Metformin in polycystic ovary syndrome: systematic review and meta-analysis

The original publication may be found at www.bmj.comObjective To assess the effectiveness of metformin in improving clinical and biochemical features of polycystic ovary syndrome. Design Systematic review and meta-analysis. Data sources Randomised controlled trials that investigated the effect of metformin compared with either placebo or no treatment, or compared with an ovulation induction agent. Selection of studies 13 trials were included for analysis, including 543 women with polycystic ovary syndrome that was defined by using biochemical or ultrasound evidence. Main outcome measure Pregnancy and ovulation rates. Secondary outcomes of clinical and biochemical features of polycystic ovary syndrome. Results Meta-analysis showed that metformin is effective in achieving ovulation in women with polycystic ovary syndrome, with odds ratios of 3.88 (95% confidence interval 2.25 to 6.69) for metformin compared with placebo and 4.41 (2.37 to 8.22) for metformin and clomifene compared with clomifene alone. An analysis of pregnancy rates shows a significant treatment effect for metformin and clomifene (odds ratio 4.40, 1.96 to 9.85). Metformin has an effect in reducing fasting insulin concentrations, blood pressure, and low density lipoprotein cholesterol. We found no evidence of any effect on body mass index or waist:hip ratio. Metformin was associated with a higher incidence of nausea, vomiting, and other gastrointestinal disturbance. Conclusions Metformin is an effective treatment for anovulation in women with polycystic ovary syndrome. Its choice as a first line agent seems justified, and there is some evidence of benefit on variables of the metabolic syndrome. No data are available regarding the safety of metformin in long term use in young women and only limited data on its safety in early pregnancy. It should be used as an adjuvant to general lifestyle improvements and not as a replacement for increased exercise and improved diet.Jonathan M Lord, Ingrid H K Flight, Robert J Norma

Long-Term Trends in Phytoplankton Chlorophyll a and Size Structure in the Benguela Upwelling System

This is the final version. Available from American Geophysical Union (AGU) via the DOI in this record.The Benguela Upwelling System (BUS) is among the most productive ecosystems globally, supporting numerous fisheries and ecosystem services in Southern Africa. Sea-viewing Wide Field-of-view Sensor and Moderate-resolution Imaging Spectroradiometer-Aqua chlorophyll a (Chla) concentrations between September 1997 and February 2018 were used to investigate long-term trends in phytoplankton biomass and size structure (microphytoplankton [>20 μm], nanophytoplankton [2–20 μm], and picophytoplankton [<2 μm]) in the Northern Benguela, Southern Benguela (SB), and Agulhas Bank (AB) shelf and open ocean regions of the BUS. Trends in upwelling and correlations with Chla and size structure were examined. Increasing Chla and microphytoplankton trends occurred in the Northern Benguela shelf and open ocean, while decreases were evident on the SB shelf in all seasons. In the SB open ocean, small increases occurred during austral winter, with a decrease in spring. On the AB shelf, increases in Chla and microphytoplankton occurred in summer with decreases during the other seasons. Patterns differed in the AB open ocean, with increases in winter and spring and decreases in summer and autumn. Although R 2 values indicated that linear trends accounted for a reasonable portion of the variance, and most trends were statistically significant, they showed only small changes on the shelf domains and little to no change in the open ocean. Strong correlations between upwelling, Chla, and the size classes were observed, but distinct seasonal differences occurred in each region. This is the first 20-year analysis of phytoplankton biomass and community structure in the BUS and provides a baseline against which future changes can be monitored.NERC National Centre for Earth ObservationSouth African National Research Foundation (NRF)South African Department of Environmental Affair

Full Flight Envelope Direct Thrust Measurement on a Supersonic Aircraft

Direct thrust measurement using strain gages offers advantages over analytically-based thrust calculation methods. For flight test applications, the direct measurement method typically uses a simpler sensor arrangement and minimal data processing compared to analytical techniques, which normally require costly engine modeling and multisensor arrangements throughout the engine. Conversely, direct thrust measurement has historically produced less than desirable accuracy because of difficulty in mounting and calibrating the strain gages and the inability to account for secondary forces that influence the thrust reading at the engine mounts. Consequently, the strain-gage technique has normally been used for simple engine arrangements and primarily in the subsonic speed range. This paper presents the results of a strain gage-based direct thrust-measurement technique developed by the NASA Dryden Flight Research Center and successfully applied to the full flight envelope of an F-15 aircraft powered by two F100-PW-229 turbofan engines. Measurements have been obtained at quasi-steady-state operating conditions at maximum non-augmented and maximum augmented power throughout the altitude range of the vehicle and to a maximum speed of Mach 2.0 and are compared against results from two analytically-based thrust calculation methods. The strain-gage installation and calibration processes are also described

London region atlas of topsoil geochemistry

The London Region Atlas of Topsoil Geochemistry (LRA) is a further step towards understanding the chemical quality of soils in London, following a previous project called London Earth carried out by the British Geological Survey (BGS) (Johnson et al., 2010[1]). The main advantage of the LRA is that it includes soil geochemical data from the counties surrounding London; placing the city within the context of its rural hinterland, allowing assessments of the impact of urbanisation on soil quality. The London Region Atlas of Topsoil Geochemistry is a product derived from the BGS Geochemical Baseline Survey of the Environment (G-BASE[2]) project. The London Region Geochemical Dataset (LRD, n=8400), on which the atlas is based, includes TOPSOIL data from two complementary surveys: i) the urban London Earth (LOND) and ii) the rural South East England (SEEN). The LRA covers the Greater London Authority (GLA) and its outskirts in a rectangular area of 80x62 km. This extends from British National Grid coordinates Easting 490000–570000, and Northing 153000–215000. The urban LOND and the rural SEEN surveys contribute with 6801 and 1599 samples respectively to the LRD. The concentrations of 44 inorganic chemical elements (Al2O3, CaO, Fe2O3, K2O, MgO, MnO, Na2O, P2O5, SiO2, TiO2, Ag, As, Ba, Bi, Br, Cd, Ce, Co, Cr, Cs, Cu, Ga, Ge, Hf, I, La, Mo, Nb, Nd, Ni, Pb, Rb, Sb, Sc, Se, Sn, Sr, Th, U, V, W, Y, Zn and Zr), loss on ignition (LOI) and pH in topsoil are included in the LRA. For each element, a map showing the distribution in topsoil across the atlas area and a one-page sketch of descriptive statistics and graphs are presented. Statistics and graphs for whole dataset (LRD), London urban subset (LOND) and London surroundings rural subset (SEEN), as well as graphs of topsoil element concentrations over each simplified geology unit are shown. The LRD has been used already in a study aiming to detect geogenic (geological) signatures and controls on soil chemistry in the London region (Appleton et al., 2013[3]). It includes maps showing the distribution of Al, Si, La and I (and Th, Ca, Mn, As, Pb and Zr in supplementary material) and it is concluded that the spatial distribution of a range of elements is primarily controlled by the rocks from where soil derives, and that these geogenic patterns are still recognisable inside the urban centre. Other studies have been done that are based on data in the LRD, namely using the LOND subset or part of it. The main focus of these studies was the mercury content (Scheib et al., 2010[4]), the influence of land use on geochemistry (Knights and Scheib, 2011[5]; Lark and Scheib, 2013[6]); the bioaccessibility of pollutants such as As and Pb (Appleton et al., 2012[7]; Appleton et al., 2012[8]; Cave, 2012[9]; Appleton et al., 2013[10]; Cave et al., 2013[11]) and the lability of lead in soils (Mao et al., 2014[12]); the determination of normal background concentrations of contaminants in English soil (Ander et al., 2013[13]) and the contribution of geochemical and other environmental data to the future of the cities (Ludden et al., 2015[14]). The London Region Atlas of Topsoil Geochemistry formally presents detailed information for all chemical elements in the LRD. This information can be easily visualised and elements compared as its production and layout is standardised. Differences in topsoil element concentrations between the centre of the city and its outskirts can be assessed by observing the map and comparing statistics and graphs reported for the LOND and SEEN subsets respectively. This urban/rural contrast is particularly evident for elements such as Pb, Sb, Sn, Cu and Zn, for which mean concentrations in the urban environment are two to three times higher than those observed in the rural environment. This is a typical indicator suite of urban soil pollution reported in several other cities in the UK also (Fordyce et al., 2005[15])

Cost-Effectiveness of Robot-Assisted Radical Cystectomy vs Open Radical Cystectomy for Patients With Bladder Cancer

IMPORTANCE: The value to payers of robot-assisted radical cystectomy with intracorporeal urinary diversion (iRARC) when compared with open radical cystectomy (ORC) for patients with bladder cancer is unclear. OBJECTIVES: To compare the cost-effectiveness of iRARC with that of ORC. DESIGN, SETTING, AND PARTICIPANTS: This economic evaluation used individual patient data from a randomized clinical trial at 9 surgical centers in the United Kingdom. Patients with nonmetastatic bladder cancer were recruited from March 20, 2017, to January 29, 2020. The analysis used a health service perspective and a 90-day time horizon, with supplementary analyses exploring patient benefits up to 1 year. Deterministic and probabilistic sensitivity analyses were undertaken. Data were analyzed from January 13, 2022, to March 10, 2023. INTERVENTIONS: Patients were randomized to receive either iRARC (n = 169) or ORC (n = 169). MAIN OUTCOMES AND MEASURES: Costs of surgery were calculated using surgery timings and equipment costs, with other hospital data based on counts of activity. Quality-adjusted life-years were calculated from European Quality of Life 5-Dimension 5-Level instrument responses. Prespecified subgroup analyses were undertaken based on patient characteristics and type of diversion. RESULTS: A total of 305 patients with available outcome data were included in the analysis, with a mean (SD) age of 68.3 (8.1) years, and of whom 241 (79.0%) were men. Robot-assisted radical cystectomy was associated with statistically significant reductions in admissions to intensive therapy (6.35% [95% CI, 0.42%-12.28%]), and readmissions to hospital (14.56% [95% CI, 5.00%-24.11%]), but increases in theater time (31.35 [95% CI, 13.67-49.02] minutes). The additional cost of iRARC per patient was £1124 (95% CI, -£576 to £2824 [US $1622 (95$831 to $4075)]) with an associated gain in quality-adjusted life-years of 0.01124 (95$144 312) per quality-adjusted life-year gained. Robot-assisted radical cystectomy had a much higher probability of being cost-effective for subgroups defined by age, tumor stage, and performance status. CONCLUSIONS AND RELEVANCE: In this economic evaluation of surgery for patients with bladder cancer, iRARC reduced short-term morbidity and some associated costs. While the resulting cost-effectiveness ratio was in excess of thresholds used by many publicly funded health systems, patient subgroups were identified for which iRARC had a high probability of being cost-effective. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03049410

Cellular Origins of EGFR-Driven Lung Cancer Cells Determine Sensitivity to Therapy

Targeting the epidermal growth factor receptor (EGFR) with tyrosine kinase inhibitors (TKIs) is one of the major precision medicine treatment options for lung adenocarcinoma. Due to common development of drug resistance to first- and second-generation TKIs, third-generation inhibitors, including osimertinib and rociletinib, have been developed. A model of EGFR-driven lung cancer and a method to develop tumors of distinct epigenetic states through 3D organotypic cultures are described here. It is discovered that activation of the EGFR T790M/L858R mutation in lung epithelial cells can drive lung cancers with alveolar or bronchiolar features, which can originate from alveolar type 2 (AT2) cells or bronchioalveolar stem cells, but not basal cells or club cells of the trachea. It is also demonstrated that these clones are able to retain their epigenetic differences through passaging orthotopically in mice and crucially that they have distinct drug vulnerabilities. This work serves as a blueprint for exploring how epigenetics can be used to stratify patients for precision medicine decisions

Propylene glycol inactivates respiratory viruses and prevents airborne transmission

Viruses are vulnerable as they transmit between hosts, and we aimed to exploit this critical window. We found that the ubiquitous, safe, inexpensive and biodegradable small molecule propylene glycol (PG) has robust virucidal activity. Propylene glycol rapidly inactivates a broad range of viruses including influenza A, SARS-CoV-2 and rotavirus and reduces disease burden in mice when administered intranasally at concentrations commonly found in nasal sprays. Most critically, vaporised PG efficiently abolishes influenza A virus and SARS-CoV-2 infectivity within airborne droplets, potently preventing infection at levels well below those tolerated by mammals. We present PG vapour as a first-in-class non-toxic airborne virucide that can prevent transmission of existing and emergent viral pathogens, with clear and immediate implications for public health

The T2K ND280 Off-Axis Pi-Zero Detector

The Pi-Zero detector (P{\O}D) is one of the subdetectors that makes up the off-axis near detector for the Tokai-to-Kamioka (T2K) long baseline neutrino experiment. The primary goal for the P{\O}D is to measure the relevant cross sections for neutrino interactions that generate pi-zero's, especially the cross section for neutral current pi-zero interactions, which are one of the dominant sources of background to the electron neutrino appearance signal in T2K. The P{\O}D is composed of layers of plastic scintillator alternating with water bags and brass sheets or lead sheets and is one of the first detectors to use Multi-Pixel Photon Counters (MPPCs) on a large scale.Comment: 17 pages, submitted to NIM

Epidemiology of Mycobacterium abscessus in England: an observational study

BACKGROUND: Mycobacterium abscessus has emerged as a significant clinical concern following reports that it is readily transmissible in health-care settings between patients with cystic fibrosis. We linked routinely collected whole-genome sequencing and health-care usage data with the aim of investigating the extent to which such transmission explains acquisition in patients with and without cystic fibrosis in England. METHODS: In this retrospective observational study, we analysed consecutive M abscessus whole-genome sequencing data from England (beginning of February, 2015, to Nov 14, 2019) to identify genomically similar isolates. Linkage to a national health-care usage database was used to investigate possible contacts between patients. Multivariable regression analysis was done to investigate factors associated with acquisition of a genomically clustered strain (genomic distance <25 single nucleotide polymorphisms [SNPs]). FINDINGS: 2297 isolates from 906 patients underwent whole-genome sequencing as part of the routine Public Health England diagnostic service. Of 14 genomic clusters containing isolates from ten or more patients, all but one contained patients with cystic fibrosis and patients without cystic fibrosis. Patients with cystic fibrosis were equally likely to have clustered isolates (258 [60%] of 431 patients) as those without cystic fibrosis (322 [63%] of 513 patients; p=0·38). High-density phylogenetic clusters were randomly distributed over a wide geographical area. Most isolates with a closest genetic neighbour consistent with potential transmission had no identifiable relevant epidemiological contacts. Having a clustered isolate was independently associated with increasing age (adjusted odds ratio 1·14 per 10 years, 95% CI 1·04–1·26), but not time spent as an hospital inpatient or outpatient. We identified two sibling pairs with cystic fibrosis with genetically highly divergent isolates and one pair with closely related isolates, and 25 uninfected presumed household contacts with cystic fibrosis. INTERPRETATION: Previously identified widely disseminated dominant clones of M abscessus are not restricted to patients with cystic fibrosis and occur in other chronic respiratory diseases. Although our analysis showed a small number of cases where person-to-person transmission could not be excluded, it did not support this being a major mechanism for M abscessus dissemination at a national level in England. Overall, these data should reassure patients and clinicians that the risk of acquisition from other patients in health-care settings is relatively low and motivate future research efforts to focus on identifying routes of acquisition outside of the cystic fibrosis health-care-associated niche. FUNDING: The National Institute for Health Research, Health Data Research UK, The Wellcome Trust, The Medical Research Council, and Public Health England