Review of Causes of Maternal Deaths in Botswana in 2010

Background. In Botswana the maternal mortality ratio in 2010 was 163 per 100 000 live births. It is a priority to reduce this ratio to meet Millennium Development Goal 5 target of 21 per 100 000 live births. Objective. To investigate the underlying circumstances of maternal deaths in Botswana. Method. Fifty-six case notes from the 80 reported maternal deaths in 2010 were reviewed. Five clinicians reviewed each case independently and then together to achieve a consensus on diagnosis and underlying cause(s) of death. Results. Sixty-six percent of deaths occurred in Botswana’s two referral hospitals. Cases in which death had direct obstetric causes were fewer than cases in which cause of death was indirect. The main direct causes were haemorrhage (39%), hypertension (22%), and pregnancy-related sepsis (13%). Thirty-six (64%) deaths were in HIV-positive women, of whom 21 (58%) were receiving antiretroviral (ARV) therapy. Nineteen (34%) deaths were attributable to HIV, including 4 from complications of ARVs. Twenty-nine (52%) deaths were in the postnatal period, 19 (66%) of these in the first week. Case-note review revealed several opportunities for improved quality of care: better teamwork, communication and supportive supervision of health professionals; earlier recognition of the seriousness of complication(s) with more aggressive case-management; joint management between HIV and obstetric clinicians; screening for, and treatment of, opportunistic infections throughout the antenatal to postnatal periods; and better supply management of medications, fluids, blood for transfusion and laboratory tests. Conclusion. Integrating HIV management into maternal healthcare is essential to reduce maternal deaths in the region, alongside greater efforts to improve quality of care to avoid direct and indirect causes of death

A root-cause analysis of maternal deaths in Botswana: towards developing a culture of patient safety and quality improvement

BACKGROUND: In 2007, 95% of women in Botswana delivered in health facilities with 73% attending at least 4 antenatal care visits. HIV-prevalence in pregnant women was 28.7%. The maternal mortality ratio in 2010 was 163 deaths per 100 000 live births versus the government target of 130 for that year, indicating that the Millennium Development Goal 5 was unlikely to be met. A root-cause analysis was carried out with the aim of determining the underlying causes of maternal deaths reported in 2010, to categorise contributory factors and to prioritise appropriate interventions based on the identified causes, to prevent further deaths. METHODS: Case-notes for maternal deaths were reviewed by a panel of five clinicians, initially independently then discussed together to achieve consensus on assigning contributory factors, cause of death and whether each death was avoidable or not at presentation to hospital. Factors contributing to maternal deaths were categorised into organisational/management, personnel, technology/equipment/supplies, environment and barriers to accessing healthcare. RESULTS: Fifty-six case notes were available for review from 82 deaths notified in 2010, with 0–4 contributory factors in 19 deaths, 5–9 in 27deaths and 9–14 in nine. The cause of death in one case was not ascertainable since the notes were incomplete. The high number of contributory factors demonstrates poor quality of care even where deaths were not avoidable: 14/23 (61%) of direct deaths were considered avoidable compared to 12/32 (38%) indirect deaths. Highest ranking categories were: failure to recognise seriousness of patients’ condition (71% of cases); lack of knowledge (67%); failure to follow recommended practice (53%); lack of or failure to implement policies, protocols and guidelines (44%); and poor organisational arrangements (35%). Half the deaths had some barrier to accessing health services. CONCLUSIONS: Root-cause analysis demonstrates the interactions between patients, health professionals and health system in generating adverse outcomes for patients. The lessons provided indicate where training of undergraduate and postgraduate medical, midwifery and nursing students need to be intensified, with emphasis on evidence-based practice and adherence to protocols. Action plans and interventions aimed at changing the circumstances that led to maternal deaths can be implemented and re-evaluated

Internet-based information and self-help program for parents of children with burns: Study protocol for a randomized controlled trial

Background: A burn is one of the most traumatic and painful injuries a child can experience and it is also a very stressful experience for the parents. Given the great psychological distress and perceived lack of multi-professional support experienced by the parents, there is a need for support during in-hospital treatment as well as during recovery. The aim of the study is to develop and evaluate an internet-based information and self-help program for parents of children who have been hospitalized for burn injury. The program aims to decrease parents' symptoms of stress. Methods: Participants will consist of parents of children treated for burns between 2009 and 2013 at either of the two specialized Swedish Burn centers. The study is a two-armed randomized controlled trial with a six-week intervention group and an inactive control group, with a pre- and post-assessment, as well as a 3- and 12-month follow-up. The main outcome is stress (post-traumatic stress, general perceived stress and parental stress). The data will be analyzed with the intention-to-treat principle. The intervention is based on Cognitive-Behavior Therapy (CBT) and is inspired by Acceptance and Commitment Therapy (ACT). It is psycho-educational and provides basic skills training in communication and stress management. Conclusion: We believe that this program will offer parents of children with burns information and support, decrease symptoms of stress, and that parents will perceive the program as useful. If the program is found to be beneficial, it could be implemented in burn care as it is accessible and cost-effective

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Structural basis of PROTAC cooperative recognition for selective protein degradation

Inducing macromolecular interactions with small molecules to activate cellular signaling is a challenging goal. PROTACs (proteolysis-targeting chimeras) are bifunctional molecules that recruit a target protein in proximity to an E3 ubiquitin ligase to trigger protein degradation. Structural elucidation of the key ternary ligase-PROTAC-target species and its impact on target degradation selectivity remain elusive. We solved the crystal structure of Brd4 degrader MZ1 in complex with human VHL and the Brd4 bromodomain (Brd4BD2). The ligand folds into itself to allow formation of specific intermolecular interactions in the ternary complex. Isothermal titration calorimetry studies, supported by surface mutagenesis and proximity assays, are consistent with pronounced cooperative formation of ternary complexes with Brd4BD2. Structure-based-designed compound AT1 exhibits highly selective depletion of Brd4 in cells. Our results elucidate how PROTAC-induced de novo contacts dictate preferential recruitment of a target protein into a stable and cooperative complex with an E3 ligase for selective degradation

Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types

Protein ubiquitination is a dynamic and reversibleprocess of adding single ubiquitin molecules orvarious ubiquitin chains to target proteins. Here,using multidimensional omic data of 9,125 tumorsamples across 33 cancer types from The CancerGenome Atlas, we perform comprehensive molecu-lar characterization of 929 ubiquitin-related genesand 95 deubiquitinase genes. Among them, we sys-tematically identify top somatic driver candidates,including mutatedFBXW7with cancer-type-specificpatterns and amplifiedMDM2showing a mutuallyexclusive pattern withBRAFmutations. Ubiquitinpathway genes tend to be upregulated in cancermediated by diverse mechanisms. By integratingpan-cancer multiomic data, we identify a group oftumor samples that exhibit worse prognosis. Thesesamples are consistently associated with the upre-gulation of cell-cycle and DNA repair pathways, char-acterized by mutatedTP53,MYC/TERTamplifica-tion, andAPC/PTENdeletion. Our analysishighlights the importance of the ubiquitin pathwayin cancer development and lays a foundation fordeveloping relevant therapeutic strategies

Molecular characterization and clinical relevance of metabolic expression subtypes in human cancers.

Metabolic reprogramming provides critical information for clinical oncology. Using molecular data of 9,125 patient samples from The Cancer Genome Atlas, we identified tumor subtypes in 33 cancer types based on mRNA expression patterns of seven major metabolic processes and assessed their clinical relevance. Our metabolic expression subtypes correlated extensively with clinical outcome: subtypes with upregulated carbohydrate, nucleotide, and vitamin/cofactor metabolism most consistently correlated with worse prognosis, whereas subtypes with upregulated lipid metabolism showed the opposite. Metabolic subtypes correlated with diverse somatic drivers but exhibited effects convergent on cancer hallmark pathways and were modulated by highly recurrent master regulators across cancer types. As a proof-of-concept example, we demonstrated that knockdown of SNAI1 or RUNX1—master regulators of carbohydrate metabolic subtypes-modulates metabolic activity and drug sensitivity. Our study provides a system-level view of metabolic heterogeneity within and across cancer types and identifies pathway cross-talk, suggesting related prognostic, therapeutic, and predictive utility