Moving beyond the 'PPG': co-production and inclusion health.

Background: We frequently fail to meaningfully incorporate patient voice in the development of health services, in particular the voices of those who are most disadvantaged.

Aim: To share learning from a co-production project to improve primary care experience for those with multiple disadvantage and lived experience of trauma.

Method: We formed a collective of women (Bridging Gaps).

Improving access to general practice for and with people with severe and multiple disadvantage: a qualitative study.

Background: People with severe and multiple disadvantage (SMD) who experience combinations of homelessness, substance misuse, violence, abuse, and poor mental health have high health needs and poor access to primary care.

Aim: To improve access to general practice for people with SMD by facilitating collaborative service improvement meetings between healthcare staff, people with lived experience of SMD, and those who support them; participants were then interviewed about this work.

Design And Setting: The Bridging Gaps group is a collaboration between healthcare staff, researchers, women with lived experience of SMD, and a charity that supports them in a UK city.

Trauma-informed co-production: Collaborating and combining expertise to improve access to primary care with women with complex needs.

Introduction: Health, social care, charitable and justice sectors are increasingly recognising the need for trauma-informed services that seek to recognise signs of trauma, provide appropriate paths to recovery and ensure that services enable people rather than retraumatise. Foundational to the development of trauma-informed services is collaboration with people with lived experience of trauma. Co-production principles may provide a useful framework for this collaboration, due to their emphasis on lived experience, and intent to address power imbalances and promote equity.

Visceral adipose tissue secretome from early and late-stage oesophageal cancer patients differentially affects effector and regulatory T cells.

Aim: Visceral obesity is a key risk factor in the development of oesophagogastric junctional adenocarcinoma (OGJ), predominantly via generation of systemic low grade inflammation. Obesity-induced inflammation promotes resistance to current standards of care, enhancing tumour cell growth and survival. This study investigates the effect of the visceral adipose tissue secretome from OGJ patients with early versus advanced tumours on T-cell immunity and the role of immune checkpoint blockade in enhancing anti-tumour immunity.

FLOT and CROSS chemotherapy regimens alter the frequency of CD27 and CD69 T cells in oesophagogastric adenocarcinomas: implications for combination with immunotherapy.

Combining immunostimulatory chemotherapies with immunotherapy is an attractive strategy to enhance treatment responses in oesophagogastric junctional adenocarcinoma (OGJ). This study investigates the immunostimulatory properties of FLOT, CROSS and MAGIC chemotherapy regimens in the context of OGJ using in vitro and ex vivo models of the treatment-naïve and post-chemotherapy treated tumour microenvironment. FLOT and CROSS chemotherapy regimens increased surrogate markers of immunogenic cell death (HMGB1 and HLA-DR), whereas the MAGIC treatment regimen decreased HMGB1 and HLA-DR on OGJ cells (markedly for epirubicin).

Chemotherapy regimens induce inhibitory immune checkpoint protein expression on stem-like and senescent-like oesophageal adenocarcinoma cells.

Use of immune checkpoint inhibitors (ICIs) with chemotherapy to enhance responses in oesophageal adenocarcinoma (OAC) is an attractive approach. We identified subpopulations of OAC cells expressing inhibitory immune checkpoint (IC) ligands (PD-L1, PD-L2 and CD160) and receptors (PD-1, TIGIT, TIM-3, LAG-3 and A2aR) in vitro and in ex vivo biopsies. Combination chemotherapy regimens FLOT and CROSS promote a more immune-resistant phenotype through upregulation of IC ligands and receptors on OAC cells in vitro.

Topographical Differences of Infant Mortality in Nepal.

Background Infant mortality is a major problem in Nepal, particularly in the mountainous region of the country. Objective To identify factors that contributes to the high rate of infant mortality in the mountain zone in Nepal. Method Data were derived from the 2011 Nepal Demographic and Health Survey (NDHS).

Clinical and molecular consequences of disease-associated de novo mutations in SATB2.

Purpose: To characterize features associated with de novo mutations affecting SATB2 function in individuals ascertained on the basis of intellectual disability.

Methods: Twenty previously unreported individuals with 19 different SATB2 mutations (11 loss-of-function and 8 missense variants) were studied. Fibroblasts were used to measure mutant protein production.

Reproducibility and relative validity of food group intake in a food frequency questionnaire developed for Nepalese diet.

We developed a food frequency questionnaire (FFQ) designed to measure the dietary practices of adult Nepalese. The present study examined the validity and reproducibility of the FFQ. To evaluate the reproducibility of the FFQ, 116 subjects completed two 115-item FFQ across a four-month interval.

Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR): review of phenotype associated with KIF11 mutations.

Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR) (MIM No.152950) is a rare autosomal dominant condition for which a causative gene has recently been identified. Mutations in the kinesin family member 11 (KIF11) gene have now been described in 16 families worldwide.

Complex rearrangement of the exon 6 genomic region among Opitz G/BBB Syndrome MID1 alterations.

Opitz G/BBB Syndrome (OS) is a multiple congenital anomaly disorder characterized by developmental defects of midline structures. The most relevant clinical signs are ocular hypertelorism, hypospadias, cleft lip and palate, laryngo-tracheo-esophageal abnormalities, imperforate anus, and cardiac defects. Developmental delay, intellectual disability and brain abnormalities are also present.

Assessment of graduate public health education in Nepal and perceived needs of faculty and students.

Background: Despite the large body of evidence suggesting that effective public health infrastructure is vital to improving the health status of populations, many universities in developing countries offer minimal opportunities for graduate training in public health. In Nepal, for example, only two institutions currently offer a graduate public health degree. Both institutions confer only a general Masters in Public Health (MPH), and together produce 30 graduates per year.

The classification and diagnostic algorithm for primary lymphatic dysplasia: an update from 2010 to include molecular findings.

Historically, primary lymphoedema was classified into just three categories depending on the age of onset of swelling; congenital, praecox and tarda. Developments in clinical phenotyping and identification of the genetic cause of some of these conditions have demonstrated that primary lymphoedema is highly heterogenous. In 2010, we introduced a new classification and diagnostic pathway as a clinical and research tool.

Mutation in vascular endothelial growth factor-C, a ligand for vascular endothelial growth factor receptor-3, is associated with autosomal dominant milroy-like primary lymphedema.

Rationale: Mutations in vascular endothelial growth factor (VEGF) receptor-3 (VEGFR3 or FLT4) cause Milroy disease, an autosomal dominant condition that presents with congenital lymphedema. Mutations in VEGFR3 are identified in only 70% of patients with classic Milroy disease, suggesting genetic heterogeneity.

Objective: To investigate the underlying cause in patients with clinical signs resembling Milroy disease in whom sequencing of the coding region of VEGFR3 did not reveal any pathogenic variation.

Recent combined hormonal contraceptives (CHCs) and the risk of thromboembolism and other cardiovascular events in new users.

Background: Combined hormonal contraceptives (CHCs) place women at increased risk of venous thromboembolic events (VTEs) and arterial thrombotic events (ATEs), including acute myocardial infarction and ischemic stroke. There is concern that three recent CHC preparations [drospirenone-containing pills (DRSPs), the norelgestromin-containing transdermal patch (NGMN) and the etonogestrel vaginal ring (ETON)] may place women at even higher risk of thrombosis than other older low-dose CHCs with a known safety profile.

Study Design: All VTEs and all hospitalized ATEs were identified in women, ages 10-55 years, from two integrated health care programs and two state Medicaid programs during the time period covering their new use of DRSP, NGMN, ETON or one of four low-dose estrogen comparator CHCs.

FLT4/VEGFR3 and Milroy disease: novel mutations, a review of published variants and database update.

Milroy disease (MD) is an autosomal dominantly inherited primary lymphedema. In 1998, the gene locus for MD was mapped to 5q35.3 and variants in the VEGFR3 (FLT4) gene, encoding vascular endothelial growth factor receptor 3 (VEGFR3), were identified as being responsible for the majority of MD cases.

Mutations in KIF11 cause autosomal-dominant microcephaly variably associated with congenital lymphedema and chorioretinopathy.

We have identified KIF11 mutations in individuals with syndromic autosomal-dominant microcephaly associated with lymphedema and/or chorioretinopathy. Initial whole-exome sequencing revealed heterozygous KIF11 mutations in three individuals with a combination of microcephaly and lymphedema from a microcephaly-lymphedema-chorioretinal-dysplasia cohort. Subsequent Sanger sequencing of KIF11 in a further 15 unrelated microcephalic probands with lymphedema and/or chorioretinopathy identified additional heterozygous mutations in 12 of them.

ADHD drugs and serious cardiovascular events in children and young adults.

Background: Adverse-event reports from North America have raised concern that the use of drugs for attention deficit-hyperactivity disorder (ADHD) increases the risk of serious cardiovascular events.

Methods: We conducted a retrospective cohort study with automated data from four health plans (Tennessee Medicaid, Washington State Medicaid, Kaiser Permanente California, and OptumInsight Epidemiology), with 1,200,438 children and young adults between the ages of 2 and 24 years and 2,579,104 person-years of follow-up, including 373,667 person-years of current use of ADHD drugs. We identified serious cardiovascular events (sudden cardiac death, acute myocardial infarction, and stroke) from health-plan data and vital records, with end points validated by medical-record review.

Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome).

We report an allelic series of eight mutations in GATA2 underlying Emberger syndrome, an autosomal dominant primary lymphedema associated with a predisposition to acute myeloid leukemia. GATA2 is a transcription factor that plays an essential role in gene regulation during vascular development and hematopoietic differentiation. Our findings indicate that haploinsufficiency of GATA2 underlies primary lymphedema and predisposes to acute myeloid leukemia in this syndrome.

Pierpont syndrome: a collaborative study.

Pierpont syndrome is a multiple congenital anomaly syndrome with learning disability first described in 1998. There are only three patients with Pierpont syndrome who have previously been published in the literature. Details of a series of patients with features of this condition were therefore obtained retrospectively to better characterize its key features.

Rapid identification of mutations in GJC2 in primary lymphoedema using whole exome sequencing combined with linkage analysis with delineation of the phenotype.

Background: Primary lymphoedema describes a chronic, frequently progressive, failure of lymphatic drainage. This disorder is frequently genetic in origin, and a multigenerational family in which eight individuals developed postnatal lymphoedema of all four limbs was ascertained from the joint Lymphoedema/Genetic clinic at St George's Hospital.

Methods: Linkage analysis was used to determine a locus, and exome sequencing was employed to look for causative variants.

Frequency of purchase and associated costs of assistive technology for Washington State Medicaid program enrollees with spina bifida by age.

Background: Assistive technology (AT) is one strategy to mitigate or eliminate barriers to independence for individuals with disabilities, including those with spina bifida (SB). However, little is known about current use and costs of AT for people with SB, including the cost burden to medical insurance payees.

Objective: The aim of this study was to evaluate frequency of AT purchases and their associated costs for individuals with SB covered by the Washington State Medicaid program.

IRF6 Screening of Syndromic and a priori Non-Syndromic Cleft Lip and Palate Patients: Identification of a New Type of Minor VWS Sign.

Van der Woude syndrome (VWS), caused by dominant IRF6 mutation, is the most common cleft syndrome. In 15% of the patients, lip pits are absent and the phenotype mimics isolated clefts. Therefore, we hypothesized that some of the families classified as having non-syndromic inherited cleft lip and palate could have an IRF6 mutation.

Emberger syndrome-primary lymphedema with myelodysplasia: report of seven new cases.

Four reports have been published on an association between acute myeloid leukaemia (AML) and primary lymphedema, with or without congenital deafness. We report seven new cases, including one extended family, confirming this entity as a genetic syndrome. The lymphedema typically presents in one or both lower limbs, before the hematological abnormalities, with onset between infancy and puberty and frequently affecting the genitalia.