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CONTEXT: Next-generation sequencing (NGS) analysis of sporadic medullary thyroid carcinoma (sMTC) has led to increased detection of somatic mutations, including RET M918T, which has been considered a negative prognostic indicator. OBJECTIVE: This study aimed to determine the association between clinicopathologic behavior and somatic mutation identified on clinically motivated NGS. METHODS: In this retrospective cohort study, patients with sMTC who underwent NGS to identify somatic mutations for treatment planning were identified. Clinicopathologic factors, time to distant metastatic disease (DMD), disease-specific survival (DSS), and overall survival (OS) were compared between somatic mutations. RESULTS: Somatic mutations were identified in 191 sMTC tumors, including RET M918T (53.4%), other RET codons (10.5%), RAS (18.3%), somatic RET indels (8.9%), and RET/RAS wild-type (WT) status (8.9%). The median age at diagnosis was 50 years (range, 11-83); 46.1% were female. When comparing patients with RET M918T, RET-Other, and RET WT (which included RAS and RET/RAS WT), there were no differences in sex, TNM category, systemic therapy use, time to DMD, DSS, or OS. On multivariate analysis, older age at diagnosis (HR 1.05, P < .001; HR 1.06, P< .001) and M1 stage at diagnosis (HR 3.17, P = .001; HR 2.98, P = .001) were associated with decreased DSS and OS, respectively, but mutation cohort was not. When comparing RET M918T to RET indels there was no significant difference in time to DMD, DSS, or OS between the groups. CONCLUSION: Somatic RET mutations do not portend compromised DSS or OS in a cohort of sMTC patients who underwent clinically motivated NGS.

Yves Flattet,1 Nicolas Garin,1,2 Jacques Serratrice,1 Arnaud Perrier,1 Jérome Stirnemann,1 Sebastian Carballo1 1Department of Internal Medicine, Service of General Internal Medicine, Geneva University Hospitals, Geneva, 2Service of Internal Medicine, Riviera Chablais Hospital, Monthey, Switzerland Background: Acute exacerbations are the leading causes of hospitalization and mortality in patients with COPD. Prognostic tools for patients with chronic COPD exist, but there are scarce data regarding acute exacerbations. We aimed to identify the prognostic factors of death and readmission after exacerbation of COPD.Methods: This was a retrospective study conducted in the Department of Internal Medicine of Geneva University Hospitals. All patients admitted to the hospital with a diagnosis of exacerbation of COPD between 2008 and 2011 were included. The studied variables included comorbidities, Global Initiative for Chronic Obstructive Lung Disease (GOLD) severity classification, and biological and clinical parameters. The main outcome was death or readmission during a 5-year follow-up. The secondary outcome was death. Survival analysis was performed (log-rank and Cox).Results: We identified a total of 359 patients (195 men and 164 women, average age 72 years). During 5-year follow-up, 242 patients died or were hospitalized for the exacerbation of COPD. In multivariate analysis, age (hazard ratio [HR] 1.03, 95% CI 1.02–1.05; P

Oxygenated organic molecules (OOMs) play an important role in the formation of atmospheric aerosols. Due to various analytical challenges with respect to measuring organic vapors, uncertainties remain regarding the formation and fate of OOMs. The chemical ionization Orbitrap (CI-Orbitrap) mass spectrometer has recently been shown to be a powerful technique that is able to accurately identify gaseous organic compounds due to its greater mass resolution. Here, we present the ammonium-ion-based CI-Orbitrap (NH4+-Orbitrap) as a technique capable of measuring a wide range of gaseous OOMs. The performance of the NH4+-Orbitrap is compared with that of state-of-the-art mass spectrometers, including a nitrate-ion-based chemical ionization atmospheric pressure interface coupled to a time-of-flight mass spectrometer (NO3--LTOF), a new generation of proton transfer reaction-TOF mass spectrometer (PTR3-TOF), and an iodide-based CI-TOF mass spectrometer equipped with a Filter Inlet for Gases and AEROsols (I−-CIMS). The instruments were deployed simultaneously in the Cosmic Leaving OUtdoors Droplets (CLOUD) chamber at the European Organization for Nuclear Research (CERN) during the CLOUD14 campaign in 2019. Products generated from α-pinene ozonolysis under various experimental conditions were simultaneously measured by the mass spectrometers. The NH4+-Orbitrap was able to identify the widest range of OOMs (i.e., O ≥ 2), from less-oxidized species to highly oxygenated organic molecules (HOMs). Excellent agreement was found between the NH4+-Orbitrap and the NO3--LTOF with respect to characterizing HOMs and with the PTR3-TOF for the less-oxidized monomeric species. OOM concentrations measured by NH4+-Orbitrap were estimated using calibration factors derived from the OOMs with high time-series correlations during the side-by-side measurements. As with the other mass spectrometry techniques used during this campaign, the detection sensitivity of the NH4+-Orbitrap to OOMs is greatly affected by relative humidity, which may be related to changes in ionization efficiency and/or multiphase chemistry. Overall, this study shows that NH4+-ion-based chemistry associated with the high mass resolution of the Orbitrap mass analyzer can measure almost all inclusive compounds. As a result, it is now possible to cover the entire range of compounds, which can lead to a better understanding of the oxidation processes.

Objective Describe trends in health care utilization, demographic characteristics and patient pathways among patients with musculoskeletal disorders (MSD) in Norway.Design Register-based cohort study.Settings Data were obtained from two Norwegian National registries; the Norwegian Control and Payment of Health Reimbursements Database (KUHR) and the Norwegian Patient Registry (NPR).Subjects Patients with MSD according to ICPC-2 and ICD-10 during 2014–2017.Main outcome measures Patient pathways from the first contact and the following two years, described in a Sankey Diagram for all MSD patients and three common diagnoses: spine pain, osteoarthritis (OA) and fibromyalgia (FM).Result About 26% of the Norwegian population consulted PHC annually while 7% were treated in SHC. Mean age was 47 and 53 years in PHC and SHC, respectively. The proportion of women increased by age. Spine pain was the most common diagnosis; 33% and 22% in PHC and SHC, respectively. Over 90% visited a GP first, 50% of them were treated by PT and/or in SHC during follow-up. Patients visiting the PT first were less likely to be treated in SHC. OA patients were most likely to be treated by more than one health care professional (>70%).Conclusion One third of the Norwegian population consulted health care services due to MSD annually between 2014–2017. GP was the most consulted health care professional. Among MSD patients with long-term use of health care services, 50% were treated by a PT and/or in SHC in addition to a GP.

Abstract Centrioles are the core constituent of centrosomes, microtubule-organizing centers involved in directing mitotic spindle assembly and chromosome segregation in animal cells. In sexually reproducing species, centrioles degenerate during oogenesis and female meiosis is usually acentrosomal. Centrioles are retained during male meiosis and, in most species, are reintroduced with the sperm during fertilization, restoring centriole numbers in embryos. In contrast, the presence, origin, and function of centrioles in parthenogenetic species is unknown. We found that centrioles are maternally inherited in two species of asexual parthenogenetic nematodes and identified two different strategies for maternal inheritance evolved in the two species. In Rhabditophanes diutinus, centrioles organize the poles of the meiotic spindle and are inherited by both the polar body and embryo. In Disploscapter pachys, the two pairs of centrioles remain close together and are inherited by the embryo only. Our results suggest that maternally-inherited centrioles organize the embryonic spindle poles and act as a symmetry-breaking cue to induce embryo polarization. Thus, in these parthenogenetic nematodes, centrioles are maternally-inherited and functionally replace their sperm-inherited counterparts in sexually reproducing species.

The choice of stones by the ancient Greeks to build edifices remains an open question. If the use of local materials seems generalized, allochthonous stones are usually also present but lead to obvious extra costs. The current work aims to have an exhaustive view of the origins of the stones used in the Sanctuary of Delphi. Located on the Parnassus zone, on the hanging wall of a large normal fault related to the Corinth Rift, this Apollo Sanctuary is mainly built of limestones, breccia, marbles, as well as more recent poorly consolidated sediments generally called pôros in the literature. To overpass this global view, the different lithologies employed in the archaeological site have been identified, as well as the local quarries, in order to find their origins. The different limestones are autochthons and come from the Upper Jurassic – Cretaceous carbonate platform of the Tethys Ocean involved in the Hellenides orogen. Those limestones of the Parnassus Massif constitute the majority of the rock volume in the site; a specific facies of Maastrichtian limestone called “Profitis Ilias limestone” has been used for the more prestigious edifices such as the Apollo Temple. The corresponding ancient quarry is located few kilometers west of the sanctuary. Then, slope breccia has been largely used in the sanctuary: it crops out in and around the site and is laying on top of the carbonates. Finally, the pôros appear to be very variable and seven different facies have been documented, including travertine, oolitic grainstone, marine carbonates and coarse-grained sandstones. All these recent facies exist in the south-east shore of the Gulf of Corinth, although – except for the grainstone – the quarries are not yet known.

Abstract Background The impact of social frailty on older adults is profound including mortality risk, functional decline, falls, and disability. However, effective strategies that respond to the needs of socially frail older adults are lacking and few studies have unpacked how social determinants operate or how interventions can be adapted during periods requiring social distancing and isolation such as the COVID-19 pandemic. To address these gaps, we conducted a scoping review using JBI methodology to identify interventions that have the best potential to help socially frail older adults (age ≥65 years). Methods We searched MEDLINE, CINAHL (EPSCO), EMBASE and COVID-19 databases and the grey literature. Eligibility criteria were developed using the PICOS framework. Our results were summarized descriptively according to study, patient, intervention and outcome characteristics. Data synthesis involved charting and categorizing identified interventions using a social frailty framework. Results Of 263 included studies, we identified 495 interventions involving ~124,498 older adults who were mostly female. The largest proportion of older adults (40.5%) had a mean age range of 70-79 years. The 495 interventions were spread across four social frailty domains: social resource (40%), self-management (32%), social behavioural activity (28%), and general resource (0.4%). Of these, 189 interventions were effective for improving loneliness, social and health and wellbeing outcomes across psychological self-management, self-management education, leisure activity, physical activity, Information Communication Technology and socially assistive robot interventions. Sixty-three interventions were identified as feasible to be adapted during infectious disease outbreaks (e.g., COVID-19, flu) to help socially frail older adults. Conclusions Our scoping review identified promising interventions with the best potential to help older adults living with social frailty.

Abstract Background The advanced access (AA) model is among the most recommended innovations for improving timely access in primary care (PC). AA is based on core pillars such as comprehensive planning for care needs and supply, regularly adjusting supply to demand, optimizing appointment systems, and interprofessional collaborative practices. Exposure of family medicine residents to AA within university-affiliated family medicine groups (U-FMGs) is a promising strategy to widen its dissemination and improve access. Using four AA pillars as a conceptual model, this study aimed to determine the theoretical compatibility of Quebec’s university-affiliated clinics’ residency programs with the key principles of AA. Methods A cross-sectional online survey was sent to the chief resident and academic director at each participating clinic. An overall response rate of 96% (44/46 U-FMGs) was obtained. Results No local residency program was deemed compatible with all four considered pillars. On planning for needs and supply, only one quarter of the programs were compatible with the principles of AA, owing to residents in out-of-clinic rotations often being unavailable for extended periods. On regularly adjusting supply to demand, 54% of the programs were compatible. Most (82%) programs’ appointment systems were not very compatible with the AA principles, mostly because the proportion of the schedule reserved for urgent appointments was insufficient. Interprofessional collaboration opportunities in the first year of residency allowed 60% of the programs to be compatible with this pillar. Conclusions Our study highlights the heterogeneity among local residency programs with respect to their theoretical compatibility with the key principles of AA. Future research to empirically test the hypotheses raised by this study is warranted.

Abstract The interaction of rarefied gases with functionalized surfaces is of great importance in technical applications such as gas separation membranes and catalysis. To investigate the influence of functionalization and rarefaction on gas flow rate in a defined geometry, pressure-driven gas flow experiments with helium and carbon dioxide through plain and alkyl-functionalized microchannels are performed. The experiments cover Knudsen numbers from 0.01 to 200 and therefore the slip flow regime up to free molecular flow. To minimize the experimental uncertainty which is prevalent in micro flow experiments, a methodology is developed to make optimal use of the measurement data. The results are compared to an analysis-based hydraulic closure model (ACM) predicting rarefied gas flow in straight channels and to numerical solutions of the linearized S-model and BGK kinetic equations. The experimental data shows that if there is a difference between plain and functionalized channels, it is likely obscured by experimental uncertainty. This stands in contrast to previous measurements in smaller geometries and demonstrates that the surface-to-volume ratio of 0.4 $$\upmu$$ μ m $$^{-1}$$ - 1 seems to be too small for the functionalization to have a strong influence and highlights the importance of geometric scale for surface effects. These results also shed light on the molecular reflection characteristics described by the TMAC.

Hydroxyl radical (OH) is a key oxidant that triggers atmospheric oxidation chemistry in both gas and aqueous phases. The current understanding of its aqueous sources is mainly based on known bulk (photo)chemical processes, uptake from gaseous OH, or related to interfacial O3 and NO3 radical-driven chemistry. Here, we present experimental evidence that OH radicals are spontaneously produced at the air-water interface of aqueous droplets in the dark and the absence of known precursors, possibly due to the strong electric field that forms at such interfaces. The measured OH production rates in atmospherically relevant droplets are comparable to or significantly higher than those from known aqueous bulk sources, especially in the dark. As aqueous droplets are ubiquitous in the troposphere, this interfacial source of OH radicals should significantly impact atmospheric multiphase oxidation chemistry, with substantial implications on air quality, climate, and health.

Monitoring melanoma incidence time trends by tumour thickness is essential to understanding the evolution of melanoma occurrence and guiding prevention strategies. To assess long-term incidence trends, tumour thickness was extracted from pathology reports in the Cancer Registry of Norway (1983–2007) and the Norwegian Melanoma Registry (2008–2019), n = 45,635 patients. Across all anatomic sites, T1 (≤ 1 mm) incidence increased most (men annual percentage change [AAPC] = 4.6, 95% confidence interval [95% CI] 4.2–5.0; women AAPC = 3.2, 95% CI 2.8–3.6); the increase was steep until 1989/90, followed by a plateau, and a further steep increase from 2004/05. Increased incidence was also observed for T2 (>1.0–2.0) melanoma (men AAPC = 2.8, 95% CI 2.4–3.2; women AAPC = 1.5, 95% CI 1.1–1.9), and T3 (>2.0–4.0) in men (AAPC = 1.4, 95% CI 0.9–1.9). T4 (>4.0) melanoma followed a similar overall pattern (men AAPC = 1.3, 95% CI 0.9–1.7, head/neck, upper limbs, and trunk; women AAPC = 0.9, 95% CI 0.4–1.4, upper limbs and trunk). Men had the highest T3 and T4 incidence and the sex difference increased with age. Regarding birth cohorts, age-specific incidence increased in all T categories in the oldest age groups, while stabilizing in younger patients born after 1950. Overall, the steep increase in T1 melanoma was not accompanied by a decrease in thick melanoma.

BackgroundPatient navigation interventions (PNIs) can provide personalized support and promote appropriate coordination or continuation of health and social care services. Online PNIs have demonstrated excellent potential for improving patient knowledge, transition readiness, self-efficacy, and use of services. However, the characteristics (ie, intervention type, mode of delivery, duration, frequency, outcomes and outcome measures, underlying theories or mechanisms of change of the intervention, and impact) of existing online PNIs to support the health and social needs of individuals with illness remain unclear. ObjectiveThis scoping review of the existing literature aims to identify the characteristics of existing online PNIs reported in the literature. MethodsA scoping review based on the guidelines outlined in the Joanna Briggs Institute framework was conducted. A search for peer-reviewed literature published between 1989 and 2022 on online PNIs was conducted using MEDLINE, CINAHL, Embase, PsycInfo, and Cochrane Library databases. Two independent reviewers conducted 2 levels of screening. Data abstraction was conducted to outline key study characteristics (eg, study design, population, and intervention characteristics). The data were analyzed using descriptive statistics and qualitative content analysis. ResultsA total of 100 studies met the inclusion criteria. Our findings indicate that a variety of study designs are used to describe and evaluate online PNIs, with literature being published between 2003 and 2022 in Western countries. Of these studies, 39 (39%) studies were randomized controlled trials. In addition, we noticed an increase in reported online PNIs since 2019. The majority of studies involved White females with a diagnosis of cancer and a lack of participants aged 70 years or older was observed. Most online PNIs provide support through navigation, self-management and lifestyle changes, counseling, coaching, education, or a combination of support. Variation was noted in terms of mode of delivery, duration, and frequency. Only a small number of studies described theoretical frameworks or change mechanisms to guide intervention. ConclusionsTo our knowledge, this is the first review to comprehensively synthesize the existing literature on online PNIs, by focusing on the characteristics of interventions and studies in this area. Inconsistency in reporting the country of publication, population characteristics, duration and frequency of interventions, and a lack of the use of underlying theories and working mechanisms to inform intervention development, provide guidance for the reporting of future online PNIs.