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Background & Aims: Tacrolimus has been associated with recurrence of primary biliary cholangitis (PBC) after liver transplantation (LT), which in turn may reduce survival. This study aimed to assess the association between the type of calcineurin inhibitor used and long-term outcomes following LT in patients with PBC. Methods: Survival analyses were used to assess the association between immunosuppressive drugs and graft or patient survival among adult patients with PBC in the European Liver Transplant Registry. Patients who received a donation after brain death graft between 1990 and 2021 with at least 1 year of event-free follow-up were included. Results: In total, 3,175 patients with PBC were followed for a median duration of 11.4 years (IQR 5.9–17.9) after LT. Tacrolimus (Tac) was registered in 2,056 (64.8%) and cyclosporin in 819 (25.8%) patients. Following adjustment for recipient age, recipient sex, donor age, and year of LT, Tac was not associated with higher risk of graft loss (adjusted hazard ratio [aHR] 1.07, 95% CI 0.92-1.25, p = 0.402) or death (aHR 1.06, 95% CI 0.90-1.24, p = 0.473) over cyclosporin. In this model, maintenance mycophenolate mofetil (MMF) was associated with a lower risk of graft loss (aHR 0.72, 95% CI 0.60-0.87, p

To understand and describe neurotoxicity mechanistically, we must first understand the processes and responses that occur within neuronal cell systems after the administration of a chemical. The dataset we present is a collection of experimental results from the literature that comprises various neurotoxic endpoints in human-derived in vitro models, allowing for easy data analysis. Currently available and free databases such as the EPA's ToxCast, which focuses on forecasting toxic health risks, are created by collecting reports on cytotoxicity testing and creating mathematical fits that could help predict the effects of a given chemical on various types of cells. We, in contrast, provide a smaller, raw, and heterogeneous dataset created solely of results on human-derived cell models that not only summarises the cytotoxic effects of certain substances but also creates a possibility for analysing the significance of the experimental set-up for the prediction of outcome.

Several lines of preclinical evidence indicate that combining PI3K and CDK4/6 inhibitors may further enhance the efficacy of hormonal therapy by overcoming de novo and acquired resistance to PI3K and CDK4/6 blockade. We evaluated the combination of abemaciclib, letrozole and LY3023414 (an orally available, selective inhibitor of the class I PI3K isoforms and mTORC1/2) in recurrent endometrial cancer (EC). This study was terminated prematurely after 5 patients initiated protocol therapy due to discontinuation of further development of LY3023414. We report our findings from these patients, including one with recurrent endometrioid EC with AKT1, CTNNB1 and ESR1 hotspot mutations who had previously progressed through letrozole/everolimus and achieved a partial response to letrozole/abemaciclib/LY3023414.

Summary: The study investigates the interplay of neutrophils and natural-killer cells (NK) in mediating osseoresorption during infection of molar-incisor-pattern-periodontitis (MIPP). Human neutrophils from periodontally healthy and MIPP patients were inoculated with the periopathogen Aggregatibacter-actinomycetemcomitans (JP2) and their supernatants were exposed to NK to study their function and osteoclastogenesis promotion. A mouse MIPP model was used to compare disease progression following NK versus neutrophils depletion. The exposure of primary NK to supernatants of neutrophils inoculated with JP2 led to NK cell arrest and activation with enhanced osteoprotegerin expression. Incubation of monocytes with NK led to osteoclastogenesis, whereas NK that were pre-exposed to healthy neutrophil supernatant showed reduced osteoclastogenesis. In mice, NK depletion led to the similar bone phenotype as the neutrophil’s depletion highlighting their role on osseoprotection. The present study portrays a key crosstalk between neutrophils and NK cells during JP2 infection as a central mechanism that regulates bone loss.

Introduction: Infra-red (IR) and visible light (VL) based systems developed for transmission of information about physical quantities (e.g. humidity, temperature) out from closed areas, cannot be effectively employed in case of specific conditions in a targeted environment (because of fog or vapor for example). Objectives: In this work, we introduce a concept of wireless short-range transmitter and receiver to sense physical quantities, for instance temperature, with slow variation. The proposed concept is able to transmit analog-based information from isolated environments (e.g. aquariums or environments for plant growing) with high immunity against vapor and fog that limits standard optical (laser, IR band) methods of communication. Methods: In this work, a new concept of short range radiofrequency (RF) communication device consisting of transmitting and receiving parts build from active devices fabricated in 0.35 μm I3T25 3.3 V CMOS process and ferrite antennas is selected. RF part uses medium-wave propagation within 10 mm distance at frequency 700 kHz. Such an approach offers minimal path loss of the radiated energy of a signal and low-gain amplification required for restoration of similar levels as available at the transmitting side. Results: The processing of base-band signals of simple (sine wave) and complex (electrocardiogram) character was verified experimentally through the system. Application example of temperature monitoring in a closed environment, based on a temperature sensor (thermistor), verifies operationability in temperature range from 10 °C up to 50 °C. Conclusion: Compared to state-of-the-art solution, the presented concept has several advantages, for instance: less complexity; using of simpler type of modulation and demodulation; lower power consumption and significantly reduced issues caused by an environment with special transmission conditions (e.g. fog and vapor). The obtained results are in good agreement with expectations. Among others, the presented system brings beneficial performances for similar applications targeting on monitoring of low-frequency or slowly varying signals.

Standard-of-care immunotherapy for non–muscle-invasive bladder cancer (NMIBC) with intravesical Bacillus Calmettte-Guérin (BCG) is associated with adverse events (AEs), disease recurrence/progression, and supply shortages. Preclinical data have shown that intravesical instillation of Ty21a/Vivotif, the oral vaccine against typhoid fever, may be an effective and safer alternative to BCG. We assessed the safety of intravesical Ty21a in NMIBC. For ethical reasons, patients with low- or intermediate-risk NMIBC not requiring BCG immunotherapy were enrolled. To determine the maximum tolerated dose, escalating doses of Ty21a/Vivotif were intravesically instilled in three patients once a week for 4 wk in phase 1a. In phase 1b, ten patients received the selected dose (1 × 108 CFU) once a week for 6 wk, as for standard BCG therapy. At this dose, all patients completed their treatment. Most patients experienced minor systemic AEs, while half reported mild local bladder AEs. AEs only occurred after one or two instillations for 40% of the patients. Ty21a bacteria were only recovered in three out of 72 urinary samples at 1 wk after instillation. Intravesical Ty21a might be well tolerated with no cumulative side effects, no fever >39 °C, and lower risk of bacterial persistence than with BCG. Ty21a treatment thus warrants clinical trials to explore its safety and antitumor efficacy in high-risk NMIBC. This trial is registered on ClinicalTrials.gov as NCT03421236. Patient summary: We examined the safety of a new intra-bladder immunotherapy for non–muscle-invasive bladder cancer as an alternative to the standard BCG treatment. Our data show that the Ty21a vaccine might be well tolerated. Further studies are needed to determine the safety and antitumor efficacy of this treatment.

Background & Aims: Management of combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is not well-defined. Therefore, we evaluated the management of cHCC-CCA using an online hospital-wide multicentre survey sent to expert centres. Methods: A survey was sent to members of the European Network for the Study of Cholangiocarcinoma (ENS-CCA) and the International Cholangiocarcinoma Research Network (ICRN), in July 2021. To capture the respondents’ contemporary decision-making process, a hypothetical case study with different tumour size and number combinations was embedded. Results: Of 155 surveys obtained, 87 (56%) were completed in full and included for analysis. Respondents represented Europe (68%), North America (20%), Asia (11%), and South America (1%) and included surgeons (46%), oncologists (29%), and hepatologists/gastroenterologists (25%). Two-thirds of the respondents included at least one new patient with cHCC-CCA per year. Liver resection was reported as the most likely treatment for a single cHCC-CCA lesion of 2.0–6.0 cm (range: 73–93%) and for two lesions, one up to 6 cm and a second well-defined lesion of 2.0 cm (range: 60–66%). Nonetheless, marked interdisciplinary differences were noted. Surgeons mainly adhered to resection if technically feasible, whereas up to half of the hepatologists/gastroenterologists and oncologists switched to alternative treatment options with increasing tumour burden. Fifty-one (59%) clinicians considered liver transplantation as an option for patients with cHCC-CCA, with the Milan criteria defining the upper limit of inclusion. Overall, well-defined cHCC-CCA treatment policies were lacking and management was most often dependent on local expertise. Conclusions: Liver resection is considered the first-line treatment of cHCC-CCA, with many clinicians supporting liver transplantation within limits. Marked interdisciplinary differences were reported, depending on local expertise. These findings stress the need for a well-defined multicentre prospective trial comparing treatments, including liver transplantation, to optimise the therapeutic management of cHCC-CCA. Impact and implications: Because the treatment of combined hepatocellular-cholangiocarcinoma (cHCC-CCA), a rare form of liver cancer, is currently not well-defined, we evaluated the contemporary treatment of this rare tumour type through an online survey sent to expert centres around the world. Based on the responses from 87 clinicians (46% surgeons, 29% oncologists, 25% hepatologists/gastroenterologists), representing four continents and 25 different countries, we found that liver resection is considered the first-line treatment of cHCC-CCA, with many clinicians supporting liver transplantation within limits. Nonetheless, marked differences in treatment decisions were reported among the different specialties (surgeon vs. oncologist vs. hepatologist/gastroenterologist), highlighting the urgent need for a standardisation of therapeutic strategies for patients with cHCC-CCA.

The paper presents the collection of physicochemical parameters of bisphenol A (BPA) and its sulfate (BPAS) and glucuronide (BPAG) conjugates, accompanied by data characterizing their absorption, distribution, metabolism and excretion (ADME) behavior following oral administration of BPA. The data were collected from open literature sources and publicly available databases. Additionally, data calculated by using the MarvinSketch 18.30.0 software or predicted by relevant QSAR models built in Simcyp® Simulator were also used. All data were analysed and are fit for purpose if necessary to ensure a reliable prediction of pharmacokinetics of BPA and its conjugates. The data selection process and reasoning for fitting is provided to allow critical assessment and to ensure data transparency. Finally, the sensitivity analysis was performed to assess the influence of the selected parameters on the PBPK model predictions.

Background: Buprenorphine treatment has been associated with reduced non-prescribed opioid use and opioid related overdose (OD). We evaluated initial outcomes of rapid induction onto extended-release injectable buprenorphine (BUP-XR) within 7 days of emergency department presentation for unintentional OD. Methods: Between February 2019-February 2021, N = 19 patients with opioid use disorder received buprenorphine/naloxone (4/1 mg), followed by BUP-XR (300 mg) at induction and continued BUP-XR outpatient for 6 months. Primary outcomes included adverse events, repeat OD, and death. Results: For patients who received at least one dose of BUP-XR, there were no treatment related serious adverse events or symptoms of precipitated withdrawal. In addition, there were no repeat visits for ODs or deaths within 6 months of the initial OD. Discussion: These preliminary findings support the need for larger controlled clinical trials to examine the safety and efficacy of rapid induction of BUP-XR in patients with opioid use disorder at high risk of opioid OD. Rapid induction onto long-lasting injectable buprenorphine may be a promising and protective treatment approach in the future.

Background & Aims: When listing for liver transplantation, one can transplant as soon as possible or introduce a test-of-time to better select patients, as the tumor’s biological behavior is observed. Knowing the degree of harm caused by time itself is essential to advise patients and decide on the maximum duration of the test-of-time. Therefore, we investigated the causal effect of waiting time on post-transplant survival for patients with hepatocellular carcinoma. Methods: We analyzed the UNOS-OPTN dataset and exploited a natural experiment created by blood groups. Relations between variables and assumptions were described in a causal graph. Selection bias was addressed by inverse probability weighting. Confounding was avoided using instrumental variable analysis, with an additive hazards model in the second stage. The causal effect was evaluated by estimating the difference in 5-year overall survival if all patients waited 2 months instead of 12 months. Upper bounds of the test-of-time were evaluated for probable scenarios by means of simulation. Results: The F-statistic of the first stage was 86.3. The effect of waiting 12 months vs. 2 months corresponded with a drop in overall survival rate of 5.07% (95% CI 0.277–9.69) and 8.33% (95% CI 0.47–15.60) at 5- and 10-years post-transplant, respectively. The median survival dropped by 3.41 years from 16.21 years (95% CI 15.98–16.60) for those waiting 2 months to 12.80 years (95% CI 10.72–15.90) for those waiting 12 months. Conclusions: From a patient’s perspective, the choice between ablate-and-wait vs. immediate transplantation is in favor of immediate transplantation. From a policy perspective, the extra waiting time can be used to increase the utility of scarce donor livers. However, the duration of the test-of-time is bounded, and it likely should not exceed 8 months. Impact and implications: When listing patients with liver cancer for transplantation, it is unclear whether a test-of-time or immediate transplantation offer better outcomes at the population level. In this study, we found that increased liver transplant waiting times are detrimental in patients with liver cancer. Furthermore, our simulation showed that a pre-operative observational period can be useful to ensure good donor liver allocation, but that its duration should not exceed 8 months.

Duchenne muscular dystrophy (DMD), originating from the lack of functional dystrophin, clinically manifests as devastating disease of skeletal muscles with progressive cardiac involvement. HMOX1 promoter polymorphism may reflect different activity of heme oxygenase-1 (HO-1) that may be critical for DMD progression.Here we generated human induced pluripotent stem cell (hiPSC) lines from healthy donors-derived peripheral blood mononuclear cells with different variants of HMOX1 promoter (GT repeats), and engineered by CRISPR/Cas9-mediated deletion of exon 50 of DMD gene. Such in vitro model could add to molecular understanding of DMD and verify the prognostic value of HMOX1 promoter polymorphism.

Accurately identifying needle tip and seed positions for low dose rate prostate brachytherapy on MRI images is challenging. Uncertainties in locating needle tip positions can lead to misplacement of seeds compared to planned coordinates. Furthermore uncertainty in establishing true seed positions on the images, leads to uncertainty in the dose distributions.In this study, a novel phantom has been designed for the analysis of I-125 seed and needle tip detection and tip image distortion. The phantom utilises a gel that mimics prostate tissue in MRI, to evaluate the uncertainty in establishing seed and needle tip positions. Reults are reported for the IsoSeed (Bebig) source, in clinically relevant seed arrangements, and for a novel nitinol needle.The choice of MRI sequence impacts the accuracy of detecting the needle tips and seeds. This is most prevelant when the seeds are in clusters, at the boundary of the prostate and at 90˚ to the long axis of the scanner. Detected needle tip position, when the MRI metal artefact correction algorithm was used, was measured consistently inferior to the actual position (mean tip at -2.3 ± 1.5 mm (k = 2), p = 0.03).We have demonstrated the design of a phantom that can be used to quantitatively assess seed and needle tip positions simultaneously, to establish the accuracy of detection, or presence of artefacts on MRI.

A code C⊆{0,1,2}nis said to be trifferent with length n when for any three distinct elements of C there exists a coordinate in which they all differ. Defining T(n)as the maximum cardinality of trifferent codes with length n, T(n)is unknown for n≥5. In this note, we use an optimized search algorithm to show that T(5)=10and T(6)=13.

Summary: Background: Primary Ovarian Insufficiency (POI), a public health problem, affects 1-3.7% of women under 40 yielding infertility and a shorter lifespan. Most causes are unknown. Recently, genetic causes were identified, mostly in single families. We studied an unprecedented large cohort of POI to unravel its molecular pathophysiology. Methods: 375 patients with 70 families were studied using targeted (88 genes) or whole exome sequencing with pathogenic/likely-pathogenic variant selection. Mitomycin-induced chromosome breakages were studied in patients’ lymphocytes if necessary. Findings: A high-yield of 29.3% supports a clinical genetic diagnosis of POI. In addition, we found strong evidence of pathogenicity for nine genes not previously related to a Mendelian phenotype or POI: ELAVL2, NLRP11, CENPE, SPATA33, CCDC150, CCDC185, including DNA repair genes: C17orf53(HROB), HELQ, SWI5 yielding high chromosomal fragility. We confirmed the causal role of BRCA2, FANCM, BNC1, ERCC6, MSH4, BMPR1A, BMPR1B, BMPR2, ESR2, CAV1, SPIDR, RCBTB1 and ATG7 previously reported in isolated patients/families. In 8.5% of cases, POI is the only symptom of a multi-organ genetic disease. New pathways were identified: NF-kB, post-translational regulation, and mitophagy (mitochondrial autophagy), providing future therapeutic targets. Three new genes have been shown to affect the age of natural menopause supporting a genetic link. Interpretation: We have developed high-performance genetic diagnostic of POI, dissecting the molecular pathogenesis of POI and enabling personalized medicine to i) prevent/cure comorbidities for tumour/cancer susceptibility genes that could affect life-expectancy (37.4% of cases), or for genetically-revealed syndromic POI (8.5% of cases), ii) predict residual ovarian reserve (60.5% of cases). Genetic diagnosis could help to identify patients who may benefit from the promising in vitro activation-IVA technique in the near future, greatly improving its success in treating infertility. Funding: Université Paris Saclay, Agence Nationale de Biomédecine.

Background: Climate change has been described as the largest public health concern of the 21st century. In response to climate change over 50 countries have pledged to go carbon neutral in the provision of health care services and telemedicine can be an integral part of decreasing emissions related travel associated with health care. While telemedicine rapidly expanded to increase access to care during the Covid-19 pandemic, the impact of telerehabilitation on climate change as part of the provision of physical rehabilitation services has not been assessed. This study focuses on physical medicine and rehabilitation physicians in an urban physical medicine and rehabilitation (PM&R) department and assesses patient satisfaction with synchronous video visits (SVVs) as well as the estimated value of SVVs in travel savings and carbon emissions. Materials and methods: We conducted a retrospective chart review, implemented a patient survey, and conducted a commuter analysis to report our experience using SVVs to provide follow-up care across multiple rehabilitation sub-specialties Results: A total of 154 SVVs were conducted before the pandemic over an 18-month period. The most commonly addressed issues during the SVVs were rehabilitation and medication management, followed by equipment, lab and imaging results. About one-third of the patients (31%) were non-ambulatory at the time of their SVV. On average, SVVs reduced travel distance (95 miles), travel time (2.23 h), travel cost ($15) and carbon emissions. Discussion: The use of telerehabilitation should be an integral part of decreasing the carbon footprint of provision of physical medicine and rehabilitation services.

Objective: Transcatheter aortic valve implantation (TAVI) is rapidly replacing cardiac surgery due to its minimal invasiveness and practicality. Midterm immunological studies on the biocompatibility of galactose-alpha-1,3-galactose (α-Gal)–carrying bioprosthetic heart valves for TAVI are not available. In this study we investigated whether bioprosthetic heart valves employed for TAVI augment an α-Gal–specific antibody-dependent and antibody-independent immune response 3 months after TAVI implantation. Methods: This prospective observational study included 27 patients with severe aortic valve stenosis undergoing TAVI and 10 patients with severe mitral valve regurgitation treated with a transcatheter MitraClip (Abbott Laboratories, Abbott Park, Ill) procedure. Blood samples were drawn before and 90 days after treatment at a routine checkup. Serum samples were analyzed using enzyme-linked immunosorbent assay. Serum concentrations of α-Gal–specific immunoglobulin (Ig) G, IgG subclasses and IgE, complement factor 3a, NETosis-specific citrullinated H3, and the systemic inflammation markers soluble suppression of tumorigenicity and interleukin 33 were evaluated. Results: Three months after TAVI, we found significantly increased serum concentrations of α-Gal–specific IgG3, complement factor complement factor 3a, citrullinated H3 levels, and soluble suppression of tumorigenicity (P = .002, P = .001, P = .025, and P = .039, respectively). Sensitization of α-Gal–specific IgE antibodies occurred in 55% of all patients after TAVI. Conclusions: Our results indicate that TAVI elicits a midterm, specific humoral immune response against α-Gal and causes an unspecific humoral inflammation compared with patients undergoing MitraClip implantation. This observation will lead to a better understanding of postintervention morbidity and the long-term durability of bioprostheses and indicates that caution is appropriate when designing implantation strategies for younger patients.

Objective: Faciocraniosynostoses (FCS) are malformations affecting the development of the bones of the skull and face, due to the premature closure of one or more craniofacial sutures, mostly secondary to activating Fibroblast Growth Factor Receptor (FGFR) 1–3 mutations. Gain-of-function FGFR3 mutations are also responsible for various conditions referred to as osteochondrodysplasia (OCD), characterized by structural and functional abnormalities of growth plate cartilages. We hypothesized that patients with FGFR-related faciocraniosynostoses may present extra-cranial growth anomalies. Study design: We retrospectively collected height and weight data from a cohort of 70 patients. Included patients were admitted for FGFR-related FCS between 2000 and 2021 at the Craniofacial Unit of Necker – Enfants Malades University Hospital in Paris, France. Results: We showed that FGFR-related faciocraniosynostoses had significantly reduced heights and weights relative to controls, and that two specific time periods (1–3 years and > 8 years of age) were associated with lower height and weight values. Four patients had received growth hormone treatment but remained below normal values for growth in height and weight. Conclusions: Patients with FGFR-related faciocraniosynostoses have clinically significant extra-cranial anomalies which are not currently investigated and managed in usual protocols; these patients could benefit from a systematic pre-pubertal endocrine assessment. More generally, our results extend the scope of extracranial anomalies in FGFR-related faciocraniosynostoses and support the hypothesis that all conditions with activating FGFR mutations affect both membranous ossification and long bones.

Summary: T cell pathology in the skin leads to monocyte influx, but we have little understanding of the fate of recruited cells within the diseased niche, or the long-term impact on cutaneous immune homeostasis. By combining a murine model of acute graft-versus-host disease (aGVHD) with analysis of patient samples, we demonstrate that pathology initiates dermis-specific macrophage differentiation and show that aGVHD-primed macrophages continue to dominate the dermal compartment at the relative expense of quiescent MHCIIint cells. Exposure of the altered dermal niche to topical haptens after disease resolution results in hyper-activation of regulatory T cells (Treg), but local breakdown in tolerance. Disease-imprinted macrophages express increased IL-1β and are predicted to elicit altered TNF superfamily interactions with cutaneous Treg, and we demonstrate the direct loss of T cell regulation within the resolved skin. Thus, T cell pathology leaves an immunological scar in the skin marked by failure to re-set immune homeostasis.

Uterine serous carcinoma (USC) is an uncommon subtype of endometrial cancer with a poor prognosis. USCs have genomic alterations in the PI3K pathway. A prior phase II study of AKT inhibitor MK-2206 (an allosteric AKT inhibitor, primarily affecting AKT1 and AKT2) in endometrial cancers resulted in progression-free survival (PFS) of ≥6 months in five out of seven patients with USC. To further assess the activity of MK-2206 in USC, we designed a phase II, single-stage assessment of MK-2206 in patients with advanced or recurrent high-grade serous endometrial cancer, who had received up to two lines of prior therapy. MK-2206 (135 mg) was administered orally once per week, in continuous 28-day cycles. Fourteen patients received treatment. The most common treatment-related adverse events were diarrhea (36%), acneiform rash (36%), nausea (29%), fatigue (29%), and hyperglycemia (21%); most events were grade 1–2. One confirmed partial response was observed in a patient who was also alive and progression-free at 6 months. One additional patient was alive and progression-free at 6 months. The clinical benefit rate was 14.3% (95% CI: 1.8 to 42.8). Five patients had stable disease (35.7%) and seven had progressive disease (50%); one was unevaluable. Median PFS was 2 months (95% CI: 1.6 to 4.4) and median overall survival was 6.4 months (95% CI: 5.1 to not reached). In summary, MK-2206 had limited activity in USC, although a few patients achieved sustained progression-free intervals in this study and in the previously reported phase II trial of MK-2206. Further investigations are needed to identify features associated with response.

Background & Aims: TIGIT is a co-inhibitory receptor, and its suitability as a target for cancer immunotherapy in HCC is unknown. PD1 blockade is clinically effective in about 20% of advanced HCC patients. Here we aim to determine whether co-blockade of TIGIT/PD1 has added value to restore functionality of HCC tumor-infiltrating T cells (TILs). Methods: Mononuclear leukocytes were isolated from tumors, paired tumor-free liver tissues (TFL) and peripheral blood of HCC patients, and used for flow cytometric phenotyping and functional assays. CD3/CD28 T-cell stimulation and antigen-specific assays were used to study the ex vivo effects of TIGIT/PD1 single or dual blockade on T-cell functions. Results: TIGIT was enriched, whereas its co-stimulatory counterpart CD226 was down-regulated on PD1high CD8+ TILs. PD1high TIGIT+ CD8+ TILs co-expressed exhaustion markers TIM3 and LAG3 and demonstrated higher TOX expression. Furthermore, this subset showed decreased capacity to produce IFN-γ and TNF-α. Expression of TIGIT-ligand CD155 was up-regulated on tumor cells compared with hepatocytes in TFL. Whereas single PD1 blockade preferentially enhanced ex vivo functions of CD8+ TILs from tumors with PD1high CD8+ TILs (high PD1 expressers), co-blockade of TIGIT and PD1 improved proliferation and cytokine production of CD8+ TILs from tumors enriched for PD1int CD8+ TILs (low PD1 expressers). Importantly, ex vivo co-blockade of TIGIT/PD1 improved proliferation, cytokine production, and cytotoxicity of CD8+ TILs compared with single PD1 blockade. Conclusions: Ex vivo, co-blockade of TIGIT/PD1 improves functionality of CD8+ TILs that do not respond to single PD1 blockade. Therefore co-blockade of TIGIT/PD1 could be a promising immune therapeutic strategy for HCC patients.

Summary: Background: Time in range (TIR) goals are rarely met in children with type 1 diabetes, except at the cost of increased hypoglycaemia episodes. Our objective was to evaluate the safety and efficiency of the Diabeloop DBL4K (Diabeloop, Grenoble, France) hybrid closed-loop system in prepubescent children. Methods: We did a multicentre, open-label, randomised, controlled, non-inferiority, two-session crossover study in the paediatric endocrinology departments of three university hospitals in France and Belgium. Eligible participants were aged 6–12 years with type 1 diabetes for at least 1 year, glycated haemoglobin A1C 9% (75 mmol/mol) or less, and insulin pump treatment for at least 3 months. Participants were randomly assigned (1:1) to a closed-loop device or sensor-augmented pump (open loop) therapy. Randomisation was by a permuted block randomisation scheme, using an interactive web-based response system, and was stratified on centre (block size 6). The assessed closed-loop device, the Diabeloop for Kids DBL4K hybrid closed-loop system, is an automated blood glucose regulation system composed of a handset, insulin pump, and continuous glucose monitor. The open-loop system is defined as a sensor-augmented pump therapy composed of the usual insulin pump used by the patient and a continuous glucose monitor. A 72-h in-patient period was followed by a 6-week home phase. After a 1-week washout period, the participants crossed over to the other device. The primary outcome, assessed in the intention-to-treat population, was the mean proportion of time spent in hypoglycaemia (3·9 mmol/L [

Our study was carried out to evaluate the effect of lipoic acid (LA) on the densitometric properties, structure and mechanical strength of the mandible of Wistar rats with developing osteopenia. The study used 42 sham-operated (SHO) and ovariectomized (OVX) rats. The OVX rats were randomly divided (n = 6) onto two controls treated subcutaneously with physiological saline (OVX-PhS) and 17β-estradiol (OVX-E2), respectively, and onto four experimental OVX groups that received LA in the doses of 12.5, 25, 50 and 100 mg/kg/day for 28 days. The results demonstrated that the lack of estrogen brought about osteopenic bone changes, especially in the trabecular compartment. In addition, while the usage of LA in the doses of 12.5 and 25 LA had no effect in OVX rats, the dose of 100 effectively inhibited osteopenic changes of the mandible. This dose maintained structural, densitometric and mechanical parameters at levels like that in the SHO and OVX-E2 groups by inhibiting the destructive influence of oxidative stress. Dose 50, however, was revealed to be the most effective. It not only inhibited atrophic changes and the influence of oxidative stress, but also stimulated the formation of mandibular bone tissue. Our results suggest that the administration of LA is effective in preventing atrophic changes in the mandibular bone tissue in conditions of ovarian hormone deficiency and suggest its potential in the therapy of osteoporosis.

Fireweed (Epilobium angustifolium L.) has attracted attention due to its numerous biological activities. In the present work, we produced a polyphenol-rich freeze-dried infusion (407.02 ± 7.10 mg GAE/g) in order to measure, for the first time, the evolution of anticholinesterase activity during in vitro digestion. During the ‘gastric’ phase, there was an increase in the inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity followed by a decrease during the ‘small intestinal’ phase. A strong correlation between total polyphenolic content (TPC) and the anticholinesterase activity of the digested fluids was observed (r = 0.90 for TPC/AChE; r = 0.88 for TPC/BChE, p

Summary: RANTES is implicated in allergic asthma and in T cell-dependent clearance of infection. RANTES receptor family comprises CCR1, CCR3, and CCR5, which are G-protein-coupled receptors consisting of seven transmembrane helices. Infections with respiratory viruses like Rhinovirus cause induction of RANTES production by epithelial cells. Here, we studied the role of RANTES in the peripheral blood mononuclear cells in cohorts of children with and without asthma and validated and extended this study to the airways of adults with and without asthma. We further translated these studies to a murine model of asthma induced by house dust mite allergen in wild-type RANTES and CCR5-deficient mice. Here we show an unpredicted therapeutic role of RANTES in the resolution of allergen-induced asthma by orchestrating the transition of effector GATA-3+CD4+ T cells into immune-regulatory-type T cells and inflammatory eosinophils into resident eosinophils as well as increased IL-10 production in the lung.

Compared to conventional face-to-face psychological treatments, internet-based cognitive-behavioral therapy (iCBT) presents an innovative alternative that has been found to be effective in the treatment of anxiety disorders. The current study provides a meta-analysis investigating the efficacy of disorder-specific guided self-help (Gsh) iCBT compared to various active and inactive control conditions, with focus on adult panic disorder sufferers with or without agoraphobia (PD/A). Systematic literature search yielded 13 randomized controlled trials (RCTs) (N = 1214) that met the eligibility criteria for this study. We found no statistically significant differences between Gsh iCBT and various active CBT interventions in reducing PD/A symptoms at both post-test (g = 0.015, k = 10) and follow-up (g = 0.113, k = 6) levels. Also, comorbid anxiety and depression were reduced equivalently at post-test (g = 0.004, k = 6) and follow-up (g = 0.004, k = 6). Quality of life was equally improved at post-test (g = −0.100, k = 5) and follow-up (g = 0.074, k = 2). When compared to inactive controls, we found large effect sizes in PD/A (g = −0.892, k = 9) and comorbid anxiety and depression (g = −0.723, k = 9) symptoms, and moderate change in quality of life (g = −0.484, k = 3) at post-test. There was no difference between Guided self-help iCBT and Self-help iCBT in PD/A (g = −0.025, k = 3) and comorbid anxiety and depression (g = −0.025, k = 3) at post-test. Baseline severity, country of original research and adherence to the treatment in form of initial uptake were identified as statistically significant moderators of the iCBT treatment.

A food product matrix and functional additives used to manufacture it are one of the key factors influencing the fermentation processes in the intestine and the bioavailability of minerals. The aim of this study was to analyse the effect of acidified and non-acidified milk gels with highly-purified (1-3)-, (1-3)(1-4)-, and (1-3)(1-6)-β-glucan on: gastrointestinal tract parameters, intestinal metabolic activity, and bioavailability of minerals in growing rats. Concentrations of ammonia, short-chain volatile fatty acids as well as bacterial enzyme activity, blood biochemistry, and bioavailability of Ca, Zn, Mn and Fe were significantly affected by β-glucan structure. The availability of minerals was higher upon the use of branched β-glucans. Milk gel acidity significantly influenced body weight gain, activity of faecal bacterial enzymes, blood levels of triglycerides and glucose, and bioavailability of all investigated mineral compounds. The use of branched β-glucans resulted in the most and least intense fermentation processes in the caecum, respectively.

Car ownership is growing very rapidly in China; whilst this is a reflection of sustained economic growth, it presents a major challenge to Chinese transport policymakers. The consequences of China's motorization also extend beyond the national borders, however, via mechanisms such as increased demand for new automobiles produced in North America and Europe and the global atmospheric concentration of greenhouse gases. Chinese cities are also experimenting with innovative transport policies to manage increasing car ownership, which in a number of cases go beyond the menu of policy options that have traditionally been considered in the West. Despite policy interest for these reasons, China's motorization process is poorly understood, in part due to a scarcity of relevant data.This paper contributes to the body of literature regarding this phenomenon by drawing on a unique data resource: the 2011 wave of the China Household Finance Survey (n = 8438 households). This is a disaggregate national-scale survey dataset developed to monitor economic conditions in China, though to the authors' knowledge the CHFS has not previously been employed to study patterns of car ownership.We report a set of three analyses, to identify factors associated with: 1) whether a household owns at least one car, 2) multiple car ownership, and 3) whether a household owns a new car. Amongst other empirical results, we find that living in a rural area is negatively associated with car ownership, net of confounding effects, and that within towns/cities poor accessibility (i.e. long travel time) to the town/city centre is also negatively associated with car ownership. These findings regarding spatial effects are contrary to typical findings in the West, where car ownership is generally lowest in urban centres.An earlier version of this study was presented at the 2017 Transportation Research Board conference. Keywords: Car ownership, China household finance survey, Motorisation, Developing country, Logistic regression

Summary: Single-cell transcriptomics suffer from sensitivity limits that restrict low abundance transcript identification, affects clustering and can hamper downstream analyses. Here, we describe Constellation sequencing (Constellation-Seq), a molecular transcriptome filter that delivers two orders of magnitude sensitivity gains by maximizing read utility while reducing the data sparsity and sequencing costs. The technique reliably measures changes in gene expression and was demonstrated by resolving rare dendritic cell populations from a peripheral blood mononuclear cell sample sample and exploring their biology with extreme resolution. The simple and powerful method is fully compatible with standard scRNA-Seq library preparation protocols and can be used for hypothesis testing, marker validation or investigating pathways.

Recent interest has focused on the use of high-fibre foods as potential ingredients for lowering the glycaemic index of most carbohydrate-based meals. The objective of this study was to examine glycaemic responses to two defined breakfasts. The reference breakfast and the test breakfast differed only in the type of bread (white vs. wholemeal), and were administered three times to volunteers (2 men, 8 women). Capillary blood glucose was monitored in the fasting state 15, 30, 45, 60, 75, 90, 105 and 120 min after breakfast consumption. The incremental areas under the glucose response curves were calculated for each type of breakfast and compared with those of glucose to determine the glycaemic indices. The glycaemic index of the reference breakfast was 26.6 (±6.2), with that of the test breakfast significantly lower at 18.1 (±6.0). The mixed-food test breakfast with wholemeal bread was rich in soluble fibre (β-glucans) for a lower glycaemic load than the white bread, and provided a lower glycaemic response in the volunteers. The inter-volunteer variability in glycaemic index was large, with some showing lower responses to the test breakfast (glycaemic index, 12.4–21.1) and some showing high responses to the test breakfast (glycaemic index, 25.9–27.4). Keywords: Glycaemic index, White bread, Wholemeal bread, Breakfast

This paper demonstrates the role of curly kale fermentation by autochthonous lactic acid bacteria in the formation of bioactive derivatives of phenolic compounds which may have anticancer properties. LC-MS and HPLC analyses were performed and the content of polyphenols in curly kale before and during fermentation were determined. Bioactive properties of salicylic and gentisic acids were tested in experiments on tumor (HT29, SW620) and normal (CCD841CoTr) epithelial cell lines. In this study, gentisic and salicylic acids were thoroughly examined. Gentisic acid has not been detected in Brasssicaceae vegetables so far, and the presence of both these acids was noted in fermented curly kale for the first time. Our results indicated that both salicylic and gentisic acids decreased the number of HT29 cells simultaneously with reduction of the intercellular interactions between these cells. Moreover, immunomodulatory and anti-inflammatory activity of gentisic acid was observed.

Primary liver tissue cancer types are renowned to display a consistent increase in global disease burden and mortality, thus needing more effective diagnostics and treatments. Yet, integrative research efforts to identify cell-of-origin for these cancers by utilizing human specimen data were poorly established. To this end, we analyzed previously published whole-genome sequencing data for 384 tumor and progenitor tissues along with 423 publicly available normal tissue epigenomic features and single cell RNA-seq data from human livers to assess correlation patterns and extended this information to conduct in-silico prediction of the cell-of-origin for primary liver cancer subtypes. Despite mixed histological features, the cell-of-origin for mixed hepatocellular carcinoma/intrahepatic cholangiocarcinoma subtype was predominantly predicted to be hepatocytic origin. Individual sample-level predictions also revealed hepatocytes as one of the major predicted cell-of-origin for intrahepatic cholangiocarcinoma, thus implying trans-differentiation process during cancer progression. Additional analyses on the whole genome sequencing data of hepatic progenitor cells suggest these cells may not be a direct cell-of-origin for liver cancers. These results provide novel insights on the nature and potential contributors of cell-of-origins for primary liver cancers.

Summary: Degradation of transcripts in human nuclei is primarily facilitated by the RNA exosome. To obtain substrate specificity, the exosome is aided by adaptors; in the nucleoplasm, those adaptors are the nuclear exosome-targeting (NEXT) complex and the poly(A) (pA) exosome-targeting (PAXT) connection. How these adaptors guide exosome targeting remains enigmatic. Employing high-resolution 3′ end sequencing, we demonstrate that NEXT substrates arise from heterogenous and predominantly pA− 3′ ends often covering kilobase-wide genomic regions. In contrast, PAXT targets harbor well-defined pA+ 3′ ends defined by canonical pA site use. Irrespective of this clear division, NEXT and PAXT act redundantly in two ways: (1) regional redundancy, where the majority of exosome-targeted transcription units produce NEXT- and PAXT-sensitive RNA isoforms, and (2) isoform redundancy, where the PAXT connection ensures fail-safe decay of post-transcriptionally polyadenylated NEXT targets. In conjunction, this provides a two-layered targeting mechanism for efficient nuclear sorting of the human transcriptome. : Wu et al. demonstrate that the nuclear exosome adaptor NEXT targets poly(A)− RNAs with poorly defined 3′ ends, whereas the PAXT connection targets poly(A)+ RNAs derived from canonical poly(A) sites. NEXT substrates become polyadenylated in the absence of NEXT, causing fail-safe RNA decay via PAXT. Keywords: nuclear RNA turnover, NEXT complex, PAXT connection, 3′ end sequencing, pA+/pA− RNA

Background: Contrast-induced acute kidney injury (CI-AKI) is a common cause of hospital-acquired AKI and a serious complication of percutaneous coronary intervention. Objective: The aim of the present study was to assess whether remote ischemic preconditioning (RIPC) reduces the incidence of CI-AKI. Methods: We conducted a prospective, randomized, sham-controlled clinical study. The study included 101 patients admitted to the Intensive Cardiac Therapy Clinic of Medical University of Lodz for elective percutaneous coronary intervention. The participants were randomly assigned in a 1:1 ratio to either a control group (n = 51) or an RIPC group (n = 50). In the latter, RIPC was achieved before percutaneous coronary intervention by 4 cycles of 5-minute inflation of a cuff on the left upper arm to 200 mm Hg followed by 5-minute deflation. In the control group, a deflated cuff was placed on the left arm for 40 minutes. Serum creatinine concentration was measured to check for the presence of CI-AKI within 48 to 72 hours of percutaneous coronary intervention. Serum neutrophil gelatinase-associated lipocalin level was also measured within 3 hours. Results: CI-AKI occurred in 2 patients from the RIPC group (4%) and 3 patients from the control group (5.9%), but the difference was not significant (P = 0.98). The patients who developed CI-AKI also demonstrated increased serum neutrophil gelatinase-associated lipocalin concentrations (the area under the receiver operator characteristic curve = 0.97; 95% CI, 0.938–1.00; P < 0.00) and the optimal cutoff point value was 118.9 ng/mL. Conclusions: The use of RIPC before elective percutaneous coronary intervention was not found to prevent CI-AKI. ClinicalTrials.gov identifier: NCT03761368. (Curr Ther Res Clin Exp. 2020; 81:XXX–XXX)

In multiple sclerosis, pathological changes of both tissue iron and myelin occur, yet these factors have not been characterized in a longitudinal fashion using the novel iron- and myelin-sensitive quantitative susceptibility mapping (QSM) MRI technique. We investigated disease-relevant tissue changes associated with myelin loss and iron accumulation in multiple sclerosis deep gray matter (DGM) over two years. One-hundred twenty (120) multiple sclerosis patients and 40 age- and sex-matched healthy controls were included in this prospective study. Written informed consent and local IRB approval were obtained from all participants. Clinical testing and QSM were performed both at baseline and at follow-up. Brain magnetic susceptibility was measured in major DGM structures. Temporal (baseline vs. follow-up) and cross-sectional (multiple sclerosis vs. controls) differences were studied using mixed factorial ANOVA analysis and appropriate t-tests. At either time-point, multiple sclerosis patients had significantly higher susceptibility in the caudate and globus pallidus and lower susceptibility in the thalamus. Over two years, susceptibility increased significantly in the caudate of both controls and multiple sclerosis patients. Inverse thalamic findings among MS patients suggest a multi-phase pathology explained by simultaneous myelin loss and/or iron accumulation followed by iron depletion and/or calcium deposition at later stages. Keywords: Quantitative susceptibility mapping, QSM, Iron, Multiple sclerosis, Longitudinal study

Short stature is associated with increased LDL-cholesterol levels and coronary artery disease in adults. We investigated the relationship of stature to LDL levels in children in the West Virginia Coronary Artery Risk Detection in Appalachian Communities (CARDIAC) Project to determine whether the genetically determined inverse relationship observed in adults would be evident in fifth graders. A cross-sectional survey of schoolchildren was assessed for cardiovascular risk factors. Data collected at school screenings over 18 years in WV schools were analyzed for 63,152 fifth-graders to determine relationship of LDL to stature with consideration of age, gender, and BMI. The first (shortest) quartile showed an LDL level of 93.6 mg/dl compared with an LDL level of 89.7 mg/dl for the fourth (tallest) quartile. Each incremental increase of 1 SD of height lowered LDL by 0.049 mg/dl (P < 0.0001). Multivariate analysis showed LDL to vary inversely as a function of the first (lowest) quartile of height after controlling for gender, median age, BMI percentile for age and gender, and year of screening. The odds ratio for LDL ≥ 130 mg/dl for shortest versus tallest quartile is 1.266 (95% CL 1.162–1.380). The odds ratio for LDL ≥ 160 mg/dl is 1.456 (95% CL 1.163–1.822). The relationship between short stature and LDL, noted in adults, is confirmed in childhood.

Bone disorders are a group of varied acute and chronic traumatic, degenerative, malignant or congenital conditions affecting the musculoskeletal system. They are prevalent in society and, with an ageing population, the incidence and impact on the population’s health is growing. Severe persisting pain and limited mobility are the major symptoms of the disorder that impair the quality of life in affected patients. Current therapies only partially treat the disorders, offering management of symptoms, or temporary replacement with inert materials. However, during the last few years, the options for the treatment of bone disorders have greatly expanded, thanks to the advent of regenerative medicine. Skeletal cell-based regeneration medicine offers promising reparative therapies for patients. Mesenchymal stem (stromal) cells from different tissues have been gradually translated into clinical practice; however, there are a number of limitations. The introduction of reprogramming methods and the subsequent production of induced pluripotent stem cells provides a possibility to create human-specific models of bone disorders. Furthermore, human-induced pluripotent stem cell-based autologous transplantation is considered to be future breakthrough in the field of regenerative medicine. The main goal of the present paper is to review recent applications of induced pluripotent stem cells in bone disease modeling and to discuss possible future therapy options. The present article contributes to the dissemination of scientific and pre-clinical results between physicians, mainly orthopedist and thus supports the translation to clinical practice.

The increasing prevalence of energy drink (ED) use and its link with negative behaviors and adverse health outcomes has garnered much attention. Use of EDs combined with alcohol among college students has been of particular interest. It is unclear if these relationships develop in the context of college, or if similar associations exist in younger individuals. The present study examined associations between ED consumption patterns and other substance use in an adolescent, school-based sample. Participants were N = 3743 students attending 8th, 10th or 12th grade in a suburban central Virginia public school system who completed a prevention needs assessment survey in 2012. Chi-square analyses and logistic regressions were used to compare rates of alcohol, tobacco and other drug use across three ED use groups: moderate/heavy (12.6%), light (30.5%), and non-users (57%). Over 40% of the sample reported recent (past month) ED use, with males more likely to report moderate/heavy ED use than females (14.0% and 11.1%, respectively; p = 0.02). After adjusting for gender and grade, ED use group predicted lifetime alcohol, tobacco and other drug use (all p

Primary aldosteronism (PA) is the most common form of secondary hypertension. Mutations in KCNJ5, ATP1A1, ATP2B3 and CACNA1D are found in aldosterone producing adenoma (APA) and familial hyperaldosteronism (FH). A recurrent mutation in CACNA1H (coding for Cav3.2) was identified in a familial form of early onset PA. Here we performed whole exome sequencing (WES) in patients with different types of PA to identify new susceptibility genes. Four different heterozygous germline CACNA1H variants were identified. A de novo Cav3.2 p.Met1549Ile variant was found in early onset PA and multiplex developmental disorder. Cav3.2 p.Ser196Leu and p.Pro2083Leu were found in two patients with FH, and p.Val1951Glu was identified in one patient with APA. Electrophysiological analysis of mutant Cav3.2 channels revealed significant changes in the Ca2+ current properties for all mutants, suggesting a gain of function phenotype. Transfections of mutant Cav3.2 in H295R-S2 cells led to increased aldosterone production and/or expression of genes coding for steroidogenic enzymes after K+ stimulation. Identification of CACNA1H mutations associated with early onset PA, FH, and APA suggests that CACNA1H might be a susceptibility gene predisposing to PA with different phenotypic presentations, opening new perspectives for genetic diagnosis and management of patients with PA.

Previously identified single nucleotide polymorphisms (SNPs) in genome wide association studies (GWAS) of cardiovascular disease (CVD) in participants of mostly European descent were tested for association with subclinical cardiovascular disease (sCVD), coronary artery calcium score (CAC) and carotid intima media thickness (CIMT) in the Multi-Ethnic Study of Atherosclerosis (MESA). The data in this data in brief article correspond to the article Common Genetic Variants and Subclinical Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis [1]. This article includes the demographic information of the participants analyzed in the article as well as graphical displays and data tables of the association of the selected SNPs with CAC and of the meta-analysis across ethnicities of the association of CIMT-c (common carotid), CIMT-I (internal carotid), CAC-d (CAC as dichotomous variable with CAC>0) and CAC-c (CAC as continuous variable, the log of the raw CAC score plus one) and CVD. The data tables corresponding to the 9p21 fine mapping experiment as well as the power calculations referenced in the article are also included. Keywords: Single nucleotide polymorphism (SNP), Common genetic variant, Subclincal atherosclerosis, Coronary artery calcium (CAC), Carotid intima-media thickness (CIMT)

An antiviral component of the human innate immune system—the APOBEC cytidine deaminases—was recently identified as a prominent source of mutations in cancers. Here, we investigated the distribution of APOBEC-induced mutations across the genomes of 119 breast and 24 lung cancer samples. While the rate of most mutations is known to be elevated in late-replicating regions that are characterized by reduced chromatin accessibility and low gene density, we observed a marked enrichment of APOBEC mutations in early-replicating regions. This unusual mutagenesis profile may be associated with a higher propensity to form single-strand DNA substrates for APOBEC enzymes in early-replicating regions and should be accounted for in statistical analyses of cancer genome mutation catalogs aimed at understanding the mechanisms of carcinogenesis as well as highlighting genes that are significantly mutated in cancer.

Strategies that simultaneously enhance the survival and glucose responsiveness of insulin-producing β cells will greatly augment β cell replacement therapies in type 1 diabetes (T1D). We show that genetic and pharmacologic mimetics of the phosphorylated BCL-2 homology 3 (BH3) domain of BAD impart β-cell-autonomous protective effects in the face of stress stimuli relevant to β cell demise in T1D. Importantly, these benefits translate into improved engraftment of donor islets in transplanted diabetic mice, increased β cell viability in islet grafts, restoration of insulin release, and diabetes reversal. Survival of β cells in this setting is not merely due to the inability of phospho-BAD to suppress prosurvival BCL-2 proteins but requires its activation of the glucose-metabolizing enzyme glucokinase. Thus, BAD phospho-BH3 mimetics may prove useful in the restoration of functional β cell mass in diabetes.

Development and function of pancreatic β cells involve the regulated activity of specific transcription factors. RFX6 is a transcription factor essential for mouse β cell differentiation that is mutated in monogenic forms of neonatal diabetes. However, the expression and functional roles of RFX6 in human β cells, especially in pathophysiological conditions, are poorly explored. We demonstrate the presence of RFX6 in adult human pancreatic endocrine cells. Using the recently developed human β cell line EndoC-βH2, we show that RFX6 regulates insulin gene transcription, insulin content, and secretion. Knockdown of RFX6 causes downregulation of Ca2+-channel genes resulting in the reduction in L-type Ca2+-channel activity that leads to suppression of depolarization-evoked insulin exocytosis. We also describe a previously unreported homozygous missense RFX6 mutation (p.V506G) that is associated with neonatal diabetes, which lacks the capacity to activate the insulin promoter and to increase Ca2+-channel expression. Our data therefore provide insights for understanding certain forms of neonatal diabetes.

A measurement of the azimuthal asymmetry in dihadron production in deep-inelastic scattering of muons on transversely polarised proton (NH3) targets is presented. They provide independent access to the transversity distribution functions through the measurement of the Collins asymmetry in single hadron production. The data were taken in the year 2010 with the COMPASS spectrometer using a 160 GeV/c muon beam of the CERN SPS, increasing by a factor of about four the overall statistics with respect to the previously published data taken in the year 2007. The measured sizeable asymmetry is in good agreement with the published data. An approximate equality of the Collins asymmetry and the dihadron asymmetry is observed, suggesting a common physical mechanism in the underlying fragmentation.

Spin-averaged asymmetries in the azimuthal distributions of positive and negative hadrons produced in deep inelastic scattering were measured using the CERN SPS longitudinally polarised muon beam at 160 GeV/c and a 6LiD target. The amplitudes of the three azimuthal modulations cos⁡ϕh, cos⁡2ϕh and sin⁡ϕh were obtained binning the data separately in each of the relevant kinematic variables x, z or pTh and binning in a three-dimensional grid of these three variables. The amplitudes of the cos⁡ϕh and cos⁡2ϕh modulations show strong kinematic dependencies both for positive and negative hadrons.