Global disparities in surgeons’ workloads, academic engagement and rest periods: the on-calL shIft fOr geNEral SurgeonS (LIONESS) study

: The workload of general surgeons is multifaceted, encompassing not only surgical procedures but also a myriad of other responsibilities. From April to May 2023, we conducted a CHERRIES-compliant internet-based survey analyzing clinical practice, academic engagement, and post-on-call rest. The questionnaire featured six sections with 35 questions. Statistical analysis used Chi-square tests, ANOVA, and logistic regression (SPSS® v. 28). The survey received a total of 1.046 responses (65.4%). Over 78.0% of responders came from Europe, 65.1% came from a general surgery unit; 92.8% of European and 87.5% of North American respondents were involved in research, compared to 71.7% in Africa. Europe led in publishing research studies (6.6 ± 8.6 yearly). Teaching involvement was high in North America (100%) and Africa (91.7%). Surgeons reported an average of 6.7 ± 4.9 on-call shifts per month, with European and North American surgeons experiencing 6.5 ± 4.9 and 7.8 ± 4.1 on-calls monthly, respectively. African surgeons had the highest on-call frequency (8.7 ± 6.1). Post-on-call, only 35.1% of respondents received a day off. Europeans were most likely (40%) to have a day off, while African surgeons were least likely (6.7%). On the adjusted multivariable analysis HDI (Human Development Index) (aOR 1.993) hospital capacity > 400 beds (aOR 2.423), working in a specialty surgery unit (aOR 2.087), and making the on-call in-house (aOR 5.446), significantly predicted the likelihood of having a day off after an on-call shift. Our study revealed critical insights into the disparities in workload, access to research, and professional opportunities for surgeons across different continents, underscored by the HDI

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Bem3, a Cdc42 GTPase-activating protein, traffics to an intracellular compartment and recruits the secretory Rab GTPase Sec4 to endomembranes

Cell polarity is essential for many cellular functions including division and cell-fate determination. Although RhoGTPase signaling and vesicle trafficking are both required for the establishment of cell polarity, the mechanisms by which they are coordinated are unclear. Here, we demonstrate that the yeast RhoGAP (GTPase activating protein), Bem3, is targeted to sites of polarized growth by the endocytic and recycling pathways. Specifically, deletion of SLA2 or RCY1 led to mislocalization of Bem3 to depolarized puncta and accumulation in intracellular compartments, respectively. Bem3 partitioned between the plasma membrane and an intracellular membrane-bound compartment. These Bem3-positive structures were polarized towards sites of bud emergence and were mostly observed during the pre-mitotic phase of apical growth. Cell biological and biochemical approaches demonstrated that this intracellular Bem3 compartment contained markers for both the endocytic and secretory pathways, which were reminiscent of the Spitzenkörper present in the hyphal tips of growing fungi. Importantly, Bem3 was not a passive cargo, but recruited the secretory Rab protein, Sec4, to the Bem3-containing compartments. Moreover, Bem3 deletion resulted in less efficient localization of Sec4 to bud tips during early stages of bud emergence. Surprisingly, these effects of Bem3 on Sec4 were independent of its GAP activity, but depended on its ability to efficiently bind endomembranes. This work unveils unsuspected and important details of the relationship between vesicle traffic and elements of the cell polarity machinery: (1) Bem3, a cell polarity and peripherally associated membrane protein, relies on vesicle trafficking to maintain its proper localization; and (2) in turn, Bem3 influences secretory vesicle trafficking

Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial

Background: Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist being examined in an ongoing phase 3 trial in adults with IgA nephropathy. We report the prespecified interim analysis of the primary proteinuria efficacy endpoint, and safety. Methods: PROTECT is an international, randomised, double-blind, active-controlled study, being conducted in 134 clinical practice sites in 18 countries. The study examines sparsentan versus irbesartan in adults (aged ≥18 years) with biopsy-proven IgA nephropathy and proteinuria of 1·0 g/day or higher despite maximised renin-angiotensin system inhibitor treatment for at least 12 weeks. Participants were randomly assigned in a 1:1 ratio to receive sparsentan 400 mg once daily or irbesartan 300 mg once daily, stratified by estimated glomerular filtration rate at screening (30 to 1·75 g/day). The primary efficacy endpoint was change from baseline to week 36 in urine protein-creatinine ratio based on a 24-h urine sample, assessed using mixed model repeated measures. Treatment-emergent adverse events (TEAEs) were safety endpoints. All endpoints were examined in all participants who received at least one dose of randomised treatment. The study is ongoing and is registered with ClinicalTrials.gov, NCT03762850. Findings: Between Dec 20, 2018, and May 26, 2021, 404 participants were randomly assigned to sparsentan (n=202) or irbesartan (n=202) and received treatment. At week 36, the geometric least squares mean percent change from baseline in urine protein-creatinine ratio was statistically significantly greater in the sparsentan group (-49·8%) than the irbesartan group (-15·1%), resulting in a between-group relative reduction of 41% (least squares mean ratio=0·59; 95% CI 0·51-0·69; p<0·0001). TEAEs with sparsentan were similar to irbesartan. There were no cases of severe oedema, heart failure, hepatotoxicity, or oedema-related discontinuations. Bodyweight changes from baseline were not different between the sparsentan and irbesartan groups. Interpretation: Once-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy. Safety of sparsentan was similar to irbesartan. Future analyses after completion of the 2-year double-blind period will show whether these beneficial effects translate into a long-term nephroprotective potential of sparsentan. Funding: Travere Therapeutics

Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial

BackgroundSparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis.MethodsPROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1·0 g per day despite maximised renin–angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850.FindingsBetween Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White) . Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6–110) was −2·7 mL/min per 1·73 m2 per year versus −3·8 mL/min per 1·73 m2 per year (difference 1·1 mL/min per 1·73 m2 per year, 95% CI 0·1 to 2·1; p=0·037); total 2-year slope (day 1–week 110) was −2·9 mL/min per 1·73 m2 per year versus −3·9 mL/min per 1·73 m2 per year (difference 1·0 mL/min per 1·73 m2 per year, 95% CI −0·03 to 1·94; p=0·058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (−42·8%, 95% CI −49·8 to −35·0, with sparsentan versus −4·4%, −15·8 to 8·7, with irbesartan; geometric least-squares mean ratio 0·60, 95% CI 0·50 to 0·72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0·7, 95% CI 0·4 to 1·2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals.InterpretationOver 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function

Search for CPCP violation in ttH and tH production in multilepton channels in proton-proton collisions at s\sqrt{s} = 13 TeV

International audienceThe charge-parity (CP) structure of the Yukawa interaction between the Higgs (H) boson and the top quark is measured in a data sample enriched in the t$\overline{\textrm{t}}$H and tH associated production, using 138 fb$^{−1}$ of data collected in proton-proton collisions at $\sqrt{s}$ = 13 TeV by the CMS experiment at the CERN LHC. The study targets events where the H boson decays via H → WW or H → ττ and the top quarks decay via t → Wb: the W bosons decay either leptonically or hadronically, and final states characterized by the presence of at least two leptons are studied. Machine learning techniques are applied to these final states to enhance the separation of CP -even from CP -odd scenarios. Two-dimensional confidence regions are set on κ$_{t}$ and $\overset{\sim }{\kappa } _{t}$, which are respectively defined as the CP -even and CP -odd top-Higgs Yukawa coupling modifiers. No significant fractional CP -odd contributions, parameterized by the quantity |${f}_{CP}^{\textrm{Htt}}$| are observed; the parameter is determined to be |${f}_{CP}^{\textrm{Htt}}$| = 0.59 with an interval of (0.24, 0.81) at 68% confidence level. The results are combined with previous results covering the H → ZZ and H → γγ decay modes, yielding two- and one-dimensional confidence regions on κ$_{t}$ and $\overset{\sim }{\kappa } _{t}$, while |${f}_{CP}^{\textrm{Htt}}$| is determined to be |${f}_{CP}^{\textrm{Htt}}$| = 0.28 with an interval of |${f}_{CP}^{\textrm{Htt}}$| < 0.55 at 68% confidence level, in agreement with the standard model CP -even prediction of |${f}_{CP}^{\textrm{Htt}}$| = 0.[graphic not available: see fulltext

Search for high-mass exclusive γγ\gamma\gamma→\to WW and γγ\gamma\gamma→\to ZZ production in proton-proton collisions at s\sqrt{s} = 13 TeV

A search is performed for exclusive high-mass $\gamma\gamma$$\to$ WW and $\gamma\gamma$$\to$ ZZ production in proton-proton collisions using intact forward protons reconstructed in near-beam detectors, with both weak bosons decaying into boosted and merged jets. The analysis is based on a sample of proton-proton collisions collected by the CMS and TOTEM experiments at $\sqrt{s}$ = 13 TeV, corresponding to an integrated luminosity of 100 fb$^{−1}$. No excess above the standard model background prediction is observed, and upper limits are set on the pp → pWWp and pp → pZZp cross sections in a fiducial region defined by the diboson invariant mass m(VV) > 1 TeV (with V = W, Z) and proton fractional momentum loss 0.04 < $ξ$ < 0.20. The results are interpreted as new limits on dimension-6 and dimension-8 anomalous quartic gauge couplings.[graphic not available: see fulltext

Search for a charged Higgs boson decaying into a heavy neutral Higgs boson and a W boson in proton-proton collisions at s=\sqrt{s} = 13 TeV

A search for a charged Higgs boson ${\mathrm{\tilde{H}^{\pm}}}$ decaying into a heavy neutral Higgs boson H and a W boson is presented. The analysis targets the H decay into a pair of tau leptons with at least one of them decaying hadronically and with an additional electron or muon present in the event. The search is based on proton-proton collision data recorded by the CMS experiment during 2016-2018 at $\sqrt{s} =$ 13 TeV, corresponding to an integrated luminosity of 138 fb$^{-1}$. The data are consistent with standard model background expectations. Upper limits at 95% confidence level are set on the product of the cross section and branching fraction for an ${\mathrm{\tilde{H}^{\pm}}}$ in the mass range of 300-700 GeV, assuming an H with a mass of 200 GeV. The observed limits range from 0.085 pb for an ${\mathrm{\tilde{H}^{\pm}}}$ mass of 300 GeV to 0.019 pb for a mass of 700 GeV. These are the first limits on ${\mathrm{\tilde{H}^{\pm}}}$ production in the ${\mathrm{\tilde{H}^{\pm}}} \to \mathrm{H} \mathrm{W^{\pm}}$ decay channel at the LHC.A search for a charged Higgs boson H$^{±}$ decaying into a heavy neutral Higgs boson H and a W boson is presented. The analysis targets the H decay into a pair of tau leptons with at least one of them decaying hadronically and with an additional electron or muon present in the event. The search is based on proton-proton collision data recorded by the CMS experiment during 2016–2018 at $\sqrt{s}$ = 13 TeV, corresponding to an integrated luminosity of 138 fb$^{−1}$. The data are consistent with standard model background expectations. Upper limits at 95% confidence level are set on the product of the cross section and branching fraction for an H$^{±}$ in the mass range of 300–700 GeV, assuming an H with a mass of 200 GeV. The observed limits range from 0.085 pb for an H$^{±}$ mass of 300 Ge V to 0.019 pb for a mass of 700 GeV. These are the first limits on H$^{±}$ production in the H$^{±}$→ HW$^{±}$ decay channel at the LHC.[graphic not available: see fulltext]A search for a charged Higgs boson H$^\pm$ decaying into a heavy neutral Higgs boson H and a W boson is presented. The analysis targets the H decay into a pair of tau leptons with at least one of them decaying hadronically and with an additional electron or muon present in the event. The search is based on proton-proton collision data recorded by the CMS experiment during 2016-2018 at $\sqrt{s}$ = 13 TeV, corresponding to an integrated luminosity of 138 fb$^{-1}$. The data are consistent with standard model background expectations. Upper limits at 95% confidence level are set on the product of the cross section and branching fraction for an H$^\pm$ in the mass range of 300-700 GeV, assuming an H with a mass of 200 GeV. The observed limits range from 0.085 pb for an H$^\pm$ mass of 300 GeV to 0.019 pb for a mass of 700 GeV. These are the first limits on H$^\pm$ production in the H$^\pm$ $\to$ HW$^\pm$ decay channel at the LHC

Measurement of the Higgs boson inclusive and differential fiducial production cross sections in the diphoton decay channel with pp collisions at s \sqrt{s} = 13 TeV

The measurements of the inclusive and differential fiducial cross sections of the Higgs boson decaying to a pair of photons are presented. The analysis is performed using proton-proton collisions data recorded with the CMS detector at the LHC at a centre-of-mass energy of 13 TeV and corresponding to an integrated luminosity of 137 fb$^{−1}$. The inclusive fiducial cross section is measured to be ${\sigma}_{\textrm{fid}}={73.4}_{-5.3}^{+5.4}{\left(\textrm{stat}\right)}_{-2.2}^{+2.4}\left(\textrm{syst}\right)$ fb, in agreement with the standard model expectation of 75.4 ± 4.1 fb. The measurements are also performed in fiducial regions targeting different production modes and as function of several observables describing the diphoton system, the number of additional jets present in the event, and other kinematic observables. Two double differential measurements are performed. No significant deviations from the standard model expectations are observed.[graphic not available: see fulltext