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46,XX individuals born with severely masculinized genitals due to congenital adrenal hyperplasia (CAH) who have been assigned male at birth and reared male can successfully establish a male gender identity/role, find employment, marry, function sexually with a female partner, and develop positive mental health status. While there were a few individuals who reportedly did not fare well or who changed gender to female, the majority of those identifying as males appear to have an overall good quality of life. Parental/family support, along with the support of others, appears essential to a positive outcome as a male, or as a female. This paper suggests that serious consideration should be given to male gender assignment and rearing and, in certain situations, is justified. Disorders of sex differentiation teams should inform parents about the option for male assignment and rearing in 46,XX CAH infants with severe genital masculinization, which is a rare condition. To provide this option is concordant with the principles of ethics, transparency and with the Endocrine Society Guidelines and the American Academy of Pediatrics’ policy of fully informed consent.

A rarely reported phenomenon of rapid-tempo puberty in which the physical changes of puberty and testosterone levels increase very rapidly has not been reported outside apart from in two reviews. The resulting rapid advancement of skeletal age causes early completion of growth with shorter adult stature than expected. This appears to be genetic given its occurrence in the present report in two families, one with three brothers, one with two. We also describe potential treatments and found for the youngest that early initiation of standard therapy preserved or reclaimed adult height (AH) potential. The foreshortened AH in this situation involves rapidly advancing puberty resulting from high circulating testosterone levels leading to rapid advance in skeletal age. This was recognized earlier among younger brothers and treatment with gonadotropin-releasing analogues, growth hormone (GH) and/or aromatase inhibitor therapy (AIT) was tried. Two brothers in family A and family B were treated. Case 5 started treatment early enough so his AH was within target height (mid-parental height) range. Cases 2, 3, 4 were tried on GH and/or AIT with outcomes suggesting benefit. The prevalence and mechanism of rapid-tempo puberty requires further study. Furthermore, as illustrated by two of the current cases, this phenomenon may have a heightened prevalence, or at least may occur, in children previously diagnosed with constitutional delay of growth, underscoring the need to be cautious in assurance of a normal AH outcomes in this population, based on data from a single assessment.

IntroductionElective aspects of surgical management of pediatric differences of sex development (DSD) are associated with controversy. We examined North American pediatric urologist and endocrinologist perspectives regarding recommended and existing informed consent elements for written consent documents prior to pediatric genital surgery.MethodsFocus groups with pediatric urologist and endocrinologist members of the Societies for Pediatric Urology (SPU, n=8) or Pediatric Endocrine Society (PES, n=8) were held to identify elements of informed consent for DSD-related urogenital surgery. Elements were subsequently included in web-based surveys in 2003 and 2020 (SPU: n=121 and 143; PES: n=287 and 111, respectively). Participants rated their level of agreement with including each element in informed consent documents. In 2020, participants reported whether documents they use in clinical practice incorporate these elements.ResultsFocus groups identified four elements of informed consent: on-going debate over pediatric genital surgery; potential needs for multiple procedures; possible gender change and surgical reversal; and non-surgical alternatives. Across both years and both specialties, a majority (79% to 98%) endorsed the four elements, with significant between-group differences. Significantly more PES than SPU participants reported not knowing whether specific elements were included in current written informed consent; of those who knew, the majority (66% to 91%) reported inclusion.DiscussionSpecialists agree with including these four elements in written informed consent documents. Endocrinologists are not always familiar with the exact elements included. The degree to which non-surgeon members of the care team should be involved in the written informed consent process is an open question.

Current guidelines for gender assignment for all 46,XX congenital adrenal hyperplasia (CAH) continue to be female. This decision is most challenging for individuals with a 46,XX karyotype born with (CAH) having severely masculinized genitalia (Prader 4 or 5). They may be at significant risk for quality of life (QoL) and psychological health. More outcome information currently exists for such individuals assigned male than female. Most available data for those raised females do not indicate the extent of masculinization at birth, so there are minimal outcome data to compare with those raised males. Gender dissatisfaction among those raised females may be related to the degree of prenatal androgen excess in the brain evidenced by external genital masculinization. Also, additional brain maturation after birth, especially during puberty, is impacted by postnatal androgen excess resulting from inadequate androgen suppression. The purpose of this perspective is to suggest that both female and male assignment be considered. Most who have been raised male at birth have positive adult outcomes. This consideration should occur after discussions with full disclosure to the parents. The lack of more outcome data highlights the need for further information. This perspective also suggests that surgery should be deferred whether assigned female or male at least until gender identity is apparent to preserve the potential for male sexual function and prevent irrevocable loss of sensitive erotic tissue. While the gender fluidity is recognized, it is important to consider potential subsequent need for gender reassignment and extent of masculinization, particularly at the time of gender determination.

Aperiodic discharge of brine at Blood Falls forms a red-tinged fan at the terminus of Taylor Glacier, Antarctica. Samples from this discharge provide an opportunity for mineralogical study at a Martian analogue study site. Environmental samples were collected in the field and analyzed in the laboratory using Fourier transform infrared, Raman, visible to near-infrared, and Mössbauer spectroscopies. Samples were further characterized using microprobe and inductively coupled plasma optical emission spectroscopy for chemistry, and x-ray diffraction, scanning electron microscopy, and transmission electron microscopy for mineralogy, crystallography, and chemistry. The mineralogy of these samples is dominated by the carbonate minerals calcite and aragonite, accompanied by quartz, feldspar, halide, and clay minerals. There is no strong evidence for crystalline iron oxide/hydroxide phases, but compositionally and morphologically diverse iron- and chlorine-rich amorphous nanospheres are found in many of the samples. These results showcase the strengths and weaknesses of different analytical methods and underscore the need for multiple complementary techniques to inform the complicated mineralogy at this locale. These analyses suggest that the red color at Blood Falls arises from oxidation of dissolved Fe2+ in the subglacial fluid that transforms upon exposure to air to form nanospheres of amorphous hydroxylated mixed-valent iron-containing material, with color also influenced by other ions in those structures. Finally, the results provide a comprehensive mineralogical analysis previously missing from the literature for an analogue site with a well-studied sub-ice microbial community. Thus, this mineral assemblage could indicate a habitable environment if found elsewhere in the Solar System.

The multiple factors that determine outcomes for individuals with visible developmental errors and/or atypical development of the reproductive system are not fully understood. This case report of an individual with Bosma arhinia microphthalmia syndrome causing severe facial anomalies and hypogonadotropic hypogonadism is used to highlight factors that impacted his adjustment from childhood through adulthood. Key factors include his temperament, intact cognitive ability, and pragmatic approach for controlling his physical and social environment. His successful adjustment even in the face of significant early life challenges demonstrates that positive outcomes are attainable for individuals with significant developmental errors. His story and experiences with the health-care system offer insight into some factors that may be pertinent to resilience and lifelong adjustment for patients with similar conditions and the importance of continually seeking the patient’s perspective to tailor treatment across the lifespan.

Marine phytoplankton play critical roles in the biogeochemistry of open and coastal oceans. However, the impact that individual species have on an ecosystem-wide scale can strongly depend on the production of cellular compounds, especially those that are climatically active such as dimethylsulfide (DMS). Herein, we use sorting flow cytometry to separate a distinct phytoplankton population from four samples taken along the Patagonian shelf near the Falkland Islands. Morphological, genetic, and biochemical analyses demonstrated that three of the sorted samples were dominated by a bloom of the dinoflagellate Prorocentrum minimum. Cellular quotas of the DMS-precursor dimethylsulfoniopropionate (DMSP) ranged from 1.23–4.11 pg cell−1 in the same population at different sampling stations. Causes of this variability may be due to different growth stages of the P. minimum bloom or changes in other environmental variables. Overall, in situ intracellular DMSP concentrations were lower than what would be expected based on previous, culture-based measurements. We demonstrate the difficulties inherent in sorting individual phytoplankton species from natural samples in order to determine in situ species-specific cellular quotas of important biogeochemical compounds.

The potential impact of elevated sea surface temperature (SST) and pCO2 on algal community structure and particulate dimethylsulfoniopropionate (DMSPp) concentrations in the southeastern Bering Sea was examined using a shipboard “Ecostat” continuous culture system. The ecostat system was used to mimic the conditions projected to exist in the world's oceans by the end of this century (i.e. elevated pCO2 (750 ppm) and elevated SST (ambient + 4°C). Two experiments were conducted using natural phytoplankton assemblages from the high-nutrient low-chlorophyll (HNLC) central basin and from the middle domain of the southeastern continental shelf. At the HNLC site, the relative abundances of haptophytes and pelagophytes were higher and the relative abundance of diatoms lower under “greenhouse” conditions (i.e. combined 750 ppm CO2 and elevated temperature) than control conditions (380 ppm CO2 and ambient temperature). This shift in algal community structure was accompanied by increases in DMSPp (2–3 fold), DMSPp:Chl a (2–3 fold) and DMSP:PON (2 fold). At the continental shelf site, the changes in the relative abundances of haptophytes, pelagophytes and diatoms under “greenhouse” conditions were similar to those observed at the HNLC site, with 2.5 fold increases in DMSPp, 50–100% increases in DMSPp:Chl a and 1.8 fold increases in DMSP:PON. At both locations, changes in community structure and the DMSPp parameters were largely driven by increasing temperature. The observed changes were also consistent with the phytoplankton-DMS-albedo climate feedback mechanism proposed in the Charlson-Lovelock-Andreae-Warren (CLAW) hypothesis.

The Ross Sea is home to some of the largest phytoplankton blooms in the Southern Ocean. Primary production in this system has previously been shown to be iron limited in the summer and periodically iron and vitamin B12 colimited. In this study, we examined trace metal limitation of biological activity in the Ross Sea in the austral spring and considered possible implications for vitamin B12 nutrition. Bottle incubation experiments demonstrated that iron limited phytoplankton growth in the austral spring while B12, cobalt, and zinc did not. This is the first demonstration of iron limitation in a Phaeocystis antarctica-dominated, early season Ross Sea phytoplankton community. The lack of B12 limitation in this location is consistent with previous Ross Sea studies in the austral summer, wherein vitamin additions did not stimulate P. antarctica growth and B12 was limiting only when bacterial abundance was low. Bottle incubation experiments and a bacterial regrowth experiment also revealed that iron addition directly enhanced bacterial growth. B12 uptake measurements in natural water samples and in an iron fertilized bottle incubation demonstrated that bacteria serve not only as a source for vitamin B12, but also as a significant sink, and that iron additions enhanced B12 uptake rates in phytoplankton but not bacteria. Additionally, vitamin uptake rates did not become saturated upon the addition of up to 95 pM B12. A rapid B12 uptake rate was observed after 13 min, which then decreased to a slower constant uptake rate over the next 52 hours. Results from this study highlight the importance of iron availability in limiting early season Ross Sea phytoplankton growth and suggest that rates of vitamin B12 production and consumption may be impacted by iron availability.

Background: The evidence on harms and benefits of e-cigarettes partly concerns whether their use encourages smokers to quit. We addressed this using data from the nationally representative PATH study, with detailed accounting for potential confounding variables. Methods: We considered adults aged 25+. Our original analyses, reported in version 1 of this paper, used data for Waves 1 to 3, separate analyses considering Waves 1 to 2, 2 to 3 and 1 to 3. These related baseline ever e-cigarette use (or e-product use at Wave 2) to quitting at follow-up, adjusting for confounders derived from 55 candidates. Sensitivity analyses omitted ever other product users, linked quitting to current e-cigarette use, and used values of some predictors modified using follow-up data. Additional analyses used data for Waves 1 to 4, separately considering sustained, delayed and temporary quitting during Waves 1 to 3, 2 to 4 and 1 to 4. Sensitivity analyses considered 30-day quitting, restricted attention to smokers attempting to quit, and considered ever smokeless tobacco or snus use. Results: In the original analyses, unadjusted odds ratios (ORs) of quitting smoking for ever e-cigarette use were 1.29 (95% CI 1.01-1.66), 1.52 (1.26-1.83) and 1.47 (1.19-1.82) for the Wave 1 to 2, 2 to 3, and 1 to 3 analyses. These reduced after adjustment, to 1.23 (0.94-1.61), 1.51 (1.24-1.85) and 1.39 (1.11-1.74). Quitting rates remained elevated in users in all sensitivity analyses. The additional analyses found associations of e-cigarette use with sustained, delayed and temporary quitting, associations little affected by considering 30-day quitting, and only slightly reduced restricting attention to quit attempters. Ever use of smokeless tobacco or snus also predicted increased quitting. Conclusions: As does most evidence from clinical trials, other analyses of PATH, and other epidemiological studies, our results suggest using e-cigarettes helps adult smokers to quit.

Introduction ACOSOG-Z0011(Z11) trial showed that axillary node clearance (ANC) may be omitted in women with ≤2 positive nodes undergoing breast conserving surgery (BCS) and whole breast radiotherapy (RT). A confirmatory study is needed to clarify the role of axillary treatment in women with ≤2 macrometastases undergoing BCS and groups that were not included in Z11 for example, mastectomy and those with microscopic extranodal invasion. The primary objective of POsitive Sentinel NOde: adjuvant therapy alone versus adjuvant therapy plus Clearance or axillary radiotherapy (POSNOC) is to evaluate whether for women with breast cancer and 1 or 2 macrometastases, adjuvant therapy alone is non-inferior to adjuvant therapy plus axillary treatment, in terms of 5-year axillary recurrence.Methods and analysis POSNOC is a pragmatic, multicentre, non-inferiority, international trial with participants randomised in a 1:1 ratio. Women are eligible if they have T1/T2, unifocal or multifocal invasive breast cancer, and 1 or 2 macrometastases at sentinel node biopsy, with or without extranodal extension. In the intervention group women receive adjuvant therapy alone, in the standard care group they receive ANC or axillary RT. In both groups women receive adjuvant therapy, according to local guidelines. This includes systemic therapy and, if indicated, RT to breast or chest wall. The UK Radiotherapy Trials Quality Assurance Group manages the in-built radiotherapy quality assurance programme. Primary endpoint is 5-year axillary recurrence. Secondary outcomes are arm morbidity assessed by Lymphoedema and Breast Cancer Questionnaire and QuickDASH questionnaires; quality of life and anxiety as assessed with FACT B+4 and State/Trait Anxiety Inventory questionnaires, respectively; other oncological outcomes; economic evaluation using EQ-5D-5L. Target sample size is 1900. Primary analysis is per protocol. Recruitment started on 1 August 2014 and as of 9 June 2021, 1866 participants have been randomised.Ethics and dissemination Protocol was approved by the National Research Ethics Service Committee East Midlands—Nottingham 2 (REC reference: 13/EM/0459). Results will be submitted for publication in peer-reviewed journals.Trial registration number ISRCTN54765244; NCT0240168Cite Now

Background: Modelling disease risk from e-cigarette use requires knowing how much e-cigarette uptake affects a smoker’s cigarette consumption. From Waves 1-3 of the US PATH study and other evidence, we sought answers to three questions: (Q1) Does consumption differ between dual users and exclusive smokers? (Q2) Does initiating e-cigarettes affect cigarette consumption? (Q3) Is baseline consumption related to later initiation of e-cigarettes? Methods: Consumption data from PATH were corrected for clear recording errors, with e-cigarette use classified as established or every day, and adjustment made for demographics, use of alcohol, drugs and other tobacco products, and age of starting smoking. Searches identified other studies published since 2008, with Q1 answered from cross-sectional studies, and Q2 and Q3 also from prospective studies. Results: (Q1) In PATH, consumption in current every day e-cigarette users was 2-3 cigarettes per day lower in dual users, with no difference seen in established users. From 31 published studies, consumption was no lower in dual users for current or ever e-cigarette users. (Q2) In PATH study consistent decreases in consumption occurred in those becoming every day dual users with increases seen in those reverting to exclusive smoking. Thirteen published studies consistently showed reduced consumption in those becoming dual users. (Q3) Three studies consistently showed greater consumption in smokers subsequently initiating e-cigarettes, but no significant difference was seen for PATH. Conclusions: Assessment is complicated by the few every day e-cigarette users in PATH, and between-study variability in quantifying e-cigarette use and presentation of results. As taking up e-cigarettes is associated with reducing consumption, finding no clear cross-sectional difference between dual users and exclusive smokers suggests smokers taking up e-cigarettes had higher consumption initially, limited evidence supporting this. Given the much lower disease risk of e-cigarettes vs. cigarettes, smokers becoming dual users should somewhat reduce their disease risk.

Background: The evidence on harms and benefits of e-cigarettes partly concerns whether their use encourages smokers to quit. We addressed this using data from the nationally representative PATH study, with detailed accounting for potential confounding variables. Methods: We considered adults aged 25+. Our original analyses, reported in version 1 of this paper, used data for Waves 1 to 3, separate analyses considering Waves 1 to 2, 2 to 3 and 1 to 3. These related baseline ever e-cigarette use (or e-product use at Wave 2) to quitting at follow-up, adjusting for confounders derived from 55 candidates. Sensitivity analyses omitted ever other product users, linked quitting to current e-cigarette use, and used values of some predictors modified using follow-up data. Additional analyses used data for Waves 1 to 4, separately considering sustained, delayed and temporary quitting during Waves 1 to 3, 2 to 4 and 1 to 4. Sensitivity analyses considered 30-day quitting, restricted attention to smokers attempting to quit, and considered ever smokeless tobacco or snus use. Results: In the original analyses, unadjusted odds ratios (ORs) of quitting smoking forever e-cigarette use were 1.29 (95% CI 1.01-1.66), 1.52 (1.26-1.83) and 1.47 (1.19-1.82) for the Wave 1 to 2, 2 to 3, and 1 to 3 analyses. These reduced after adjustment, to 1.23 (0.94-1.61), 1.51 (1.24-1.85) and 1.39 (1.11-1.74). Quitting rates remained elevated in users in all sensitivity analyses. The additional analyses found associations of e-cigarette use with sustained, delayed and temporary quitting, associations little affected by considering 30-day quitting, and only slightly reduced restricting attention to quit attempters. Ever use of smokeless tobacco or snus also predicted increased quitting. Conclusions: As does most evidence from clinical trials, other analyses of PATH, and other epidemiological studies, our results suggest using e-cigarettes helps adult smokers to quit.

Background: Interest exists in whether youth e-cigarette use (“vaping”) increases risk of initiating cigarette smoking. Using Waves 1 and 2 of the US PATH study we previously reported adjustment for vaping propensity using Wave 1 variables explained about 80% of the unadjusted relationship. Here data from Waves 1 to 3 are used to avoid over-adjustment if Wave 1 vaping affected variables recorded then. Methods: Main analyses M1 and M2 concerned Wave 2 never smokers who never vaped by Wave 1, linking Wave 2 vaping to Wave 3 smoking initiation, adjusting for predictors of vaping based on Wave 1 data using differing propensity indices. M3 was similar but derived the index from Wave 2 data. Sensitivity analyses excluded Wave 1 other tobacco product users, included other product use as another predictor, or considered propensity for smoking or any tobacco use, not vaping. Alternative analyses used exact age (not previously available) as a confounder not grouped age, attempted residual confounding adjustment by modifying predictor values using data recorded later, or considered interactions with age. Results: In M1, adjustment removed about half the excess OR (i.e. OR–1), the unadjusted OR, 5.60 (95% CI 4.52-6.93), becoming 3.37 (2.65-4.28), 3.11 (2.47-3.92) or 3.27 (2.57-4.16), depending whether adjustment was for propensity as a continuous variable, as quintiles, or the variables making up the propensity score. Many factors had little effect: using grouped or exact age; considering other products; including interactions; or using predictors of smoking or tobacco use rather than vaping. The clearest conclusion was that analyses avoiding over-adjustment explained about half the excess OR, whereas analyses subject to over-adjustment explained about 80%. Conclusions: Although much of the unadjusted gateway effect results from confounding, we provide stronger evidence than previously of some causal effect of vaping, though doubts still remain about the completeness of adjustment.

Background: Part of the evidence on harms and benefits of e-cigarettes concerns whether using e-cigarettes encourages smokers to quit. With limited results from controlled trials, and weaknesses in much epidemiological data, we addressed this using nationally representative prospective study data, with detailed accounting for factors associated with quitting. Methods: Analyses used data for adults aged 25+ years from Waves 1 to 3 of the US PATH study. Separate analyses concerned follow-up from Waves 1 to 2, 2 to 3 and 1 to 3. The main analyses related baseline ever e-cigarette use (or e-product use at Wave 2) to having quit at follow-up, adjusting for predictors of quitting derived from 55 candidates. Sensitivity analyses omitted adults who had never used other products, linked quitting to current rather than ever e-cigarette use, used modified values of some predictors using later recorded data, or (in Wave 1 to 3 analysis only) also adjusted for quitting by Wave 2. Results: In the main analyses, unadjusted odds ratios (ORs) of quitting for ever e-cigarette use were 1.29 (95% CI 1.01-1.66), 1.52 (1.26-1.83) and 1.47 (1.19-1.82) for the Wave 1 to 2, 2 to 3, and 1 to 3 analyses. These estimates reduced after adjustment, to 1.23 (0.94-1.61), 1.51 (1.24-1.85) and 1.39 (1.11-1.74). The final models, including between six and nine predictors, always included household income, everyday/someday smoking, wanting to smoke after waking and having tried quitting, with other variables included in specific analyses. Quitting rates remained elevated in e-cigarette users in all sensitivity analyses. ORs were increased where other product users were omitted. Adjusted ORs of quitting for current e-cigarette use were 1.41 (1.06-1.89), 1.30 (1.01-1.67) and 1.56 (1.21-2.00). Conclusions: The results suggest e-cigarettes may assist adult smokers to quit, particularly in individuals not using other nicotine products, and who are current e-cigarette users.

Background: Modelling disease risk from e-cigarette use requires knowing how much e-cigarette uptake affects a smoker’s cigarette consumption. From Waves 1-3 of the US PATH study and other evidence, we sought answers to three questions: (Q1) Does consumption differ between dual users and exclusive smokers? (Q2) Does initiating e-cigarettes affect cigarette consumption? (Q3) Is baseline consumption related to later initiation of e-cigarettes? Methods: Consumption data from PATH were corrected for clear recording errors, with e-cigarette use classified as established or every day, and adjustment made for demographics, use of alcohol, drugs and other tobacco products, and age of starting smoking. Searches identified other studies published since 2008, with Q1 answered from cross-sectional studies, and Q2 and Q3 also from prospective studies. Results: (Q1) In PATH, consumption in current every day e-cigarette users was 2-3 cigarettes per day lower in dual users, with no difference seen in established users. From 31 published studies, consumption was no lower in dual users for current or ever e-cigarette users. (Q2) In PATH study consistent decreases in consumption occurred in those becoming every day dual users with increases seen in those reverting to exclusive smoking. Thirteen published studies consistently showed reduced consumption in those becoming dual users. (Q3) Three studies consistently showed greater consumption in smokers subsequently initiating e-cigarettes, but no significant difference was seen for PATH. Conc lusions: Assessment is complicated by the few every day e-cigarette users in PATH, and between-study variability in quantifying e-cigarette use and presentation of results. As taking up e-cigarettes is associated with reducing consumption, finding no clear cross-sectional difference between dual users and exclusive smokers suggests smokers taking up e-cigarettes had higher consumption initially, limited evidence supporting this. Given the much lower disease risk of e-cigarettes vs. cigarettes, smokers becoming dual users should somewhat reduce their disease risk.

Background: Interest exists in whether youth e-cigarette use (“vaping”) increases risk of initiating cigarette smoking. Using Waves 1 and 2 of the US PATH study we reported that adjustment for vaping propensity using Wave 1 variables explained about 80% of the unadjusted relationship. Here we use data from Waves 1 to 3 to avoid over-adjustment if Wave 1 vaping affected variables recorded then. Methods: Our main analysis M1 concerned Wave 2 never smokers who never vaped by Wave 1, linking Wave 2 vaping to Wave 3 smoking initiation, adjusting for Wave 1 predictors. We conducted sensitivity analyses that: excluded Wave 1 other tobacco product users; included other product use as an extra predictor; or considered propensity for smoking or any tobacco use, rather than vaping. We also conducted analyses that: adjusted for propensity as derived originally; ignored Wave 1 data; used exact age (not previously available) as a confounder rather than grouped age; attempted residual confounding adjustment by modifying predictor values using data recorded later; or considered interactions with age. Results: In M1, adjustment removed about half the excess OR (i.e. OR–1), the unadjusted OR, 5.60 (95% CI 4.52-6.93), becoming 3.37 (2.65-4.28), 3.11 (2.47-3.92) or 3.27 (2.57-4.16), depending whether adjustment was for propensity as a continuous variable, as quintiles, or for the variables making up the propensity score. Many factors had little effect: using grouped or exact age; considering other products; including interactions; or using predictors of smoking or tobacco use rather than vaping. The clearest conclusion was that analyses avoiding over-adjustment explained about half the excess OR, whereas analyses subject to over-adjustment explained about 80%. Conclusions: Although much of the unadjusted gateway effect results from confounding, we provide stronger evidence than previously of some causal effect of vaping, though some doubts still remain about the completeness of adjustment.

Background: Some evidence suggests environmental tobacco smoke (ETS) might cause chronic obstructive pulmonary disease (COPD). We reviewed available epidemiological data in never smokers. Methods: We identified epidemiological studies providing estimates of relative risk (RR) with 95% confidence interval (CI) for various ETS exposure indices. Confounder-adjusted RRs for COPD were extracted, or derived using standard methods. Meta-analyses were conducted for each exposure index, with tests for heterogeneity and publication bias. For the main index (spouse ever smoked or nearest equivalent), analyses investigated variation in RR by location, publication period, study type, sex, diagnosis, study size, confounder adjustment, never smoker definition, and exposure index definition. Results: Twenty-eight relevant studies were identified; nine European or Middle Eastern, nine Asian, eight American and two from multiple countries. Five were prospective, seven case-control and 16 cross-sectional. The COPD definition involved death or hospitalisation in seven studies, GOLD stage 1+ criteria in twelve, and other definitions in nine. For the main index, random-effects meta-analysis of 33 heterogeneous (p Conclusions: Although the evidence strongly suggests that ETS increases COPD, study weaknesses and absence of well-designed large studies preclude reliable effect estimation. More definitive evidence is required.

Background: Anthracycline- and taxane-based regimens form the mainstay of chemotherapy treatment in metastatic breast cancer. In patients who develop resistance to these agents, management options are limited and there is no standard of care. Thus, investigation into other chemotherapeutic agents is warranted. Methods: In this non-randomised prospective trial, patients with human epidermal growth factor 2 (HER-2)-negative locally advanced or metastatic breast cancer that were anthracycline- and taxane-resistant were treated with carboplatin at a dose equivalent to an area under the concentration–time curve of 4.5 mg/ml.min on day 1 and gemcitabine 1500 mg/m 2 on day 2 of every 2-week cycle. The primary end point was overall response rate. Results: A total of five patients were enrolled prior to early termination due to difficulty in recruitment. The principal reason for recruitment difficulty was mandating anthracycline and taxane pre-treatment and HER-2 negativity. One patient had a complete response, one had a partial response, one had stable disease and two had progressive disease. Grade 4 neutropenia occurred in two patients. Conclusions: In this patient population, inclusion criteria that are too stringent may result in difficulties reaching recruitment targets. Carboplatin in combination with gemcitabine appears to be a safe option for treatment of patients with locally advanced or metastatic breast cancer. Due to the small sample size, it is not possible to draw firm conclusions regarding efficacy from this trial. Registration: EU Clinical Trials Register ID 2005-005164-83, registered on 10 April 2006.

Background: Some evidence suggests environmental tobacco smoke (ETS) might cause chronic obstructive pulmonary disease (COPD). We reviewed available epidemiological data in never smokers. Methods: We identified epidemiological studies providing estimates of relative risk (RR) with 95% confidence interval (CI) for various ETS exposure indices. Confounder-adjusted RRs for COPD were extracted, or derived using standard methods. Meta-analyses were conducted for each exposure index, with tests for heterogeneity and publication bias. For the main index (spouse ever smoked or nearest equivalent), analyses investigated variation in RR by location, publication period, study type, sex, diagnosis, study size, confounder adjustment, never smoker definition, and exposure index definition. Results: Twenty-eight relevant studies were identified; nine European or Middle Eastern, nine Asian, eight American and two from multiple countries. Five were prospective, seven case-control and 16 cross-sectional. The COPD definition involved death or hospitalisation in seven studies, GOLD stage 1+ criteria in twelve, and other definitions in nine. For the main index, random-effects meta-analysis of 33 heterogeneous (p Conclusions: Although the evidence suggests ETS increases COPD, study weaknesses and absence of well-designed large studies preclude reliable estimation of the effect. More definitive evidence is required.

Background: To present up-to-date meta-analyses of evidence from Japan relating smoking to major smoking-related diseases. Methods: We restricted attention to lung cancer, chronic obstructive pulmonary disease (COPD), ischemic heart disease (IHD) and stroke, considering relative risks (RRs) for current and ex-smokers relative to never smokers. Evidence by amount smoked and time quit was also considered. For IHD and stroke only, studies had to provide age-adjusted RRs, with age-specific results considered. For each disease we extended earlier published databases to include more recent studies. Meta-analyses were conducted, with random-effects RRs and tests of heterogeneity presented. Results: Of 40 studies, 26 reported results for lung cancer and 7 to 9 for each other disease. For current smoking, RRs (95%CIs) were lung cancer 3.59 (3.25-3.96), COPD 3.57 (2.72-4.70), IHD 2.21 (1.96-2.50) and stroke 1.40 (1.25-1.57). Ex-smoking RRs were lower. Data for lung cancer and IHD showed a clear tendency for RRs to rise with increasing amount smoked and decrease with increasing time quit. Dose-response data were unavailable for COPD and unclear for stroke, where the association was weaker. Conclusions: Compared to studies in other Asian and Western countries, current smoking RRs were quite similar for IHD and stroke. The comparison is not clear for COPD, where the Japanese data, mainly from cross-sectional studies, is limited. For lung cancer, the RRs are similar to those in other Asian countries, but substantially lower than in Western countries. Explanations for this are unclear, but less accurate reporting of smoking by Japanese may contribute to the difference.

Background: Some evidence suggests environmental tobacco smoke (ETS) might cause chronic obstructive pulmonary disease (COPD). We reviewed available epidemiological data in never smokers. Methods: We identified epidemiological studies providing estimates of relative risk (RR) with 95% confidence interval (CI) for various ETS exposure indices. Confounder-adjusted RRs for COPD were extracted, or derived using standard methods. Meta-analyses were conducted for each exposure index, with tests for heterogeneity and publication bias. For the main index (spouse ever smoked or nearest equivalent), analyses investigated variation in RR by location, publication period, study type, sex, diagnosis, study size, confounder adjustment, never smoker definition, and exposure index definition. Results: Twenty-eight relevant studies were identified; nine European or Middle Eastern, nine Asian, eight American and two from multiple countries. Five were prospective, seven case-control and 16 cross-sectional. The COPD definition involved death or hospitalisation in seven studies, GOLD stage 1+ criteria in twelve, and other definitions in nine. For the main index, random-effects meta-analysis of 33 heterogeneous (p Conclusions: Although the evidence suggests ETS increases COPD, study weaknesses and absence of well-designed large studies precludes reliable inference of causality. More definitive evidence is required.