing and 2.5-3 Hz generalized periodic discharges consistent with NCSE. Seizures were initially refractory to lorazepam, increasing doses of levetiracetam, and phenobarbital, requiring a midazolam drip titrated to 50-70% burst suppression for resolution. Methylprednisolone and tocilizumab were used to treat neurotoxicity and cytokine release syndrome, respectively. Empiric antibiotics were used for sepsis. After cessation of sedatives on D19, mental status improved to near baseline. PET/CT just prior to discharge showed a complete response of the DLBCL (Deauville 3). She was discharged on D37 with no further seizure activity. Unfortunately, a 3-month interval PET/CT demonstrated disease progression which continued through salvage pembrolizumab eventually leading to death 1.2 years post-CAR-T infusion. This case illustrates the clinical management challenges of a complex and rare neurotoxic side effect of CAR-T cell therapy, namely NCSE following status epilepticus.

Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study.

BACKGROUND: Combination nivolumab plus ipilimumab was efficacious in patients with asymptomatic melanoma brain metastases (MBM) in CheckMate 204, but showed low efficacy in patients with symptomatic MBM. Here, we provide final 3-year follow-up data from the trial. METHODS: This open-label, multicentre, phase 2 study (CheckMate 204) included adults (aged ≥18 years) with measurable MBM (0·5-3·0 cm in diameter). Asymptomatic patients (cohort A) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and no neurological symptoms or baseline corticosteroid use; symptomatic patients (cohort B) had an ECOG performance status of 0-2 with stable neurological symptoms and could be receiving low-dose dexamethasone. Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg was given intravenously every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks for up to 2 years, until disease progression or unacceptable toxicity. The primary endpoint was intracranial clinical benefit rate (complete responses, partial responses, or stable disease lasting ≥6 months) assessed in all treated patients. Intracranial progression-free survival and overall survival were key secondary endpoints. This study is registered with ClinicalTrials.gov, NCT02320058. FINDINGS: Between Feb 19, 2015, and Nov 1, 2017, 119 (72%) of 165 screened patients were enrolled and treated: 101 patients were asymptomatic (cohort A; median follow-up 34·3 months [IQR 14·7-36·4]) and 18 were symptomatic (cohort B; median follow-up 7·5 months [1·2-35·2]). Investigator-assessed intracranial clinical benefit was observed in 58 (57·4% [95% CI 47·2-67·2]) of 101 patients in cohort A and three (16·7% [3·6-41·4]) of 18 patients in cohort B; investigator-assessed objective response was observed in 54 (53·5% [43·3-63·5]) patients in cohort A and three (16·7% [3·6-41·4]) patients in cohort B. 33 (33%) patients in cohort A and three (17%) patients in cohort B had an investigator-assessed intracranial complete response. For patients in cohort A, 36-month intracranial progression-free survival was 54·1% (95% CI 42·7-64·1) and overall survival was 71·9% (61·8-79·8). For patients in cohort B, 36-month intracranial progression-free survival was 18·9% (95% CI 4·6-40·5) and overall survival was 36·6% (14·0-59·8). The most common grade 3-4 treatment-related adverse events (TRAEs) were increased alanine aminotransferase and aspartate aminotransferase (15 [15%] of 101 patients each) in cohort A; no grade 3 TRAEs occurred in more than one patient each in cohort B, and no grade 4 events occurred. The most common serious TRAEs were colitis, diarrhoea, hypophysitis, and increased alanine aminotransferase (five [5%] of each among the 101 patients in cohort A); no serious TRAE occurred in more than one patient each in cohort B. There was one treatment-related death (myocarditis in cohort A). INTERPRETATION: The durable 3-year response, overall survival, and progression-free survival rates for asymptomatic patients support first-line use of nivolumab plus ipilimumab. Symptomatic disease in patients with MBM remains difficult to treat, but some patients achieve a long-term response with the combination. FUNDING: Bristol Myers Squibb.

The impact of global health opportunities on residency selection.

BACKGROUND: An increasing number of medical trainees across specialties desire and expect Global Health (GH) experiences during training. It is useful for residency programs to know the impact that offering GH opportunities has on resident recruitment. The study objectives were to explore the importance of GH opportunities in residency selection among fourth-year medical students, examine the relationship between interest in GH and career plans, and describe students' perspectives on prior GH experiences. METHODS: The authors administered an electronic survey to all fourth-year medical students attending 12 different US institutions in February 2020. Data from the ten schools who were able to comply with the survey distribution methodology and with response rates above 25% were analyzed using descriptive statistics and Pearson's correlation. RESULTS: A total of 707 fourth-year medical students from the included schools completed the survey out of 1554 possible students (46% response rate). One third of respondents ranked the presence of GH experiences in residency as moderately or very important and 26% felt that the presence of a formal GH curriculum was at least moderately important, with variation noted among specialties. After training, 65% of students envision practicing internationally in some capacity. A desire to care for underserved patients in their careers was significantly correlated with an interest in GH experiences during residency. CONCLUSIONS: The opportunity to be involved in GH experiences during training can be an important factor for many medical students when considering residency choice, and the availability of these opportunities may be a valuable recruitment tool. Students valuing GH opportunities during residency are more interested in working with underserved populations in their future careers.

Global Health Partnerships During the COVID-19 Pandemic: Perspectives and Insights from International Partners.

Global health partnerships (GHPs) have encountered many challenges during the coronavirus disease 2019 (COVID-19) pandemic. New perspectives and insights are needed to guide GHPs when navigating current and future collaborations. This study aimed to understand perspectives and insights of international partners regarding how the COVID-19 pandemic impacted their GHPs with institutions in the United States. We performed a cross-sectional qualitative study conducted through virtual semi-structured interviews performed between June 12, 2020 and July 22, 2020. We queried academic institutions based in the United States to refer individuals from their corresponding international GHP organizations. We invited these individuals to participate in virtual interviews that were audio-recorded and transcribed. We analyzed data qualitatively to identify themes. Eighty-four United States partners provided e-mail addresses for international partners. Ten individuals from these GHPs completed the interview. Participants reported overall positive experiences with their United States-based partners during the pandemic. The following themes emerged: imbalanced decision-making; worry about partnership continuity; opportunity to optimize communication within partnerships; interest in incorporating technology to facilitate engagement; and a desire for increased bilateral exchanges. Several challenges appeared to exist before COVID-19 and were highlighted by the pandemic. Most respondents were optimistic regarding the future of their GHPs. However, concerns were expressed regarding the implications of fewer in-person international experiences with United States trainees and the desire for stronger communication. Although our results do not represent the perspectives and insights of all GHPs, they provide considerations for the future. We urge institutions in the United States to re-examine and strive for equitable relationships with their international partners.

Safety and efficacy of the combination of nivolumab plus ipilimumab in patients with melanoma and asymptomatic or symptomatic brain metastases (CheckMate 204).

BACKGROUND: In patients with melanoma and asymptomatic brain metastases (MBM), nivolumab plus ipilimumab provided an intracranial response rate of 55%. Here, we present the first report for patients who were symptomatic and/or required corticosteroids and updated data for asymptomatic patients. METHODS: Patients with measurable MBM, 0.5-3.0 cm, were enrolled into Cohort A (asymptomatic) or Cohort B (stable neurologic symptoms and/or receiving corticosteroids). Nivolumab, 1 mg/kg, and ipilimumab, 3 mg/kg, were given intravenously every 3 weeks ×4, followed by nivolumab, 3 mg/kg, every 2 weeks until progression, unacceptable toxicity, or 24 months. The primary endpoint was intracranial clinical benefit rate (CBR; complete response [CR], partial response [PR], or stable disease ≥6 months). RESULTS: Symptomatic patients (N = 18) received a median of one nivolumab and ipilimumab combination dose and had an intracranial CBR of 22.2%. Two of 12 patients on corticosteroids had CR; 2 responded among the 6 not on corticosteroids. Median intracranial progression-free survival (PFS) and overall survival (OS) were 1.2 and 8.7 months, respectively. In contrast, with 20.6 months of follow-up, we confirmed an intracranial CBR of 58.4% in asymptomatic patients (N = 101); median duration of response, PFS, and OS were not reached. No new safety signals were observed. CONCLUSIONS: Nivolumab plus ipilimumab provides durable clinical benefit for asymptomatic patients with MBM and should be considered for first-line therapy. This regimen has limited activity in MBM patients with neurologic symptoms and/or requiring corticosteroids, supporting the need for alternative approaches and methods to reduce the dependency on corticosteroids. Clinical trial registration. ClinicalTrials.gov, NCT02320058.

Delivering nutrition interventions to women and children in conflict settings: a systematic review.

BACKGROUND: Low/middle-income countries (LMICs) face triple burden of malnutrition associated with infectious diseases, and non-communicable diseases. This review aims to synthesise the available data on the delivery, coverage, and effectiveness of the nutrition programmes for conflict affected women and children living in LMICs. METHODS: We searched MEDLINE, Embase, CINAHL, and PsycINFO databases and grey literature using terms related to conflict, population, and nutrition. We searched studies on women and children receiving nutrition-specific interventions during or within five years of a conflict in LMICs. We extracted information on population, intervention, and delivery characteristics, as well as delivery barriers and facilitators. Data on intervention coverage and effectiveness were tabulated, but no meta-analysis was conducted. RESULTS: Ninety-one pubblications met our inclusion criteria. Nearly half of the publications (n=43) included population of sub-Saharan Africa (n=31) followed by Middle East and North African region. Most publications (n=58) reported on interventions targeting children under 5 years of age, and pregnant and lactating women (n=27). General food distribution (n=34), micronutrient supplementation (n=27) and nutrition assessment (n=26) were the most frequently reported interventions, with most reporting on intervention delivery to refugee populations in camp settings (n=63) and using community-based approaches. Only eight studies reported on coverage and effectiveness of intervention. Key delivery facilitators included community advocacy and social mobilisation, effective monitoring and the integration of nutrition, and other sectoral interventions and services, and barriers included insufficient resources, nutritional commodity shortages, security concerns, poor reporting, limited cooperation, and difficulty accessing and following-up of beneficiaries. DISCUSSION: Despite the focus on nutrition in conflict settings, our review highlights important information gaps. Moreover, there is very little information on coverage or effectiveness of nutrition interventions; more rigorous evaluation of effectiveness and delivery approaches is needed, including outside of camps and for preventive as well as curative nutrition interventions. PROSPERO REGISTRATION NUMBER: CRD42019125221.

Delivering maternal and neonatal health interventions in conflict settings: a systematic review.

BACKGROUND: While much progress was made throughout the Millennium Development Goals era in reducing maternal and neonatal mortality, both remain unacceptably high, especially in areas affected by humanitarian crises. While valuable guidance on interventions to improve maternal and neonatal health in both non-crisis and crisis settings exists, guidance on how best to deliver these interventions in crisis settings, and especially in conflict settings, is still limited. This systematic review aimed to synthesise the available literature on the delivery on maternal and neonatal health interventions in conflict settings. METHODS: We searched MEDLINE, Embase, CINAHL and PsycINFO databases using terms related to conflict, women and children, and maternal and neonatal health. We searched websites of 10 humanitarian organisations for relevant grey literature. Publications reporting on conflict-affected populations in low-income and middle-income countries and describing a maternal or neonatal health intervention delivered during or within 5 years after the end of a conflict were included. Information on population, intervention, and delivery characteristics were extracted and narratively synthesised. Quantitative data on intervention coverage and effectiveness were tabulated but no meta-analysis was undertaken. RESULTS: 115 publications met our eligibility criteria. Intervention delivery was most frequently reported in the sub-Saharan Africa region, and most publications focused on displaced populations based in camps. Reported maternal interventions targeted antenatal, obstetric and postnatal care; neonatal interventions focused mostly on essential newborn care. Most interventions were delivered in hospitals and clinics, by doctors and nurses, and were mostly delivered through non-governmental organisations or the existing healthcare system. Delivery barriers included insecurity, lack of resources and lack of skilled health staff. Multi-stakeholder collaboration, the introduction of new technology or systems innovations, and staff training were delivery facilitators. Reporting of intervention coverage or effectiveness data was limited. DISCUSSION: The relevant existing literature focuses mostly on maternal health especially around the antenatal period. There is still limited literature on postnatal care in conflict settings and even less on newborn care. In crisis settings, as much as in non-crisis settings, there is a need to focus on the first day of birth for both maternal and neonatal health. There is also a need to do more research on how best to involve community members in the delivery of maternal and neonatal health interventions. PROSPERO REGISTRATION NUMBER: CRD42019125221.

We are part of the problem: the role of children's hospitals in addressing health inequity.

Racism is an ongoing public health crisis that undermines health equity for all children in hospitals across our nation. The presence and impact of institutionalized racism contributes to health inequity and is under described in the medical literature. In this review, we focus on key interdependent areas to foster inclusion, diversity, and equity in Children's Hospitals, including 1) promotion of workforce diversity 2) provision of anti-racist, equitable hospital patient care, and 3) prioritization of academic scholarship focused on health equity research, quality improvement, medical education, and advocacy. We discuss the implications for clinical and academic practice.Plain Language Summary: Racism in Children's Hospitals harms children. We as health-care providers and hospital systems are part of the problem. We reviewed the literature for the best ways to foster inclusion, diversity, and equity in hospitals. Hospitals can be leaders in improving child health equity by supporting a more diverse workforce, providing anti-racist patient care, and prioritizing health equity scholarship.

Intracranial Tumor Control After Immune-Related Adverse Events and Discontinuation of Immunotherapy for Melanoma.

OBJECTIVE: Immunotherapy for patients with melanoma with brain metastasis has significantly improved outcomes; however, it has also been characterized by potentially dangerous immune-related adverse events (IRAEs). Several reports have suggested that these reactions can precede improved treatment responses. For intracranial disease control, we sought to identify if such an association exists. METHODS: We conducted a retrospective chart review of patients with melanoma who underwent immunotherapy treatment after diagnosis of brain metastasis. The study cohort was then stratified into 2 groups based on their history of developing an IRAE that prompted discontinuation of that regimen. The primary outcome variable included intracranial progression-free survival (PFS). Kaplan-Meier and Cox proportional hazard analyses were used to evaluate survival and predictors of outcomes. RESULTS: Fifty-two patients met the inclusion criteria, 17 of whom experienced severe IRAEs that led to discontinuation of immunotherapy. Median intracranial PFS was 19.9 versus 10.5 months (P = 0.053) in patients who did and did not experience severe IRAEs prompting discontinuation, respectively. No additional outcome benefits were identified for systemic PFS or overall survival (mean, 33.1 months and 27.6 months, respectively). Multivariable analysis identified BRAF mutation status as a negative prognosticator of brain progression (P = 0.013; hazard ratio, 3.90). Initial treatment with BRAF inhibitor was also a negative predictor of all-cause mortality (P = 0.015; hazard ratio, 10.73). CONCLUSIONS: Immune-related adverse events may signify an underlying immunogenic response that has intracranial disease control benefits. Despite their associated side effects, immunotherapies continue to show promising outcomes as a first-line agent for melanoma with brain metastasis.

Delivery of sexual and reproductive health interventions in conflict settings: a systematic review.

BACKGROUND: It is essential to provide comprehensive sexual and reproductive health (SRH) interventions to women affected by armed conflict, but there is a lack of evidence on effective approaches to delivering such interventions in conflict settings. This review synthesised the available literature on SRH intervention delivery in conflict settings to inform potential priorities for further research and additional guidance development. METHODS: We searched MEDLINE, Embase, CINAHL and PsycINFO databases using terms related to conflict, women and children, and SRH. We searched websites of 10 humanitarian organisations for relevant grey literature. Publications reporting on conflict-affected populations in low-income and middle-income countries and describing an SRH intervention delivered during or within 5 years after the end of a conflict were included. Information on population, intervention and delivery characteristics were extracted and narratively synthesised. Quantitative data on intervention coverage and effectiveness were tabulated, but no meta-analysis was undertaken. RESULTS: 110 publications met our eligibility criteria. Most focused on sub-Saharan Africa and displaced populations based in camps. Reported interventions targeted family planning, HIV/STIs, gender-based violence and general SRH. Most interventions were delivered in hospitals and clinics by doctors and nurses. Delivery barriers included security, population movement and lack of skilled health staff. Multistakeholder collaboration, community engagement and use of community and outreach workers were delivery facilitators. Reporting of intervention coverage or effectiveness data was limited. DISCUSSION: There is limited relevant literature on adolescents or out-of-camp populations and few publications reported on the use of existing guidance such as the Minimal Initial Services Package. More interventions for gender-based violence were reported in the grey than the indexed literature, suggesting limited formal research in this area. Engaging affected communities and using community-based sites and personnel are important, but more research is needed on how best to reach underserved populations and to implement community-based approaches. PROSPERO REGISTRATION NUMBER: CRD42019125221.

Delivering water, sanitation and hygiene interventions to women and children in conflict settings: a systematic review.

BACKGROUND: Access to safe water and sanitation facilities and the adoption of effective hygiene practices are fundamental to reducing maternal and child morbidity and mortality globally. In armed conflict settings, inadequate water, sanitation and hygiene (WASH) infrastructure poses major health risks for women and children. This review aimed to synthesise the existing information on WASH interventions being delivered to women and children in conflict settings in low-income and middle-income countries (LMICs) and to identify the personnel, sites and platforms being used to deliver such interventions. METHODS: We conducted a systematic search for publications indexed in four databases, and grey literature was searched through the websites of humanitarian agencies and organisations. Eligible publications reported WASH interventions delivered to conflict-affected women or children. We extracted and synthesised information on intervention delivery characteristics, as well as barriers and facilitators. RESULTS: We identified 58 eligible publications reporting on the delivery of WASH interventions, mostly in Sub-Saharan Africa. Non-Governmental Organization (NGO)/United Nations (UN) agency staff were reported to be involved in delivering interventions in 62% of publications, with the most commonly reported delivery site being community spaces (50%). Only one publication reported quantitative data on intervention effectiveness among women or children. DISCUSSION: This review revealed gaps in the current evidence on WASH intervention delivery in conflict settings. Little information is available on the delivery of water treatment or environmental hygiene interventions, or about the sites and personnel used to deliver WASH interventions. Limited quantitative data on WASH intervention coverage or effectiveness with respect to women or children are important gaps, as multiple factors can affect how WASH services are accessed differently by women and men, and the hygiene needs of adolescent girls and boys differ; these factors must be taken into account when delivering interventions in conflict settings. PROSPERO REGISTRATION NUMBER: CRD42019125221.