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During the present century, about 1 billion people will die of smoking-related conditions if current trends persist; a substantial proportion due to cardiovascular disease.1 In today's Lancet, Koon Teo and colleagues2 provide a wealth of new data documenting the causal link between smoking and acute myocardial infarction in over 12000 cases from around the world. Rastogi and colleagues reported a relative risk of 8-1 for myocardial infarction from smoking more than ten beedies a day in men in India.1 Extending the data on beedies, Teo and colleagues found that sheesha, tobacco smoked through a water pipe, has effects similar to other forms of tobacco.

Inflammation is known to be a major component of atherosclerosis, and cigarette smoking is known to induce a systemic inflammatory response. We therefore, investigated possible gene-environment interactions between various inflammation-related gene polymorphisms and cigarette smoking on the risk of myocardial infarction (MI) in the Physician's Health Study (PHS), a cohort of initially healthy middle-aged men. We used a nested case-control design consisting of 522 MI cases and 2,089 controls derived from PHS. Eleven inflammatory polymorphisms were studied using logistic regression analysis: eotaxin (ala23thr), intercellular adhesion molecule 1 (gly241arg), interleukin-4 (582C>T), interleukin-4 receptor (ile75val, gln576arg), interleukin-6 (-174G>C), interleukin-10 (-571C>A), P-selectin (val640leu, thr756pro, ser330asn), and vascular cell adhesion molecule 1 (-1594T>C). Interactions of smoking with all the three modes of inheritance (additive, dominant, recessive) were tested. Statistically significant (P<0.05) interaction terms were found for interleukin-4 receptor (ile75val), with odds ratios of 0.52 (95%CI:0.29-0.95) for Ile-Val and 0.34 (95%CI:0.14-0.83) for Val-Val, compared to the wildtype Ile-Ile; for interleukin-6 (-174G>C) with odds ratios of 2.16 (1.14-4.09) for GC and 0.81 (0.31-2.12) for CC, compared to the wildtype GG; and for P-selectin (ser330asn) with odds ratios of 0.48 (0.24-0.95) for Ser-Asn and 1.08 (0.29-3.93) for Asn-Asn, compared to the wildtype Ser-Ser, with these effects occurring only among the smokers. These data raise the possibility of interaction between the smoking status and certain inflammatory polymorphisms on the risk of MI in men. However, these results should be interpreted with caution due to the potential for false positive results that can arise from analyses with multiple comparisons.

Sohrab Shah, Samuel Aparicio and colleagues analyze whole genomes and single cells from ovarian cancers in the peritoneal cavity to establish patterns of disease spread. They determine the clonal relationships between multiple tumor sites and characterize the migratory potential of genomically diverse clones. We performed phylogenetic analysis of high-grade serous ovarian cancers (68 samples from seven patients), identifying constituent clones and quantifying their relative abundances at multiple intraperitoneal sites. Through whole-genome and single-nucleus sequencing, we identified evolutionary features including mutation loss, convergence of the structural genome and temporal activation of mutational processes that patterned clonal progression. We then determined the precise clonal mixtures comprising each tumor sample. The majority of sites were clonally pure or composed of clones from a single phylogenetic clade. However, each patient contained at least one site composed of polyphyletic clones. Five patients exhibited monoclonal and unidirectional seeding from the ovary to intraperitoneal sites, and two patients demonstrated polyclonal spread and reseeding. Our findings indicate that at least two distinct modes of intraperitoneal spread operate in clonal dissemination and highlight the distribution of migratory potential over clonal populations comprising high-grade serous ovarian cancers.

We present an overview of the National Science Foundation’s Daniel K. Inouye Solar Telescope (DKIST), its instruments, and support facilities. The 4 m aperture DKIST provides the highest-resolution observations of the Sun ever achieved. The large aperture of DKIST combined with state-of-the-art instrumentation provide the sensitivity to measure the vector magnetic field in the chromosphere and in the faint corona, i.e. for the first time with DKIST we will be able to measure and study the most important free-energy source in the outer solar atmosphere – the coronal magnetic field. Over its operational lifetime DKIST will advance our knowledge of fundamental astronomical processes, including highly dynamic solar eruptions that are at the source of space-weather events that impact our technological society. Design and construction of DKIST took over two decades. DKIST implements a fast (f/2), off-axis Gregorian optical design. The maximum available field-of-view is 5 arcmin. A complex thermal-control system was implemented in order to remove at prime focus the majority of the 13 kW collected by the primary mirror and to keep optical surfaces and structures at ambient temperature, thus avoiding self-induced local seeing. A high-order adaptive-optics system with 1600 actuators corrects atmospheric seeing enabling diffraction limited imaging and spectroscopy. Five instruments, four of which are polarimeters, provide powerful diagnostic capability over a broad wavelength range covering the visible, near-infrared, and mid-infrared spectrum. New polarization-calibration strategies were developed to achieve the stringent polarization accuracy requirement of 5×10 −4 . Instruments can be combined and operated simultaneously in order to obtain a maximum of observational information. Observing time on DKIST is allocated through an open, merit-based proposal process. DKIST will be operated primarily in “service mode” and is expected to on average produce 3 PB of raw data per year. A newly developed data center located at the NSO Headquarters in Boulder will initially serve fully calibrated data to the international users community. Higher-level data products, such as physical parameters obtained from inversions of spectro-polarimetric data will be added as resources allow.

Arterial spin labeling (ASL) at ultra‑high field MRI at 7 T provides enhanced signal‑to‑noise ratio and spatial resolution, enabling more sensitive functional imaging. The objective of this study was to investigate regional perfusion changes and their relationship to perceived pain during sustained capsaicin‑induced nociception. Twenty‑seven healthy right‑handed volunteers (mean age 31.9 ± 4.1 years; 12 female) underwent two MRI sessions: at baseline and during capsaicin-induced tonic pain. Participants rated pain and were classified as responders or weak responders. MRI included T1‑weighted structural imaging, resting BOLD‑fMRI and 3D turbo‑FLASH pCASL. Images were segmented, normalized to MNI space, and CBF maps calculated. Mean CBF was extracted from gray matter and 10 predefined pain‑matrix regions. Voxel‑wise linear regression analyzed correlations between CBF and pain ratings, with false discovery rate correction. Group differences between responders and weak responders were assessed voxel‑wise. Global gray matter CBF was unchanged between baseline and capsaicin conditions and did not differ by responder status. However, CBF increased significantly with pain in a network including the contralateral insular cortex, primary and secondary somatosensory cortices, supplementary motor area, bilateral anterior cingulate cortex, right dorsolateral prefrontal cortex and contralateral thalamus. Average perfusion in these regions rose by 8-15% and correlated strongly with pain scores (r ≈ 0.66; p < 0.001). Weak responders showed higher CBF in right fusiform and bilateral primary visual cortices and lower CBF in bilateral superior frontal gyrus compared with responders. In conclusion, pCASL at 7 T enables quantitative mapping of brain perfusion during sustained pain. Sustained capsaicin stimulation increases regional CBF in a distributed cortico‑subcortical network, with perfusion changes closely tracking perceived pain intensity. These findings demonstrate that tonic nociception engages broader associative networks and highlight the utility of ultra‑high field ASL for studying chronic pain mechanisms.

BackgroundThe standard treatment for non-metastatic castration sensitive prostate cancer (nmCSPC) is androgen deprivation therapy (ADT) or surveillance. This study evaluated the potential synergy of immunotherapy and enzalutamide (without ADT) in nmCSPC. In addition, the immunologic impact of enzalutamide was also evaluated in men with normal testosterone.MethodsPatients with rising prostate-specific antigen (PSA) after definitive therapy, normal testosterone and no radiographic metastasis were randomized to enzalutamide for 3 months with/without PROSTVAC for 6 months. Thereafter, patients could be retreated with another 3 month course of enzalutamide when PSA returned to baseline. Immune profiles were evaluated in these patients.ResultsThirty-eight patients were randomized with a median PSA=4.38 ng/dL and PSA doubling time=4.1 months. No difference was observed between the two groups for PSA growth kinetics, but PSA responses to enzalutamide were noteworthy regardless of PROSTVAC. The median PSA decline after short-course enzalutamide without ADT/testosterone lowering therapy was 99% in both courses. The median time to PSA recovery to baseline after each 84-day course of enzalutamide was also noteworthy because of the duration of response after enzalutamide was discontinued. After the first and second 3 month cycle of enzalutamide, PSA recovery to baseline took a median 224 (range 84–1246) and 189 days (78–400), respectively. The most common adverse events related to the enzalutamide were grade 1 fatigue (71%) and grade 1 breast pain/nipple tenderness (81%). The only grade 3 toxicity was aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation in two patients. Enzalutamide was independently associated with immune changes, increasing natural killer cells, naïve-T cells, and decreasing myeloid-derived suppressor cells.ConclusionsThree months of enzalutamide without ADT induced substantial PSA control beyond the treatment period and was repeatable, perhaps representing an alternative to intermittent ADT in nmCSPC. In addition, enzalutamide was associated with immune changes that could be relevant as future immune combinations are developed.Trail registration numberclinicaltrials.gov (NCT01875250).

Background Telemedical interventions have been shown to reduce mortality and morbidity and improve the quality of life of chronic heart failure (CHF) patients. During the Covid-19 pandemic remote coaching gained further importance; however, it is not clear if Covid-19-specific telecoaching has a long-lasting impact on behaviour change. Methods Patients were pre-existing participants in a combined tele-monitoring and telecoaching programme for CHF. A total of 419 patients were assessed with a standardised questionnaire immediately before and three weeks after a COVID-19-specific telecoaching in April 2020, as well as eight months later. The aim of the study was to observe changes in knowledge and behaviour regarding COVID-19 risk reduction measures, number of medical contacts and self-perceived health risk over time following the telecoaching module. Results After telecoaching, patients spontaneously recalled significantly more COVID-19-specific risk reduction measures rising from an average of 2.1 items prior to coaching to 2.5 at short- and long-term follow-up ( p  = 0.0002). The number of self-reported medical contacts were significantly lower at short-term than at long-term follow-up (30% vs. 42%, p  = 0.0060 family doctor, 5% vs. 12%, p  = 0.0014 hospital). CHF patients perceived themselves as low risk for a severe COVID-19 infection, and this perception did not change after telecoaching. No difference in social isolation or concern over time were noted. Conclusions Our longitudinal observational study suggests a possible effect of a single COVID-19-specific telecoaching module on knowledge about the disease and complying with risk reduction measures, which seems to persist over time. These results should be interpreted with caution in the context of increasing public awareness and public health campaigns.

We use two cases of design activism to examine designers' forms of positionality—or, the relations that enter into the formation of design interventions and the ways that a designer's situation affects the matter of those designs. We argue, by recognizing the stakes of their interventions and by mapping their contingencies, designers call into question the promise of their reforms—opening opportunities for responsive revision.

Background Germany hosts a large number of refugees from war-affected countries. The integration of refugees, in particular young refugees from the Middle East, is one of the major current social challenges in Germany. Mental disorders, first of all post-traumatic stress disorder (PTSD) that results from war experiences, are common among young refugees and interfere with quality of life as well as functional integration. Evidence regarding effective treatment options for this population is scarce. In this trial, we aim to evaluate the pragmatic, short-term psychotherapy Narrative Exposure Therapy for Children (KIDNET) for the treatment of young refugees in Germany. Methods In a rater-blinded, multi-center, randomized-controlled trial, KIDNET is compared to treatment as usual (TAU) within the general health care system. A total number of 80 young refugees who fulfill the diagnostic criteria of PTSD will be randomized to either KIDNET or TAU. Diagnostic interviews will take place at baseline before treatment as well as 6 and 12 months thereafter. They will assess exposure to traumatic events, PTSD and comorbid symptoms, as well as parameters of integration. Discussion The results of this study should provide evidence regarding effective treatment options for young refugees in Germany, a population that has been understudied and received only limited access to mental health care so far. Next to the effects of treatment on mental health outcomes, integration parameters will be investigated. Therefore, this study should provide broad insights into treatment options for young refugees and their potential implications on successful integration. Trial registration German Clinical Trials Register (Deutsches Register Klinischer Studien; DRKS), ID: DRKS00017222. Registered on 15 May 2019.