Automated sleep staging in people with intellectual disabilities using heart rate and respiration variability.

BACKGROUND: People with intellectual disabilities (ID) have a higher risk of sleep disorders. Polysomnography (PSG) remains the diagnostic gold standard in sleep medicine. However, PSG in people with ID can be challenging, as sensors can be burdensome and have a negative influence on sleep. Alternative methods of assessing sleep have been proposed that could potentially transfer to less obtrusive monitoring devices. The goal of this study was to investigate whether analysis of heart rate variability and respiration variability is suitable for the automatic scoring of sleep stages in sleep-disordered people with ID. METHODS: Manually scored sleep stages in PSGs of 73 people with ID (borderline to profound) were compared with the scoring of sleep stages by the CardioRespiratory Sleep Staging (CReSS) algorithm. CReSS uses cardiac and/or respiratory input to score the different sleep stages. Performance of the algorithm was analysed using input from electrocardiogram (ECG), respiratory effort and a combination of both. Agreement was determined by means of epoch-per-epoch Cohen's kappa coefficient. The influence of demographics, comorbidities and potential manual scoring difficulties (based on comments in the PSG report) was explored. RESULTS: The use of CReSS with combination of both ECG and respiratory effort provided the best agreement in scoring sleep and wake when compared with manually scored PSG (PSG versus ECG = kappa 0.56, PSG versus respiratory effort = kappa 0.53 and PSG versus both = kappa 0.62). Presence of epilepsy or difficulties in manually scoring sleep stages negatively influenced agreement significantly, but nevertheless, performance remained acceptable. In people with ID without epilepsy, the average kappa approximated that of the general population with sleep disorders. CONCLUSIONS: Using analysis of heart rate and respiration variability, sleep stages can be estimated in people with ID. This could in the future lead to less obtrusive measurements of sleep using, for example, wearables, more suitable to this population.

What are the essential components of antenatal care? A systematic review of the literature and development of signal functions to guide monitoring and evaluation.

BACKGROUND: Antenatal care (ANC) is one of the key care packages required to reduce global maternal and perinatal mortality and morbidity. OBJECTIVES: To identify the essential components of ANC and develop signal functions. SEARCH STRATEGY: MESH headings for databases including Cinahl, Cochrane, Global Health, Medline, PubMed and Web of Science. SELECTION CRITERIA: Papers and reports on content of ANC published from 2000 to 2020. DATA COLLECTION AND ANALYSIS: Narrative synthesis of data and development of signal function through 7 consensus-building workshops with 184 stakeholders. MAIN RESULTS: A total of 221 papers and reports are included from which 28 essential components of ANC were extracted and used to develop 15 signal functions with the equipment, medication and consumables required for implementation of each. Signal functions for the prevention and management of infectious diseases (malaria, HIV, tuberculosis, syphilis and tetanus) can be applied depending on population disease burden. Screening and management of pre-eclampsia, gestational diabetes, anaemia, mental and social health (including intimate partner violence) are recommended universally. Three signal functions address monitoring of fetal growth and wellbeing, and identification and management of obstetric complications. Promotion of health and wellbeing via education and support for nutrition, cessation of substance abuse, uptake of family planning, recognition of danger signs and birth preparedness are included as essential components of ANC. CONCLUSIONS: New signal functions have been developed which can be used for monitoring and evaluation of content and quality of ANC. Country adaptation and validation is recommended.

Reducing maternal deaths by skills-and-drills training in managing obstetric emergencies: A before-and-after observational study.

BACKGROUND: The institutional maternal mortality ratio (iMMR) in South Africa (SA) is still unacceptably high. A key recommendation from the National Committee on Confidential Enquiries into Maternal Deaths has been to improve the availability and quality of care for women suffering obstetric emergencies. OBJECTIVES: To determine whether there was a change in the number of maternal deaths and in the iMMR over time that could be attributed to the training of >80% of healthcare professionals by means of a specifically designed emergency obstetric care (EmOC) training programme. METHODS: A before-and-after study was conducted in 12 healthcare districts in SA, with the remaining 40 districts serving as a comparison group. Twelve 'most-in-need' healthcare districts in SA were selected using a composite scoring system. Multiprofessional skills-and-drills workshops were held off-site using the Essential Steps in Managing Obstetric Emergencies and Emergency Obstetric Simulation Training programme. Eighty percent or more of healthcare professionals providing maternity care in each district were trained between October 2012 and March 2015. Institutional births and maternal deaths were assessed for the period January 2011 - December 2016 and a before-and-after-training comparison was made. The number of maternal deaths and the iMMR were used as outcome measures. RESULTS: A total of 3 237 healthcare professionals were trained at 346 workshops. In all, 1 248 333 live births and 2 212 maternal deaths were identified and reviewed for cause of death as part of the SA confidential enquiries. During the same period there were 5 961 maternal deaths and 5 439 870 live births in the remaining 40 districts. Significant reductions of 29.3% in the number of maternal deaths (risk ratio (RR) 0.71, 95% confidence interval (CI) 0.66 - 0.77) and 17.5% in the number of maternal deaths from direct obstetric causes (RR 0.825, 95% CI 0.73 - 0.93) were recorded. When comparing the percentage change in iMMR for equivalent before-and-after periods, there was a greater reduction in all categories of causes of maternal death in the intervention districts than in the comparison districts. CONCLUSIONS: Implementing a skills-and-drills EmOC training package was associated with a significant reduction in maternal deaths.

Obstetrics knowledge and skills training as a catalyst for change.

BACKGROUND: Poor emergency obstetric care has been shown by national confidential enquiries into maternal deaths to contribute to a number of maternal deaths in South Africa. OBJECTIVES: To assess whether a structured training course can improve knowledge and skills and whether this can influence the capacity of a healthcare facility to provide basic and comprehensive emergency obstetric care signal functions. METHODS: A baseline survey was conducted to assess the seven basic emergency obstetric and neonatal care signal functions in 51 community health centres (CHCs) and the nine comprehensive emergency care signal functions in 62 district hospitals (DHs). A re-assessment was conducted 1 year after saturation training had been provided in each district. The delegates were trained using a structured training programme (Essential Steps in Managing Obstetric Emergencies, ESMOE) and their knowledge and skills were tested before and after the training. Saturation training was considered to have been achieved once 80% of the healthcare professionals involved in maternity care had been trained. RESULTS: There was a significant improvement in the knowledge and skills of doctors, namely by 16.8% and 32.8%, respectively, of advanced midwives by 13.7% and 29.0%, and of professional nurses with midwifery by 16.1% and 31.2%. The seven basic emergency care functions improved from 60.8% to 67.8% in the CHCs and from 90.7% to 92.5% in the DHs before and after training. If the two signal functions that are not within the scope of practice of professional nurses with midwifery are excluded (viz. assisted delivery and manual vacuum aspiration), the functionality of CHCs increased from 85.1% to 94.9%. CONCLUSIONS: The ESMOE training programme improved knowledge and skills, but there was a modest improvement in the functionality of the facilities. Improvement in functionality requires changes in the structure of the health system, including changing the scope of practice of professional nurses with midwifery and employing more advanced midwives in CHCs.

Assigning cause of maternal death: a comparison of findings by a facility-based review team, an expert panel using the new ICD-MM cause classification and a computer-based program (InterVA-4).

OBJECTIVE: To compare methodology used to assign cause of and factors contributing to maternal death. DESIGN: Reproductive Age Mortality Study. SETTING: Malawi. POPULATION: Maternal deaths among women of reproductive age. METHODS: We compared cause of death as assigned by a facility-based maternal death review team, an expert panel using the International Classification of Disease, 10th revision (ICD-10) cause classification for deaths during pregnancy, childbirth and the puerperium (ICD-MM) and a computer-based probabilistic program (InterVA-4). MAIN OUTCOME MEASURES: Number and cause of maternal deaths. RESULTS: The majority of maternal deaths occurred at a health facility (94/151; 62.3%). The estimated maternal mortality ratio was 363 per 100 000 live births (95% CI 307-425). There was poor agreement between cause of death assigned by a facility-based maternal death review team and an expert panel (κ = 0.37, 86 maternal deaths). The review team considered 36% of maternal deaths to be indirect and caused by non-obstetric complications (ICD-MM Group 7) whereas the expert panel considered only 17.4% to be indirect maternal deaths with 33.7% due to obstetric haemorrhage (ICD-MM Group 3). The review team incorrectly assigned a contributing condition rather than cause of death in up to 15.1% of cases. Agreement between the expert panel and InterVA-4 regarding cause of death was good (κ = 0.66, 151 maternal deaths). However, contributing conditions are not identified by InterVA-4. CONCLUSIONS: Training in the use of ICD-MM is needed for healthcare providers conducting maternal death reviews to be able to correctly assign underlying cause of death and contributing factors. Such information can help to identify what improvements in quality of care are needed. TWEETABLE ABSTRACT: For maternal deaths assigning cause of death is best done by an expert panel and helps to identify where quality of care needs to be improved.

Targeted inhibition of metastatic melanoma through interference with Pin1-FOXM1 signaling.

Melanoma is the most lethal form of skin cancer and successful treatment of metastatic melanoma remains challenging. BRAF/MEK inhibitors only show a temporary benefit due to rapid occurrence of resistance, whereas immunotherapy is mainly effective in selected subsets of patients. Thus, there is a need to identify new targets to improve treatment of metastatic melanoma. To this extent, we searched for markers that are elevated in melanoma and are under regulation of potentially druggable enzymes. Here, we show that the pro-proliferative transcription factor FOXM1 is elevated and activated in malignant melanoma. FOXM1 activity correlated with expression of the enzyme Pin1, which we found to be indicative of a poor prognosis. In functional experiments, Pin1 proved to be a main regulator of FOXM1 activity through MEK-dependent physical regulation during the cell cycle. The Pin1-FOXM1 interaction was enhanced by BRAF(V600E), the driver oncogene in the majority of melanomas, and in extrapolation of the correlation data, interference with\ Pin1 in BRAF(V600E)-driven metastatic melanoma cells impaired both FOXM1 activity and cell survival. Importantly, cell-permeable Pin1-FOXM1-blocking peptides repressed the proliferation of melanoma cells in freshly isolated human metastatic melanoma ex vivo and in three-dimensional-cultured patient-derived melanoids. When combined with the BRAF(V600E)-inhibitor PLX4032 a robust repression in melanoid viability was obtained, establishing preclinical value of patient-derived melanoids for prognostic use of drug sensitivity and further underscoring the beneficial effect of Pin1-FOXM1 inhibitory peptides as anti-melanoma drugs. These proof-of-concept results provide a starting point for development of therapeutic Pin1-FOXM1 inhibitors to target metastatic melanoma.

Basic and comprehensive emergency obstetric and neonatal care in 12 South African health districts.

AIM: To assess the functionality of healthcare facilities with respect to providing the signal functions of basic and comprehensive emergency obstetric care in 12 districts. SETTING: Twelve districts were selected from the 52 districts in South Africa, based on the number of maternal deaths, the institutional maternal mortality ratio and the stillbirth rate for the district. METHODS: All community health centres (CHCs) and district, regional and tertiary hospitals were visited and detailed information was obtained on the ability of the facility to perform the basic (BEmONC) and comprehensive (CEmONC) emergency obstetric and neonatal care signal functions. RESULTS: Fifty-three CHCs, 63 district hospitals (DHs), 13 regional hospitals and 4 tertiary hospitals were assessed. None of the CHCs could perform all seven BEmONC signal functions; the majority could not give parenteral antibiotics (68%), perform manual removal of the placenta (58%), do an assisted delivery (98%) or perform manual vacuum aspiration of the uterus in a woman with an uncomplicated incomplete miscarriage (96%). Seventeen per cent of CHCs could not bag-and-mask ventilate a neonate. Less than half (48%) of the DHs could perform all nine CEmONC signal functions (81% could perform eight of the nine functions), 24% could not perform caesarean sections, and 30% could not perform assisted deliveries. CONCLUSIONS: The ability of the CHCs and district hospitals to perform the signal functions (lifesaving services) of basic and comprehensive emergency obstetric care was poor in many of the districts studied. This implies that safe maternity care was not consistently available at many facilities conducting births.

Pioglitazone treatment restores in vivo muscle oxidative capacity in a rat model of diabetes.

AIM: To determine the effect of pioglitazone treatment on in vivo and ex vivo muscle mitochondrial function in a rat model of diabetes. METHODS: Both the lean, healthy rats and the obese, diabetic rats are Zucker Diabetic Fatty (ZDF) rats. The homozygous fa/fa ZDF rats are obese and diabetic. The heterozygous fa/+ ZDF rats are lean and healthy. Diabetic Zucker Diabetic Fatty rats were treated with either pioglitazone (30 mg/kg/day) or water as a control (n = 6 per group), for 2 weeks. In vivo ¹H and ³¹P magnetic resonance spectroscopy was performed on skeletal muscle to assess intramyocellular lipid (IMCL) content and muscle oxidative capacity, respectively. Ex vivo muscle mitochondrial respiratory capacity was evaluated using high-resolution respirometry. In addition, several markers of mitochondrial content were determined. RESULTS: IMCL content was 14-fold higher and in vivo muscle oxidative capacity was 26% lower in diabetic rats compared with lean rats, which was, however, not caused by impairments of ex vivo mitochondrial respiratory capacity or a lower mitochondrial content. Pioglitazone treatment restored in vivo muscle oxidative capacity in diabetic rats to the level of lean controls. This amelioration was not accompanied by an increase in mitochondrial content or ex vivo mitochondrial respiratory capacity, but rather was paralleled by an improvement in lipid homeostasis, that is lowering of plasma triglycerides and muscle lipid and long-chain acylcarnitine content. CONCLUSION: Diminished in vivo muscle oxidative capacity in diabetic rats results from mitochondrial lipid overload and can be alleviated by redirecting the lipids from the muscle into adipose tissue using pioglitazone treatment.

Using the new ICD-MM classification system for attribution of cause of maternal death--a pilot study.

Understanding the causes of and factors contributing to maternal deaths is critically important for development of interventions that reduce the global burden of maternal mortality and morbidity. The International Classification of Diseases-Maternal Mortality (ICD-MM) classification of cause of death during pregnancy, childbirth and the puerperium was applied to data obtained from maternal death reviews (MDR) for 4558 maternal deaths from five countries in sub-Saharan Africa. None of the data sets identified type of maternal death. Information obtained via MDR is generally sufficient to agree on classification of cause of death to the levels of type and group. The terms 'underlying cause of death' and 'contributing conditions' were used differently in different settings and a specific underlying cause of death was frequently not recorded. Application of ICD-MM resulted in the reclassification of 3.1% (9/285) of cases to the group 'unanticipated complications of management', previously recorded as obstetric haemorrhage or unknown. An increased number of cases were assigned to the groups pregnancy-related infection (5.6-10.2%) and pregnancies with abortive outcome (3.4-4.9%) when a clear distinction was made between women who died 'with' HIV/AIDS of obstetric causes (direct maternal death) and AIDS-related indirect maternal deaths (group 'non-obstetric complications'). Similarly, anaemia and obstructed labour were more frequently identified as contributing factors than underlying cause of death. It would be helpful if MDR forms could have explicitly stated variables called: type, group and underlying cause of death as well as a dedicated section to the most frequently occurring contributing conditions recognised in that setting.

Cause of and contributing factors to maternal deaths; a cross-sectional study using verbal autopsy in four districts in Bangladesh.

Verbal autopsy used at community level is an accepted method to identify cause of death and factors contributing to death. Maternal deaths occurring in four districts in Bangladesh over a period of 24 months were identified and community health workers were trained to conduct a verbal autopsy. Of 571 maternal deaths identified almost half (273, 47.8%) occurred at facility level, 97 (17.0%) died en route to a healthcare facility and 201 (35.2%) maternal deaths occurred at home. The majority of maternal deaths occurred in the postpartum period (78.8%) in the first 6 hours after giving birth (41.6% of all postpartum deaths). Women who had accessed care at a healthcare facility were less likely to die in the first 6 hours when compared with women who died at home (relative risk 0.70; 95% confidence interval 0.56-0.88) 70.4% (402) of deaths were classified as direct maternal deaths, 12.4% (71) as indirect and 13.8% (79) as unspecified. The most common cause of death was haemorrhage (38%), followed by eclampsia (20%) and sepsis (8.1%). Almost three out of four women who died had sought care for complications during the index pregnancy. Most mothers who died in Bangladesh had accessed care. It is now crucial that the quality of care received at health facility level is improved. This includes a refocus on strengthening healthcare providers' knowledge and skills to recognise and manage complications and provide emergency obstetric care. The enabling environment must be in place as well as ensuring a fully functional referral pathway between healthcare facilities.

Establishing cause of maternal death in Malawi via facility-based review and application of the ICD-MM classification.

Maternal death review (MDR) is an accepted process that is implemented across Malawi and 'underlying cause of death' is assigned by healthcare providers using a standard MDR form. Mixed-methods approach. Key informant interviews with eight stakeholders involved in MDR. Secondary analysis of MDR forms for 54 maternal deaths. Comparison of assigned cause of death by healthcare providers conducting MDR at health facility level with cause assigned by researchers using the International Classification of Diseases Maternal Mortality (ICD-MM) classification. MDR teams, analysts and policymakers reported facing challenges in completing the forms, analysing and using information. The concepts of underlying (primary) and contributing (secondary) causes of death are often misunderstood. Healthcare providers using only MDR forms reported cause of death as non-obstetric complications in 39.6% and pregnancy-related infection in 11.3% of cases. For 30.2% of cases, no clear clinical cause of death was recorded. The most commonly assigned underlying cause of death using ICD-MM was obstetric haemorrhage (32.1%), non-obstetric complications (24.5%) and pregnancy-related infection (22.6%). There was poor agreement between cause(s) of maternal death assigned by healthcare providers in the field and trained researchers using the new ICD-MM classification (κ statistic; 0.219). The majority of cases could be reclassified using the ICD-MM and this provided a more specific cause of death. A more structured and user-friendly MDR form is required. Accurate classification of cause of death is important. Dissemination of, and training in the use of the new ICD-MM classification system will be helpful to healthcare providers conducting MDR in Malawi.

Causes of and factors associated with stillbirth in low- and middle-income countries: a systematic literature review.

BACKGROUND: Annually, 2.6 million stillbirths occur worldwide, 98% in developing countries. It is crucial that we understand causes and contributing factors. METHODS: We conducted a systematic review of studies reporting factors associated with and cause(s) of stillbirth in low- and middle-income countries (2000-13). Narrative synthesis to compare similarities and differences between studies with similar outcome categories. MAIN RESULTS: A total of 142 studies with 2.1% from low-income settings were investigated; most report on stillbirths occurring at health facility level. Definition of stillbirth varied; 10.6% of studies (mainly upper middle-income countries) used a cut-off point of ≥22 weeks of gestation and 32.4% (mainly lower income countries) used ≥28 weeks of gestation. Factors reported to be associated with stillbirth include poverty and lack of education, maternal age (>35 or <20 years), parity (1, ≥5), lack of antenatal care, prematurity, low birthweight, and previous stillbirth. The most frequently reported cause of stillbirth was maternal factors (8-50%) including syphilis, positive HIV status with low CD4 count, malaria and diabetes. Congenital anomalies are reported to account for 2.1-33.3% of stillbirths, placental causes (7.4-42%), asphyxia and birth trauma (3.1-25%), umbilical problems (2.9-33.3%), and amniotic and uterine factors (6.5-10.7%). Seven different classification systems were identified but applied in only 22% of studies that could have used a classification system. A high percentage of stillbirths remain 'unclassified' (3.8-57.4%). CONCLUSION: To build capacity for perinatal death audit, clear guidelines and a suitable classification system to assign cause of death must be developed. Existing classification systems may need to be adapted. Better data and more data are urgently needed.

Physical activity is the key determinant of skeletal muscle mitochondrial function in type 2 diabetes.

CONTEXT: Conflicting data exist on mitochondrial function and physical activity in type 2 diabetes mellitus (T2DM) development. OBJECTIVE: The aim was to assess mitochondrial function at different stages during T2DM development in combination with physical exercise in longstanding T2DM patients. DESIGN AND METHODS: We performed cross-sectional analysis of skeletal muscle from 12 prediabetic 11 longstanding T2DM male subjects and 12 male controls matched by age and body mass index. INTERVENTION: One-year intrasubject controlled supervised exercise training intervention was done in longstanding T2DM patients. MAIN OUTCOME MEASUREMENTS: Extensive ex vivo analyses of mitochondrial quality, quantity, and function were collected and combined with global gene expression analysis and in vivo ATP production capacity after 1 yr of training. RESULTS: Mitochondrial density, complex I activity, and the expression of Krebs cycle and oxidative phosphorylation system-related genes were lower in longstanding T2DM subjects but not in prediabetic subjects compared with controls. This indicated a reduced capacity to generate ATP in longstanding T2DM patients only. Gene expression analysis in prediabetic subjects suggested a switch from carbohydrate toward lipid as an energy source. One year of exercise training raised in vivo skeletal muscle ATP production capacity by 21 ± 2% with an increased trend in mitochondrial density and complex I activity. In addition, expression levels of ß-oxidation, Krebs cycle, and oxidative phosphorylation system-related genes were higher after exercise training. CONCLUSIONS: Mitochondrial dysfunction is apparent only in inactive longstanding T2DM patients, which suggests that mitochondrial function and insulin resistance do not depend on each other. Prolonged exercise training can, at least partly, reverse the mitochondrial impairments associated with the longstanding diabetic state.

The 'Making it Happen' programme in India and Bangladesh.

A training package designed to train health care providers in the management of common obstetric and newborn complications using a competency based 'skills and drills' approach is used in Bangladesh and India as one of the interventions under the 'Making it Happen' programme. The programme was commenced in 2009 and aims to reduce maternal and newborn mortality and morbidity by improving health care providers' capacity to deliver Essential (Emergency) Obstetric and Newborn Care (EOC&NC) thus increasing the availability and quality of these services. Preliminary results indicate that the training package has improved knowledge and skills of trained health care providers and ensures more signal functions of EOC are provided.

Maternal mortality and Millennium Development Goal 5.

INTRODUCTION: The maternal mortality ratio (MMR) is a key indicator for measurement of progress against Millennium Development Goal 5 (MDG 5). For many countries, especially those with a presumed high number of maternal deaths, only estimates are available. SOURCES OF DATA: Recent global estimates and the reasons for high maternal mortality are reviewed. AREAS OF AGREEMENT: There is international consensus that efforts to reduce maternal mortality globally need to be intensified. AREAS OF CONTROVERSY: Many countries lack accurate data on number of deaths in women of reproductive age and number of births. Therefore, statistical modelling has been used to calculate estimates, which generally have wide confidence intervals and may be disputed by individual countries. GROWING POINTS: There is renewed focus on MMR as 2015 approaches. AREAS TIMELY FOR DEVELOPING RESEARCH: There is a need to adapt and implement methods for measuring maternal mortality to generate more accurate estimates. More data on cause of death are needed.