Combining phenotypic and genomic data to improve prediction of binary traits.

Plant breeders want to develop cultivars that outperform existing genotypes. Some characteristics (here 'main traits') of these cultivars are categorical and difficult to measure directly. It is important to predict the main trait of newly developed genotypes accurately. In addition to marker data, breeding programs often have information on secondary traits (or 'phenotypes') that are easy to measure. Our goal is to improve prediction of main traits with interpretable relations by combining the two data types using variable selection techniques. However, the genomic characteristics can overwhelm the set of secondary traits, so a standard technique may fail to select any phenotypic variables. We develop a new statistical technique that ensures appropriate representation from both the secondary traits and the genotypic variables for optimal prediction. When two data types (markers and secondary traits) are available, we achieve improved prediction of a binary trait by two steps that are designed to ensure that a significant intrinsic effect of a phenotype is incorporated in the relation before accounting for extra effects of genotypes. First, we sparsely regress the secondary traits on the markers and replace the secondary traits by their residuals to obtain the effects of phenotypic variables as adjusted by the genotypic variables. Then, we develop a sparse logistic classifier using the markers and residuals so that the adjusted phenotypes may be selected first to avoid being overwhelmed by the genotypic variables due to their numerical advantage. This classifier uses forward selection aided by a penalty term and can be computed effectively by a technique called the one-pass method. It compares favorably with other classifiers on simulated and real data.

Opportunities to accelerate immunization progress in middle-income countries.

There has been increasing recognition of vaccine access challenges in middle-income countries and the need for increased action, particularly in countries that are not eligible for or have transitioned out of Gavi, the Vaccine Alliance support. These countries' immunization systems are more vulnerable than ever as the COVID-19 pandemic exacerbates existing programme challenges, increasing the risk of delayed vaccine introductions, backsliding immunization coverage rates, and increased coverage inequity. The potential health and equity impact of improving immunization outcomes in middle-income countries is substantial. Modelling suggests that the introduction of pneumococcal conjugate vaccine and vaccines for rotavirus and human papillomavirus in this set of Gavi-transitioned and non-Gavieligible middle-income countries in 2020 could have saved an estimated 70,000 lives if 90 % coverage had been reached. Further, increasing coverage for already-introduced vaccines to 90 % could have saved an additional estimated 16,000 lives. Over the past decade, stakeholders have made considerable efforts to identify immunization challenges in middle-income countries as documented in the 2015 SAGE-endorsed Shared Partner Middle-Income Country Strategy. In the coming decade, new global platforms like Gavi 5.0 and the Immunization Agenda 2030 provide opportunities to align on MIC strategies and provide coordinated global support to middle-income countries. The international COVID-19 pandemic response has the potential to lay the foundation for long term support beyond the scope of COVID-19 to non-Gavi eligible middle-income countries. Meanwhile regional mechanisms to address immunization barriers in middle-income countries have grown in number and strength, offering sustainable platforms for cross-country collaboration and the provision of tailored technical support. To ensure that these opportunities are successfully acted upon and that middle-income countries achieve the Immunization Agenda 2030 goals, comprehensive, multi-stakeholder consultations were conducted to identify areas of action with the greatest potential to accelerate immunization progress. Stakeholders should work together to put these findings, highlighted in this paper, into action, adapting their approaches to specific country contexts and learning from and building on existing efforts.

Amplification of pulsed light with arbitrary frequency chirps on nanosecond timescales.

We have developed a system for producing amplified pulses of frequency-chirped light at 780 nm on nanosecond timescales. The system starts with tunable cw laser light and employs a pair of fiber-based phase modulators, a semiconductor optical amplifier, and a tapered amplifier to achieve chirp rates exceeding 3 GHz/10 ns and peak powers greater than 1 W. Driving the modulators with an arbitrary waveform generator enables arbitrary chirp shapes, such as two-frequency linear chirps. We overcome the optical power limitations of the modulators by duty cycling and avoid unseeded operation of the tapered amplifier by multiplexing the chirped pulses with "dummy" light from a separate diode laser.

Discovery of LYC-55716: A Potent, Selective, and Orally Bioavailable Retinoic Acid Receptor-Related Orphan Receptor-γ (RORγ) Agonist for Use in Treating Cancer.

Retinoic acid receptor-related orphan receptor γ (RORc, RORγ, or NR1F3) is the nuclear receptor master transcription factor that drives the function and development of IL-17-producing T helper cells (Th17), cytotoxic T cells (Tc17), and subsets of innate lymphoid cells. Activation of RORγ+ T cells in the tumor microenvironment is hypothesized to render immune infiltrates more effective at countering tumor growth. To test this hypothesis, a family of benzoxazines was optimized to provide LYC-55716 (37c), a potent, selective, and orally bioavailable small-molecule RORγ agonist. LYC-55716 decreases tumor growth and enhances survival in preclinical tumor models and was nominated as a clinical development candidate for evaluation in patients with solid tumors.

Intellectual property and access to medicines: mapping public attitudes toward pharmaceuticals during the United States-Mexico-Canada Agreement (USMCA) negotiation process.

BACKGROUND: Transparency and accountability are essential components at all stages of the trade negotiation process. This study evaluates the extent to which these principles were upheld in the United States' public consultation process during the negotiation of the United States-Mexico-Canada Agreement (USMCA), with respect to public comments about the pharmaceutical sector and access to medicines. RESULTS: The public consultation process occurred before the start of official negotiations and was overseen by the Office of the United States Trade Representative (USTR). It included both written comments and oral testimony about US trade negotiation objectives. Of the written comments that specifically discussed issues relating to pharmaceuticals, the majority were submitted by private individuals, members of the pharmaceutical industry, and civil society organizations. Nearly all comments submitted by non-industry groups indicated that access to medicines was a priority issue in the renegotiated agreement, with specific reference to price affordability. By contrast, more than 50% of submissions received from members or affiliates of the pharmaceutical industry advocated for strengthened pharmaceutical intellectual property rights, greater regulatory data protections, or both. This study reveals mixed outcomes with respect to the level of transparency achieved in the US trade negotiation process. Though input from the public at-large was actively solicited, the extent to which these comments were considered in the content of the final agreement is unclear. A preliminary comparison of the analyzed comments with the USTR's final negotiating objectives and the final text of the USMCA shows that several provisions that were advanced exclusively by the pharmaceutical industry and ultimately adopted in the final agreement were opposed by the majority of non-industry stakeholders. CONCLUSIONS: Negotiators could increase public transparency when choosing to advance one competing trade objective over another by actively providing the public with clear rationales for their negotiation positions, as well as details on how public comments are taken into account to form these rationales. Without greater clarity on these aspects, the public consultation process risks appearing to serve as a cursory government mechanism, lacking in accountability and undermining public trust in both the trade negotiation process and its outcomes.

EIA effectiveness in Vietnam: key stakeholder perceptions.

In line with its rapidly transforming economy, thousands of development proposals undergo Environmental Impact Assessment (EIA) in Vietnam each year. Since its inception in 1993, Vietnam's EIA system has undergone numerous amendments via a suite of legislative reforms to the Law on Environmental Protection (LEP) and its associated Circulars and Decrees, a testament to the Government's will to improve environmental performance. Here we evaluate the effectiveness of Vietnam's EIA system through a unique empirical study focusing on those engaged in the EIA system undertaken in Hanoi in 2016 comprising 20 semi-structured interviews with respondents from government, NGOs, academia, and industry. By evaluating the effectiveness of the EIA system in Vietnam from the stakeholder perspective, this paper aims to identify where, how, and why the EIA system is effective or otherwise. Stakeholders vary in their perceptions of the system. Those external to it identified several inhibiting characteristics. Results suggest that like other developing countries and jurisdictions, Vietnam's EIA procedural performance falls short of EIA goals. Criticisms of discordant dual planning law and environmental management laws, fragmented decision making, conflicts of interest in appraisal committee appointments, and information deprivation that impedes public participation suggest that like other developing countries and jurisdictions, Vietnam's EIA performance, in practice, faces several challenges that potentially undermine its role in environmental protection.

Basal ganglia calcification in hypoparathyroidism and pseudohypoparathyroidism: local and systemic metabolic mechanisms.

BACKGROUND: Hypoparathyroidism and pseudohypoparathyroidism are rare disorders of mineral metabolism which may be associated with soft tissue calcification in the basal ganglia in the brain, and occasionally the skin and other tissues. The basal ganglia are the most common sites of calcification in the central nervous system in these disorders, and were first associated with this manifestation in a report from the Mayo Clinic in 1939. The reasons why the basal ganglia are a common site of soft tissue calcification in these rare disorders has been a matter of investigation for many years. FINDINGS: Due to recent increased understanding of phosphate transport and new insights gained from mRNA expression in the basal ganglia, the pathophysiology of basal ganglia calcification (BGC) is now clearer. There is evidence that the absence of parathyroid hormone in hypoparathyroidism may play a direct role, but this is clearly not the case in pseudohypoparathyroidism, which is associated with increased parathyroid hormone levels. Maintaining the calcium/phosphorus ratio as close to normal as possible, and maintaining normal serum phosphate levels, may help mitigate the progression of BGC. There is no evidence of regression of BGC with conventional treatment, and long-term data with adjunctive or replacement therapy with parathyroid hormone or its analogues are not yet available. PURPOSE OF THE REVIEW: This review will focus on the pathophysiology of BGC in hypoparathyroidism and pseudohypoparathyroidism, and review the proposed pathophysiologic mechanisms, as well as the clinical implications of BGC on patient quality of life.

Biomechanical Computed Tomography analysis (BCT) for clinical assessment of osteoporosis.

The surgeon general of the USA defines osteoporosis as "a skeletal disorder characterized by compromised bone strength, predisposing to an increased risk of fracture." Measuring bone strength, Biomechanical Computed Tomography analysis (BCT), namely, finite element analysis of a patient's clinical-resolution computed tomography (CT) scan, is now available in the USA as a Medicare screening benefit for osteoporosis diagnostic testing. Helping to address under-diagnosis of osteoporosis, BCT can be applied "opportunistically" to most existing CT scans that include the spine or hip regions and were previously obtained for an unrelated medical indication. For the BCT test, no modifications are required to standard clinical CT imaging protocols. The analysis provides measurements of bone strength as well as a dual-energy X-ray absorptiometry (DXA)-equivalent bone mineral density (BMD) T-score at the hip and a volumetric BMD of trabecular bone at the spine. Based on both the bone strength and BMD measurements, a physician can identify osteoporosis and assess fracture risk (high, increased, not increased), without needing confirmation by DXA. To help introduce BCT to clinicians and health care professionals, we describe in this review the currently available clinical implementation of the test (VirtuOst), its application for managing patients, and the underlying supporting evidence; we also discuss its main limitations and how its results can be interpreted clinically. Together, this body of evidence supports BCT as an accurate and convenient diagnostic test for osteoporosis in both sexes, particularly when used opportunistically for patients already with CT. Biomechanical Computed Tomography analysis (BCT) uses a patient's CT scan to measure both bone strength and bone mineral density at the hip or spine. Performing at least as well as DXA for both diagnosing osteoporosis and assessing fracture risk, BCT is particularly well-suited to "opportunistic" use for the patient without a recent DXA who is undergoing or has previously undergone CT testing (including hip or spine regions) for an unrelated medical condition.

Angiostrongylus cantonensis and the giant African snail ­ threat or not?

Objective: Angiostrongylus cantonensis or the rat lungworm can cause eosinophilic meningitis in humans. The Giant African snail has been reported to be a suitable intermediate host for this parasite. As the population of Giant African snails has recently exploded, there is an increased risk of transmission of this helminths to humans residing in this country. Therefore the objective of this study is to detect the presence of the rat lungworm in the Giant African Snails in Trinidad by conventional polymerase chain reaction (PCR). Design and Methodology: A total of 178 Giant African snails were collected from ten different locations throughout Trinidad. DNA was extracted from 25 mg of the mantle of each Giant African snail using the DNeasy® PoweSoil® Kit. Conventional PCR was performed using the primers AngioF1 and AngioR1 to amplify a 1,134bp fragment of the 18S rRNA gene of Angiostrongylus spp. The PCR reactions and conditions were are adapted from Qvarnstrom et al in 2007(1). Results: Six of the DNA extracted samples were positive for Angiostrongylus spp. by conventional PCR. Conclusion: Giant African snails in Trinidad are a suitable intermediate host for the rat lungworm and can increase transmission of these helminths to humans. Therefore Angiostrongylus cantonensis infection should be considered to be a differential for eosinophilic meningitis in humans.

Impact of somatic molecular profiling on clinical trial outcomes in rare epithelial gynecologic cancer patients.

OBJECTIVES: Conducting clinical trials in rare malignancies is challenging due to the limited number of patients and differences in biologic behavior. We investigated the feasibility and clinical utility of using genomic profiling for rare gynecologic malignancies. METHODS: Rare epithelial gynecologic cancer patients were analyzed for somatic variants through an institutional molecular profiling program using the Sequenom MassArray platform or the TruSeq Amplicon Cancer Panel on the MiSeq platform. Clinical trial outcomes by RECIST 1.1, and time on treatment were evaluated. RESULTS: From March 2012 to November 2015, 767 gynecologic patients were enrolled and 194 (27%) were classified as rare epithelial malignancies. At least one somatic mutation was identified in 72% of patients, most commonly in TP53 (39%), KRAS (28%) and PIK3CA (27%). A total of 14% of patients were treated on genotype-matched trials. There were no significant differences in overall response rate between genotype-matched versus unmatched trials, nor in median time on treatment between genotype trials and the immediate prior systemic standard treatment. Among 13 evaluable Low Grade Serous ovarian cancer patients treated on genotype-matched trials with MEK inhibitor-based targeted combinations, there were four partial responses. CONCLUSIONS: Somatic molecular profiling is feasible and enables the identification of patients with rare gynecologic cancers who are candidates for genotype-matched clinical trials. Genotype-matched trials, predominantly MEK-based combinations in KRAS and/or NRAS mutant Low Grade Serous ovarian cancer patients, and genotype-unmatched trials, have shown potential clinical activity. Prospective trials with integrated genotyping are warranted to assess the clinical utility of next generation sequencing tests as a standard clinical application in rare malignancies.

Developing the latest framework to measure and incentivise pharmaceutical industry contributions to health research and development.

Major pharmaceutical companies contribute important expertise to health research and development (R&D), particularly in their ability to develop and bring pharmaceuticals to market. The Access to Medicine Index evaluates how 20 of the world's largest pharmaceutical companies are directing R&D efforts towards the needs of people living in low- and middle-income countries. In dissemination of its findings, the Index stimulates pharmaceutical companies to expand R&D activities in this direction. The Index methodology is reviewed every 2 years, most recently for the 2018 Index, to ensure their R&D activity is benchmarked against current health R&D priorities as defined by the global health community. The review is based on consensus-building processes involving global health stakeholders. In the latest review, two main changes to the methodology were made that will further deepen the Index's analysis of (1) how far companies' R&D activity aligns with global health priorities; and (2) whether companies make plans to ensure resulting innovations reach populations in need globally. These changes will be applied in the 2018 Access to Medicine Index. Importantly, the methodology review process highlighted the need for further prioritisation from the global health community, in particular to emphasise to innovators which product innovations are needed most critically to address the burden of non-communicable diseases in low- and middle-income countries. Should such prioritisations be developed, the Index can play an important role in tracking and stimulating company contributions towards them.

Defining the global health system and systematically mapping its network of actors.

BACKGROUND: The global health system has faced significant expansion over the past few decades, including continued increase in both the number and diversity of actors operating within it. However, without a stronger understanding of what the global health system encompasses, coordination of actors and resources to address today's global health challenges will not be possible. METHODS: This study presents a conceptually sound and operational definition of the global health system. Importantly, this definition can be applied in practice to facilitate analysis of the system. The study tested the analytical helpfulness of this definition through a network mapping exercise, whereby the interconnected nature of websites representing actors in the global health system was studied. RESULTS: Using a systematic methodology and related search functions, 203 global health actors were identified, representing the largest and most transparent list of its kind to date. Identified global health actors were characterized and the structure of their social network revealed intriguing patterns in relationships among actors. CONCLUSIONS: These findings provide a foundation for future inquiries into the global health system's structure and dynamics that are critical if we are to better coordinate system activities and ensure successful response to our most pressing global health challenges.

Prognostic Significance of Human Papilloma Virus and p16 Expression in Patients with Vulvar Squamous Cell Carcinoma who Received Radiotherapy.

AIMS: Human papilloma virus (HPV) has been identified as an aetiological agent in a subset of patients with vulvar squamous cell carcinoma (VSCC). The prognostic role of HPV status in VSCC patients treated with radiotherapy has not yet been determined. We investigated the associations between HPV, p16 and clinical outcome in these women. MATERIALS AND METHODS: Patients undergoing potentially curative radiation treatment for VSCC at a single institution from 2000 to 2009 were retrospectively identified. Those who received definitive or peri-operative radiotherapy as part of treatment, and who had available pathological specimens, were included for analysis. HPV infection was detected using Roche Linear array hybridisation and p16 by immunohistochemistry. The locoregional relapse (LRR) rate was estimated using a cumulative incidence function to account for competing risks. Disease-free survival (DFS) and overall survival were analysed using the Kaplan-Meier method. The median follow-up was 4.9 years. RESULTS: Forty patients were suitable for analysis, with a median age of 69.5 years. HPV was detected in 14/40 (35%) patients, HPV16 being the most common serotype (79%). Patients with HPV-positive tumours had lower 5 year LRR compared with those with HPV-negative tumours (14.3% versus 79.3%, Gray test P = 0.003). Tumour p16 positivity was also associated with lower 5 year LRR (15.4% versus 81.2%, Gray test P = 0.002). Patients with p16-positive tumours had higher 5 year DFS compared with those with p16-negative tumours (62% versus 7%, Log-rank test P = 0.02). CONCLUSIONS: We have identified a favourable prognostic group in VSCC, with p16-positive patients showing improved outcomes. p16 has the potential to be a predictive marker allowing the identification of women more likely to have a favourable response to radiotherapy.

Cardiovascular, obstetric and neonatal outcomes in women with previous fontan repair.

OBJECTIVES: To determine cardiovascular, obstetric and neonatal outcomes of pregnancies in women who have a Fontan circulation. METHODS: A retrospective case note review of all women with a Fontan circulation who attended the joint obstetric cardiac antenatal clinic at St Mary's Hospital, Manchester (UK) between 2004 and 2016 was performed. RESULTS: In total, there were 19 pregnancies in 9 women with a history of Fontan repair. 23 women with univentricular physiology attended in this time period. 10 pregnancies (53%) resulted in live births; 1 in a stillbirth at 31 weeks gestation and 8 in miscarriage. Cardiovascular complications occurred in 2 pregnancies (11%). There were no thrombotic events, arrhythmias, myocardial infarction, or endocarditis in the antenatal or postnatal period. Obstetric complications included miscarriage (26% first trimester, 16% second trimester), along with premature delivery (24-36+6) (80%) and fetal growth restriction (70%). The majority of women were delivered by caesarean section (60%). CONCLUSIONS: Women who become pregnant following a Fontan repair carry an increased risk of cardiovascular complications. Fetal and neonatal complication rates are high and emphasize the importance of thorough, multidisciplinary, pre-conceptual assessment and counseling to allow patients to make informed decisions regarding future pregnancy.

Association of the serotonin transporter-linked polymorphic region genotype with lower bone mineral density.

The serotonin transporter-linked polymorphic region (5-HTTLPR) of the serotonin transporter gene (SLC6A4) S allele is linked to pathogenesis of depression and slower response to selective serotonin reuptake inhibitors (SSRIs); depression and SSRIs are independently associated with bone loss. We aimed to determine whether 5-HTTLPR was associated with bone loss. This cross-sectional study included psychiatric patients with both 5-HTTLPR analysis and bone mineral density (BMD) assessment (hip and spine Z-scores if age <50 years and T-scores if ⩾50 years). BMD association with 5-HTTLPR was evaluated under models with additive allele effects and dominant S allele effects using linear regression models. Patients were stratified by age (<50 and ⩾50 years) and sex. Of 3016 patients with 5-HTTLPR genotyping, 239 had BMD assessments. Among the younger patients, the S allele was associated with lower Z-scores at the hip (P=0.002, dominant S allele effects; P=0.004, additive allele effects) and spine (P=0.0006, dominant S allele effects; P=0.01, additive allele effects). In sex-stratified analyses, the association of the S allele with lower BMD in the younger patients was also significant in the subset of women (P⩽0.003 for both hip and spine BMD under the additive allele effect model). In the small group of men younger than 50 years, the S allele was marginally associated with higher spine BMD (P=0.05). BMD T-scores were not associated with 5-HTTLPR genotypes in patients 50 years or older. The 5-HTTLPR variants may modify serotonin effects on bone with sex-specific effects.

Genotype-matched treatment for patients with advanced type I epithelial ovarian cancer (EOC).

BACKGROUND: Genomic alterations that activate the MAPK signaling pathway frequently occur in Type I Epithelial Ovarian Cancers (EOCs). We evaluated therapeutic response outcomes in patients with type I EOC treated with genotype-matched therapy on clinical trials enrolled in a prospective molecular profiling program. MATERIAL AND METHODS: Formalin fixed paraffin embedded tumor tissues were prospectively screened for genomic alterations using MALDI-ToF mass-spectrometry platform or targeted sequencing using the Illumina MiSeq TruSeq Amplicon Cancer Panel. Treatment outcomes on genotype-matched trials were retrospectively reviewed using RECIST version 1.1 and Gynecological Cancer Intergroup CA125 related-response criteria RESULTS: 55 patients with type I EOC underwent molecular profiling, 41 (75%) low grade serous (LGS), 9 (16%) clear cell (CC), and 5 (9%) mucinous (MC) histologies. Thirty-five patients (64%) were found to have ≥1 somatic mutations: 23 KRAS, 6 NRAS, 5 PIK3CA, 2 PTEN, 1 BRAF, 1 AKT, 1 TP53, and 1 CTNNB1. Fifteen patients were subsequently enrolled in genotype-matched phase I or II trials, including 14 patients with KRAS/NRAS mutations treated with MEK inhibitor targeted combinations. Among 14 RECIST evaluable patients, there were 7 partial responses (PR), 7 stable disease (SD) and 1 disease progression (PD). CA125 responses were observed in 10/10 evaluable KRAS/NRAS mutant patients treated with MEK inhibitor combinations CONCLUSIONS: Genotyping and targeted sequencing of Type I EOCs frequently identifies actionable mutations. Matched treatment with MEK-based combination therapy in KRAS and/or NRAS mutant type I EOC patients is an active therapeutic strategy.

Palliative home parenteral nutrition: Clinical service evaluation and identifying potential prognostic factors to assist with patient selection.

BACKGROUND AND AIMS: Home parenteral nutrition (HPN) for palliation has little evidence supporting existing guidance. Patient selection remains challenging. We aimed to evaluate use of palliative HPN in our service against ESPEN guidance, and to identify potential prognostic indicators. METHODS: Palliative care patients commenced on HPN were identified. Medical notes, computer records and HPN database were accessed to identify patient demographics, primary diagnosis and aetiology of intestinal failure, blood test results potentially associated with prognosis (eGFR, albumin, CRP, Hb), presence of ascites, and PN duration. By dichotomising blood results Kaplan-Meier survival plots were derived to identify potential associations with survival. RESULTS: From the HPN database of 111 patients, 20 (18%) were identified as palliative. Six were male (30%), median age (interquartile range (IQR)) 56.4 (51.5-66.8) years. Four patients commenced palliative HPN between 2000 and 2006, while 2007-2013 there were 16. The median number (IQR) of nights on HPN was 85 (19-352). The most common indication was gastro-intestinal obstruction (n = 13, 65%) and short bowel syndrome following palliative surgical resection (n = 4, 20%). Kaplan-Meier survival plots identified worse prognosis on HPN if the presenting albumin was ≤30 g/L p = 0.016. CONCLUSION: The use of HPN in palliative care is increasing. Current patient selection meets with ESPEN guidance with respect to aetiology of intestinal failure and length of survival on PN. We suggest that a low albumin (not a marker of malnutrition) may help to predict those who are likely to survive less long on palliative HPN. A multi-centre prospective study, also examining quality of life would help define improved guidance.

Pregnancy outcomes in women with mechanical prosthetic heart valves: a prospective descriptive population based study using the United Kingdom Obstetric Surveillance System (UKOSS) data collection system.

OBJECTIVE: To describe the incidence of mechanical prosthetic heart valves (MPHV) in pregnancy in the UK; rates of maternal and fetal complications in this group of women, and whether these vary with the anticoagulation used during pregnancy. DESIGN: Prospective descriptive population-based study. SETTING: All consultant-led maternity units in the UK. POPULATION: All women with an MPHV who were pregnant between 1 February 2013 and 31 January 2015. METHODS: Collection and analysis of anonymous data relating to pregnancy management and outcome, using the UKOSS notification and data collection system. MAIN OUTCOME MEASURES: Maternal death, serious maternal morbidity, poor fetal outcome. RESULTS: Data were obtained for 58 women giving an estimated incidence of 3.7 (95% CI 2.7-4.7) per 100 000 maternities. There were five maternal deaths (9%); a further 24 (41%) suffered serious maternal morbidity. There was a poor fetal outcome from 26 (47%) pregnancies. Only 16 (28%) women had a good maternal and good fetal outcome. Low-molecular-weight heparin (LMWH) was used throughout pregnancy by 71% of women. Of these, 83% required rapid dose escalation in the first trimester. Monitoring regimens lacked consistency. CONCLUSIONS: This study has estimated the incidence of MPHV in pregnant women in the UK. It includes the largest cohort managed with LMWH throughout pregnancy reported to date. It demonstrates a high rate of maternal death, and serious maternal and fetal morbidity. Women with MPHVs, and their clinicians need to appreciate the significant maternal and fetal risks involved in pregnancy. Care should be concentrated in specialist centres. TWEETABLE ABSTRACT: High rates of poor maternal and fetal outcomes in pregnant women with mechanical prosthetic heart valves.

Primary hyperparathyroidism: review and recommendations on evaluation, diagnosis, and management. A Canadian and international consensus.

The purpose of this review is to assess the most recent evidence in the management of primary hyperparathyroidism (PHPT) and provide updated recommendations for its evaluation, diagnosis and treatment. A Medline search of "Hyperparathyroidism. Primary" was conducted and the literature with the highest levels of evidence were reviewed and used to formulate recommendations. PHPT is a common endocrine disorder usually discovered by routine biochemical screening. PHPT is defined as hypercalcemia with increased or inappropriately normal plasma parathyroid hormone (PTH). It is most commonly seen after the age of 50 years, with women predominating by three to fourfold. In countries with routine multichannel screening, PHPT is identified earlier and may be asymptomatic. Where biochemical testing is not routine, PHPT is more likely to present with skeletal complications, or nephrolithiasis. Parathyroidectomy (PTx) is indicated for those with symptomatic disease. For asymptomatic patients, recent guidelines have recommended criteria for surgery, however PTx can also be considered in those who do not meet criteria, and prefer surgery. Non-surgical therapies are available when surgery is not appropriate. This review presents the current state of the art in the diagnosis and management of PHPT and updates the Canadian Position paper on PHPT. An overview of the impact of PHPT on the skeleton and other target organs is presented with international consensus. Differences in the international presentation of this condition are also summarized.