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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.

Understanding the keyhole porosity formation is important in laser powder bed fusion. Here the authors reveal the dynamics of keyhole fluctuation, and collapse that induces bubble formation with three main stages of evolution; growth, shrinkage, and being captured by the solidification front.

Although therapeutically efficacious, ipilimumab can exhibit dose-limiting toxicity that prevents maximal efficacious clinical outcomes and can lead to discontinuation of treatment. We hypothesized that an acidic pH-selective ipilimumab (pH Ipi), which preferentially and reversibly targets the acidic tumor microenvironment over the neutral periphery, may have a more favorable therapeutic index. While ipilimumab has pH-independent CTLA-4 affinity, pH Ipi variants have been engineered to have up to 50-fold enhanced affinity to CTLA-4 at pH 6.0 compared to pH 7.4. In hCTLA-4 knock-in mice, these variants have maintained anti-tumor activity and reduced peripheral activation, a surrogate marker for toxicity. pH-sensitive therapeutic antibodies may be a differentiating paradigm and a novel modality for enhanced tumor targeting and improved safety profiles.

Abstract In recent years there has been an increasing effort in improving the performance of Nb3Sn for high-field applications, in particular for the fabrication of conductors suitable for the realization of the Future Circular Collider (FCC) at CERN. This challenging task has led to the investigation of new routes to advance the high-field pinning properties, the irreversibility and the upper critical fields (H Irr and H c2 , respectively). The effect of hafnium addition to the standard Nb-4Ta alloy has been recently demonstrated to be particularly promising and, in this paper, we investigate the origins of the observed improvements of the superconducting properties. Electron microscopy, Extended X-ray Absorption Fine Structure Spectroscopy (EXAFS) and Atom Probe Tomography (APT) characterization clearly show that, in presence of oxygen, both fine Nb3Sn grains and HfO2 nanoparticles form. Although EXAFS is unable to detect significant amounts of Hf in the A15 structure, APT does indeed reveal some residual intragrain metallic Hf. To investigate the layer properties in more detail, we created a microbridge from a thin lamella extracted by Focused Ion Beam (FIB) and measured the transport properties of Ta-Hf-doped Nb3Sn. H c2 (0) is enhanced to 30.8 T by the introduction of Hf, ~ 1 T higher than those of only Ta-doped Nb3Sn, and, even more importantly the position of the pinning force maximum exceeds 6 T, against the typical ~ 4.5–4.7 T of the only Ta-doped material. These results show that the improvements generated by Hf addition can significantly enhance the high-field performance, bringing Nb3Sn closer to the requirements necessary for FCC realization.

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.

Abstract Elemental type-II superconducting niobium is the material of choice for superconducting radiofrequency cavities used in modern particle accelerators, light sources, detectors, sensors, and quantum computing architecture. An essential challenge to increasing energy efficiency in rf applications is the power dissipation due to residual magnetic field that is trapped during the cool down process due to incomplete magnetic field expulsion. New SRF cavity processing recipes that use surface doping techniques have significantly increased their cryogenic efficiency. However, the performance of SRF Nb accelerators still shows vulnerability to a trapped magnetic field. In this manuscript, we report the observation of a direct link between flux trapping and incomplete flux expulsion with spatial variations in microstructure within the niobium. Fine-grain recrystallized microstructure with an average grain size of 10–50 µm leads to flux trapping even with a lack of dislocation structures in grain interiors. Larger grain sizes beyond 100–400 µm do not lead to preferential flux trapping, as observed directly by magneto-optical imaging. While local magnetic flux variations imaged by magneto-optics provide clarity on a microstructure level, bulk variations are also indicated by variations in pinning force curves with sequential heat treatment studies. The key results indicate that complete control of the niobium microstructure will help produce higher performance superconducting resonators with reduced rf losses1 related to the magnetic flux trapping.

Higher education is starting to embrace its role in promoting student wellbeing and life skills, especially given the concerning levels of poor mental health and uncertainties in the future job market. Yet, many of the published studies evaluating positive educational teaching methods thus far are limited to interventions delivered to small student cohorts and/or imbedded within elective wellbeing courses, and are focussed on developed Western countries. This study addressed this gap by investigating the effectiveness of an institution-wide compulsory course informed by the principles of Seligman’s Wellbeing Theory. The course was delivered at a British university in a developing country in Southeast Asia. It purposefully sought to nurture growth-oriented outcomes (including self-awareness, positive emotions, and personal effectiveness) and was taken by an entire cohort of year one undergraduate students. We tested the effectiveness of the curriculum content and staff coaching style in achieving life skills, and evaluated how these perceptions influenced students’ subjective wellbeing. A convergent mixed-methods design was used with 350 survey respondents and 11 interviewees. Perceived life skills scores showed a 2.5% improvement at the end of the course. Partial Least Squares Structural Equation Modelling tested the predicted relationships between variables. All relationships were statistically significant, but the influence of course design and educators’ style on life skills acquisition (50.8% of the variance) was moderate, while the effect on subjective happiness and life satisfaction (4–5% of the variance) was very weak. Qualitative data indicated that while quantifiable benefits to wellbeing might not be immediate, students did anticipate longer-term benefits for happiness and life satisfaction. This finding suggests that such a novel educational approach is well-received by Asian students and may sow the seeds for future benefit by positively impacting on their skills, behaviours, attitudes, and values. To achieve optimal flourishing at university, we recommend exploring teaching practises that combine positive education with coaching psychology practises.

Cancer stem cells (CSCs) initiate tumor formation and are known to be resistant to chemotherapy. A metabolic alteration in CSCs plays a critical role in stemness and survival. However, the association between mitochondrial energy metabolism and the redox system remains undefined in colon CSCs. In this study, we assessed the role of the Sulfiredoxin-Peroxiredoxin (Srx-Prx) redox system and mitochondrial oxidative phosphorylation (OXPHOS) in maintaining the stemness and survival of colon CSCs. Notably, Srx contributed to the stability of PrxI, PrxII, and PrxIII proteins in colon CSCs. Increased Srx expression promoted the stemness and survival of CSCs and was important for the maintenance of the mitochondrial OXPHOS system. Furthermore, Nrf2 and FoxM1 led to OXPHOS activation and upregulated expression of Srx-Prx redox system-related genes. Therefore, the Nrf2/FoxM1-induced Srx-Prx redox system is a potential therapeutic target for eliminating CSCs in colon cancer.

To prevent oxygen contamination, additive manufacturing (AM) techniques normally operate in an inert gas chamber (GC). An alternative method, useful for large builds and components repair, is the application of localised shielding gas (LSG). The effect of oxygen contamination on Ti6242 during directed energy deposition (DED) AM using an inert GC compared to LSG was investigated by in situ synchrotron x-ray experiments. When processing in LSG mode, the amount of oxygen absorbed from the atmosphere was sufficient to reverse the Marangoni flow leading to an alteration of the molten pool geometry and strongly influencing defect formation. Microstructural analysis reveals that, at high oxygen levels, the commonly developed α' martensitic microstructure was completely suppressed, forming precipitation of a tetra modal microstructure of α phase consisting of globular, primary and secondary lamellae (in colonies) and basketweave structure. These results help elucidate the influence of oxygen contamination in additively manufactured Ti alloys, potentially enabling improved industrial practices for AM of titanium alloy.

Abstract High energy X-ray phase contrast tomography is tremendously beneficial to the study of thick and dense materials with poor attenuation contrast. Recently, the X-ray speckle-based imaging technique has attracted widespread interest because multimodal contrast images can now be retrieved simultaneously using an inexpensive wavefront modulator and a less stringent experimental setup. However, it is time-consuming to perform high resolution phase tomography with the conventional step-scan mode because the accumulated time overhead severely limits the speed of data acquisition for each projection. Although phase information can be extracted from a single speckle image, the spatial resolution is deteriorated due to the use of a large correlation window to track the speckle displacement. Here we report a fast data acquisition strategy utilising a fly-scan mode for near field X-ray speckle-based phase tomography. Compared to the existing step-scan scheme, the data acquisition time can be significantly reduced by more than one order of magnitude without compromising spatial resolution. Furthermore, we have extended the proposed speckle-based fly-scan phase tomography into the previously challenging high X-ray energy region (120 keV). This development opens up opportunities for a wide range of applications where exposure time and radiation dose are critical.

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.

Expression of the checkpoint molecule programmed cell death protein 1 (PD-1) is considered a marker of T cells exhaustion. Here the authors show that CD8T cells isolated from breast cancer patients are perfectly functional despite PD-1 expression while those isolated from melanoma patients are not.

Purpose: This study aimed to explore the associations between dose-volume parameters of localized breast irradiation, longitudinal interleukin-6 soluble receptor (sIL-6R), and leukocyte counts as markers of an immune-mediated response and fatigue as a centrally-driven behavior. Methods and Materials: This prospective cohort study recruited 100 women who were diagnosed with stage 0-IIIa breast cancer, prescribed 40 Gy in 15 fractions over 3 weeks adjuvant radiation therapy, and had no prior or concurrent chemotherapy. Dose-volume parameters were derived from treatment plans and related to serum sIL-6R concentrations, leukocyte counts, and a validated measure of self-reported fatigue at baseline, after 10 and 15 fractions, and 4 weeks after radiation therapy. Results: sIL-6R concertation was significantly higher in patients with a total volume of tissue irradiated within the 50% isodose >2040 cm3 (P = .003). When controlling for body mass index, this result only remained significant after treatment. The volume of liver irradiated within the 10% isodose correlated with the sIL-6R concentration during and after radiation therapy (ρ = .3-.4; P = .03-.007). The 38% of the cohort that was classified as fatigued had a higher mean sIL-6sR concentration at all observation points, but the differences were only statistically significant during radiation therapy: Mean (standard deviation [SD]) after 15 fractions for fatigued patients was 47.6 ng/dL (11.2 SD) versus 41.6 ng/dL (11.4 SD) for nonfatigued patients (P = .01). Cohort leukocyte counts and leukocyte subsets decreased consistently from baseline and the values for the fatigued group were 4% lower at baseline and between 7% and 9% lower during and after treatment compared with those of the nonfatigued group but the differences were not statistically significant. Conclusions: This is the first study to show that localized irradiation induces increased systemic sIL-6R during treatment in participants who reported elevated levels of fatigue before, during, and after treatment. This behavioral response appears to reflect a variation in innate host immunity, which then mediates the cellular and/or psychological stress of radiation therapy.

Additive manufacturing of metals is now widely available, but the interaction of the metal powder with the laser remains unclear. Here, the authors use X-rays to image melt features and pore behaviour during laser melting of powders.