Adaptive Biosensing and Neuromorphic Classification Based on an Ambipolar Organic Mixed Ionic–Electronic Conductor

Organic mixed ionic–electronic conductors (OMIECs) are central to bioelectronic applications such as biosensors, health-monitoring devices, and neural interfaces, and have facilitated efficient next-generation brain-inspired computing and biohybrid systems. Despite these examples, smart and adaptive circuits that can locally process and optimize biosignals have not yet been realized. Here, a tunable sensing circuit is shown that can locally modulate biologically relevant signals like electromyograms (EMGs) and electrocardiograms (ECGs), that is based on a complementary logic inverter combined with a neuromorphic memory element, and that is constructed from a single polymer mixed conductor. It is demonstrated that a small neuromorphic array based on this material effects high classification accuracy in heartbeat anomaly detection. This high-performance material allows for straightforward monolithic integration, which reduces fabrication complexity while also achieving high on/off ratios with excellent ambient p- and n-type stability in transistor performance. This material opens a route toward simple and straightforward fabrication and integration of more sophisticated adaptive circuits for future smart bioelectronics

A New Approach to Assess the Gastrocnemius Muscle Volume in Rodents Using Ultrasound; Comparison with the Gastrocnemius Muscle Index

Introduction: The purpose of this study was to determine the reliability and validity of a new non-invasive ultrasound technique to measure gastrocnemius muscle atrophy after nerve denervation in an animal model. Methods: In sixteen rodents an eight mm sciatic nerve gap was created. In the following 8 weeks, each week, two rodents were euthanized and the gastrocnemius muscle was examined using two different ultrasound systems and two investigators. The standardized ultrasound measurement protocol consisted of identifying pre-defined anatomical landmarks: 1) the fibula, 2) the fibular nerve, and 3) the junction between the most distal point of the semitendinosus muscle and gastrocnemius muscle. Consequently, we measured the muscle thickness as the length of the line between the fibula and the junction between the two muscles, perpendicular to the fibular nerve. After the ultrasound recording, the muscle mass was determined. Results: A steep decline of muscle weight of 24% was observed after one week. In the following weeks, the weight further decreased and then remained stable from 6 weeks onwards, resulting in a maximal muscle weight decrease of 82%. The correlation coefficient was >0.96 between muscle diameter and weight using both ultrasound systems. The inter-rater reliability was excellent for both devices on the operated side (ICC of 0.99 for both ultrasound systems) and good for the non-operated site (ICC's: 0.84 & 0.89). The difference between the muscle mass ratio and the muscle thickness ratio was not more than 5% with two outliers of approximately 13%. Discussion: We have developed an innovative, highly reliable technique for quantifying muscle atrophy after nerve injury. This technique allows serial measurements in the same animal over time. This is a significant advantage compared to the conventional technique for quantifying muscle atrophy, which requires sacrificing the animal

Increased risk of HPV-associated genital cancers in men and women as a consequence of pre-invasive disease

To assess the excess risk of HPV‐associated cancer (HPVaC) in two at‐risk groups – women with a previous diagnosis of high grade cervical intraepithelial neoplasia (CIN3) and both men and women treated for non‐cervical pre‐invasive ano‐genital disease. All CIN3 cases diagnosed in 1989‐2015 in Scotland were extracted from the Scottish cancer registry (SMR06). All cases of pre‐invasive penile, anal, vulval, and vaginal disease diagnosed in 1990‐2015 were identified within the NHS pathology databases in the two largest NHS health boards in Scotland. Both were linked to SMR06 to extract subsequent incidence of HPVaC following the diagnosis of CIN3 or pre‐invasive disease. Standardised incidence ratios were calculated for the risk of acquiring HPVaC for the two at‐risk groups compared with the general Scottish population. Among 69714 females in Scotland diagnosed with CIN3 (890360.9 person‐years), 179 developed non‐cervical HPVaC. CIN3 cases were at 3.2‐fold (95% CI: 2.7 to 3.7) increased risk of developing non‐cervical HPVaC, compared to the general female population. Among 1235 patients diagnosed with non‐cervical pre‐invasive disease (9667.4 person‐years), 47 developed HPVaC. Individuals with non‐cervical pre‐invasive disease had a substantially increased risk of developing HPVaC ‐ 15.5‐fold (95% CI: 11.1 to 21.1) increased risk for females and 28‐fold (11.3 to 57.7) increased risk for males. We report a significant additional risk of HPV‐associated cancer in those have been diagnosed with pre‐invasive HPV‐associated lesions including but not confined to the cervix. Uncovering the natural history of pre‐invasive disease has potential for determining screening, prevention and treatment

Imaging of pediatric great vessel stents: Computed tomography or magnetic resonance imaging?

__Background:__ Complications might occur after great vessel stent implantation in children. Therefore follow- up using imaging is warranted. __Purpose:__ To determine the optimal imaging modality for the assessment of stents used to treat great vessel obstructions in children. __Material and methods:__ Five different large vessel stents were evaluated in an in-vitro setting. All stents were expanded to the maximal vendor recommended diameter (20mm; n = 4 or 10mm; n = 1), placed in an anthropomorphic chest phantom and imaged with a 256-slice CT-scanner. MRI images were acquired at 1.5T using a multi-slice T2-weighted turbo spin echo, an RFspoiled three-dimensional T1-weighted Fast Field Echo and a balanced turbo field echo 3D seq

Safety, Immunogenicity, and Protective Efficacy of Intradermal Immunization with Aseptic, Purified, Cryopreserved Plasmodium falciparum Sporozoites in Volunteers Under Chloroquine Prophylaxis

Immunization of volunteers under chloroquine prophylaxis by bites of *Plasmodium falciparum* sporozoite (PfSPZ)–infected mosquitoes induces > 90% protection against controlled human malaria infection (CHMI). We studied intradermal immunization with cryopreserved, infectious PfSPZ in volunteers taking chloroquine (PfSPZ chemoprophylaxis vaccine [CVac]). Vaccine groups 1 and 3 received 3x monthly immunizations with 7.5 x 10^4 PfSPZ. Control groups 2 and 4 received normal saline. Groups 1 and 2 underwent CHMI (#1) by mosquito bite 60 days after the third immunization. Groups 3 and 4 were boosted 168 days after the third immunization and underwent CHMI (#2) 137 days later. Vaccinees (11/20, 55%) and controls (6/10, 60%) had the same percentage of mild to moderate solicited adverse events. After CHMI #1, 8/10 vaccinees (group 1) and 5/5 controls (group 2) became parasitemic by microscopy; the two negatives were positive by quantitative real-time polymerase chain reaction (qPCR). After CHMI #2, all vaccinees in group 3 and controls in group 4 were parasitemic by qPCR. Vaccinees showed weak antibody and no detectable cellular immune responses. Intradermal immunization with up to 3 x 10^5 PfSPZ-CVac was safe, but induced only minimal immune responses and no sterile protection against Pf CHMI. INTRODUCTIO

Safety and Efficacy of Nivolumab Monotherapy in Recurrent or Metastatic Cervical, Vaginal, or Vulvar Carcinoma: Results From the Phase I/II CheckMate 358 Trial

Purpose: Nivolumab was assessed in patients with virus-associated tumors in the phase I/II CheckMate 358 trial (ClinicalTrials.gov identifier: NCT02488759). We report on patients with recurrent/metastatic cervical, vaginal, or vulvar cancers. Patients and methods: Patients received nivolumab 240 mg every 2 weeks. Although patients with unknown human papillomavirus status were enrolled, patients known to have human papillomavirus-negative tumors were ineligible. The primary end point was objective response rate. Duration of response (DOR), progression-free survival, and overall survival were secondary end points. Safety and patient-reported outcomes were exploratory end points. Results: Twenty-four patients (cervical, n = 19; vaginal/vulvar, n = 5) were enrolled. Most patients had received prior systemic therapy for metastatic disease (cervical, 78.9%; vaginal/vulvar, 80.0%). Objective response rates were 26.3% (95% CI, 9.1 to 51.2) for cervical cancer and 20.0% (95% CI, 0.5 to 71.6) for vaginal/vulvar cancers. At a median follow-up of 19.2 months, median DOR was not reached (range, 23.3 to 29.5+ months; + indicates a censored observation) in the five responding patients in the cervical cohort; the DOR was 5.0 months in the single responding patient in the vaginal/vulvar cohort. Median overall survival was 21.9 months (95% CI, 15.1 months to not reached) among patients with cervical cancer. Any-grade treatment-related adverse events were reported in 12 of 19 patients (63.2%) in the cervical cohort and all five patients in the vaginal/vulvar cohort; there were no treatment-related deaths. In the cervical cohort, nivolumab treatment generally resulted in stabilization of patient-reported outcomes associated with health status and health-related quality of life. Conclusion: The efficacy of nivolumab in patients with recurrent/metastatic cervical and vaginal or vulvar cancers is promising and warrants additional investigation. No new safety signals were identified with nivolumab treatment in this population

Level models of continuing professional development evaluation: a grounded review and critique

Continuing professional development (CPD) evaluation in education has been heavily influenced by ‘level models’, deriving from the work of Kirkpatrick and Guskey in particular, which attempt to trace the processes through which CPD interventions achieve outcomes. This paper considers the strengths and limitations of such models, and in particular the degree to which they are able to do justice to the complexity of CPD and its effects. After placing level models within the broader context of debates about CPD evaluation, the paper reports our experience of developing such models heuristically for our own evaluation practice. It then draws on positivist, realist and constructivist traditions to consider some more fundamental ontological and epistemological questions to which they give rise. The paper concludes that level models can be used in a number of ways and with differing emphases, and that choices made about their use will need to reflect both theoretical choices and practical considerations

Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: Is riboflavin supplementation effective?

Background: Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy. Results: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation. Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and

Age at first birth in women is genetically associated with increased risk of schizophrenia

Prof. Paunio on PGC:n jäsenPrevious studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is -0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health.Peer reviewe

Authentic leadership and followers' in-role and extra-role performance: the mediating role of followers' learning goal orientation

This study examined whether and why authentic leadership predicts followers' performance. We hypothesized that authentic leadership predicts followers' learning goal orientation (goal to develop and improve), which, in turn, predicts followers' in-role and (civic virtue) extra-role performance. A multilevel, multisource, time-lagged study, conducted in telecommunications companies in Pakistan, among 115 supervisors and 345 reports supported indirect relations between authentic leadership and (1) follower in-role and (2) extra-role performance (civic virtue) mediated by followers' learning goal orientation