Adsorbate dissociation due to heteromolecular electronic energy transfer from fluorobenzene thin films.

Study of the near-UV photodissociation dynamics for monolayer (ML) quantities of CH3I on thin films of a series of fluorobenzenes and benzene (1-25 ML) grown on a Cu(100) substrate finds that in addition to gas-phase-like neutral photodissociation, CH3I dissociation can be enhanced via electronic energy transfer to the CH3I following photoabsorption in several of the thin films studied. Distinct CH3 photofragment kinetic energy distributions are found for CH3I photodissociation on C6H5F, 1,4-C6H4F2 and C6H6 thin films, and distinguished from neutral photodissociation pathways using polarized incident light. The effective photodissociation cross section for CH3I on these thin films is increased as compared to that for the higher F-count fluorobenzene thin films due to the additional photodissociation pathway available. Quenching by the metal substrate of the photoexcitation via this new pathway suggests a significantly longer timescale for excitation than that of neutral CH3I photodissociation. The observations support a mechanism in which neutral photoexcitation in the thin film (i.e. an exciton) is transported to the interface with CH3I, and transfers the electronic excitation to the CH3I which then dissociates. The unimodal CH3 photofragment distribution and observed kinetic energies on the fluorobenzene thin films suggest that the dissociation occurs via the 3Q1 excited state of CH3I.

The association of new-onset diabetes with subsequent diagnosis of pancreatic cancer-novel use of a large administrative database.

BACKGROUND: Screening options for pancreatic ductal adenocarcinoma (PDAC) are limited. New-onset type 2 diabetes (NoD) is associated with subsequent diagnosis of PDAC in observational studies and may afford an opportunity for PDAC screening. We evaluated this association using a large administrative database. METHODS: Patients were identified using claims data from the OptumLabs® Data Warehouse. Adult patients with NoD diagnosis were matched 1:3 with patients without NoD using age, sex and chronic obstructive pulmonary disease (COPD) status. The event of PDAC diagnosis was compared between cohorts using the Kaplan-Meier method. Factors associated with PDAC diagnosis were evaluated with Cox's proportional hazards modeling. RESULTS: We identified 640 421 patients with NoD and included 1 921 263 controls. At 3 years, significantly more PDAC events were identified in the NoD group vs control group (579 vs 505; P < 0.001). When controlling for patient factors, NoD was significantly associated with elevated risk of PDAC (HR 3.474, 95% CI 3.082-3.920, P < 0.001). Other factors significantly associated with PDAC diagnosis were increasing age, increasing age among Black patients, and COPD diagnosis (P ≤ 0.05). CONCLUSIONS: NoD was independently associated with subsequent diagnosis of PDAC within 3 years. Future studies should evaluate the feasibility and benefit of PDAC screening in patients with NoD.

Opioid analgesic effects on subjective well-being in the operating theatre.

Exposure to opioid analgesics due to surgery increases the risk of new persistent opioid use. A mechanistic hypothesis for opioids' abuse liability rests on the belief that, in addition to pain relief, acute opioid treatment improves well-being (e.g. via euphoria) and relieves anxiety. However, opioids do not consistently improve mood in laboratory studies of healthy non-opioid users. This observational study determined how two commonly used opioid analgesics affected patients' subjective well-being in standard clinical practice. Day surgery patients rated how good and how anxious they felt before and after an open-label infusion of remifentanil (n = 159) or oxycodone (n = 110) in the operating theatre before general anaesthesia. One minute after drug injection, patients reported feeling intoxicated (> 6/10 points). Anxiety was reduced after opioids, but this anxiolytic effect was modest (remifentanil Cohen's d = 0.21; oxycodone d = 0.31). There was moderate to strong evidence against a concurrent improvement in well-being (Bayes factors > 6). After remifentanil, ratings of 'feeling good' were significantly reduced from pre-drug ratings (d = 0.28). After oxycodone, one in three participants felt better than pre-drug. Exploratory ordered logistic regressions revealed a link between previous opioid exposure and opioid effects on well-being, as only 14 of the 80 opioid-naïve patients reported feeling better after opioid injection. The odds of improved well-being ratings after opioids were higher in patients with previous opioid exposure and highest in patients with > 2 weeks previous opioid use (adjusted OR = 4.4). These data suggest that opioid-induced improvement of well-being is infrequent in opioid-naïve patients. We speculate that peri-operative exposure could increase risk of persistent use by rendering subsequent positive opioid effects on well-being more likely.

Antitumor activity of ipilimumab or BRAF ± MEK inhibition after pembrolizumab treatment in patients with advanced melanoma: analysis from KEYNOTE-006.

BACKGROUND: Antitumor activity of ipilimumab or BRAF ± MEK inhibitors (BRAFi ± MEKi) following pembrolizumab administration in melanoma is poorly characterized. PATIENTS AND METHODS: In the phase III KEYNOTE-006 study, patients with unresectable stage III/IV melanoma received pembrolizumab (10 mg/kg) once every 2 or 3 weeks (Q3W) or ipilimumab (3 mg/kg) Q3W. The current post hoc analysis evaluates outcomes with ipilimumab or BRAFi ± MEKi as first subsequent systemic therapy after pembrolizumab administration and includes patients who completed or discontinued pembrolizumab after one or more dose. Pembrolizumab arms were pooled. RESULTS: At data cut-off (4 December 2017), median follow-up was 46.9 months. Of 555 pembrolizumab-treated patients, first subsequent therapy was ipilimumab for 103 (18.6%) and BRAFi ± MEKi for 59 (10.6%) [33 received BRAFi + MEKi, 26 BRAFi alone; 37 (62.7%) were BRAFi ± MEKi naïve]. In the subsequent ipilimumab group, ORR with previous pembrolizumab was 17.5% [1 complete response (CR); 17 partial response (PR)]; 79.6% had discontinued pembrolizumab due to progressive disease (PD); median overall survival (OS) was 21.5 months. ORR with subsequent ipilimumab was 15.5%; 11/16 responses (8 CRs; 3 PRs) were ongoing. ORR with subsequent ipilimumab was 9.7% for patients with PD as best response to pembrolizumab. Median OS from ipilimumab initiation was 9.8 months. In the subsequent BRAFi ± MEKi group, ORR with previous pembrolizumab was 13.5% (8 PR); 76.3% had discontinued pembrolizumab due to PD; median OS was 17.9 months. ORR with subsequent BRAFi ± MEKi was 30.5%, 7/18 responses (4 CR, 3 PR) were ongoing. Median OS from BRAFi ± MEKi initiation was 12.9 months. ORR for BRAFi ± MEKi-naïve patients who received subsequent BRAFi ± MEKi was 43.2%; 6/16 were ongoing (3 CR, 3 PR). CONCLUSIONS: Ipilimumab and BRAFi ± MEKi have antitumor activity as first subsequent therapy after pembrolizumab in patients with advanced melanoma.

Survival after antireflux surgery versus medication in patients with reflux oesophagitis or Barrett's oesophagus: multinational cohort study.

BACKGROUND: The aim was to examine the hypothesis that antireflux surgery with fundoplication improves long-term survival compared with antireflux medication in patients with reflux oesophagitis or Barrett's oesophagus. METHOD: Individuals aged between 18 and 70 years with reflux oesophagitis or Barrett's oesophagus (intestinal metaplasia) documented from in-hospital and specialized outpatient care were selected from national patient registries in Denmark, Finland, Iceland, and Sweden from 1980 to 2014. The study investigated all-cause mortality and disease-specific mortality, comparing patients who had undergone open or laparoscopic antireflux surgery with fundoplication versus those using antireflux medication. Multivariable Cox regression analysis was used to estimate hazard ratios (HRs) with 95 per cent confidence intervals for all-cause mortality and disease-specific mortality, adjusted for sex, age, calendar period, country, and co-morbidity. RESULTS: Some 240 226 patients with reflux oesophagitis or Barrett's oesophagus were included, of whom 33 904 (14.1 per cent) underwent antireflux surgery. The risk of all-cause mortality was lower after antireflux surgery than with use of medication (HR 0.61, 95 per cent c.i. 0.58 to 0.63), and lower after laparoscopic (HR 0.56, 0.52 to 0.60) than open (HR 0.80, 0.70 to 0.91) surgery. After antireflux surgery, mortality was decreased from cardiovascular disease (HR 0.58, 0.55 to 0.61), respiratory disease (HR 0.62, 0.57 to 0.66), laryngeal or pharyngeal cancer (HR 0.35, 0.19 to 0.65), and lung cancer (HR 0.67, 0.58 to 0.80), but not from oesophageal cancer (HR 1.05, 0.87 to 1.28), compared with medication, The decreased mortality rates generally remained over time. CONCLUSION: In patients with reflux oesophagitis or Barrett's oesophagus, antireflux surgery is associated with lower mortality from all causes, cardiovascular disease, respiratory disease, laryngeal or pharyngeal cancer, and lung cancer, but not from oesophageal cancer, compared with antireflux medication.

Socio-economic inequalities in fragility fracture incidence: a systematic review and meta-analysis of 61 observational studies.

Individuals with low socio-economic status (SES) have a more than 25% higher risk of fragility fractures than individuals with high SES. Body mass index and lifestyle appear to mediate the effect of SES on fracture risk. Strategies to prevent fractures should aim to reduce unhealthy behaviours through tackling structural inequalities. INTRODUCTION: This systematic review and meta-analysis aimed to evaluate the impact of socio-economic status (SES) on fragility fracture risk. METHODS: Medline, Embase, and CINAHL databases were searched from inception to 28 April 2021 for studies reporting an association between SES and fragility fracture risk among individuals aged ≥50 years. Risk ratios (RR) were combined in meta-analyses using random restricted maximum likelihood models, for individual-based (education, income, occupation, cohabitation) and area-based (Index of Multiple Deprivation, area income) SES measures. RESULTS: A total of 61 studies from 26 different countries including more than 19 million individuals were included. Individual-based low SES was associated with an increased risk of fragility fracture (RR 1.27 [95% CI 1.12, 1.44]), whilst no clear association was seen when area-based measures were used (RR 1.08 [0.91, 1.30]). The strength of associations was influenced by the type and number of covariates included in statistical models: RR 2.69 [1.60, 4.53] for individual-based studies adjusting for age, sex and BMI, compared with RR 1.06 [0.92, 1.22] when also adjusted for health behaviours (smoking, alcohol, and physical activity). Overall, the quality of the evidence was moderate. CONCLUSION: Our results show that low SES, measured at the individual level, is a risk factor for fragility fracture. Low BMI and unhealthy behaviours are important mediators of the effect of SES on fracture risk. Strategies to prevent fractures and reduce unhealthy behaviours should aim to tackle structural inequalities in society thereby reducing health inequalities in fragility fracture incidence.

Contrasting mechanisms for photodissociation of methyl halides adsorbed on thin films of C6H6 and C6F6.

The mechanisms for photodissociation of methyl halides (CH3X, X = Cl, Br, I) have been studied for these molecules when adsorbed on thin films of C6H6 or C6F6 on copper single crystals, using time-of-flight spectroscopy with 248 nm and 193 nm light. For CH3Cl and CH3Br monolayers adsorbed on C6H6, two photodissociation pathways can be identified - neutral photodissociation similar to the gas-phase, and a dissociative electron attachment (DEA) pathway due to photoelectrons from the metal. The same methyl halides adsorbed on a C6F6 thin film display only neutral photodissociation, with the DEA pathway entirely absent due to intermolecular quenching via a LUMO-derived electronic band in the C6F6 thin film. For CH3I adsorbed on a C6F6 thin film, illumination with 248 nm light results in CH3 photofragments departing due to neutral photodissociation via the A-band absorption. When CH3I monolayers on C6H6 thin films are illuminated at the same wavelength, additional new photodissociation pathways are observed that are due to absorption in the molecular film with energy transfer leading to dissociation of the CH3I molecules adsorbed on top. The proposed mechanism for this photodissociation is via a charge-transfer complex for the C6H6 layer and adsorbed CH3I.

The implementation of routine procedural transvaginal sonography to decrease retained products of conception: a quality improvement initiative.

BACKGROUND: Retained products of conception (POC) following uterine evacuation can lead to adverse sequelae, including hemorrhage, endometritis, intrauterine adhesions, and reoperation. Use of procedural transvaginal sonography (TVUS) in the operating room has been proposed to help decrease retained POC. METHODS: A retrospective review of all first trimester uterine evacuation procedures from 1/2015 to 2/2017 was performed, noting use of transabdominal ultrasonography, retained products of conception, and complications. A practice change was implemented in May 2018, in which routine intra-procedural TVUS use was initiated. A second retrospective chart review was conducted to assess for post-implementation incidence of retained POC, re-operation, and associated complications. RESULTS: Prior to intra-procedural TVUS implementation, 130 eligible procedures were performed during the specified timeframe, with 9/130 (6.9%) incidence of retained products of conception. TAUS was performed in 59/130 (45.4%) of procedures, and 4/9 (44.4%) of those with retained products. There were eight re-operative procedures in seven patients, and two patients were treated with misoprostol. Complications included hemorrhage, Asherman's syndrome and endometritis. Following implementation, 95 first trimester procedures were performed with transvaginal sonography, with 0 (0%) cases of retained POC (p = 0.01), no incidences of re-operation (p = 0.02), and one case of Asherman's syndrome. TVUS findings led to additional focused suction curettage in 20/95 (21.0%) of procedures. The endometrium was measured on procedure completion in 64 procedures, with a mean thickness of 5.5 mm (1-12 mm). CONCLUSION: Implementation of routine TVUS during uterine evacuation may reduce the incidence of retained POC and associated reoperation rates. Further multi-center trials are needed to confirm this finding.

Increased risk of eosinophilic esophagitis with poor environmental quality as measured by the Environmental Quality Index.

Geographic differences in eosinophilic esophagitis (EoE) prevalence suggest the possibility that environmental exposures contribute to EoE pathogenesis. We aimed to examine the association between environmental quality and risk of EoE, using the Environmental Quality Index (EQI), which provides quantification of environmental quality in five domains: air, land, water, built, and sociodemographic for all counties in the United States. To do this, we performed a case-control study in a large pathology database. EoE cases were defined by ≥15 eosinophils per high-power field with other pathologic diagnoses excluded; controls did not have EoE. The pathology data were geocoded and linked with the EQI by county of residence. Logistic regression was used to estimate odds ratio (OR and 95% confidence interval [CI]) of EoE with overall EQI and for each domain, after adjusting for sex, age, and proportion minority race or ethnicity at the county level (higher EQI score indicates worse environmental quality). Of 29,802 EoE cases and 593,329 controls analyzed, odds of EoE were highest in the worst quintile of EQI (OR 1.25; 95% CI: 1.04-1.50), which was largely explained by poor scores in the water domain (OR: 1.33; 1.17-1.50). Conversely, odds of EoE were reduced with higher scores in the air domain (OR: 0.87, 0.74-1.03) and land domain (OR 0.87; 0.76-0.99). Poor EQI, mostly reflected by poor water quality, was associated with increased odds of EoE, while poor air and land quality were inversely associated with EoE. Additional work to identify specific water pollutants that may have an etiologic role in EoE may be warranted.

Reintervention or mortality within 90 days of bariatric surgery: population-based cohort study.

BACKGROUND: Bariatric surgery carries a risk of severe postoperative complications, sometimes leading to reinterventions or even death. The incidence and risk factors for reintervention and death within 90 days after bariatric surgery are unclear, and were examined in this study. METHODS: This population-based cohort study included all patients who underwent bariatric surgery in one of the five Nordic countries between 1980 and 2012. Data on surgical and endoscopic procedures, diagnoses and mortality were retrieved from national high-quality and complete registries. Multivariable Cox regression analysis was used to calculate hazard ratios (HRs), adjusted for country, age, sex, co-morbidity, type of surgery and approach, year and hospital volume of bariatric surgery. RESULTS: Of 49 977 patients, 1111 (2·2 per cent) had a reintervention and 95 (0·2 per cent) died within 90 days of bariatric surgery. Risk factors for the composite outcome reintervention/mortality were older age (HR 1·65, 95 per cent c.i. 1·36 to 2·01, for age at least 50 years versus less than 30 years) and co-morbidity (HR 2·66, 1·53 to 4·62, for Charlson co-morbidity index score 2 or more versus 0). The risk of reintervention/mortality was decreased for vertical banded gastroplasty compared with gastric bypass (HR 0·37, 0·28 to 0·48) and more recent surgery (HR 0·51, 0·39 to 0·67, for procedures undertaken in 2010 or later versus before 2000). Sex, surgical approach (laparoscopic versus open) and hospital volume did not influence risk of reintervention/mortality, but laparoscopic surgery was associated with a lower risk of 90-day mortality (HR 0·29, 0·16 to 0·53). CONCLUSION: Reintervention and death were uncommon events within 90 days of bariatric surgery even in this unselected nationwide cohort from five countries. Older patients with co-morbidities have an increased relative risk of these outcomes.

ANTECEDENTES: La cirugía bariátrica conlleva un riesgo de complicaciones postoperatorias graves, que algunas veces ocasionan reintervenciones o incluso son causa de mortalidad. La incidencia y los factores de riesgo de reinterveniones y mortalidad a los 90 días tras cirugía bariátrica no están claros, y fueron examinados en este estudio. MÉTODOS: Todos los pacientes que fueron sometidos a cirugía bariátrica en uno de los cinco países nórdicos en 1980-2012 fueron incluidos en un estudio de cohortes de base poblacional. Los datos de los procedimientos quirúrgicos y endoscópicos, diagnóstico, y mortalidad se obtuvieron a partir de registros nacionales completos y de alta calidad. Mediante una regresión de Cox multivariable se obtuvieron los cocientes de riesgos instantáneos (hazard ratios, HR) y los intervalos de confianza 95% (i.c. del 95%) ajustados por país, edad, sexo, comorbilidad, y tipo, abordaje, año y volumen de casos de cirugía bariátrica del hospital. RESULTADOS: De un total de 49.977 pacientes, 1.111 (2,2%) precisaron una reintervención y 95 (0,2%) fallecieron durante los primeros 90 días tras la cirugía bariátrica. Los factores de riesgo para el resultado compuesto reintervención/mortalidad fueron la edad avanzada (HR = 1,7 (i.c. del 95% 1,4-2,0) edad ≥ 50 versus < 30 años)) y la comorbilidad (HR = 2,7 (i.c. del 95% 1,5-4,6) puntuación del índice de comorbilidad de Charlson ≥ 2 versus 0)). Se observó una disminución de los HRs tras la gastroplastia vertical con banda en comparación con el bypass gástrico (HR = 0,4, (i.c. del 95% 0,3-0,5)) y el periodo de estudio más reciente (HR = 0,5 (i.c. del 95% 0,4-0,7) ≥ 2010 versus < 2000)). El sexo, el abordaje quirúrgico laparoscópico versus abierto y el volumen del hospital no influyeron sobre el riesgo de reintervención/mortalidad, pero la cirugía laparoscópica se asoció con una mortalidad a los 90 días más baja (HR 0,3, i.c. del 95% 0,2-0,5). CONCLUSIÓN: La reintervención y la mortalidad son eventos infrecuentes durante los primeros 90 días tras la cirugía bariátrica, incluso en esta cohorte nacional y no seleccionada de cinco paises. Los pacientes mayores con comorbilidades tienen un riesgo relativo aumentado de reintervención y mortalidad.

Association between fear of hypoglycemia and physical activity in youth with type 1 diabetes: The SEARCH for diabetes in youth study.

BACKGROUND: Youth with type 1 diabetes (T1D) are encouraged to participate in physical activity (PA). Studies have identified fear of hypoglycemia (FOH) as a barrier to participating in PA. OBJECTIVES: To examine (a) PA patterns in youth with T1D by age group and (b) the relationship between both parental and youth FOH and youth PA. METHODS: A cross-sectional analysis from the SEARCH cohort study visit of youth ages 10 to 17 years with T1D (n = 1129) was conducted. Linear regression models estimated the association between self-reported number of days of vigorous PA (VPA) and moderate PA (MPA) and both youth- and parent-reported FOH. Multivariable models were adjusted for age, sex, race, duration of T1D, HbA1c, use of continuous glucose monitoring (CGM), recent severe hypoglycemia, primary insulin regimen, and BMI. RESULTS: Participants were 52% female, had mean (sd) age 14.4 (4.2) years, diabetes duration 7.5 years (1.8), HbA1c 9.2% (1.7). Older youth were less likely to engage in VPA (P < .01), or sports teams (P < .01), but more likely to engage in MPA (P < .01). Higher youth FOH (behavior subscale) was associated with increased levels of VPA (ß (se) 0.30 (0.11), P = .01) but not significantly associated with MPA (P = .06). There was no statistically significant association between parental FOH and youth PA. CONCLUSIONS: In SEARCH participants with T1D, VPA, and team sports participation declined with age, while MPA increased. We observed that higher scores on the youth FOH behavioral subscale were associated with increased VPA levels, suggesting that FOH may be less of a barrier to PA than previously thought.

Detection of norovirus infections in Denmark, 2011-2018.

Norovirus (NoV) infections occur very frequently yet are rarely diagnosed. In Denmark, NoV infections are not under surveillance. We aimed to collect and describe existing laboratory-based NoV data. National NoV laboratory data were collected for 2011-2018, including information on patient identification number, age and sex, requesting physician, analysis date and result. We defined positive patient-episodes by using a 30-day time window and performed descriptive and time series analysis. Diagnostic methods used were assessed through a survey. We identified 15 809 patient-episodes (11%) out of 142 648 tested patients with an increasing trend, 9366 in 2011 vs. 32 260 in 2018. This corresponded with a gradual introduction of polymerase chain reaction analysis in laboratories. The highest positivity rate was in patients aged <5 years (15%) or >85 years (17%). There was a large difference in test performance over five Danish geographical regions and a marked seasonal variation with peaks from December to February. This is the first analysis of national NoV laboratory data in Denmark. A future laboratory-based surveillance system may benefit public health measures by describing trend, burden and severity of seasons and possibly pinpoint hospital outbreaks.

Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001.

BACKGROUND: Pembrolizumab demonstrated robust antitumor activity and safety in the phase Ib KEYNOTE-001 study (NCT01295827) of advanced melanoma. Five-year outcomes in all patients and treatment-naive patients are reported herein. Patients whose disease progressed following initial response and who received a second course of pembrolizumab were also analyzed. PATIENTS AND METHODS: Patients aged ≥18 years with previously treated or treatment-naive advanced/metastatic melanoma received pembrolizumab 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks until disease progression, intolerable toxicity, or patient/investigator decision to withdraw. Kaplan-Meier estimates of overall survival (OS) and progression-free survival (PFS) were calculated. Objective response rate and PFS were based on immune-related response criteria by investigator assessment (data cut-off, September 1, 2017). RESULTS: KEYNOTE-001 enrolled 655 patients with melanoma; median follow-up was 55 months. Estimated 5-year OS was 34% in all patients and 41% in treatment-naive patients; median OS was 23.8 months (95% CI, 20.2-30.4) and 38.6 months (95% CI, 27.2-not reached), respectively. Estimated 5-year PFS rates were 21% in all patients and 29% in treatment-naive patients; median PFS was 8.3 months (95% CI, 5.8-11.1) and 16.9 months (95% CI, 9.3-35.5), respectively. Median response duration was not reached; 73% of all responses and 82% of treatment-naive responses were ongoing at data cut-off; the longest response was ongoing at 66 months. Four patients [all with prior response of complete response (CR)] whose disease progressed during observation subsequently received second-course pembrolizumab. One patient each achieved CR and partial response (after data cut-off). Treatment-related AEs (TRAEs) occurred in 86% of patients and resulted in study discontinuation in 7.8%; 17% experienced grade 3/4 TRAE. CONCLUSIONS: This 5-year analysis of KEYNOTE-001 represents the longest follow-up for pembrolizumab to date and confirms the durable antitumor activity and tolerability of pembrolizumab in advanced melanoma. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov, NCT01295827.

Use of archival versus newly collected tumor samples for assessing PD-L1 expression and overall survival: an updated analysis of KEYNOTE-010 trial.

BACKGROUND: In KEYNOTE-010, pembrolizumab versus docetaxel improved overall survival (OS) in patients with programmed death-1 protein (PD)-L1-positive advanced non-small-cell lung cancer (NSCLC). A prespecified exploratory analysis compared outcomes in patients based on PD-L1 expression in archival versus newly collected tumor samples using recently updated survival data. PATIENTS AND METHODS: PD-L1 was assessed centrally by immunohistochemistry (22C3 antibody) in archival or newly collected tumor samples. Patients received pembrolizumab 2 or 10 mg/kg Q3W or docetaxel 75 mg/m2 Q3W for 24 months or until progression/intolerable toxicity/other reason. Response was assessed by RECIST v1.1 every 9 weeks, survival every 2 months. Primary end points were OS and progression-free survival (PFS) in tumor proportion score (TPS) ≥50% and ≥1%; pembrolizumab doses were pooled in this analysis. RESULTS: At date cut-off of 24 March 2017, median follow-up was 31 months (range 23-41) representing 18 additional months of follow-up from the primary analysis. Pembrolizumab versus docetaxel continued to improve OS in patients with previously treated, PD-L1-expressing advanced NSCLC; hazard ratio (HR) was 0.66 [95% confidence interval (CI): 0.57, 0.77]. Of 1033 patients analyzed, 455(44%) were enrolled based on archival samples and 578 (56%) on newly collected tumor samples. Approximately 40% of archival samples and 45% of newly collected tumor samples were PD-L1 TPS ≥50%. For TPS ≥50%, the OS HRs were 0.64 (95% CI: 0.45, 0.91) and 0.40 (95% CI: 0.28, 0.56) for archival and newly collected samples, respectively. In patients with TPS ≥1%, OS HRs were 0.74 (95% CI: 0.59, 0.93) and 0.59 (95% CI: 0.48, 0.73) for archival and newly collected samples, respectively. In TPS ≥50%, PFS HRs were similar across archival [0.63 (95% CI: 0.45, 0.89)] and newly collected samples [0.53 (95% CI: 0.38, 0.72)]. In patients with TPS ≥1%, PFS HRs were similar across archival [0.82 (95% CI: 0.66, 1.02)] and newly collected samples [0.83 (95% CI: 0.68, 1.02)]. CONCLUSION: Pembrolizumab continued to improve OS over docetaxel in intention to treat population and in subsets of patients with newly collected and archival samples. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01905657.

Timing of HPV16-E6 antibody seroconversion before OPSCC: findings from the HPVC3 consortium.

BACKGROUND: Human papillomavirus type 16 (HPV16)-E6 antibodies are detectable in peripheral blood before diagnosis in the majority of HPV16-driven oropharyngeal squamous cell carcinoma (OPSCC), but the timing of seroconversion is unknown. PATIENTS AND METHODS: We formed the HPV Cancer Cohort Consortium which comprises nine population cohorts from Europe, North America and Australia. In total, 743 incident OPSCC cases and 5814 controls provided at least one pre-diagnostic blood sample, including 111 cases with multiple samples. Median time between first blood collection and OPSCC diagnosis was 11.4 years (IQR = 6-11 years, range = 0-40 years). Antibodies against HPV16-E6 were measured by multiplex serology (GST fusion protein based Luminex assay). RESULTS: HPV16-E6 seropositivity was present in 0.4% of controls (22/5814; 95% CI 0.2% to 0.6%) and 26.2% (195/743; 95% CI 23.1% to 29.6%) of OPSCC cases. HPV16-E6 seropositivity increased the odds of OPSCC 98.2-fold (95% CI 62.1-155.4) in whites and 17.2-fold (95% CI 1.7-170.5) in blacks. Seropositivity in cases was more frequent in recent calendar periods, ranging from 21.9% pre-1996 to 68.4% in 2005 onwards, in those with blood collection near diagnosis (lead time <5 years). HPV16-E6 seropositivity increased with lead time: 0.0%, 13.5%, 23.7%, and 38.9% with lead times of >30 years (N = 24), 20-30 years (N = 148), 10-20 years (N = 228), and <10 years (N = 301 cases) (p-trend < 0.001). Of the 47 HPV16-E6 seropositive cases with serially-collected blood samples, 17 cases seroconverted during follow-up, with timing ranging from 6 to 28 years before diagnosis. For the remaining 30 cases, robust seropositivity was observed up to 25 years before diagnosis. CONCLUSIONS: The immune response to HPV16-driven tumorigenesis is most often detectable several decades before OPSCC diagnosis. HPV16-E6 seropositive individuals face increased risk of OPSCC over several decades.

Disentangling the genetic effects of refugial isolation and range expansion in a trans-continentally distributed species.

In wide-ranging taxa with historically dynamic ranges, past allopatric isolation and range expansion can both influence the current structure of genetic diversity. Considering alternate historical scenarios involving expansion from either a single refugium or from multiple refugia can be useful in differentiating the effects of isolation and expansion. Here, we examined patterns of genetic variability in the trans-continentally distributed painted turtle (Chrysemys picta). We utilized an existing phylogeographic dataset for the mitochondrial control region and generated additional data from nine populations for the mitochondrial control region (n = 302) and for eleven nuclear microsatellite loci (n = 247). We created a present-day ecological niche model (ENM) for C. picta and hindcast this model to three reconstructions of historical climate to define three potential scenarios with one, two, or three refugia. Finally, we employed spatially-explicit coalescent simulations and an approximate Bayesian computation (ABC) framework to test which scenario best fit the observed genetic data. Simulations indicated that phylogeographic and multilocus population-level sampling both could differentiate among refugial scenarios, although inferences made using mitochondrial data were less accurate when a longer coalescence time was assumed. Furthermore, all empirical genetic datasets were most consistent with expansion from a single refugium based on ABC. Our results indicate a stronger role for post-glacial range expansion, rather than isolation in allopatric refugia followed by range expansion, in structuring diversity in this species. To distinguish among complex historical scenarios, we recommend explicitly modeling the effects of range expansion and evaluating alternate refugial scenarios for wide-ranging taxa.

Practical implementation of the planar and spatial rotator in a complex tissue: the brain.

In neuroscience, application of widely used stereological local volume estimators, including the planar rotator, is challenged by the combination of a complex tissue organisation and an estimator requirement of either isotropic or vertical sections, i.e. randomly oriented tissue. The spatial rotator is applicable with any tissue orientation but is sensitive to projection artefacts. The challenge is thus to select the most appropriate method for individual analyses. In this study, agreement between estimates of mean cell volume acquired with the vertical planar and the spatial rotator is assessed for two brain regions with different types of cytoarchitecture (motor cortex and hippocampal cornu ammonis 1). The possibility of using the planar rotator in tissues cut in an arbitrary direction is explored and requirements for a theoretically unbiased result as well as histological considerations are provided. LAY DESCRIPTION: Cells may change volume both during disease and with advancing age. Assessment of the volume of individual cells can therefore serve as a useful indicator of general tissue state. Most available methods to estimate cell volume in tissue sections, however, require that the tissue analysed has random orientation. Particularly for complex tissues such as the brain this is a challenge as identification, delineation and subdivision of many brain areas rely heavily on the use of anatomical atlases where illustrations depict the tissue in a few well-known orientations. In this study, the practical application of two different methods for estimating mean cell volumes in tissues cut in a preferred orientation is evaluated. Requirements for the feasibility of cell volume estimation without random tissue orientation as well as histological considerations are provided.

The Zinc Linchpin Motif in the DNA Repair Glycosylase MUTYH: Identifying the Zn2+ Ligands and Roles in Damage Recognition and Repair.

The DNA base excision repair (BER) glycosylase MUTYH prevents DNA mutations by catalyzing adenine (A) excision from inappropriately formed 8-oxoguanine (8-oxoG):A mismatches. The importance of this mutation suppression activity in tumor suppressor genes is underscored by the association of inherited variants of MUTYH with colorectal polyposis in a hereditary colorectal cancer syndrome known as MUTYH-associated polyposis, or MAP. Many of the MAP variants encompass amino acid changes that occur at positions surrounding the two-metal cofactor-binding sites of MUTYH. One of these cofactors, found in nearly all MUTYH orthologs, is a [4Fe-4S]2+ cluster coordinated by four Cys residues located in the N-terminal catalytic domain. We recently uncovered a second functionally relevant metal cofactor site present only in higher eukaryotic MUTYH orthologs: a Zn2+ ion coordinated by three Cys residues located within the extended interdomain connector (IDC) region of MUTYH that connects the N-terminal adenine excision and C-terminal 8-oxoG recognition domains. In this work, we identified a candidate for the fourth Zn2+ coordinating ligand using a combination of bioinformatics and computational modeling. In addition, using in vitro enzyme activity assays, fluorescence polarization DNA binding assays, circular dichroism spectroscopy, and cell-based rifampicin resistance assays, the functional impact of reduced Zn2+ chelation was evaluated. Taken together, these results illustrate the critical role that the "Zn2+ linchpin motif" plays in MUTYH repair activity by providing for proper engagement of the functional domains on the 8-oxoG:A mismatch required for base excision catalysis. The functional importance of the Zn2+ linchpin also suggests that adjacent MAP variants or exposure to environmental chemicals may compromise Zn2+ coordination, and ability of MUTYH to prevent disease.

Risk factors for requiring cholecystectomy for gallstone disease in a prospective population-based cohort study.

BACKGROUND: The relationship between different lifestyle factors and the risk of needing cholecystectomy for gallstone disease is not clear. This study aimed to assess the association between anthropometric, lifestyle and sociodemographic risk factors and the subsequent risk of requiring cholecystectomy for gallstone disease during long-term follow-up in a defined population cohort. METHODS: Data from a large population-based cohort study performed from 1995 to 1997 were used (the second Norwegian Nord-Trøndelag health study, HUNT2). Following HUNT2, from 1998 to 2011, all patients operated on for gallstone disease with cholecystectomy at the two hospitals in the county, Levanger Hospital and Namsos Hospital, were identified. A Cox proportional hazards model was used for multivariable risk analysis. RESULTS: The HUNT2 cohort included 65 237 individuals (69·5 per cent response rate), aged 20-99 years. During a median follow-up of 15·3 (range 0·6-16·4) years, 1162 cholecystectomies were performed. In multivariable analysis, overweight individuals (body mass index (BMI) 25·0-29·9 kg/m(2) ) had a 58 per cent increased risk of cholecystectomy compared with individuals with normal weight (BMI less than 25·0 kg/m(2) ). Obese individuals (BMI 30 kg/m(2) or above) had a twofold increased risk. Increasing waist circumference independently increased the risk of cholecystectomy. In women, current hormone replacement therapy (HRT) increased the risk, whereas hard physical activity and higher educational level were associated with reduced risk of cholecystectomy. CONCLUSION: High BMI and waist circumference increased the risk of having cholecystectomy for both sexes. In women, the risk was increased by HRT, and decreased by hard physical activity and higher educational level.

Stereological estimation of particle shape and orientation from volume tensors.

In the present paper, we describe new robust methods of estimating cell shape and orientation in 3D from sections. The descriptors of 3D cell shape and orientation are based on volume tensors which are used to construct an ellipsoid, the Miles ellipsoid, approximating the average cell shape and orientation in 3D. The estimators of volume tensors are based on observations in several optical planes through sampled cells. This type of geometric sampling design is known as the optical rotator. The statistical behaviour of the estimator of the Miles ellipsoid is studied under a flexible model for 3D cell shape and orientation. In a simulation study, the lengths of the axes of the Miles ellipsoid can be estimated with coefficients of variation of about 2% if 100 cells are sampled. Finally, we illustrate the use of the developed methods in an example, involving neurons in the medial prefrontal cortex of rat.