Making stillbirths visible: a systematic review of globally reported causes of stillbirth.

BACKGROUND: Stillbirth is a global health problem. The World Health Organization (WHO) application of the International Classification of Diseases for perinatal mortality (ICD-PM) aims to improve data on stillbirth to enable prevention. OBJECTIVES: To identify globally reported causes of stillbirth, classification systems, and alignment with the ICD-PM. SEARCH STRATEGY: We searched CINAHL, EMBASE, Medline, Global Health, and Pubmed from 2009 to 2016. SELECTION CRITERIA: Reports of stillbirth causes in unselective cohorts. DATA COLLECTION AND ANALYSIS: Pooled estimates of causes were derived for country representative reports. Systems and causes were assessed for alignment with the ICD-PM. Data are presented by income setting (low, middle, and high income countries; LIC, MIC, HIC). MAIN RESULTS: Eighty-five reports from 50 countries (489 089 stillbirths) were included. The most frequent categories were Unexplained, Antepartum haemorrhage, and Other (all settings); Infection and Hypoxic peripartum (LIC), and Placental (MIC, HIC). Overall report quality was low. Only one classification system fully aligned with ICD-PM. All stillbirth causes mapped to ICD-PM. In a subset from HIC, mapping obscured major causes. CONCLUSIONS: There is a paucity of quality information on causes of stillbirth globally. Improving investigation of stillbirths and standardisation of audit and classification is urgently needed and should be achievable in all well-resourced settings. Implementation of the WHO Perinatal Mortality Audit and Review guide is needed, particularly across high burden settings. FUNDING: HR, SH, SHL, and AW were supported by an NHMRC-CRE grant (APP1116640). VF was funded by an NHMRC-CDF (APP1123611). TWEETABLE ABSTRACT: Urgent need to improve data on causes of stillbirths across all settings to meet global targets. PLAIN LANGUAGE SUMMARY: Background and methods Nearly three million babies are stillborn every year. These deaths have deep and long-lasting effects on parents, healthcare providers, and the society. One of the major challenges to preventing stillbirths is the lack of information about why they happen. In this study, we collected reports on the causes of stillbirth from high-, middle-, and low-income countries to: (1) Understand the causes of stillbirth, and (2) Understand how to improve reporting of stillbirths. Findings We found 85 reports from 50 different countries. The information available from the reports was inconsistent and often of poor quality, so it was hard to get a clear picture about what are the causes of stillbirth across the world. Many different definitions of stillbirth were used. There was also wide variation in what investigations of the mother and baby were undertaken to identify the cause of stillbirth. Stillbirths in all income settings (low-, middle-, and high-income countries) were most frequently reported as Unexplained, Other, and Haemorrhage (bleeding). Unexplained and Other are not helpful in understanding why a baby was stillborn. In low-income countries, stillbirths were often attributed to Infection and Complications during labour and birth. In middle- and high-income countries, stillbirths were often reported as Placental complications. Limitations We may have missed some reports as searches were carried out in English only. The available reports were of poor quality. Implications Many countries, particularly those where the majority of stillbirths occur, do not report any information about these deaths. Where there are reports, the quality is often poor. It is important to improve the investigation and reporting of stillbirth using a standardised system so that policy makers and healthcare workers can develop effective stillbirth prevention programs. All stillbirths should be investigated and reported in line with the World Health Organization standards.

Colonic microbiota can promote rapid local improvement of murine colitis by thioguanine independently of T lymphocytes and host metabolism.

OBJECTIVE: Mercaptopurine (MP) and pro-drug azathioprine are 'first-line' oral therapies for maintaining remission in IBD. It is believed that their pharmacodynamic action is due to a slow cumulative decrease in activated lymphocytes homing to inflamed gut. We examined the role of host metabolism, lymphocytes and microbiome for the amelioration of colitis by the related thioguanine (TG). DESIGN: C57Bl/6 mice with or without specific genes altered to elucidate mechanisms responsible for TG's actions were treated daily with oral or intrarectal TG, MP or water. Disease activity was scored daily. At sacrifice, colonic histology, cytokine message, caecal luminal and mucosal microbiomes were analysed. RESULTS: Oral and intrarectal TG but not MP rapidly ameliorated spontaneous chronic colitis in Winnie mice (point mutation in Muc2 secretory mucin). TG ameliorated dextran sodium sulfate-induced chronic colitis in wild-type (WT) mice and in mice lacking T and B lymphocytes. Remarkably, colitis improved without immunosuppressive effects in the absence of host hypoxanthine (guanine) phosphoribosyltransferase (Hprt)-mediated conversion of TG to active drug, the thioguanine nucleotides (TGN). Colonic bacteria converted TG and less so MP to TGN, consistent with intestinal bacterial conversion of TG to so reduce inflammation in the mice lacking host Hprt. TG rapidly induced autophagic flux in epithelial, macrophage and WT but not Hprt-/- fibroblast cell lines and augmented epithelial intracellular bacterial killing. CONCLUSIONS: Treatment by TG is not necessarily dependent on the adaptive immune system. TG is a more efficacious treatment than MP in Winnie spontaneous colitis. Rapid local bacterial conversion of TG correlated with decreased intestinal inflammation and immune activation.

MUC13 protects colorectal cancer cells from death by activating the NF-κB pathway and is a potential therapeutic target.

MUC13 is a transmembrane mucin glycoprotein that is over produced by many cancers, although its functions are not fully understood. Nuclear factor-κB (NF-κB) is a key transcription factor promoting cancer cell survival, but therapeutically targeting this pathway has proved difficult because NF-κB has pleiotropic functions. Here, we report that MUC13 prevents colorectal cancer cell death by promoting two distinct pathways of NF-kB activation, consequently upregulating BCL-XL. MUC13 promoted tumor necrosis factor (TNF)-induced NF-κB activation by interacting with TNFR1 and the E3 ligase, cIAP1, to increase ubiquitination of RIPK1. MUC13 also promoted genotoxin-induced NF-κB activation by increasing phosphorylation of ATM and SUMOylation of NF-κB essential modulator. Moreover, elevated expression of cytoplasmic MUC13 and NF-κB correlated with colorectal cancer progression and metastases. Our demonstration that MUC13 enhances NF-κB signaling in response to both TNF and DNA-damaging agents provides a new molecular target for specific inhibition of NF-κB activation. As proof of principle, silencing MUC13 sensitized colorectal cancer cells to killing by cytotoxic drugs and inflammatory signals and abolished chemotherapy-induced enrichment of CD133+ CD44+ cancer stem cells, slowed xenograft growth in mice, and synergized with 5-fluourouracil to induce tumor regression. Therefore, these data indicate that combining chemotherapy and MUC13 antagonism could improve the treatment of metastatic cancers.

Developmental structuralist approach to the classification of adaptive and pathologic personality organizations: infancy and early childhood.

Traditional classification of psychopathology is based on either symptom clusters or etiology. The authors suggest the use of a developmental structuralist approach, which focuses on an organism's manner of organizing and differentiating its experience of the world (structures) at each developmental level. The authors describe their postulated development stages of infancy and early childhood and discuss the implications of their approach for understanding adaptive and maladaptive infant functioning, environmental patterns, and principles of preventive intervention. In addition to diagnosis and preventive or therapeutic planning, this approach may be valuable for longitudinal studies and assessing developmental progression and/or outcome because continuity can be observed in terms of developmental level of adaptability rather than specific behaviors and because its provides a set of "baseline" functions to assess clinically relevant aspects of development.

Connecticut State Special Olympics: observations and recommendations.

The Connecticut State Special Olympics provides an opportunity for thousands of developmentally challenged children and adults to participate in athletic events. This paper retrospectively reviews the demographics and documentation of medical problems in 1994, 1995, and 1996 Summer Games. The 1994 and 1995 summer games took place at the Coast Guard Academy and Connecticut College in New London. The 1996 summer games occurred at Fairfield and Sacred Heart Universities in Fairfield. The mean age of the participants ranged from 30 to 32 years of age. Minor trauma made up the largest percentage of encounters. Most of these injuries were sprains or strains to the lower extremities. The more serious injuries included dislocations and fractures. The incidence of seizure remained stable over these years. A comparison of the 1994, 1995, and 1996 games revealed a nearly 600 fold increase in heat-related dehydration in Fairfield as compared to the 1994 and 1995 games in New London. The highest incidence of sunburn occurred in 1995 despite the availability of sunblock. A concerted effort to reduce sunburn in the 1996 games in Fairfield resulted in a marked decrease of sunburn despite the higher temperatures, but an increase in chemical irritation to the eyes. Recommendations are presented to decrease the incidence of medical problems.

Human placental sulfate transporter mRNA profiling from term pregnancies identifies abundant SLC13A4 in syncytiotrophoblasts and SLC26A2 in cytotrophoblasts.

Sulfate is an important nutrient for fetal growth and development. The fetus has no mechanism for producing its own sulfate and is therefore totally reliant on sulfate from the maternal circulation via placental sulfate transport. To build a model of directional sulfate transport in the placenta, we investigated the relative abundance of the 10 known sulfate transporter mRNAs in human placenta from uncomplicated term pregnancies. SLC13A4 and SLC26A2 were the most abundant sulfate transporter mRNAs, which localized to syncytiotrophoblast and cytotrophoblast cells, respectively. These findings indicate important physiological roles for SLC13A4 and SLC26A2 in human placental sulfate transport.

Ovarian vascular pedicle sign in ovarian metastasis arising from gall bladder carcinoma.

A case of a large mass in the pelvis confirmed to be a rare ovarian metastasis arising from a primary adenocarcinoma of the gall bladder is presented. The value of the recently described ovarian pedicle sign in confirming the organ of origin of the pelvic mass is emphasized.