Anatomy and physiology of the autonomic nervous system: Implication on the choice of diagnostic/monitoring tools in 2023.

The autonomic nervous system (ANS) harmoniously regulates all internal organic functions (heart rate, blood pressure, vasomotion, digestive tract motility, endocrinal secretions) and adapts them to the needs. It's the control of so-called vegetative functions, which allows homeostasis but also allostasis of our body. ANS is divided into two systems often understood as antagonistic and complementary: the sympathetic and the parasympathetic systems. However, we currently know of many situations of co-activation of the two systems. Long seen as acting through "reflex" control loops passing through the integration of peripheral information and the efferent response to the peripheral organ, more recent electrophysiological and brain functional imaging knowledge has been able to identify the essential role of the central autonomic network. This element complicates the understanding of the responses of the reflex loops classically used to identify and quantify dysautonomia. Finding the "ANS" tools best suited for the clinician in their daily practice is a challenge that we will attempt to address in this work.

Analysis of cellular water content in T cells reveals a switch from slow metabolic water gain to rapid water influx prior to cell division.

Cell growth is driven by the acquisition and synthesis of both dry biomass and water mass. In this study, we examine the increase of water mass in T cell during cell growth. We found that T-cell growth is characterized by an initial phase of slow increase in cellular water, followed by a second phase of rapid increase in water content. To study the origin of the water gain, we developed a novel methodology we call cold aqua trap-isotope ratio mass spectrometry, which allows analysis of the isotope composition of intracellular water. Applying cold aqua trap-isotope ratio mass spectrometry, we discovered that glycolysis-coupled metabolism of water accounts on average for 11 fl out of the 20 fl of water gained per cell during the initial slow phase. In addition, we show that at the end of the rapid phase before initiation of cell division, a water influx occurs, increasing the cellular water mass by threefold. Thus, we conclude that activated T cells switch from metabolizing water to rapidly taking up water from the extracellular medium prior to cell division. Our work provides a method to analyze cell water content as well as insights into the ways cells regulate their water mass.

Germline-focused analysis of tumour-detected variants in 49,264 cancer patients: ESMO Precision Medicine Working Group recommendations.

BACKGROUND: The European Society for Medical Oncology Precision Medicine Working Group (ESMO PMWG) was reconvened to update its 2018/19 recommendations on follow-up of putative germline variants detected on tumour-only sequencing, which were based on an analysis of 17 152 cancers. METHODS: We analysed an expanded dataset including 49 264 paired tumour-normal samples. We applied filters to tumour-detected variants based on variant allele frequency, predicted pathogenicity and population variant frequency. For 58 cancer-susceptibility genes, we then examined the proportion of filtered tumour-detected variants of true germline origin [germline conversion rate (GCR)]. We conducted subanalyses based on the age of cancer diagnosis, specific tumour types and 'on-tumour' status (established tumour-gene association). RESULTS: Analysis of 45 472 nonhypermutated solid malignancy tumour samples yielded 21 351 filtered tumour-detected variants of which 3515 were of true germline origin. 3.1% of true germline pathogenic variants were absent from the filtered tumour-detected variants. For genes such as BRCA1, BRCA2 and PALB2, the GCR in filtered tumour-detected variants was >80%; conversely for TP53, APC and STK11 this GCR was <2%. CONCLUSION: Strategic germline-focused analysis can prioritise a subset of tumour-detected variants for which germline follow-up will produce the highest yield of most actionable true germline variants. We present updated recommendations around germline follow-up of tumour-only sequencing including (i) revision to 5% for the minimum per-gene GCR, (ii) inclusion of actionable intermediate penetrance genes ATM and CHEK2, (iii) definition of a set of seven 'most actionable' cancer-susceptibility genes (BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6 and RET) in which germline follow-up is recommended regardless of tumour type.

Short-course subcutaneous treatment with PQ Grass strongly improves symptom and medication scores in grass allergy.

BACKGROUND: A modified grass allergen subcutaneous immunotherapy (SCIT) product with MicroCrystalline Tyrosine and monophosphoryl lipid-A as an adjuvant system (Grass MATA MPL [PQ Grass]) is being developed as short-course treatment of grass-pollen allergic rhinitis (SAR) and/or rhinoconjunctivitis. We sought to evaluate the combined symptom and medication score (CSMS) of the optimized cumulative dose of 27,600 standardized units (SU) PQ Grass in a field setting prior to embarking on a pivotal Phase III trial. METHODS: In this exploratory, randomized, double-blind, placebo-controlled trial subjects were enrolled across 14 sites (Germany and the United States of America). Six pre-seasonal subcutaneous injections of PQ Grass (using conventional or extended regimens) or placebo were administered to 119 subjects (aged 18-65 years) with moderate-to-severe SAR with or without asthma that was well-controlled. The primary efficacy endpoint was CSMS during peak grass pollen season (GPS). Secondary endpoints included Rhinoconjunctivitis Quality of Life Questionnaire standardized (RQLQ-S) and allergen-specific IgG4 response. RESULTS: The mean CSMS compared to placebo was 33.1% (p = .0325) and 39.5% (p = .0112) for the conventional and extended regimens, respectively. An increase in IgG4 was shown for both regimens (p < .01) as well as an improvement in total RQLQ-S for the extended regimen (mean change -0.72, p = .02). Both regimens were well-tolerated. CONCLUSIONS: This trial demonstrated a clinically relevant and statistically significant efficacy response to PQ Grass. Unprecedented effect sizes were reached for grass allergy of up to ≈40% compared to placebo for CSMS after only six PQ Grass injections. Both PQ Grass regimens were considered equally safe and well-tolerated. Based on enhanced efficacy profile extended regime will be progressed to the pivotal Phase III trial.

Reporting quality of interventions using a wearable activity tracker to improve physical activity in patients with inflammatory arthritis or osteoarthritis: a systematic review.

To assess the reporting quality of interventions aiming at promoting physical activity (PA) using a wearable activity tracker (WAT) in patients with inflammatory arthritis (IA) or hip/knee osteoarthritis (OA). A systematic search was performed in eight databases (including PubMed, Embase and Cochrane Library) for studies published between 2000 and 2022. Two reviewers independently selected studies and extracted data on study characteristics and the reporting of the PA intervention using a WAT using the Consensus on Exercise Reporting Template (CERT) (12 items) and Consolidated Standards of Reporting Trials (CONSORT) E-Health checklist (16 items). The reporting quality of each study was expressed as a percentage of reported items of the total CERT and CONSORT E-Health (50% or less = poor; 51-79% = moderate; and 80-100% = good reporting quality). Sixteen studies were included; three involved patients with IA and 13 with OA. Reporting quality was poor in 6/16 studies and moderate in 10/16 studies, according to the CERT and poor in 8/16 and moderate in 8/16 studies following the CONSORT E-Health checklist. Poorly reported checklist items included: the description of decision rule(s) for determining progression and the starting level, the number of adverse events and how adherence or fidelity was assessed. In clinical trials on PA interventions using a WAT in patients with IA or OA, the reporting quality of delivery process is moderate to poor. The poor reporting quality of the progression and tailoring of the PA programs makes replication difficult. Improvements in reporting quality are necessary.

PERFORMANCE OF SIX SCREENING SCORES FOR OBSTRUCTIVE SLEEP APNOEA IN AN AFRICAN POPULATION.

Introduction: A screening tool for obstructive sleep apnoea (OSA) is useful in low-income countries where it may be difficult to access sleep recordings. The objective of this study was to assess the performance of six screening scores compared with objective sleep recording in an African population sample. Methods: This analysis is based on the "Benin Sleep and Society" (BeSAS) populational study in which respiratory polygraphy (PG) was performed using a type III device and OSA screening questionnaires (STOP, STOP-Bang, Berlin, NOSAS [≥ 8 and ≥ 5), No-Apnea, GOAL) were administered to participants. PG-defined OSA severity categories were defined according to the apnoea-hypopnoea index (AHI): mild (AHI 5 to <15/h), moderate (AHI 15 to <30/h) or severe (AHI≥30/h), and these were compared to score findings. Results: A total of 1810 subjects (mean age 45.4±14.6 years; 57.3% women) were included. For moderate to severe OSA, the area under the receiving operating characteristic (ROC) curve was greatest for GOAL and No-Apnea (0.70), followed by NoSAS5 (0.69). The highest sensitivity values were for NoSAS5 (0.73), No-Apnea (0.72), and GOAL (0.69), while NoSAS8 had the highest specificity (0.91), followed by Berlin (0.88) and GOAL (0.71). All scores performed poorly with respect to the positive predictive value (PPV), which was highest with NoSAS8 (0.38). Conclusion: This study provides the first comparison of the performance of screening scores for OSA in an African population. Although still low, PPV was highest with NoSAS8. Hence, NoSAS8 would be the screening method of choice for OSA in resource-constrained settings where formal sleep recordings are not accessible.

EVALUATION OF A MODIFIED EPWORTH SLEEPINESS SCALE TO RELIABLY ASSESS EXCESSIVE DAYTIME SLEEPINESS IN LOW-INCOME COUNTRIES: RESULTS FROM THE BENIN SOCIETY AND SLEEP (BESAS) STUDY.

Background: The Epworth Sleepiness Scale (ESS) is a tool widely used to assess excessive daytime sleepiness. Unfortunately, it is not reliable in low-income countries where situations such as reading a book, watching TV or driving a car are not common. The aim of this study was thus to assess the performance of a modified version of the Epworth scale in a low-income country. Methods: We used data from the Benin Society and Sleep (BeSAS) study where the ESS and a modified ESS (mESS) were administered to participants. In the mESS, questions four questions over eight were redesigned to reflect common living situations in Benin. The internal coherence of the mESS was assessed using the Cronbach alpha coefficient (CAC). The discriminatory ability of the scale was assessed by comparing the mean scores according to reported sleep quality, insomnia complaints and apnea-hypopnea index (AHI). Results: A total of 2909 participants were recruited, 1129 were male (38.9%) with a mean age (SD) of 44.7 (14.5) y. Overall, 52.4% (1526) completed all the mESS questions while 453 (15.6%) completed the standard ESS. The CAC of the mES was 0.86 showing good internal coherence. Concerning the discriminatory ability, mean scores for mESS were 7.8 for participants with ISI < 8 vs 9.2 for participants with ISI≥8 (p<0.001), 7.8 for participants withPSQI<5 vs 8.3 for participants with PSQI≥5 (p=0.03). No difference was found when comparing the participants participants using different cut-offs of AHI (15 and 30). Conclusion: The mES is more reliable than ES in the Beninese population. mESS shows good internal coherence and differentiates between insomniacs vs non-insomniacs and between good and poor sleepers. Although the mES is not a perfect score, it appears more relevant in the Benin population than the original Epworth scale but needs further validation/improvement in other low-income countries.

[Implementation of pharmaceutical consultations in oncohematology in a teaching hospital: Over one year outcomes]. / Mise en place de consultations pharmaceutiques en oncohématologie dans un centre hospitalo-universitaire : résultats à plus d'un an.

The development of Oral Cancer Therapies (OAT) raises the question of the therapeutic adherence of patients, put in difficulty by the isolation of the patient in the management of treatment and adverse reactions. Accompanying processes are developing, such as Pharmaceutical Consultations (PC), whose monitoring and education objectives are multiple. The PCs and their implementation are presented here, as well as the first results at 15months. The scope of the PCs was first defined, as well as their organization and supporting documents. A patient's medication history is carried out before the PC, then analyzed. The initial PC incorporates a discussion about patient's health habits, followed by information on the OAT, which is closed by the delivery of a follow-up diary. The follow-up PCs, distributed over the course of the first year following the initiation, allow to correct the erroneous knowledge of the patient, to support him in his difficulties and to detect any adverse effects. From May 2019 to August 2020, 81.2% of the 32 patients who initiated OAT took part in CP. A pharmacotherapeutic problem is encountered in 65.4% of them and a drug interaction with alternative or complementary medicines in 62.5% of patients which consuming. The PCs developed provide new elements compared to the recommendations and provide support for patients with toxicities that weaken their medical care throughout their care pathway.

APOBEC mutagenesis, kataegis, chromothripsis in EGFR-mutant osimertinib-resistant lung adenocarcinomas.

BACKGROUND: Studies of targeted therapy resistance in lung cancer have primarily focused on single-gene alterations. Based on prior work implicating apolipoprotein b mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) mutagenesis in histological transformation of epidermal growth factor receptor (EGFR)-mutant lung cancers, we hypothesized that mutational signature analysis may help elucidate acquired resistance to targeted therapies. PATIENTS AND METHODS: APOBEC mutational signatures derived from an Food and Drug Administration-cleared multigene panel [Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT)] using the Signature Multivariate Analysis (SigMA) algorithm were validated against the gold standard of mutational signatures derived from whole-exome sequencing. Mutational signatures were decomposed in 3276 unique lung adenocarcinomas (LUADs), including 93 paired osimertinib-naïve and -resistant EGFR-mutant tumors. Associations between APOBEC and mechanisms of resistance to osimertinib were investigated. Whole-genome sequencing was carried out on available EGFR-mutant lung cancer samples (10 paired, 17 unpaired) to investigate large-scale genomic alterations potentially contributing to osimertinib resistance. RESULTS: APOBEC mutational signatures were more frequent in receptor tyrosine kinase (RTK)-driven lung cancers (EGFR, ALK, RET, and ROS1; 25%) compared to LUADs at large (20%, P < 0.001); across all subtypes, APOBEC mutational signatures were enriched in subclonal mutations (P < 0.001). In EGFR-mutant lung cancers, osimertinib-resistant samples more frequently displayed an APOBEC-dominant mutational signature compared to osimertinib-naïve samples (28% versus 14%, P = 0.03). Specifically, mutations detected in osimertinib-resistant tumors but not in pre-treatment samples significantly more frequently displayed an APOBEC-dominant mutational signature (44% versus 23%, P < 0.001). EGFR-mutant samples with APOBEC-dominant signatures had enrichment of large-scale genomic rearrangements (P = 0.01) and kataegis (P = 0.03) in areas of APOBEC mutagenesis. CONCLUSIONS: APOBEC mutational signatures are frequent in RTK-driven LUADs and increase under the selective pressure of osimertinib in EGFR-mutant lung cancer. APOBEC mutational signature enrichment in subclonal mutations, private mutations acquired after osimertinib treatment, and areas of large-scale genomic rearrangements highlights a potentially fundamental role for APOBEC mutagenesis in the development of resistance to targeted therapies, which may be potentially exploited to overcome such resistance.

Measurements of Strong-Interaction Effects in Kaonic-Helium Isotopes at Sub-eV Precision with X-Ray Microcalorimeters.

We have measured the 3d→2p transition x rays of kaonic ^{3}He and ^{4}He atoms using superconducting transition-edge-sensor microcalorimeters with an energy resolution better than 6 eV (FWHM). We determined the energies to be 6224.5±0.4(stat)±0.2(syst) eV and 6463.7±0.3(stat)±0.1(syst) eV, and widths to be 2.5±1.0(stat)±0.4(syst) eV and 1.0±0.6(stat)±0.3(stat) eV, for kaonic ^{3}He and ^{4}He, respectively. These values are nearly 10 times more precise than in previous measurements. Our results exclude the large strong-interaction shifts and widths that are suggested by a coupled-channel approach and agree with calculations based on optical-potential models.

Women who smoke during pregnancy are more likely to be referred to an obstetrician during pregnancy and birth: results from a cohort study.

BACKGROUND: Women who smoke during pregnancy make less use of prenatal care; the relation of smoking behavior with the use of other forms of maternal healthcare is unknown. The objective of this study is to investigate the association between women's smoking behavior and their use of healthcare during pregnancy, birth and six weeks postpartum. METHODS: We analyzed data from the Dutch Midwifery Case Registration System (VeCaS), period 2012-2019. We included women with a known smoking status, singleton pregnancies, and who had their first appointment before 24 weeks of gestation with the primary care midwife. We compared three groups: non-smokers, early stoppers (stopped smoking in the first trimester), and late- or non-stoppers (stopped smoking after the first trimester or continued smoking). Descriptive statistics were used to report maternal healthcare utilization (during pregnancy, birth and six weeks postpartum), statistical differences between the groups were calculated with Kruskal-Wallis tests. Multivariable logistic regression was conducted to assess the association between smoking behavior and referrals to primary, secondary or tertiary care. RESULTS: We included 41 088 pregnant women. The groups differed significantly on maternal healthcare utilization. The late- or non-stoppers initiated prenatal care later and had less face-to-face consultations with primary care midwives during pregnancy. Compared to the non-smokers, the early- and late- or non-stoppers were statistically signficiantly more likely to be referred to the obstetrician during pregnancy and birth. Postpartum, the early- and late- or non-stoppers were statistically signficantly less likely to be referred to the obstetrician compared to the non-smokers. CONCLUSIONS: Although the early- and late- or non-stoppers initiated prenatal care later than the non-smokers, they did receive adequate prenatal care (according to the recommendations). The results suggest that not smoking during pregnancy may decrease the likelihood of referral to secondary or tertiary care. The large population of smokers being referred during pregnancy underlines the important role of the collaboration between healthcare professionals in primary and secondary or tertiary care. They need to be more aware of the importance of smoking as a medical and as a non-medical risk factor.

Broad spectral tuning of ultra-low-loss polaritons in a van der Waals crystal by intercalation.

Phonon polaritons-light coupled to lattice vibrations-in polar van der Waals crystals are promising candidates for controlling the flow of energy on the nanoscale due to their strong field confinement, anisotropic propagation and ultra-long lifetime in the picosecond range1-5. However, the lack of tunability of their narrow and material-specific spectral range-the Reststrahlen band-severely limits their technological implementation. Here, we demonstrate that intercalation of Na atoms in the van der Waals semiconductor α-V2O5 enables a broad spectral shift of Reststrahlen bands, and that the phonon polaritons excited show ultra-low losses (lifetime of 4 ± 1 ps), similar to phonon polaritons in a non-intercalated crystal (lifetime of 6 ± 1 ps). We expect our intercalation method to be applicable to other van der Waals crystals, opening the door for the use of phonon polaritons in broad spectral bands in the mid-infrared domain.

Role of Chiral Two-Body Currents in

A direct measurement of the decay width of the excited 0_{1}^{+} state of ^{6}Li using the relative self-absorption technique is reported. Our value of Γ_{γ,0_{1}^{+}→1_{1}^{+}}=8.17(14)_{stat.}(11)_{syst.} eV provides sufficiently low experimental uncertainties to test modern theories of nuclear forces. The corresponding transition rate is compared to the results of ab initio calculations based on chiral effective field theory that take into account contributions to the magnetic dipole operator beyond leading order. This enables a precision test of the impact of two-body currents that enter at next-to-leading order.

Test of Lepton-Flavor Universality in B→K

We present a measurement of R_{K^{*}}, the branching fraction ratio B(B→K^{*}µ^{+}µ^{-})/B(B→K^{*}e^{+}e^{-}), for both charged and neutral B mesons. The ratio for the charged case R_{K^{*+}} is the first measurement ever performed. In addition, we report absolute branching fractions for the individual modes in bins of the squared dilepton invariant mass q^{2}. The analysis is based on a data sample of 711 fb^{-1}, containing 772×10^{6} BB[over ¯] events, recorded at the ϒ(4S) resonance with the Belle detector at the KEKB asymmetric-energy e^{+}e^{-} collider. The obtained results are consistent with standard model expectations.

The levonorgestrel intrauterine system versus endometrial ablation for heavy menstrual bleeding: a cost-effectiveness analysis.

OBJECTIVE: To evaluate the costs and non-inferiority of a strategy starting with the levonorgestrel intrauterine system (LNG-IUS) compared with endometrial ablation (EA) in the treatment of heavy menstrual bleeding (HMB). DESIGN: Cost-effectiveness analysis from a societal perspective alongside a multicentre randomised non-inferiority trial. SETTING: General practices and gynaecology departments in the Netherlands. POPULATION: In all, 270 women with HMB, aged ≥34 years old, without intracavitary pathology or wish for a future child. METHODS: Randomisation to a strategy starting with the LNG-IUS (n = 132) or EA (n = 138). The incremental cost-effectiveness ratio was estimated. MAIN OUTCOME MEASURES: Direct medical costs and (in)direct non-medical costs were calculated. The primary outcome was menstrual blood loss after 24 months, measured with the mean Pictorial Blood Assessment Chart (PBAC)-score (non-inferiority margin 25 points). A secondary outcome was successful blood loss reduction (PBAC-score ≤75 points). RESULTS: Total costs per patient were €2,285 in the LNG-IUS strategy and €3,465 in the EA strategy (difference: €1,180). At 24 months, mean PBAC-scores were 64.8 in the LNG-IUS group (n = 115) and 14.2 in the EA group (n = 132); difference 50.5 points (95% CI 4.3-96.7). In the LNG-IUS group, 87% of women had a PBAC-score ≤75 points versus 94% in the EA group (relative risk [RR] 0.93, 95% CI 0.85-1.01). The ICER was €23 (95% CI €5-111) per PBAC-point. CONCLUSIONS: A strategy starting with the LNG-IUS was cheaper than starting with EA, but non-inferiority could not be demonstrated. The LNG-IUS is reversible and less invasive and can be a cost-effective treatment option, depending on the success rate women are willing to accept. TWEETABLE ABSTRACT: Treatment of heavy menstrual bleeding starting with LNG-IUS is cheaper but slightly less effective than endometrial ablation.

[Day/Night Variability of Coughing Events in Interstitial Lung Disease]. / Tag-/Nachtvariabilität von Hustenereignissen bei interstitiellen Lungenerkrankungen.

INTRODUCTION: Besides dyspnea a dry cough is one of the main symptoms in patients with pulmonary fibrosis. Little is known about the 24-hour-variability of this symptom. Moreover, it is unclear if other auscultation phenomena occur. METHODS: A long-term auscultation for 24-hours was performed in patients with fibrotic lung diseases (LEOSound, Löwenstein Medical GmbH & Co. KG, Medical-Electronics, Bad Ems, Germany). Coughing and wheezing sounds were recorded. For the following analysis the 24-hour period was divided into two intervals of 12 hours each (daytime and nighttime). Events were registered in epochs (at least one event in 30 seconds). RESULTS: 20 patients were included (6 with nonspecific interstitial pneumonia and 14 with idiopathic pulmonary fibrosis). On average 166 coughing epochs were recorded in a 24-hour-period (day/night 116/50; P < 0.001). Moreover, 203 wheezing epochs were registered (day/night 84/119; P = 0.273). Auscultation phenomena did not correlate with spirometric and bodyplethymographic data, nor with data of diffusion capacity. DISCUSSION: The study is showing the clinical potential of long-term auscultation in patients with fibrotic lung diseases. Especially the findings concerning the coughing symptoms were remarkable. It could be shown that there was a decrease of coughing during nighttime in comparison to daytime. In contrast to this, wheezing sounds were increasing at nighttime. The clinical relevance of this finding is yet to be assessed. Finally, there was no correlation between the severity of the disease measured by functional diagnostics and the amount of coughing.

Exogenous interleukin-2 can rescue in-vitro T cell activation and proliferation in patients with a novel capping protein regulator and myosin 1 linker 2 mutation.

Capping protein regulator and myosin 1 linker 2 (CARMIL2) deficiency is characterized by impaired T cell activation, which is attributed to defective CD28-mediated co-signaling. Herein, we aimed to analyze the effect of exogenous interleukin (IL)-2 on in-vitro T cell activation and proliferation in a family with CARMIL2 deficiency. This study included four children (one male and three females; aged 2·5-10 years at presentation). The patients presented with inflammatory bowel disease and recurrent viral infections. Genetic analysis revealed a novel homozygous 25-base pairs deletion in CARMIL2. Immunoblotting demonstrated the absence of CARMIL2 protein in all four patients and confirmed the diagnosis of CARMIL2 deficiency. T cells were activated in-vitro with the addition of IL-2 in different concentrations. CD25 and interferon (IFN)-γ levels were measured after 48 h and 5 days of activation. CD25 surface expression on activated CD8+ and CD4+ T cells was significantly diminished in all patients compared to healthy controls. Additionally, CD8+ T cells from all patients demonstrated significantly reduced IFN-γ production. When cells derived from CARMIL2-deficient patients were treated with IL-2, CD25 and IFN-γ production increased in a dose-dependent manner. T cell proliferation, as measured by Cell Trace Violet, was impaired in one patient and it was also rescued with IL-2. In conclusion, we found that IL-2 rescued T cell activation and proliferation in CARMIL2-deficient patients. Thus, IL-2 should be further studied as a potential therapeutic modality for these patients.

Choice of first line systemic treatment in pancreatic cancer among national experts.

BACKGROUND: Treatment options for patients with metastatic pancreatic cancer depend on various factors, including performance status, tumor burden and patient preferences. Metastatic pancreatic cancer is incurable and many systemic treatment options have been investigated over the past decades. This analysis of patterns of practice was performed to identify decision criteria and their impact on the choice of first-line management of metastatic pancreatic cancer. MATERIALS AND METHODS: Members of the Swiss Group for Clinical Cancer Research (SAKK) Gastrointestinal Cancer Group were contacted and agreed to participate in this analysis. Decision trees for the first line treatment of metastatic pancreatic cancer from 9 centers in Switzerland were collected and analyzed based on the objective consensus methodology to identify consensus and discrepancies in clinical decision-making. RESULTS: The final treatment algorithms included 3 decision criteria (comorbidities, performance status and age) and 5 treatment options: FOLFIRINOX, FOLFOX, gemcitabine + nab-paclitaxel, gemcitabine mono and best supportive care. CONCLUSION: We identified multiple decision criteria relevant to all participating centers. We found consensus for the treatment of young (age below 65) patients with good performance status with FOLFIRINOX. For patients with increasing age and reducing performance status there was a decreasing trend to use gemcitabine + nab-paclitaxel. Gemcitabine monotherapy was typically offered to patients in the presence of comorbidities. For patients with ECOG 3-4, most of the experts recommended BSC.

Stress, allostatic load and mental health in Indigenous Australians.

The aim of this narrative review was to demonstrate how the notion of allostatic load (AL) relates directly to the mental health disparities observed between Indigenous and non-Indigenous Australians. We also endeavored to synthesize the results of the limited number of studies examining stress and AL in Indigenous Australians in order to explore the potential public health benefits of the AL concept. A range of literature examining health inequalities, psychosocial determinants of mental illness and AL was explored to demonstrate the applicability of stress biology to the significant mental health burden faced by Indigenous Australians. Furthermore, all original studies indexed in MEDLINE that provided quantitative data on primary stress biomarkers in Indigenous Australians were selected for review. Evidence of hypothalamic-pituitary-adrenal axis dysregulation and increased AL is apparent even in the handful of studies examining stress biomarkers in Indigenous Australians. Urinary, salivary, hair and fingernail cortisol, hair cortisone, urinary epinephrine, heart rate variability and the cortisol awakening response are all AL parameters which have been shown to be dysregulated in Indigenous Australian cohorts. Furthermore, associations between some of these biomarkers, self-perceived discrimination, exposure to stressful life events and symptoms of psychiatric disorders in Indigenous Australians have also been demonstrated. The continued assessment of AL biomarkers and their relationship with past traumas, lifetime stressors and socio-economic factors amongst Indigenous Australians is important to addressing the mental health this population. Measurement of AL biomarkers in a culturally appropriate manner may lead to more targeted preventative measures, interventions and policies, which mitigate the effects of stress at both the individual and societal level.

Germline-focussed analysis of tumour-only sequencing: recommendations from the ESMO Precision Medicine Working Group.

It is increasingly common in oncology practice to perform tumour sequencing using large cancer panels. For pathogenic sequence variants in cancer susceptibility genes identified on tumour-only sequencing, it is often unclear whether they are of somatic or constitutional (germline) origin. There is wide-spread disparity regarding both the extent to which systematic 'germline-focussed analysis' is carried out upon tumour sequencing data and for which variants follow-up analysis of a germline sample is carried out. Here we present analyses of paired sequencing data from 17 152 cancer samples, in which 1494 pathogenic sequence variants were identified across 65 cancer susceptibility genes. From these analyses, the European Society of Medical Oncology Precision Medicine Working Group Germline Subgroup has generated (i) recommendations regarding germline-focussed analyses of tumour-only sequencing data, (ii) indications for germline follow-up testing and (iii) guidance on patient information-giving and consent.