Distinct plasma metabolomic signatures differentiate autoimmune encephalitis from drug-resistant epilepsy.

OBJECTIVE: Differentiating forms of autoimmune encephalitis (AE) from other causes of seizures helps expedite immunotherapies in AE patients and informs studies regarding their contrasting pathophysiology. We aimed to investigate whether and how Nuclear Magnetic Resonance (NMR)-based metabolomics could differentiate AE from drug-resistant epilepsy (DRE), and stratify AE subtypes. METHODS: This study recruited 238 patients: 162 with DRE and 76 AE, including 27 with contactin-associated protein-like 2 (CASPR2), 29 with leucine-rich glioma inactivated 1 (LGI1) and 20 with N-methyl-d-aspartate receptor (NMDAR) antibodies. Plasma samples across the groups were analyzed using NMR spectroscopy and compared with multivariate statistical techniques, such as orthogonal partial least squares discriminant analysis (OPLS-DA). RESULTS: The OPLS-DA model successfully distinguished AE from DRE patients with a high predictive accuracy of 87.0 ± 3.1% (87.9 ± 3.4% sensitivity and 86.3 ± 3.6% specificity). Further, pairwise OPLS-DA models were able to stratify the three AE subtypes. Plasma metabolomic signatures of AE included decreased high-density lipoprotein (HDL, -(CH2)n-, -CH3), phosphatidylcholine and albumin (lysyl moiety). AE subtype-specific metabolomic signatures were also observed, with increased lactate in CASPR2, increased lactate, glucose, and decreased unsaturated fatty acids (UFA, -CH2CH=) in LGI1, and increased glycoprotein A (GlycA) in NMDAR-antibody patients. INTERPRETATION: This study presents the first non-antibody-based biomarker for differentiating DRE, AE and AE subtypes. These metabolomics signatures underscore the potential relevance of lipid metabolism and glucose regulation in these neurological disorders, offering a promising adjunct to facilitate the diagnosis and therapeutics.

What makes a city 'breastfeeding-friendly'? A scoping review of indicators of a breastfeeding-friendly city.

A breastfeeding-friendly city is one where there is an enabling environment to support breastfeeding throughout the first 2 years or more of a child's life. Indicators of a breastfeeding-friendly city have yet to be identified. What are the indicators or criteria used to define breastfeeding friendliness in a geographic area such as a city and the settings within, which we have classified as community, healthcare and workplace? Three major databases and grey literature were searched. Records were screened to identify publications describing criteria such as indicators or descriptions of a breastfeeding-friendly setting, defined as 'criteria-sets'. These criteria-sets were then categorized and summarized by settings. The search up to 2 September 2021 found 119 criteria-sets from a range of settings: geographic locations (n = 33), community entities (n = 24), healthcare facilities (n = 28), workplaces (n = 28) and others (n = 6). Overall, 15 community, 22 healthcare and 9 workplace related criteria were extracted from the criteria-sets. Criteria that were consistently present in all settings were policy, training & education, skilled breastfeeding support and physical infrastructure. Some criteria-sets of geographic locations contained criteria only from a single setting (e.g., the presence of breastfeeding-friendly cafes). Criteria-sets were present for all settings as defined in this review, but few were actual indicators. Specifically, there were no existing indicators of a breastfeeding-friendly city. Several common components of the criteria-sets were identified, and these could be used in developing indicators of a breastfeeding-friendly city. Future studies should determine which of these are important and how each can be measured.

A quantitative assessment of the frequency and magnitude of heterogeneous treatment effects in studies of the health effects of social policies.

Substantial heterogeneity in effects of social policies on health across subgroups may be common, but has not been systematically characterized. Using a sample of 55 contemporary studies on health effects of social policies, we recorded how often heterogeneous treatment effects (HTEs) were assessed, for what subgroups (e.g., male, female), and the subgroup-specific effect estimates expressed as Standardized Mean Differences (SMDs). For each study, outcome, and dimension (e.g., gender), we fit a random-effects meta-analysis. We characterized the magnitude of heterogeneity in policy effects using the standard deviation of the subgroup-specific effect estimates (τ). Among the 44% of studies reporting subgroup-specific estimates, policy effects were generally small (<0.1 SMDs) with mixed impacts on health (67% beneficial) and disparities (50% implied narrowing of disparities). Across study-outcome-dimensions, 54% indicated any heterogeneity in effects, and 20% had τ > 0.1 SMDs. For 26% of study-outcome-dimensions, the magnitude of τ indicated that effects of opposite signs were plausible across subgroups. Heterogeneity was more common in policy effects not specified a priori. Our findings suggest social policies commonly have heterogeneous effects on health of different populations; these HTEs may substantially impact disparities. Studies of social policies and health should routinely evaluate HTEs.

Use of Galactagogues in a Multi-Ethnic Community in Southeast Asia: A Descriptive Study.

Purpose: Galactagogues are substances that increase breast-milk production. They can be medication, herbs or food. Use of galactagogues may be different among the major ethnic groups in Malaysia. The primary objective of this cross-sectional study is to determine the prevalence of galactagogues use among breastfeeding mothers in a multi-ethnic community. Patients and Methods: Self-administered questionnaires were distributed between November 2016 and January 2017 to mothers attending the health clinics and private hospital paediatric clinics in Penang, Malaysia, whose infants were below 6 months of age. The questionnaire enquired about use of galactagogues, types of galactagogue used, perceived effectiveness and sources of information. It also asked mothers about what they would do to increase milk supply. Results: We analyzed 322 out of 530 questionnaires distributed where 76% of mothers reported use of galactagogues; most of which were food-based: dates (66%), oats (58%) and soya bean (56%). Each major ethnic group had a different preference for galactagogues: Malays (dates), Chinese (soya bean) and Indians (oats). Only one mother used pharmacological galactagogues alone. Galactagogues were perceived to be effective by 65% of mothers who used them. Multivariate analysis showed that use of galactagogues was not related to ethnicity, education, work, perception of milk supply or use of formula milk. The most common source of information on galactagogues came from family and friends. Conclusion: Use of galactagogues is common in our population, especially food-based ones, and the choice of galactagogues differs by ethnicity. Future studies on efficacy and safety galactagogues should be focused these commonly used ones. There is also a need for qualitative studies to improve our understanding of why they are widely used in this region.

A Participatory, Needs-Based Approach to Breastfeeding Training for Confinement Centres.

With a focus on traditional practices rather than evidence-based practices, breastfeeding support is sub-optimal in confinement centres (CCs). We used a participatory, needs-based approach to develop a training module for CC staff adopting Kern's six-step approach as our conceptual framework. Of 46 identified CCs, 25 accepted our invitation to a dialogue aimed at establishing relationships and understanding their needs. An interactive training workshop was developed from the dialogue's findings. The workshop, attended by 32 CCs (101 participants), was conducted four times over a four-month period. Questions raised by the participants reflected deficits in understanding breastfeeding concepts and erroneous cultural beliefs. Correct answers rose from 20% pre-test to 51% post-test. Post-workshop feedback showed that participants appreciated the safe environment to ask questions, raise concerns and correct misconceptions. An interview conducted 14 months later showed that while some CCs improved breastfeeding support, others made no change due to conflict between breastfeeding and traditional postnatal practices, which was aggravated by a lack of support due to the COVID-19 pandemic. A participatory approach established a trustful learning environment, helping CCs appreciate the value of learning and adopting new concepts. However, cultural perceptions take time to change, hence continuous training and support are vital for sustained changes.

The serum metabolomic profile of a distinct, inflammatory subtype of acute psychosis.

A range of studies suggest that a proportion of psychosis may have an autoimmune basis, but this has not translated through into clinical practice-there is no biochemical test able to accurately identify psychosis resulting from an underlying inflammatory cause. Such a test would be an important step towards identifying who might require different treatments and have the potential to improve outcomes for patients. To identify novel subgroups within patients with acute psychosis we measured the serum nuclear magnetic resonance (NMR) metabolite profiles of 75 patients who had identified antibodies (anti-glycine receptor [GlyR], voltage-gated potassium channel [VGKC], Contactin-associated protein-like 2 [CASPR2], leucine-rich glioma inactivated 1 [LGI1], N-methyl-D-aspartate receptor [NMDAR] antibody) and 70 antibody negative patients matched for age, gender, and ethnicity. Clinical symptoms were assessed using the positive and negative syndrome scale (PANSS). Unsupervised principal component analysis identified two distinct biochemical signatures within the cohort. Orthogonal partial least squared discriminatory analysis revealed that the serum metabolomes of NMDAR, LGI1, and CASPR2 antibody psychosis patients were indistinct from the antibody negative control group while VGKC and GlyR antibody patients had significantly decreased lipoprotein fatty acids and increased amino acid concentrations. Furthermore, these patients had more severe presentation with higher PANSS scores than either the antibody negative controls or the NMDAR, LGI1, and CASPR2 antibody groups. These results suggest that a proportion of patients with acute psychosis have a distinct clinical and biochemical phenotype that may indicate an inflammatory subtype.

Mothers' hygiene experiences in confinement centres: A cohort study.

INTRODUCTION: Ethnic Malaysian Chinese used to observe the 1-month postpartum confinement period at home and many families would engage a traditional postpartum carer to help care for the mother and newborn. A recent trend has been the development of confinement centres (CCs) which are private non-healthcare establishments run by staff not trained in health care. Concerns about hygiene in CCs arose after infections were reported. We describe the practice of hand hygiene observed in CCs, the availability of resources for hygiene, and the prevalence of health-related problems in CCs. METHODS: This is a cohort study of ethnic Chinese mothers intending to breastfeed their healthy infants. They were recruited post-delivery along with a comparison group who planned to spend their confinement period at home. After their 1-month confinement period, they were contacted for a structured telephone interview about their experience. To avoid any alteration in behaviour, mothers were not told at recruitment that they had to observe hygiene practices. Multiple logistic regression was used to assess the effect of place of confinement on rates of infant health problems. RESULTS: Of 187 mothers, 88(47%) went to 27 different CCs while 99(53%) stayed at home. Response rates for the 1-month interviews were 88%(CC) versus 97%(home). Mothers in CC group stayed in one to four-bedded rooms and 92% of them had their baby sleeping separately in a common nursery described to have up to 17 babies at a time; 74% of them spent less than six hours a day with their babies; 43% noticed that CC staff had inadequate hand hygiene practices; 66% reported no hand basins in their rooms; 30% reported no soap at hand basins; 28% reported inexperienced or inadequate staff and 4% reported baby item sharing. Among the mothers staying at home, 35% employed a traditional postpartum carer for her baby; 32% did not room-in with their babies, but only 11% spent less than 6 hours a day with their babies. Of mothers who employed traditional postpartum carers, 32% did not know if their carer washed hands after changing diapers and 18% reported that their carer did not. Health problems that were probably related to infection (HPRI) like fever and cough were similar between the groups: 14%(CC) versus 14%(home) (p = 0.86). Multiple logistic regression did not show that CCs were a factor for HPRI: aOR 1.28 (95% CI 0.36 to 4.49). Three mothers reported events that could indicate transmission of infection in CCs. CONCLUSION: We found unsatisfactory hygiene practices in CCs as reported by mothers who spent their confinement period there. Although we were not able to establish any direct evidence of infection transmission but based on reports given by the mothers in this study, it is likely to be happening. Therefore, future studies, including intervention studies, are urgently needed to establish an appropriate hygiene standard in CCs as well as the best method to implement this standard. Training CC staff with hygiene knowledge so that they can be empowered to contribute to the development of these standards would be important.

Heterogeneous treatment effects in social policy studies: An assessment of contemporary articles in the health and social sciences.

PURPOSE: Social policies are important determinants of population health but may have varying effects on subgroups of people. Evaluating heterogeneous treatment effects (HTEs) of social policies is critical to determine how social policies will affect health inequities. Methods for evaluating HTEs are not standardized. Little is known about how often and by what methods HTEs are assessed in social policy and health research. METHODS: A sample of 55 articles from 2019 on the health effects of social policies were evaluated for frequency of reporting HTEs; for what subgroupings HTEs were reported; frequency of a priori specification of intent to assess HTEs; and methods used for assessing HTEs. RESULTS: A total of 24 (44%) studies described some form of HTE assessment, including by age, gender, education, race/ethnicity, and/or geography. Among studies assessing HTEs, 63% specified HTE assessment a priori, and most (71%) used descriptive methods such as stratification; 21% used statistical tests (e.g., interaction terms in a regression); and no studies used data-driven algorithms. CONCLUSIONS: Although understanding HTEs could enhance policy and practice-based efforts to reduce inequities, it is not routine research practice. Increased evaluation of HTEs across relevant subgroups is needed.

The Revolution Will Be Hard to Evaluate: How Co-Occurring Policy Changes Affect Research on the Health Effects of Social Policies.

Extensive empirical health research leverages variation in the timing and location of policy changes as quasi-experiments. Multiple social policies may be adopted simultaneously in the same locations, creating co-occurrence that must be addressed analytically for valid inferences. The pervasiveness and consequences of co-occurring policies have received limited attention. We analyzed a systematic sample of 13 social policy databases covering diverse domains including poverty, paid family leave, and tobacco use. We quantified policy co-occurrence in each database as the fraction of variation in each policy measure across different jurisdictions and times that could be explained by covariation with other policies. We used simulations to estimate the ratio of the variance of effect estimates under the observed policy co-occurrence to variance if policies were independent. Policy co-occurrence ranged from very high for state-level cannabis policies to low for country-level sexual minority-rights policies. For 65% of policies, greater than 90% of the place-time variation was explained by other policies. Policy co-occurrence increased the variance of effect estimates by a median of 57-fold. Co-occurring policies are common and pose a major methodological challenge to rigorously evaluating health effects of individual social policies. When uncontrolled, co-occurring policies confound one another, and when controlled, resulting positivity violations may substantially inflate the variance of estimated effects. Tools to enhance validity and precision for evaluating co-occurring policies are needed.

What to Do When Everything Happens at Once: Analytic Approaches to Estimate the Health Effects of Co-Occurring Social Policies.

Social policies have great potential to improve population health and reduce health disparities. Increasingly, those doing empirical research have sought to quantify the health effects of social policies by exploiting variation in the timing of policy changes across places. Multiple social policies are often adopted simultaneously or in close succession in the same locations, creating co-occurrence that must be handled analytically for valid inferences. Although this is a substantial methodological challenge for researchers aiming to isolate social policy effects, only in a limited number of studies have researchers systematically considered analytic solutions within a causal framework or assessed whether these solutions are being adopted. We designated 7 analytic solutions to policy co-occurrence, including efforts to disentangle individual policy effects and efforts to estimate the combined effects of co-occurring policies. We used an existing systematic review of social policies and health to evaluate how often policy co-occurrence is identified as a threat to validity and how often each analytic solution is applied in practice. Of the 55 studies, only in 17 (31%) did authors report checking for any co-occurring policies, although in 36 studies (67%), at least 1 approach was used that helps address policy co-occurrence. The most common approaches were adjusting for measures of co-occurring policies; defining the outcome on subpopulations likely to be affected by the policy of interest (but not other co-occurring policies); and selecting a less-correlated measure of policy exposure. As health research increasingly focuses on policy changes, we must systematically assess policy co-occurrence and apply analytic solutions to strengthen studies on the health effects of social policies.

Powering population health research: Considerations for plausible and actionable effect sizes.

Evidence for Action (E4A), a signature program of the Robert Wood Johnson Foundation, funds investigator-initiated research on the impacts of social programs and policies on population health and health inequities. Across thousands of letters of intent and full proposals E4A has received since 2015, one of the most common methodological challenges faced by applicants is selecting realistic effect sizes to inform calculations of power, sample size, and minimum detectable effect (MDE). E4A prioritizes health studies that are both (1) adequately powered to detect effect sizes that may reasonably be expected for the given intervention and (2) likely to achieve intervention effects sizes that, if demonstrated, correspond to actionable evidence for population health stakeholders. However, little guidance exists to inform the selection of effect sizes for population health research proposals. We draw on examples of five rigorously evaluated population health interventions. These examples illustrate considerations for selecting realistic and actionable effect sizes as inputs to calculations of power, sample size and MDE for research proposals to study population health interventions. We show that plausible effects sizes for population health interventions may be smaller than commonly cited guidelines suggest. Effect sizes achieved with population health interventions depend on the characteristics of the intervention, the target population, and the outcomes studied. Population health impact depends on the proportion of the population receiving the intervention. When adequately powered, even studies of interventions with small effect sizes can offer valuable evidence to inform population health if such interventions can be implemented broadly. Demonstrating the effectiveness of such interventions, however, requires large sample sizes.

Study protocol: a pilot quasi-experimental trial of tele-rehabilitation and tele-drain care post-mastectomy.

BACKGROUND: Breast cancer is the leading cancer affecting women in Singapore. Its survivors commonly experience decline in physical function and quality of life post-mastectomy, due to their upper limb morbidity and wound issues. Rehabilitation can address the aforementioned issues. When rehabilitation is accessible and easy to adhere, it can optimize recovery. Home-based tele-rehabilitation guided by healthcare professionals and self-managed by patients can potentially optimize the patients' adherence to rehabilitation and recovery. With that in mind, a team of breast cancer specialists (oncologists, nurses, and therapists) in Singapore has developed one of the first tele-rehabilitation systems for local women undergoing a unilateral mastectomy. To our knowledge, no such systems have been evaluated or proven effective as a treatment option among local breast cancer patients with acute disabilities. METHODS: This is a pilot quasi-experimental trial that aims to evaluate the feasibility of tele-rehabilitation and tele-drain care compared to usual care. Up to 40 patients (20 per group) will be recruited for this trial. They will be assigned to an intervention group that receives rehabilitation via a tele-rehabilitation system or a control group that receives rehabilitation in person at their clinic. The primary outcome of this trial is rehabilitation participation (i.e., the time spent on rehabilitation). The secondary outcomes are upper extremity functioning, perceived health, and quality of life. DISCUSSION: As part of this pilot trial, patients who opt in for the tele-rehabilitation will be asked to share their experience with and thoughts on the tele-rehabilitation system. With the evidence obtained from the tele-rehabilitation patients of this trial, we will be able to improve the current system for our future trial. Further, our additional data on rehabilitation participation, physical function, and quality of life will help us design a sufficiently powered future main trial. TRIAL REGISTRATION: The trial was approved by the National Healthcare Group's Domain Specific Review Board (#2019/00283) and registered with www.ClinicalTrials.gov (# NCT04269967 ) in February 2020.

Comparing breastfeeding experiences between mothers spending the traditional Chinese confinement period in a confinement centre and those staying at home: a cohort study.

BACKGROUND: Ethnic Chinese mothers in Malaysia adhere to 30 days of traditional postpartum practices (the "confinement period") aimed at recuperation after delivery. Recently there has been an emergence of confinement centres (CCs) where mothers stay and receive traditional confinement care. Ethnic Chinese mothers have low breastfeeding rates. There are concerns that practices in CCs could contribute to this but no data exists. We described mothers' breastfeeding experiences at CCs and identified areas for potential improvement in breastfeeding support. METHODS: Ethnic Chinese mothers intending to breastfeed their healthy infants were recruited post-delivery between August and October 2017 then, at 1 and 6 months, they were telephone interviewed about their experience. For every participant going to a CC after the birth, another mother going home ("home") for her confinement was recruited. Chi-square test was used to compare groups and multiple logistic regression was used to assess the effect of confinement place on exclusive breastfeeding. RESULTS: Of 187 mothers, 88 (47%) went to CCs. Significantly more were primipara and fewer had previous breastfeeding experience. Response rates for the 1- and 6- month interviews were 88% (CC) versus 97% (home); and 77% (CC) versus 87% (home) respectively. Exclusive breastfeeding rates were similar between the groups: 62% (CC) versus 56% (home) at 1 month (p = 0.4); and 37% (CC) versus 42% (home) at 6 months (p = 0.5). Multiple logistic regression did not show that CCs were a factor affecting exclusive breastfeeding rates at 1 month, (adjusted odds ratio [aOR] 1.7, 95% confidence interval [CI] 0.9, 3.3), or 6 months (aOR 0.9, 95% CI 0.4, 1.7). However, significantly more CC participants only fed expressed breast milk. Despite 66% of CC participants reporting that their centre supported breastfeeding, only 6 (8%) CC participants compared to 66 (69%) of home participants roomed-in with their baby (p < 0.001). The proportion encountering breastfeeding difficulties were similar between groups. CC participants sought help for breastfeeding problems mainly from CC staff and support groups while home participants obtained help from friends and healthcare professionals. CONCLUSIONS: Breastfeeding rates appeared to be similar at CCs and at home during the confinement period, but there were gaps in how CCs supported breastfeeding. Targeted training to CC staff to support breastfeeding may result in better outcomes for mothers staying in CCs.

Autophagy is deregulated in cancer-associated fibroblasts from oral cancer and is stimulated during the induction of fibroblast senescence by TGF-ß1.

Many of the characteristics ascribed to cancer-associated fibroblasts (CAFs) are shared by activated, autophagic and senescent fibroblasts. Whilst most oral squamous cell carcinomas (OSCCs) are genetically unstable (GU-OSCC), genetically stable variants (GS-OSCC) have been described and, notably, CAF activation (myofibroblast differentiation) and senescence are characteristics particularly associated with GU-OSCCs. However, it is not known whether autophagy is disrupted in these cells or whether autophagy regulates the development of the myofibroblast and senescent phenotypes. In this study, we show that senescent CAFs from GU-OSCCs contained more autophagosomes than normal human oral fibroblasts (NHOFs) and CAFs from GS-OSCCs possibly due to autophagic impairment. Further, we show that deregulation of autophagy in normal fibroblasts, either by inhibition with autophagy inhibitor, SAR405, or activation with TGF-ß1, induced fibroblast activation and senescence: In response to TGF-ß1, autophagy was induced prior to the development of the activated and senescent phenotypes. Lastly, we show that both SAR405- and TGF-ß1-treated NHOFs enhance OSCC cell migration but only TGF-ß1-treated cells increase OSCC invasion through Matrigel, indicating that TGF-ß1 has additional effects that are independent of fibroblast activation/senescence. These results suggest a functional role for autophagy in the development of myofibroblast and CAF phenotypes.

Vitamin D supplementation for term breastfed infants to prevent vitamin D deficiency and improve bone health.

BACKGROUND: Vitamin D deficiency is common worldwide, contributing to nutritional rickets and osteomalacia which have a major impact on health, growth, and development of infants, children and adolescents. Vitamin D levels are low in breast milk and exclusively breastfed infants are at risk of vitamin D insufficiency or deficiency. OBJECTIVES: To determine the effect of vitamin D supplementation given to infants, or lactating mothers, on vitamin D deficiency, bone density and growth in healthy term breastfed infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to 29 May 2020 supplemented by searches of clinical trials databases, conference proceedings, and citations. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs in breastfeeding mother-infant pairs comparing vitamin D supplementation given to infants or lactating mothers compared to placebo or no intervention, or sunlight, or that compare vitamin D supplementation of infants to supplementation of mothers. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial eligibility and risk of bias and independently extracted data. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We included 19 studies with 2837 mother-infant pairs assessing vitamin D given to infants (nine studies), to lactating mothers (eight studies), and to infants versus lactating mothers (six studies). No studies compared vitamin D given to infants versus periods of infant sun exposure. Vitamin D supplementation given to infants: vitamin D at 400 IU/day may increase 25-OH vitamin D levels (MD 22.63 nmol/L, 95% CI 17.05 to 28.21; participants = 334; studies = 6; low-certainty) and may reduce the incidence of vitamin D insufficiency (25-OH vitamin D < 50 nmol/L) (RR 0.57, 95% CI 0.41 to 0.80; participants = 274; studies = 4; low-certainty). However, there was insufficient evidence to determine if vitamin D given to the infant reduces the risk of vitamin D deficiency (25-OH vitamin D < 30 nmol/L) up till six months of age (RR 0.41, 95% CI 0.16 to 1.05; participants = 122; studies = 2), affects bone mineral content (BMC), or the incidence of biochemical or radiological rickets (all very-low certainty). We are uncertain about adverse effects including hypercalcaemia. There were no studies of higher doses of infant vitamin D (> 400 IU/day) compared to placebo. Vitamin D supplementation given to lactating mothers: vitamin D supplementation given to lactating mothers may increase infant 25-OH vitamin D levels (MD 24.60 nmol/L, 95% CI 21.59 to 27.60; participants = 597; studies = 7; low-certainty), may reduce the incidences of vitamin D insufficiency (RR 0.47, 95% CI 0.39 to 0.57; participants = 512; studies = 5; low-certainty), vitamin D deficiency (RR 0.15, 95% CI 0.09 to 0.24; participants = 512; studies = 5; low-certainty) and biochemical rickets (RR 0.06, 95% CI 0.01 to 0.44; participants = 229; studies = 2; low-certainty). The two studies that reported biochemical rickets used maternal dosages of oral D3 60,000 IU/day for 10 days and oral D3 60,000 IU postpartum and at 6, 10, and 14 weeks. However, infant BMC was not reported and there was insufficient evidence to determine if maternal supplementation has an effect on radiological rickets (RR 0.76, 95% CI 0.18 to 3.31; participants = 536; studies = 3; very low-certainty). All studies of maternal supplementation enrolled populations at high risk of vitamin D deficiency. We are uncertain of the effects of maternal supplementation on infant growth and adverse effects including hypercalcaemia. Vitamin D supplementation given to infants compared with supplementation given to lactating mothers: infant vitamin D supplementation compared to lactating mother supplementation may increase infant 25-OH vitamin D levels (MD 14.35 nmol/L, 95% CI 9.64 to 19.06; participants = 269; studies = 4; low-certainty). Infant vitamin D supplementation may reduce the incidence of vitamin D insufficiency (RR 0.61, 95% CI 0.40 to 0.94; participants = 334; studies = 4) and may reduce vitamin D deficiency (RR 0.35, 95% CI 0.17 to 0.72; participants = 334; studies = 4) but the evidence is very uncertain. Infant BMC and radiological rickets were not reported and there was insufficient evidence to determine if maternal supplementation has an effect on infant biochemical rickets. All studies enrolled patient populations at high risk of vitamin D deficiency. Studies compared an infant dose of vitamin D 400 IU/day with varying maternal vitamin D doses from 400 IU/day to > 4000 IU/day. We are uncertain about adverse effects including hypercalcaemia. AUTHORS' CONCLUSIONS: For breastfed infants, vitamin D supplementation 400 IU/day for up to six months increases 25-OH vitamin D levels and reduces vitamin D insufficiency, but there was insufficient evidence to assess its effect on vitamin D deficiency and bone health. For higher-risk infants who are breastfeeding, maternal vitamin D supplementation reduces vitamin D insufficiency and vitamin D deficiency, but there was insufficient evidence to determine an effect on bone health. In populations at higher risk of vitamin D deficiency, vitamin D supplementation of infants led to greater increases in infant 25-OH vitamin D levels, reductions in vitamin D insufficiency and vitamin D deficiency compared to supplementation of lactating mothers. However, the evidence is very uncertain for markers of bone health. Maternal higher dose supplementation (≥ 4000 IU/day) produced similar infant 25-OH vitamin D levels as infant supplementation of 400 IU/day. The certainty of evidence was graded as low to very low for all outcomes.

Deregulation of lysophosphatidic acid metabolism in oral cancer promotes cell migration via the up-regulation of COX-2.

Oral squamous cell carcinoma (OSCC) is the sixth most common cancer worldwide and accounts for 300,000 new cases yearly. The five-year survival rate is approximately 50% and the major challenges to improving patient prognosis include late presentation, treatment resistance, second primary tumours and the lack of targeted therapies. Therefore, there is a compelling need to develop novel therapeutic strategies. In this study, we have examined the effect of lysophosphatidic acid (LPA) on OSCC cell migration, invasion and response to radiation, and investigated the contribution of cyclooxygenase-2 (COX-2) in mediating the tumour promoting effects of LPA. Using the TCGA data set, we show that the expression of the lipid phosphate phosphatases (LPP), LPP1 and LPP3, was significantly down-regulated in OSCC tissues. There was no significant difference in the expression of the ENPP2 gene, which encodes for the enzyme autotaxin (ATX) that produces LPA, between OSCCs and control tissues but ENPP2 levels were elevated in a subgroup of OSCCs. To explore the phenotypic effects of LPA, we treated OSCC cell lines with LPA and showed that the lipid enhanced migration and invasion as well as suppressed the response of the cells to irradiation. We also show that LPA increased COX-2 mRNA and protein levels in OSCC cell lines and inhibition of COX-2 activity with the COX-2 inhibitor, NS398, attenuated LPA-induced OSCC cell migration. Collectively, our data show for the first time that COX-2 mediates some of the pro-tumorigenic effects of LPA in OSCC and identifies the ATX-LPP-LPA-COX-2 pathway as a potential therapeutic target for this disease.

Postpartum women's perception of antenatal breastfeeding education: a descriptive survey.

BACKGROUND: Antenatal breastfeeding education (ANBE) is provided to all pregnant women attending Ministry of Health (MOH) clinics and some private health facilities in Malaysia, in line with the WHO/UNICEF Baby-Friendly Hospital Initiative (BFHI). However, the 6 month exclusive breastfeeding prevalence remains relatively low in Malaysia, suggesting that there may be a gap between what is currently taught and what is received by the women. OBJECTIVES: To determine how women perceived their ANBE experience in the first 8 weeks postpartum including what was useful and what they would like to have been included, sources of ANBE and infant feeding practices at the time of survey. METHODS: Women during their first 8 weeks postpartum who attended MOH clinics in Penang State, Malaysia were surveyed using a self-administered questionnaire in April and May 2015. Categorical responses were presented as numbers and proportions while free text responses were compiled verbatim and categorised into themes. The perceptions of primiparous and multiparous women were compared. Multivariate logistic regression adjusted to known confounders was used to determine if ANBE was associated with exclusive breastfeeding at the time of survey. RESULTS: A total of 421 women completed the 15-item questionnaire (84% response rate) of which 282 were complete and available for analysis. Of these, 95% had received ANBE, majority (88%) from MOH clinics. Almost all women found it useful. However, there were areas both in the delivery (e.g. too short) and the content (e.g. nothing new) that were described as not useful; and areas they would like more coverage (e.g. milk expression, storage and overcoming low milk supply). The exclusive breastfeeding prevalence at the time of survey was 61%. ANBE was significantly associated with exclusive breastfeeding even after adjusting for confounders (adjusted odds ratio [aOR] 8.1, 95% confidence interval 1.7, 38.3). CONCLUSIONS: ANBE is widely implemented and perceived as useful and may be associated with exclusive breastfeeding. Our findings give insight into content that women would like more of and how delivery of ANBE could be improved, including individualized sessions and communicating at a suitable level and language. Future studies could focus on the quality of ANBE delivery.

Community Eligibility Provision and School Meal Participation among Student Subgroups.

BACKGROUND: The National School Lunch and Breakfast Programs help to reduce food insecurity and improve nutrition. The Community Eligibility Provision (CEP) enables high-poverty schools to offer breakfast and lunch at no cost to all students. This study examines associations between CEP and participation among students eligible for free or reduced-price meals ("FRPM"), possibly eligible ("near-cutoff"), or ineligible ("full-price"). METHODS: Using data from the 2013-2015 Healthy Communities Study, we compared school breakfast and lunch participation between 842 students in K-8 at 80 CEP schools and 1463 students at 118 schools without CEP. Cross-sectional difference-in-difference (DID) models compared meal participation among near-cutoff and full-price groups to that in the FRPM group. RESULTS: Overall, FRPM students had high participation in school lunch and breakfast at both types of schools. In adjusted DID models, lunch participation among near-cutoff students was 12 points higher in CEP versus comparison schools (p < .05). Among full-price students, breakfast participation was 20 points higher and lunch participation 19 points higher in CEP than comparison schools (p < .001). CONCLUSIONS: Community Eligibility Provision improves access to school breakfast and lunch in high-poverty schools, particularly for students who are near or above the cutoff for FRPM eligibility.

Oral galactagogues (natural therapies or drugs) for increasing breast milk production in mothers of non-hospitalised term infants.

BACKGROUND: Many women express concern about their ability to produce enough milk, and insufficient milk is frequently cited as the reason for supplementation and early termination of breastfeeding. When addressing this concern, it is important first to consider the influence of maternal and neonatal health, infant suck, proper latch, and feeding frequency on milk production, and that steps be taken to correct or compensate for any contributing issues. Oral galactagogues are substances that stimulate milk production. They may be pharmacological or non-pharmacological (natural). Natural galactagogues are usually botanical or other food agents. The choice between pharmacological or natural galactagogues is often influenced by familiarity and local customs. Evidence for the possible benefits and harms of galactagogues is important for making an informed decision on their use. OBJECTIVES: To assess the effect of oral galactagogues for increasing milk production in non-hospitalised breastfeeding mother-term infant pairs. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), Health Research and Development Network - Phillippines (HERDIN), Natural Products Alert (Napralert), the personal reference collection of author LM, and reference lists of retrieved studies (4 November 2019). SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs (including published abstracts) comparing oral galactagogues with placebo, no treatment, or another oral galactagogue in mothers breastfeeding healthy term infants. We also included cluster-randomised trials but excluded cross-over trials. DATA COLLECTION AND ANALYSIS: We used standard Cochrane Pregnancy and Childbirth methods for data collection and analysis. Two to four review authors independently selected the studies, assessed the risk of bias, extracted data for analysis and checked accuracy. Where necessary, we contacted the study authors for clarification. MAIN RESULTS: Forty-one RCTs involving 3005 mothers and 3006 infants from at least 17 countries met the inclusion criteria. Studies were conducted either in hospitals immediately postpartum or in the community. There was considerable variation in mothers, particularly in parity and whether or not they had lactation insufficiency. Infants' ages at commencement of the studies ranged from newborn to 6 months. The overall certainty of evidence was low to very low because of high risk of biases (mainly due to lack of blinding), substantial clinical and statistical heterogeneity, and imprecision of measurements. Pharmacological galactagogues Nine studies compared a pharmacological galactagogue (domperidone, metoclopramide, sulpiride, thyrotropin-releasing hormone) with placebo or no treatment. The primary outcome of proportion of mothers who continued breastfeeding at 3, 4 and 6 months was not reported. Only one study (metoclopramide) reported on the outcome of infant weight, finding little or no difference (mean difference (MD) 23.0 grams, 95% confidence interval (CI) -47.71 to 93.71; 1 study, 20 participants; low-certainty evidence). Three studies (metoclopramide, domperidone, sulpiride) reported on milk volume, finding pharmacological galactagogues may increase milk volume (MD 63.82 mL, 95% CI 25.91 to 101.72; I² = 34%; 3 studies, 151 participants; low-certainty evidence). Subgroup analysis indicates there may be increased milk volume with each drug, but with varying CIs. There was limited reporting of adverse effects, none of which could be meta-analysed. Where reported, they were limited to minor complaints, such as tiredness, nausea, headache and dry mouth (very low-certainty evidence). No adverse effects were reported for infants. Natural galactagogues Twenty-seven studies compared natural oral galactagogues (banana flower, fennel, fenugreek, ginger, ixbut, levant cotton, moringa, palm dates, pork knuckle, shatavari, silymarin, torbangun leaves or other natural mixtures) with placebo or no treatment. One study (Mother's Milk Tea) reported breastfeeding rates at six months with a concluding statement of "no significant difference" (no data and no measure of significance provided, 60 participants, very low-certainty evidence). Three studies (fennel, fenugreek, moringa, mixed botanical tea) reported infant weight but could not be meta-analysed due to substantial clinical and statistical heterogeneity (I2 = 60%, 275 participants, very low-certainty evidence). Subgroup analysis shows we are very uncertain whether fennel or fenugreek improves infant weight, whereas moringa and mixed botanical tea may increase infant weight compared to placebo. Thirteen studies (Bu Xue Sheng Ru, Chanbao, Cui Ru, banana flower, fenugreek, ginger, moringa, fenugreek, ginger and turmeric mix, ixbut, mixed botanical tea, Sheng Ru He Ji, silymarin, Xian Tong Ru, palm dates; 962 participants) reported on milk volume, but meta-analysis was not possible due to substantial heterogeneity (I2 = 99%). The subgroup analysis for each intervention suggested either benefit or little or no difference (very low-certainty evidence). There was limited reporting of adverse effects, none of which could be meta-analysed. Where reported, they were limited to minor complaints such as mothers with urine that smelled like maple syrup and urticaria in infants (very low-certainty evidence). Galactagogue versus galactagogue Eight studies (Chanbao; Bue Xue Sheng Ru, domperidone, moringa, fenugreek, palm dates, torbangun, moloco, Mu Er Wu You, Kun Yuan Tong Ru) compared one oral galactagogue with another. We were unable to perform meta-analysis because there was only one small study for each match-up, so we do not know if one galactagogue is better than another for any outcome. AUTHORS' CONCLUSIONS: Due to extremely limited, very low certainty evidence, we do not know whether galactagogues have any effect on proportion of mothers who continued breastfeeding at 3, 4 and 6 months. There is low-certainty evidence that pharmacological galactagogues may increase milk volume. There is some evidence from subgroup analyses that natural galactagogues may benefit infant weight and milk volume in mothers with healthy, term infants, but due to substantial heterogeneity of the studies, imprecision of measurements and incomplete reporting, we are very uncertain about the magnitude of the effect. We are also uncertain if one galactagogue performs better than another. With limited data on adverse effects, we are uncertain if there are any concerning adverse effects with any particular galactagogue; those reported were minor complaints. High-quality RCTs on the efficacy and safety of galactagogues are urgently needed. A set of core outcomes to standardise infant weight and milk volume measurement is also needed, as well as a strong basis for the dose and dosage form used.