Rethinking how development assistance for health can catalyse progress on primary health care.

Global campaigns to control HIV, tuberculosis, malaria, and vaccine-preventable illnesses showed that large-scale impact can be achieved by using additional international financing to support selected, evidence-based, high-impact investment areas and to catalyse domestic resource mobilisation. Building on this paradigm, we make the case for targeting additional international funding for selected high-impact investments in primary health care. We have identified and costed a set of concrete, evidence-based investments that donors could support, which would be expected to have major impacts at an affordable cost. These investments are in: (1) individuals and communities empowered to engage in health decision making, (2) a new model of people-centred primary care, and (3) next generation community health workers. These three areas would be supported by strengthening two cross-cutting elements of national systems. The first is the digital tools and data that support facility, district, and national managers to improve processes, quality of care, and accountability across primary health care. The second is the educational, training, and supervisory systems needed to improve the quality of care. We estimate that with an additional international investment of between US$1·87 billion in a low-investment scenario and $3·85 billion in a high-investment scenario annually over the next 3 years, the international community could support the scale-up of this evidence-based package of investments in the 59 low-income and middle-income countries that are eligible for external financing from the World Bank Group's International Development Association.

Brain gray matter changes in children at risk for sudden unexpected death in epilepsy.

BACKGROUND: Potential failing adult brain sites, stratified by risk, mediating Sudden Unexpected Death in Epilepsy (SUDEP) have been described, but are unknown in children. METHODS: We examined regional brain volumes using T1-weighted MRI images in 21 children with epilepsy at high SUDEP risk and 62 healthy children, together with SUDEP risk scores, calculated from focal seizure frequency. Gray matter tissue type was partitioned, maps normalized, smoothed, and compared between groups (SPM12; ANCOVA; covariates, age, sex, and BMI). Partial correlations between regional volumes and seizure frequency were examined (SPM12, covariates, age, sex, and BMI); 67% were at high risk for SUDEP. RESULTS: The cerebellar cortex, hippocampus, amygdala, putamen, cingulate, thalamus, and para-hippocampal gyrus showed increased gray matter volumes in epilepsy, and decreased volumes in the posterior thalamus, lingual gyrus, and temporal cortices. The cingulate, insula, and putamen showed significant positive relationships with focal seizure frequency indices using whole-brain voxel-by-voxel partial correlations. Tissue volume changes in selected sites differed in direction from adults; particularly, cerebellar sites, key for hypotensive recovery, increased rather than adult declines. CONCLUSION: The volume increases may represent expansion by inflammatory or other processes that, with sustained repetitive seizure discharge, lead to tissue volume declines described earlier in adults. IMPACT: Children with epilepsy, who are at risk for Sudden Unexplained Death, show changes in brain volume that often differ in direction of change from adults at risk for SUDEP. Sites of volume change play significant roles in mediating breathing and blood pressure, and include areas that serve recovery from prolonged apnea and marked loss of blood pressure. The extent of volume changes correlated with focal seizure frequency. Although the underlying processes contributing to regional volume changes remain speculative, regions of tissue swelling in pediatric brain areas may represent transitory conditions that later lead to tissue loss in the adult condition.

Access to community-based eye services in Meru, Kenya: a cross-sectional equity analysis.

BACKGROUND: Over 80% of blindness in Kenya is due to curable or preventable causes and 7.5 m Kenyans currently need eye services. Embedding sociodemographic data collection into screening programmes could help identify the groups facing systematic barriers to care. We aimed to determine the sociodemographic characteristics that were associated with access among patients diagnosed with an eye problem and referred for treatment in the Vision Impact Programme, currently operating in Meru County. METHOD: We used an embedded, pragmatic, cross-sectional design. A list of sociodemographic questions was developed with input from key stakeholders. The final question set included the following domains: age, gender, religion, marital status, disability, education, occupation, income, housing, assets, and health insurance. These were integrated into an app that is used to screen, refer, and check-in (register) participants within a major eye screening programme. We gathered data from 4,240 people who screened positive and were referred to their local outreach treatment clinic. We used logistic regression to identify which groups were facing the greatest barriers to accessing care. RESULTS: A quarter of those screened between April - July 2023 were found to have an eye problem and were referred, however only 46% of these people were able to access care. In our fully adjusted model, at the 0.05 level there were no statistically significant differences in the odds of attendance within the domains of disability, health insurance, housing, income, or religion. Strong evidence (p < 0.001) was found of an association between access and age, gender, and occupation; with males, younger adults, and those working in sales, services and manual jobs the least likely to receive care. CONCLUSIONS: Access to essential eye services is low and unequal in Meru, with less than a third of those aged 18-44 receiving the care they need. Future work should explore the specific barriers faced by this group.

A rapid mixed-methods assessment of Libya's primary care system.

BACKGROUND: Libya has experienced decades of violent conflict that have severely disrupted health service delivery. The Government of National Unity is committed to rebuilding a resilient health system built on a platform of strong primary care. AIM: Commissioned by the government, we set out to perform a rapid assessment of the system as it stands and identify areas for improvement. DESIGN AND SETTING: We used a rapid applied policy explanatory-sequential mixed-methods design, working with Libyan data and Libyan policymakers, with supporting interview data from other primary care policymakers working across the Middle East and North Africa region. METHOD: We used the Primary Health Care Performance Initiative framework to structure our assessment. Review of policy documents and secondary analysis of WHO and World Bank survey data informed a series of targeted policymaker interviews. We used deductive framework analysis to synthesise our findings. RESULTS: We identified 11 key documents and six key policymakers to interview. Libya has strong policy commitments to providing good quality primary care, and a high number of health staff and facilities. Access to services and trust in providers is high. However, a third of facilities are non-operational; there is a marked skew towards axillary and administrative staff; and structural challenges with financing, logistics, and standards has led to highly variable provision of care. CONCLUSION: In reforming the primary care system, the government should consolidate leadership, clarify governance structures and systems, and focus on setting national standards for human resources for health, facilities, stocks, and clinical care.

US and EU Free Trade Agreements and implementation of policies to control tobacco, alcohol, and unhealthy food and drinks: A quasi-experimental analysis.

BACKGROUND: Identifying and tackling the factors that undermine regulation of unhealthy commodities is an essential component of effective noncommunicable disease (NCD) prevention. Unhealthy commodity producers may use rules in US and EU Free Trade Agreements (FTAs) to challenge policies targeting their products. We aimed to test whether there was a statistical relationship between US and EU FTA participation and reduced implementation of WHO-recommended policies. METHODS AND FINDINGS: We performed a statistical analysis assessing the probability of at least partially implementing 10 tobacco, alcohol, and unhealthy food and drink policies in 127 countries in 2014, 2016, and 2019. We assessed differences in implementation of these policies in countries with and without US/EU FTAs. We used matching to conduct 48 covariate-adjusted quasi-experimental comparisons across 27 matched US/EU FTA members (87 country-years) and performed additional analyses and robustness checks to assess alternative explanations for our results. Out of our 48 tests, 19% (9/48) identified a statistically significant decrease in the predicted probability of at least partially implementing the unhealthy commodity policy in question, while 2% (1/48) showed an increase. However, there was marked heterogeneity across policies. At the level of individual policies, US FTA participation was associated with a 37% reduction (95%CI: -0.51 to -0.22) in the probability of fully implementing graphic tobacco warning policies, and a 53% reduction (95%CI: -0.63 to -0.43) in the probability of at least partially implementing smoke-free place policies. EU FTA participation was associated with a 28% reduction (95%CI: -0.45 to -0.10) in the probability of fully implementing graphic tobacco warning policies, and a 25% reduction (95%CI: -0.47 to -0.03) in the probability of fully implementing restrictions on child marketing of unhealthy food and drinks. There was a positive association with implementing fat limits and bans, but this was not robust. Associations with other outcomes were not significant. The main limitations included residual confounding, limited ability to discern precise mechanisms of influence, and potentially limited generalisability to other FTAs. CONCLUSIONS: US and EU FTA participation may reduce the probability of implementing WHO-recommended tobacco and child food marketing policies by between a quarter and a half-depending on the FTA and outcome in question. Governments negotiating or participating in US/EU FTAs may need to establish robust health protections and mitigation strategies to achieve their NCD mortality reduction targets.

Improvement studies for equitable and evidence-based innovation: an overview of the 'IM-SEEN' model.

BACKGROUND: Health inequalities are ubiquitous, and as countries seek to expand service coverage, they are at risk of exacerbating existing inequalities unless they adopt equity-focused approaches to service delivery. MAIN TEXT: Our team has developed an equity-focused continuous improvement model that reconciles prioritisation of disadvantaged groups with the expansion of service coverage. Our new approach is based on the foundations of routinely collecting sociodemographic data; identifying left-behind groups; engaging with these service users to elicit barriers and potential solutions; and then rigorously testing these solutions with pragmatic, embedded trials. This paper presents the rationale for the model, a holistic overview of how the different elements fit together, and potential applications. Future work will present findings as the model is operationalised in eye-health programmes in Botswana, India, Kenya, and Nepal. CONCLUSION: There is a real paucity of approaches for operationalising equity. By bringing a series of steps together that force programme managers to focus on groups that are being left behind, we present a model that can be used in any service delivery setting to build equity into routine practice.

The philosophical foundations of 'health for all' and Universal Health Coverage.

The WHO constitution calls for 'health for all' and Universal Health Coverage has been called "the ultimate expression of fairness", however it is not always clear how health systems can move towards equity. Should we prioritise the needs of the worst off? And if so, should we direct resources to these marginalised groups or marginalised individuals? This article provides an overview of the philosophical underpinnings of health equity and proportionate universalism, highlighting the trade-offs involved in operationalising a core tenant of global health practice.

Unleashing implementation research to accelerate national noncommunicable disease responses.

Noncommunicable diseases (NCDs) are the leading cause of death and disability worldwide. They exact a disproportionate toll in low and middle-income countries, and the world is not on-track to meet international targets for reductions in premature NCD mortality. Largely, we know which policies work for tackling NCDs, and the World Health Organization (WHO) has developed a package of 'best buy' policies that are highly cost effective. However, we don't necessarily know how to adapt and implement these policies in new populations and cultures. Implementation Research (IR) is emerging as a potent tool for gearing the international response, providing a scientific approach to study the processes used to implement policies and interventions and the contextual factors that affect these processes. Amidst growing interest from policymakers, we identify four main areas for action: high-level engagement with IR among international NCD leaders; domestic investment in technical capacity-building; the creation of new financing streams for IR research; and the development of multi-stakeholder engagement mechanisms that can convene and leverage the perspectives and resources of multiple actors with overlapping aims.

Peripheral nerve regeneration following injury is altered in mice lacking P2X7 receptor.

Peripheral nerve injuries are debilitating, and current clinical management is limited to surgical intervention, which often leads to poor functional outcomes. Development of pharmacological interventions aimed at enhancing regeneration may improve this. One potential pharmacological target is the P2X purinergic receptor 7 (P2X7R) expressed in Schwann cells, which is known to play a role during the development of the peripheral nerves. Herein, we analysed differences in regeneration between genetically engineered P2X7 knockout mice and wild-type controls, using in vivo and ex vivo models of peripheral nerve regeneration. We have found that the speed of axonal regeneration is unaltered in P2X7 knockout mice, nevertheless regenerated P2X7 knockout nerves are morphologically different to wild-type nerves following transection and immediate repair. Indeed, the detailed morphometric analysis at 4 and 8 weeks after injury showed evidence of delayed remyelination in P2X7 knockout mice, compared to the wild-type controls. Furthermore, the Wallerian degeneration phase was unaltered between the two experimental groups. We also analysed gene expression changes in the dorsal root ganglia neurones as a result of the peripheral nerve injury, and found changes in pathways related to pain, inflammation and cell death. We conclude that P2X7 receptors in Schwann cells may be a putative pharmacological target to control cell fate following injury, thus enhancing nerve re-myelination.

Visualizing Cholesterol in the Brain by On-Tissue Derivatization and Quantitative Mass Spectrometry Imaging.

Despite being a critical molecule in the brain, mass spectrometry imaging (MSI) of cholesterol has been under-reported compared to other lipids due to the difficulty in ionizing the sterol molecule. In the present work, we have employed an on-tissue enzyme-assisted derivatization strategy to improve detection of cholesterol in brain tissue sections. We report distribution and levels of cholesterol across specific structures of the mouse brain, in a model of Niemann-Pick type C1 disease, and during brain development. MSI revealed that in the adult mouse, cholesterol is the highest in the pons and medulla and how its distribution changes during development. Cholesterol was significantly reduced in the corpus callosum and other brain regions in the Npc1 null mouse, confirming hypomyelination at the molecular level. Our study demonstrates the potential of MSI to the study of sterols in neuroscience.

Maternal cariprazine exposure inhibits embryonic and postnatal brain cholesterol biosynthesis.

Cariprazine (CAR) is a strong inhibitor of the Dhcr7 enzyme, the last enzyme in the cholesterol biosynthesis pathway. We assessed the effects of CAR on maternally exposed Dhcr7+/- and wild-type mouse offspring, and tested the biochemical effects of CAR in human serum samples. Dhcr7+/- and wild-type time-pregnant mice were exposed to vehicle or 0.2 mg/kg CAR from E12 to E19. Levels of CAR, CAR metabolites, sterols, and oxysterols were measured in the brain of maternally exposed offspring at various time points using LC-MS/MS. Embryonic exposure to CAR significantly increased levels of 7-DHC in all organs of exposed embryos, with a particularly strong effect in the brain. Detectable levels of CAR and elevated 7-DHC were observed in the brain of newborn pups 14 days after drug exposure. In addition, CAR altered sterol metabolism in all animals analyzed, with the strongest effect on the brain of Dhcr7+/- pups born to Dhcr7+/- dams. Furthermore, CAR elevated toxic oxysterols in the brain of maternally exposed Dhcr7+/- offspring to levels approaching those seen in a mouse model of Smith-Lemli-Opitz syndrome. Finally, we observed that patients taking CAR have elevated 7-DHC in their serum. In summary, maternal DHCR7 heterozygosity, combined with offspring DHCR7 heterozygosity might represent a vulnerability factor to medications that interfere with sterol biosynthesis. Due to the conserved sterol biosynthesis between mice and humans, we suggest that the 1-3% of patient population with single-allele DHCR7 mutations might not be ideal candidates for CAR use, especially if they are nursing, pregnant or plan to become pregnant.

Projected impact of the Portuguese sugar-sweetened beverage tax on obesity incidence across different age groups: A modelling study.

BACKGROUND: Excessive consumption of sugar has a well-established link with obesity. Preliminary results show that a tax levied on sugar-sweetened beverages (SSBs) by the Portuguese government in 2017 led to a drop in sales and reformulation of these products. This study models the impact the market changes triggered by the tax levied on SSBs had on obesity incidence across various age groups in Portugal. METHODS AND FINDINGS: We performed a national market analysis and population-wide modelling study using market data for the years 2014-2018 from the Portuguese Association of Non-Alcoholic Drinks (GlobalData and Nielsen Consumer Panel), dietary data from a national survey (IAN-AF 2015-2016), and obesity incidence data from several cohort studies. Dietary energy density from SSBs was calculated by dividing the energy content (kcal/gram) of all SSBs by the total food consumption (in grams). We used the potential impact fraction (PIF) equation to model the projected impact of the tax-triggered change in sugar consumption on obesity incidence, through both volume reduction and reformulation. Results showed a reduction of 6.6 million litres of SSBs sold per year. Product reformulation led to a decrease in the average energy density of SSBs by 3.1 kcal/100 ml. This is estimated to have prevented around 40-78 cases of obesity per year between 2016 and 2018, with the biggest projected impact observed in adolescents 10 to <18 years old. The model shows that the implementation of this tax allowed for a 4 to 8 times larger projected impact against obesity than would be achieved though reformulation alone. The main limitation of this study is that the model we used includes data from various sources, which can result in biases-despite our efforts to mitigate them-related to the methodological differences between these sources. CONCLUSIONS: The tax triggered both a reduction in demand and product reformulation. These, together, can reduce obesity levels among frequent consumers of SSBs. Such taxation is an effective population-wide intervention. Reformulation alone, without the decrease in sales, would have had a far smaller effect on obesity incidence in the Portuguese population.

Addressing social determinants of noncommunicable diseases in primary care: a systematic review.

OBJECTIVE: To explore how primary care organizations assess and subsequently act upon the social determinants of noncommunicable diseases in their local populations. METHODS: For this systematic review we searched the online databases of PubMed®, MEDLINE®, Embase® and the Health Management Information Consortium from inception to 28 June 2019, along with hand-searching of references. Studies of any design that examined a primary care organization assessing social determinants of noncommunicable diseases were included. For quality assessment we used Cochrane's tool for assessing risk of bias in non-randomized studies of interventions. We used narrative data synthesis to appraise the extent to which the assessments gathered data on the domains of the World Health Organization social determinants of health framework. FINDINGS: We identified 666 studies of which 17 were included in the review. All studies used descriptive study designs. Clinic-based and household surveys and interviews were more commonly used to assess local social determinants than population-level data. We found no examples of organizations that assessed sociopolitical drivers of noncommunicable diseases; all focused on sociodemographic factors or circumstances of daily living. Nevertheless, the resulting actions to address social determinants ranged from individual-level interventions to population-wide measures and introducing representation of primary care organizations on system-level policy and planning committees. CONCLUSION: Our findings may help policy-makers to consider suitable approaches for assessing and addressing social determinants of health in their domestic context. More rigorous observational and experimental evidence is needed to ascertain whether measuring social determinants leads to interventions which mitigate unmet social needs and reduce health disparities.

Maternal aripiprazole exposure interacts with 7-dehydrocholesterol reductase mutations and alters embryonic neurodevelopment.

Mutations in both copies in the gene encoding 7-dehydrocholesterol reductase (DHCR7) cause Smith-Lemli-Opitz Syndrome (SLOS), which is characterized by a toxic elevation in 7-dehydrocholesterol (7-DHC). Aripiprazole (ARI) exposure, independent of genetic mutations, also leads to elevation of 7-DHC. We investigated the combined effect of a single-copy Dhcr7+/- mutation and maternal ARI exposure on the developing offspring brain. We generated a time-pregnant mouse model where WT and Dhcr7+/- embryos were maternally exposed to ARI or vehicle (VEH) from E12 to E19 (5 mg/kg). Levels of cholesterol, its precursors, ARI and its metabolites were measured at P0. We found that ARI and its metabolites were transported across the placenta and reached the brain of offspring. Maternal ARI exposure led to decreased viability of embryos and increased 7-DHC levels, regardless of maternal or offspring Dhcr7 genotype. In addition, Dhcr7+/- pups were more vulnerable to maternal ARI exposure than their WT littermates, and maternal Dhcr7+/- genotype also exacerbated offspring response to ARI treatment. Finally, both 7-DHC levels and 7-DHC/cholesterol ratio is the highest in Dhcr7+/- pups from Dhcr7+/- mothers exposed to ARI, underscoring a potentially dangerous interaction between maternal genotype×embryonic genotype×treatment. Our findings have important clinical implications. SLOS patients should avoid drugs that increase 7-DHC levels such as ARI, trazodone and haloperidol. In addition, treatment with 7-DHC elevating substances might be potentially unsafe for the 1-1.5% of population with single-allele disruptions of the DHCR7 gene. Finally, prenatal and parental genetic testing for DHCR7 should be considered before prescribing sterol-interfering medications during pregnancy.

Peri-ictal hypoxia is related to extent of regional brain volume loss accompanying generalized tonic-clonic seizures.

OBJECTIVES: Hypoxia, or abnormally low blood-oxygen levels, often accompanies seizures and may elicit brain structural changes in people with epilepsy which contribute to central processes underlying sudden unexpected death in epilepsy (SUDEP). The extent to which hypoxia may be related to brain structural alterations in this patient group remains unexplored. METHODS: We analyzed high-resolution T1-weighted magnetic resonance imaging (MRI) to determine brain morphometric and volumetric alterations in people with generalized tonic-clonic seizures (GTCS) recorded during long-term video-electroencephalography (VEEG), recruited from two sites (n = 22), together with data from age- and sex-matched healthy controls (n = 43). Subjects were sub-divided into those with mild/moderate (GTCS-hypox-mild/moderate, n = 12) and severe (GTCS-hypox-severe, n = 10) hypoxia, measured by peripheral oxygen saturation (SpO2 ) during VEEG. Whole-brain voxel-based morphometry (VBM) and regional volumetry were used to assess group comparisons and correlations between brain structural measurements as well as the duration and extent of hypoxia during GTCS. RESULTS: Morphometric and volumetric alterations appeared in association with peri-GTCS hypoxia, including volume loss in the periaqueductal gray (PAG), thalamus, hypothalamus, vermis, cerebellum, parabrachial pons, and medulla. Thalamic and PAG volume was significantly reduced in GTCS patients with severe hypoxia compared with GTCS patients with mild/moderate hypoxia. Brainstem volume loss appeared in both hypoxia groups, although it was more extensive in those with severe hypoxia. Significant negative partial correlations emerged between thalamic and hippocampal volume and extent of hypoxia, whereas vermis and accumbens volumes declined with increasing hypoxia duration. SIGNIFICANCE: Brain structural alterations in patients with GTCS are related to the extent of hypoxia in brain sites that serve vital functions. Although the changes are associative only, they provide evidence of injury to regulatory brain sites related to respiratory manifestations of seizures.

Modelling impacts of food industry co-regulation on noncommunicable disease mortality, Portugal.

OBJECTIVE: To model the reduction in premature deaths attributed to noncommunicable diseases if targets for reformulation of processed food agreed between the Portuguese health ministry and the food industry were met. METHODS: The 2015 co-regulation agreement sets voluntary targets for reducing sugar, salt and trans-fatty acids in a range of products by 2021. We obtained government data on dietary intake in 2015-2016 and on population structure and deaths from four major noncommunicable diseases over 1990-2016. We used the Preventable Risk Integrated ModEl tool to estimate the deaths averted if reformulation targets were met in full. We projected future trends in noncommunicable disease deaths using regression modelling and assessed whether Portugal was on track to reduce baseline premature deaths from noncommunicable diseases in the year 2010 by 25% by 2025, and by 30% before 2030. FINDINGS: If reformulation targets were met, we projected reductions in intake in 2015-2016 for salt from 7.6 g/day to 7.1 g/day; in total energy from 1911 kcal/day to 1897 kcal/day due to reduced sugar intake; and in total fat (% total energy) from 30.4% to 30.3% due to reduced trans-fat intake. This consumption profile would result in 248 fewer premature noncommunicable disease deaths (95% CI: 178 to 318) in 2016. We projected that full implementation of the industry agreement would reduce the risk of premature death from 11.0% in 2016 to 10.7% by 2021. CONCLUSION: The co-regulation agreement could save lives and reduce the risk of premature death in Portugal. Nevertheless, the projected impact on mortality was insufficient to meet international targets.

Cerebellar, limbic, and midbrain volume alterations in sudden unexpected death in epilepsy.

OBJECTIVE: The processes underlying sudden unexpected death in epilepsy (SUDEP) remain elusive, but centrally mediated cardiovascular or respiratory collapse is suspected. Volume changes in brain areas mediating recovery from extreme cardiorespiratory challenges may indicate failure mechanisms and allow prospective identification of SUDEP risk. METHODS: We retrospectively imaged SUDEP cases (n = 25), patients comparable for age, sex, epilepsy syndrome, localization, and disease duration who were high-risk (n = 25) or low-risk (n = 23), and age- and sex-matched healthy controls (n = 25) with identical high-resolution T1-weighted scans. Regional gray matter volume, determined by voxel-based morphometry, and segmentation-derived structure sizes were compared across groups, controlling for total intracranial volume, age, and sex. RESULTS: Substantial bilateral gray matter loss appeared in SUDEP cases in the medial and lateral cerebellum. This was less prominent in high-risk subjects and absent in low-risk subjects. The periaqueductal gray, left posterior and medial thalamus, left hippocampus, and bilateral posterior cingulate also showed volume loss in SUDEP. High-risk subjects showed left thalamic volume reductions to a lesser extent. Bilateral amygdala, entorhinal, and parahippocampal volumes increased in SUDEP and high-risk patients, with the subcallosal cortex enlarged in SUDEP only. Disease duration correlated negatively with parahippocampal volume. Volumes of the bilateral anterior insula and midbrain in SUDEP cases were larger the closer to SUDEP from magnetic resonance imaging. SIGNIFICANCE: SUDEP victims show significant tissue loss in areas essential for cardiorespiratory recovery and enhanced volumes in areas that trigger hypotension or impede respiratory patterning. Those changes may shed light on SUDEP pathogenesis and prospectively detect patterns identifying those at risk.

Desmosterolosis and desmosterol homeostasis in the developing mouse brain.

Cholesterol serves as a building material for cellular membranes and plays an important role in cellular metabolism. The brain relies on its own cholesterol biosynthesis, which starts during embryonic development. Cholesterol is synthesized from two immediate precursors, desmosterol and 7-dehydrocholesterol (7-DHC). Mutations in the DHCR24 enzyme, which converts desmosterol into cholesterol, lead to desmosterolosis, an autosomal recessive developmental disorder. In this study, we assessed the brain content of desmosterol, 7-DHC, and cholesterol from development to adulthood, and analyzed the biochemical, molecular, and anatomical consequences of Dhcr24 mutations on the sterol profile in a mouse model of desmosterolosis and heterozygous Dhcr24+/- carriers. Our HPLC-MS/MS studies revealed that by P0 desmosterol almost entirely replaced cholesterol in the Dhcr24-KO brain. The greatly elevated desmosterol levels were also present in the Dhcr24-Het brains irrespective of maternal genotype, persisting into adulthood. Furthermore, Dhcr24-KO mice brains showed complex changes in expression of lipid and sterol transcripts, nuclear receptors, and synaptic plasticity transcripts. Cultured Dhcr24-KO neurons showed increased arborization, which was also present in the Dhcr24-KO mouse brains. Finally, we observed a shared pathophysiological mechanism between the mouse models of desmosterolosis and Smith-Lemli-Opitz syndrome (a genetic disorder of conversion of 7-DHC to cholesterol).

The association of serotonin reuptake inhibitors and benzodiazepines with ictal central apnea.

OBJECTIVE: Ictal (ICA) and postconvulsive central apnea (PCCA) have been implicated in sudden unexpected death in epilepsy (SUDEP) pathomechanisms. Previous studies suggest that serotonin reuptake inhibitors (SRIs) and benzodiazepines (BZDs) may influence breathing. The aim of this study was to investigate if chronic use of these drugs alters central apnea occurrence in patients with epilepsy. METHODS: Patients with epilepsy admitted to epilepsy monitoring units (EMUs) in nine centers participating in a SUDEP study were consented. Polygraphic physiological parameters were analyzed, including video-electroencephalography (VEEG), thoracoabdominal excursions, and pulse oximetry. Outpatient medication details were collected. Patients and seizures were divided into SRI, BZD, and control (no SRI or BZD) groups. Ictal central apnea and PCCA, hypoxemia, and electroclinical features were assessed for each group. RESULTS: Four hundred and seventy-six seizures were analyzed (204 patients). The relative risk (RR) for ICA in the SRI group was half that of the control group (p = 0.02). In the BZD group, ICA duration was significantly shorter than in the control group (p = 0.02), as was postictal generalized EEG suppression (PGES) duration (p = 0.021). Both SRI and BZD groups were associated with smaller seizure-associated oxygen desaturation (p = 0.009; p ≪ 0.001). Neither presence nor duration of PCCA was significantly associated with SRI or BZD (p ≫ 0.05). CONCLUSIONS: Seizures in patients taking SRIs have lower occurrence of ICA, and patients on chronic treatment with BZDs have shorter ICA and PGES durations. Preventing or shortening ICA duration by using SRIs and/or BZD in patients with epilepsy may play a possible role in SUDEP risk reduction.

The development and psychometric evaluation of the Trans Discrimination Scale: TDS-21.

[Correction Notice: An Erratum for this article was reported in Vol 66(1) of Journal of Counseling Psychology (see record 2018-66276-001). In the article "The development and psychometric evaluation of the Trans Discrimination Scale: TDS-21" by Laurel B. Watson, Luke R. Allen, Mirella J. Flores, Christine Serpe, and Michelle Farrell (Journal of Counseling Psychology, 2018, Advance online publication. http://dx.doi.org/10 .1037/cou0000301), there were two errors in the Methods section of the article. In Study 1, Participants paragraph of The development and psychometric evaluation of the Trans Discrimination Scale: TDS-21 for the Methods section, the gender listed at birth was incorrect in the following sentence, The majority of participants in this study identified as trans women and along a trans feminine spectrum, were assigned male at birth, White, had attained some college but no degree, and were employed full time. The correct gender assigned at birth was predominantly female. In addition, the gender coding procedures was incorrectly described. Specifically, those who identified as FAAB and AFAB were actually coded as trans men or along a transmasculine spectrum, whereas those who identified as MAAB and AMAB were coded as trans women and along a trans feminine perspective. In Study 3, Participants paragraph of The development and psychometric evaluation of the Trans Discrimination Scale: TDS-21 for the Methods section, the gender identity listed in the following sentence was incorrect, The majority of participants identified as trans women and along the trans feminine spectrum, were assigned female at birth, White, had attained some college but no degree, and were students. Rather, participants primarily identified as non-binary trans.] To date, researchers assessing the role of discrimination in trans peoples' lives have relied upon measures that were developed and normed on LGB populations, culled specific items from large-scale survey data, or used more generalized measures of discrimination that do not specifically assess the unique forms of discrimination that trans people may encounter. Thus, the purpose of this three-part study was to develop and provide psychometric support for a measure of trans peoples' discrimination. In Study 1, a five-factor model emerged, which included: Microaggressions and Harassment, Restricted Career and Work Opportunities, Maltreatment in Health Care Settings, Harassment by Law Enforcement, and Bullying and Harassment in Educational Settings. Internal consistency estimates for subscale and total scale scores ranged from acceptable to excellent. Results from Study 2 revealed that a bifactor model provided the best fit to the data, revealing that the scale is essentially unidimensional. In addition, convergent and concurrent validity was supported, demonstrating significant positive correlations with another measure of trans discrimination, internalized transphobia, nondisclosure, negative expectations for the future, psychological distress, and perceived stress. In Study 3, results revealed excellent test-retest reliability up to a three-week period. Collectively, results suggested that the Transgender Discrimination Scale-21 (TDS-21) is a psychometrically sound measure that may be used to advance research on the role of discrimination in trans peoples' lives. (PsycINFO Database Record (c) 2019 APA, all rights reserved).