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The protection and support of breastfeeding is the most effective intervention to prevent child morbidity and mortality especially in humanitarian crisis. During the Palestine-Israel conflict healthcare services are understaffed and lack basic resources, with frequent power cuts and stock-outs of essential drugs and equipment. This case study seeks to answer the questions: (1) How does the protracted crisis in Gaza affect the breastfeeding practices of the most vulnerable population; and (2) What is the role that midwives can play in improving breastfeeding practices? The study was conducted using a mixed method approach with quantitative and qualitative methods. Purposeful selection of women and children was conducted utilising eligibility criteria, women with children less than 2 years of age were included. All the respondents were asked if they agreed to participate in the survey. A total of 63% practice early initiation of breastfeeding and 42% confirmed that their new-borns were given liquids other than breast milk during the first 3 days of life. Fifty percent of mothers addressed breast milk insufficiency by drinking additional fluids and 40% by using infant formula. Only 18% of women said that they received breastfeeding information during contact with health professionals throughout labour, delivery, and subsequent post-natal care visits. Many mothers during the focus group discussions (FGDs) confirm using milk to top up or replace breast milk. Myths and misconceptions around breastfeeding remain, while women do access antenatal care services and deliver in the health facilities. There is a need to a) adapt the recommendations of the operational guidance for infant and young child feeding in emergencies (IYCF-E) in the Gaza strip, to protect, promote and support breastfeeding and b) include skilled breastfeeding counselling in the pre-service and in-service training for midwives. Lessons learned included the importance of a) allocating additional research time, to account for interruption b) daily coordination with security officers to ensure safe access to localities c) identification of extra sites, in case of conflict escalation d) training of additional enumerators in case conflict escalation e) negotiation with authorities to ensure compliance with requirements.

ObjectivesDuring the COVID-19 pandemic, most essential services experienced some level of disruption. Disruption in LMICs was more severe than in HICs. Early reports suggested that services for maternal and newborn health were disproportionately affected, raising concerns about health equity. Most disruption indicators measure demand-side disruption, or they conflate demand-side and supply-side disruption. There is currently no published guidance on measuring supply-side disruption. The primary objective of this review was to identify methods and approaches used to measure supply-side service disruptions to maternal and newborn health services in the context of COVID-19.DesignWe carried out a systematic review and have created a typology of measurement methods and approaches using narrative synthesis.Data sourcesWe searched MEDLINE, EMBASE and Global Health in January 2023. We also searched the grey literature.Eligibility criteriaWe included empirical studies describing the measurement of supply-side service disruption of maternal and newborn health services in LMICs in the context of COVID-19.Data extraction and synthesisWe extracted the aim, method(s), setting, and study outcome(s) from included studies. We synthesised findings by type of measure (ie, provision or quality of services) and methodological approach (ie, qualitative or quantitative).ResultsWe identified 28 studies describing 5 approaches to measuring supply-side disruption: (1) cross-sectional surveys of the nature and experience of supply-side disruption, (2) surveys to measure temporal changes in service provision or quality, (3) surveys to create composite disruption scores, (4) surveys of service users to measure receipt of services, and (5) clinical observation of the provision and quality of services.ConclusionOur review identified methods and approaches for measuring supply-side service disruption of maternal and newborn health services. These indicators provide important information about the causes and extent of supply-side disruption and provide a useful starting point for developing specific guidance on the measurement of service disruption in LMICs.

Background: In humanitarian settings, strengthening health systems while responding to the health needs of crisis-affected populations is challenging and marked with evidence gaps. Drawing from a decade of family planning and postabortion care programming in humanitarian settings, this paper aims to identify strategic components that contribute to health system strengthening in such contexts. Materials and Methods: A diverse range of key informants from North Kivu (Democratic Republic of Congo, DRC) and Puntland (Somalia), including female and male community members, adolescents and adults, healthcare providers, government and community leaders, participated in qualitative interviews, which applied the World Health Organization health system building blocks framework. Data were thematically analyzed according to this framework. Results: Findings from the focus group discussions (11 in DRC, 7 in Somalia) and key informant interviews (seven in DRC, four in Somalia) involving in total 54 female and 72 male participants across both countries indicate that health programs in humanitarian settings, such as Save the Children's initiative on family planning and postabortion care, could contribute to strengthening health systems by positively influencing national policies and guidance, strengthening local coordination mechanisms, capacitating the healthcare workforce with competency-based training and supportive supervision (benefiting facilities supported by the project and beyond), developing the capacity of Ministry of Health staff in the effective management of the supply chain, actively and creatively mobilizing the community to raise awareness and create demand, and providing quality and affordable services. Financial sustainability is challenged by the chronically limited healthcare expenditure experienced in both humanitarian contexts. Conclusions: In humanitarian settings, carefully designed healthcare interventions, such as those that address the family planning and postabortion care needs of crisis-affected populations, have the potential not only to increase access to essential services but also contribute to strengthening several components of the health system while increasing the government capacity, ownership, and accountability.

This thesis begins with a critique of Quentin Meillassoux’s Après la finitude. Chapter One argues against Meillassoux’s injunction to abandon the “transcendental,” while putting forth a Lacanian solution to the “correlationist” problem. Chapter Two expounds the meaning of the Cartesian subject, with a Lacanian twist. Under this view, the subject is split, and this split carries the name “sexual difference.” The cogito is “split” qua sexual difference, whereby sexual difference names the structural antagonism/impossibility that exists in language and bears on all speaking subjects. The second chapter focuses primarily on explaining how sexual difference marks the cogito, by expanding on Alenka Zupančič’s “What is Sex,” and Lacan’s Seminar XX . Finally, Chapter Three discusses the Cartesian phenomenon of love, in looking at Descartes’ most obscure text, The Passions of the Soul. The third chapter serves as a “testing site” for the theses of the first two chapters, such that the experience of love makes explicit the argument that the cogito is split.

Autosomal dominant polycystic kidney disease (ADPKD), the most common monogenic nephropathy, is characterized by phenotypic variability that exceeds genic effects. Dysregulated metabolism and immune cell function are key disease modifiers. The tryptophan metabolites, kynurenines, produced through indoleamine 2,3-dioxygenase 1 (IDO1), are known immunomodulators. Here, we study the role of tryptophan metabolism in PKD using an orthologous disease model (C57BL/6J Pkd1 RC/RC ). We found elevated kynurenine and IDO1 levels in Pkd1 RC/RC kidneys versus wild type. Further, IDO1 levels were increased in ADPKD cell lines. Genetic Ido1 loss in Pkd1 RC/RC animals resulted in reduced PKD severity, as measured by cystic index and percentage kidney weight normalized to body weight. Consistent with an immunomodulatory role of kynurenines, Pkd1 RC/RC ; Ido1 –/– mice presented with significant changes in the cystic immune microenvironment (CME) versus controls. Kidney macrophage numbers decreased and CD8 + T cell numbers increased, both known PKD modulators. Also, pharmacological IDO1 inhibition in Pkd1 RC/RC mice and kidney-specific Pkd2 -knockout mice with rapidly progressive PKD resulted in less severe PKD versus controls, with changes in the CME similar to those in the genetic model. Our data suggest that tryptophan metabolism is dysregulated in ADPKD and that its inhibition results in changes to the CME and slows disease progression, making IDO1 a therapeutic target for ADPKD.

Innate and adaptive immune cells modulate the severity of autosomal dominant polycystic kidney disease (ADPKD), a common kidney disease with inadequate treatment options. ADPKD has parallels with cancer, in which immune checkpoint inhibitors have been shown to reactivate CD8 + T cells and slow tumor growth. We have previously shown that in PKD, CD8 + T cell loss worsens disease. This study used orthologous early-onset and adult-onset ADPKD models ( Pkd1 p.R3277C) to evaluate the role of immune checkpoints in PKD. Flow cytometry of kidney cells showed increased levels of programmed cell death protein 1 (PD-1)/cytotoxic T lymphocyte associated protein 4 (CTLA-4) on T cells and programmed cell death ligand 1 (PD-L1)/CD80 on macrophages and epithelial cells in Pkd1 RC/RC mice versus WT, paralleling disease severity. PD-L1/CD80 was also upregulated in ADPKD human cells and patient kidney tissue versus controls. Genetic PD-L1 loss or treatment with an anti–PD-1 antibody did not impact PKD severity in early-onset or adult-onset ADPKD models. However, treatment with anti–PD-1 plus anti–CTLA-4, blocking 2 immune checkpoints, improved PKD outcomes in adult-onset ADPKD mice; neither monotherapy altered PKD severity. Combination therapy resulted in increased kidney CD8 + T cell numbers/activation and decreased kidney regulatory T cell numbers correlative with PKD severity. Together, our data suggest that immune checkpoint activation is an important feature of and potential novel therapeutic target in ADPKD.

Background ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane-anchored protein involved in diverse processes including mitochondrial dynamics, mitochondrial DNA organization, and cholesterol metabolism. Biallelic deletions (null), recessive missense variants (hypomorph), and heterozygous missense variants or duplications (antimorph) in ATAD3A lead to neurological syndromes in humans. Methods To expand the mutational spectrum of ATAD3A variants and to provide functional interpretation of missense alleles in trans to deletion alleles, we performed exome sequencing for identification of single nucleotide variants (SNVs) and copy number variants (CNVs) in ATAD3A in individuals with neurological and mitochondrial phenotypes. A Drosophila Atad3a Gal4 knockin-null allele was generated using CRISPR-Cas9 genome editing technology to aid the interpretation of variants. Results We report 13 individuals from 8 unrelated families with biallelic ATAD3A variants. The variants included four missense variants inherited in trans to loss-of-function alleles (p.(Leu77Val), p.(Phe50Leu), p.(Arg170Trp), p.(Gly236Val)), a homozygous missense variant p.(Arg327Pro), and a heterozygous non-frameshift indel p.(Lys568del). Affected individuals exhibited findings previously associated with ATAD3A pathogenic variation, including developmental delay, hypotonia, congenital cataracts, hypertrophic cardiomyopathy, and cerebellar atrophy. Drosophila studies indicated that Phe50Leu, Gly236Val, Arg327Pro, and Lys568del are severe loss-of-function alleles leading to early developmental lethality. Further, we showed that Phe50Leu, Gly236Val, and Arg327Pro cause neurogenesis defects. On the contrary, Leu77Val and Arg170Trp are partial loss-of-function alleles that cause progressive locomotion defects and whose expression leads to an increase in autophagy and mitophagy in adult muscles. Conclusion Our findings expand the allelic spectrum of ATAD3A variants and exemplify the use of a functional assay in Drosophila to aid variant interpretation.

Objectives To quantify brain microstructural changes in recently diagnosed relapsing-remitting multiple sclerosis (RRMS) using longitudinal T 1 measures, and determine their associations with clinical disability. Methods Seventy-nine people with recently diagnosed (< 6 months) RRMS were recruited from a single-centre cohort sub-study, and underwent baseline and 1-year brain MRI, including variable flip angle T 1 mapping. Median T 1 was measured in white matter lesions (WML), normal-appearing white matter (NAWM), cortical/deep grey matter (GM), thalami, basal ganglia and medial temporal regions. Prolonged T 1 (≥ 2.00 s) and supramedian T 1 (relative to cohort WML values) WML voxel counts were also measured. Longitudinal change was assessed with paired t -tests and compared with Bland-Altman limits of agreement from healthy control test-retest data. Regression analyses determined relationships with Expanded Disability Status Scale (EDSS) score and dichotomised EDSS outcomes (worsening or stable/improving). Results Sixty-two people with RRMS (mean age 37.2 ± 10.9 [standard deviation], 48 female) and 11 healthy controls (age 44 ± 11, 7 female) contributed data. Prolonged and supramedian T 1 WML components increased longitudinally (176 and 463 voxels, respectively; p  < .001), and were associated with EDSS score at baseline ( p  < .05) and follow-up (supramedian: p  < .01; prolonged: p  < .05). No cohort-wide median T 1 changes were found; however, increasing T 1 in WML, NAWM, cortical/deep GM, basal ganglia and thalami was positively associated with EDSS worsening ( p  < .05). Conclusion T 1 is sensitive to brain microstructure changes in early RRMS. Prolonged WML T 1 components and subtle changes in NAWM and GM structures are associated with disability. Clinical relevance statement MRI T 1 brain mapping quantifies disability-associated white matter lesion heterogeneity and subtle microstructural damage in normal-appearing brain parenchyma in recently diagnosed RRMS, and shows promise for early objective disease characterisation and stratification. Key Points • Quantitative T 1 mapping detects brain microstructural damage and lesion heterogeneity in recently diagnosed relapsing-remitting multiple sclerosis. • T 1 increases in lesions and normal-appearing parenchyma, indicating microstructural damage, are associated with worsening disability. • Brain T 1 measures are objective markers of disability-relevant pathology in early multiple sclerosis. Graphical abstract

ObjectiveAromatic L-amino acid decarboxylase deficiency (AADCd) is a rare neurometabolic disorder resulting from variants in the dopa decarboxylase (DDC) gene. Diagnosis of AADCd is often delayed because of variable clinical presentation. Patients are frequently misdiagnosed with more common conditions, such as cerebral palsy (CP) owing to a lack of AADCd awareness. REVEAL-CP is a prospective, multicentre, multinational, interventional, non-registrational study designed to investigate the prevalence of AADCd in patients presenting with symptoms of CP and to characterise genotypes associated with high 3-O-methyldopa (3-OMD) levels in dried blood spot samples. Following the study, UK paediatric neurologist investigators completed a survey on learning opportunities to improve the early identification of patients with AADCd who may be eligible for treatment.MethodsThe REVEAL-CP study screened patient records. After exclusion of patients with genetic and/or CSF neurotransmitter analysis, 49 UK patients were identified as being suitable for 3-OMD testing. Following the study, UK investigators completed a survey developed in collaboration with PharmaGenesis London, a third-party agency, including questions requiring yes/no, Likert scale (strongly agree; somewhat agree; neither agree nor disagree; somewhat disagree; strongly disagree; don’t know) and/or qualitative responses. Consensus was reached if the majority of investigator respondents somewhat or strongly agreed to individual questions.ResultsSix investigators completed the survey and reached consensus on the following recommendations to improve AADCd patient identification in the UK: adoption of a more centralised record system between NHS trusts, particularly between community and secondary paediatric practices; implementing genetic testing as the primary diagnostic tool for patients with CP-like symptoms of unknown aetiology; increasing awareness among clinicians of the differential diagnosis of neurotransmitter disorders in patients with CP-like symptoms; and earlier use of 3-OMD testing in the diagnostic workup of patients presenting with unexplained movement disorders or CP-like symptoms, alongside testing for serum prolactin and urinary organic acids including vanillactate, through the establishment of a nationally accredited 3-OMD service.ConclusionsA greater number of patients with CP-like symptoms of unknown aetiology could be screened for AADCd, taking into consideration the investigators’ suggestions. For rare diseases like AADCd, the provision of additional resources will be key for targeted patient screening. Given the recent EMA and MHRA marketing authorisation approvals for the first licensed gene therapy for AADCd, these improved efforts for early diagnosis could prove critical to the timely and effective management of patients with AADCd.ReferencesRizzi S, et al. Behav Neurol 2022;2022:2210555.Opladen T, et al. Mol Genet Metab Rep 2016;9:61–6.Burlina A, et al. Mol Genet Metab 2021;133:56–62.Chien YH, et al. Mol Genet Metab 2016;118:259–63.