Performance of spleen stiffness measurement to rule out high-risk varices in patients with porto-sinusoidal vascular disorder.

BACKGROUND AIMS: Baveno VII consensus suggests that screening endoscopy can be spared in patients with compensated cirrhosis when spleen stiffness measurement (SSM) by vibration-controlled transient elastography (VCTE) is ≤40 kPa as they have a low probability of high-risk varices (HRV). Conversely, screening endoscopy is required in all patients with porto-sinusoidal vascular disorder (PSVD). This study aimed to evaluate the performance of SSM-VCTE to rule out HRV in patients with PSVD and signs of portal hypertension. APPROACH RESULTS: We retrospectively included patients with PSVD, ≥1 sign of portal hypertension, without history of variceal bleeding, who underwent a SSM-VCTE within 2 years before or after an upper endoscopy in 21 VALDIG centers, divided into a derivation and a validation cohort. 154 patients were included in the derivation cohort; 43% had HRV. By multivariable logistic regression analysis, SSM-VCTE >40 kPa and serum bilirubin ≥1 mg/dL were associated with HRV. SSM-VCTE ≤40 kPa combined with bilirubin <1 mg/dL had a sensitivity of 96% to rule out HRV, and could spare 38% of screening endoscopies, with 4% of HRV missed, and a 95% negative predictive value (NPV). In the validation cohort, including 155 patients, SSM combined with bilirubin could spare 21% of screening endoscopies, with 4% of HRV missed and a 94% NPV. CONCLUSION: This study gathering a total of 309 PSVD patients showed that SSM-VCTE ≤40 kPa combined with bilirubin <1 mg/dL identifies patients with PSVD and portal hypertension with a probability of HRV <5%, in whom screening endoscopy can be spared.

Association of Body Mass Index and Parkinson Disease: A Bidirectional Mendelian Randomization Study.

BACKGROUND AND OBJECTIVES: The role of body mass index (BMI) in Parkinson disease (PD) is unclear. Based on the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in PD (Courage-PD) consortium, we used 2-sample Mendelian randomization (MR) to replicate a previously reported inverse association of genetically predicted BMI with PD and investigated whether findings were robust in analyses addressing the potential for survival and incidence-prevalence biases. We also examined whether the BMI-PD relation is bidirectional by performing a reverse MR. METHODS: We used summary statistics from a genome-wide association study (GWAS) to extract the association of 501 single-nucleotide polymorphisms (SNPs) with BMI and from the Courage-PD and international Parkinson Disease Genomics Consortium (iPDGC) to estimate their association with PD. Analyses are based on participants of European ancestry. We used the inverse-weighted method to compute odds ratios (ORIVW per 4.8 kg/m2 [95% CI]) of PD and additional pleiotropy robust methods. We performed analyses stratified by age, disease duration, and sex. For reverse MR, we used SNPs associated with PD from 2 iPDGC GWAS to assess the effect of genetic liability toward PD on BMI. RESULTS: Summary statistics for BMI are based on 806,834 participants (54% women). Summary statistics for PD are based on 8,919 (40% women) cases and 7,600 (55% women) controls from Courage-PD, and 19,438 (38% women) cases and 24,388 (51% women) controls from iPDGC. In Courage-PD, we found an inverse association between genetically predicted BMI and PD (ORIVW 0.82 [0.70-0.97], p = 0.012) without evidence for pleiotropy. This association tended to be stronger in younger participants (≤67 years, ORIVW 0.71 [0.55-0.92]) and cases with shorter disease duration (≤7 years, ORIVW 0.75 [0.62-0.91]). In pooled Courage-PD + iPDGC analyses, the association was stronger in women (ORIVW 0.85 [0.74-0.99], p = 0.032) than men (ORIVW 0.92 [0.80-1.04], p = 0.18), but the interaction was not statistically significant (p-interaction = 0.48). In reverse MR, there was evidence for pleiotropy, but pleiotropy robust methods showed a significant inverse association. DISCUSSION: Using an independent data set (Courage-PD), we replicate an inverse association of genetically predicted BMI with PD, not explained by survival or incidence-prevalence biases. Moreover, reverse MR analyses support an inverse association between genetic liability toward PD and BMI, in favor of a bidirectional relation.

Portal vein thrombosis: diagnosis, management, and endpoints for future clinical studies.

Portal vein thrombosis (PVT) refers to the development of a non-malignant obstruction of the portal vein, its branches, its radicles, or a combination. This Review first provides a comprehensive overview of all aspects of PVT, namely the specifics of the portal venous system, the risk factors for PVT, the pathophysiology of portal hypertension in PVT, the interest in non-invasive tests, as well as therapeutic approaches including the effect of treating risk factors for PVT or cause of cirrhosis, anticoagulation, portal vein recanalisation by interventional radiology, and prevention and management of variceal bleeding in patients with PVT. Specific issues are also addressed including portal cholangiopathy, mesenteric ischaemia and intestinal necrosis, quality of life, fertility, contraception and pregnancy, and PVT in children. This Review will then present endpoints for future clinical studies in PVT, both in patients with and without cirrhosis, agreed by a large panel of experts through a Delphi consensus process. These endpoints include classification of portal vein thrombus extension, classification of PVT evolution, timing of assessment of PVT, and global endpoints for studies on PVT including clinical outcomes. These endpoints will help homogenise studies on PVT and thus facilitate reporting, comparison between studies, and validation of future studies and trials on PVT.

Morbidity associated with pre-hospital upper-limb tourniquet in civilian trauma: a case series.

INTRODUCTION: The widespread pre-hospital use of tourniquets, particularly in the upper limb, raises questions about associated morbidity, which has been little studied and may have serious consequences for functional prognosis. METHODS: A review of 9 patients was carried out, analyzing pre-hospital tourniquet use in terms of complications affecting recovery. RESULTS: There were serious complications: musculocutaneous nerve palsy in 1 patient, and compartment syndrome, rhabdomyolysis and ischemia-reperfusion syndrome in another. A role of prolonged pre-hospital tourniquet application in postoperative infection was also suspected in 2 patients. DISCUSSION: The risk-benefit ratio and indications for using a tourniquet on the upper limb in the pre-hospital setting need to be reconsidered.

Deficits in congenital amusia: pitch, music, speech, and beyond.

Congenital amusia is a neurodevelopmental disorder characterized by deficits of music perception and production, which are related to altered pitch processing. The present study used a wide variety of tasks to test potential patterns of processing impairment in individuals with congenital amusia (N=18) in comparison to matched controls (N=19), notably classical pitch processing tests (i.e., pitch change detection, pitch direction of change identification, and pitch short-term memory tasks) together with tasks assessing other aspects of pitch-related auditory cognition, such as emotion recognition in speech, sound segregation in tone sequences, and speech-in-noise perception. Additional behavioral measures were also collected, including text reading/copying tests, visual control tasks, and a subjective assessment of hearing abilities. As expected, amusics' performance was impaired for the three pitch-specific tasks compared to controls. This deficit of pitch perception had a self-perceived impact on amusics' quality of hearing. Moreover, participants with amusia were impaired in emotion recognition in vowels compared to controls, but no group difference was observed for emotion recognition in sentences, replicating previous data. Despite pitch processing deficits, participants with amusia did not differ from controls in sound segregation and speech-in-noise perception. Text reading and visual control tests did not reveal any impairments in participants with amusia compared to controls. However, the copying test revealed more numerous eye-movements and a smaller memory span. These results allow us to refine the pattern of pitch processing and memory deficits in congenital amusia, thus contributing further to understand pitch-related auditory cognition. Together with previous reports suggesting a comorbidity between congenital amusia and dyslexia, the findings call for further investigation of language-related abilities in this disorder even in the absence of neurodevelopmental language disorder diagnosis.

Transvaginal radiofrequency ablation of a myoma in ten key steps.

OBJECTIVE: To describe transvaginal radiofrequency ablation of myomas (TRAM) in ten keys steps. DESIGN: Video article STATEMENT OF CONSENT: The patient included in this video gave her consent for its publication online, including social media, the journal website, scientific literature websites (such as PubMed, ScienceDirect, Scopus, etc…) and other applicable sites. SUBJECT: A 38-year-old woman presenting with menometrorrhagia and consequent chronic anemia (hemoglobin 8.5 g/dl) caused by a cervical myoma measuring 51 cm3. Initially, a cervico-vaginal embolization was performed but without any improvement in symptoms. Given the complex position of the myoma (close proximity to the uterine arteries), as well as the patient's desire for future pregnancies, a TRAM was proposed. EXPOSURE: Not applicable. MAIN OUTCOME MEASURES: Volume of myoma and menometrorrhagia 6 months following treatment. RESULT(S): Not applicable CONCLUSION(S): TRAM is a quick, simple, minimally invasive and easily reproducible technique. It could be an interesting alternative to the conventional laparoscopic and open surgical treatments of myomas. There is lack of high-quality data establishing TRAM safety in infertility and pregnancy. The only available radiofrequency ablation device in the United States has specific language stating that this procedure is not recommended for women considering future pregnancy.

Functional outcomes and center of rotation restoration in total hip arthroplasty after acetabular fracture: A review of 367 hips.

BACKGROUND: Total hip arthroplasty (THA) after acetabular fracture is typically performed months or years later for posttraumatic arthritis after initial conservative treatment. But THA can be performed earlier after open reduction and internal fixation (ORIF) of the fracture. The aim of this study was to determine which strategy is best. The primary outcome measure was the radiological restoration of the hip's center of rotation (COR). The secondary outcome measures were the incidence of complications and the hip's functional scores. MATERIALS AND METHODS: A multicenter cohort was analyzed by splitting patients into three groups: group A (THA within 3weeks of fracture); group B (THA deferred after early ORIF); group C (THA more than 3weeks after fracture, without ORIF). Group B was separated into two subgroups: B- (THA less than 1year after ORIF) and B+ (THA more than 1year after ORIF). The demographics, surgical techniques, COR superior and lateral migration coefficient and functional scores (HHS, HOOS-PS and FJS) were recorded. The functional scores were gathered using PROMs. RESULTS: In all, 367 patients were included: 108 in group A, 69 in group B-, 113 in group B+ and 77 in group C. The mean follow-up was 5.8years [3.4 months-35years]. The mean age of the patients was 69.2years [SD 15; 26-101], 52years [SD 16; 19-83], 49years [SD 16; 16-85] and 58.1years [SD 17; 13-94], respectively (p<0.01). The mean ASA score was 2.13 [SD 0.70], 1.84 [SD 0.65], 1.67 [SD 0.63] and 1.79 [SD 0.60], respectively (p<0.01). A complex Letournel fracture was present in 63 patients (61%), 46 patients (71%), 48 patients (49%) and 38 patients (62%), respectively (p<0.01). A reinforcement cage was implanted in 38 patients (69%), 16 patients (62%), 5 patients (12%) and 19 patients (66%), respectively (p<0.01). Cement was used in 45 patients (45%), 23 patients (35%), 19 patients (18%) and 21 patients (32%), respectively (p<0.01). A graft was needed in 46 patients (46%), 35 patients (53%), 17 patients (16%) and 21 patients (48%), respectively (p<0.01). Posterior ORIF was done in 40 patients (46%), 32 patients (55%), 64 patients (61%) and 9 patients (82%), respectively (p<0.01). The COR lateral migration coefficient was significantly higher in group C with a mean of +0.17 (SD 0.85) [-0.27 to +6] compared to the other groups (p=0.02). The COR superior migration coefficient was comparable between groups, with a mean of +0.77 (SD 2.26) [-0.99 to 27], p>0.05. There were complications in 10 patients (9.2%), 6 patients (8.7%), 6 patients (5.3%) and 3 patients (3.9%), respectively, with no significant difference between groups. The PROMs were completed by 51% of patients. At the final review, the mean HHS was 79.2 (SD 21.8) and the mean HOOS-PS was 77.7 (SD 20.1) in the entire cohort, p>0.05. The mean FJS by group was 55.9 (30.2), 47.7 (SD 36.4), 66.1 (SD 30.4) and 65.8 (SD 30.3), respectively (p=0.02). DISCUSSION AND CONCLUSION: The B strategy (B+) yielded good outcomes in terms of function and COR restoration. When using this strategy, anterior ORIF preserves the native hip for a subsequent THA through a posterior approach. Strategy C also produces good functional outcomes but shifts the COR laterally. This study confirms the poor results of strategy A in previous publications. When the prognosis is poor, immediate mobilization after anterior ORIF followed by THA within 1year appears to be a good strategy (group B-). LEVEL OF EVIDENCE: IV, observational study.

Genetic predisposition to porto-sinusoidal vascular disorder.

Porto-sinusoidal vascular disorder is a rare liver disease. The pathophysiological mechanisms underlying the development of porto-sinusoidal vascular disorder are unknown. Isolated cases of porto-sinusoidal vascular disorder associated with gene mutations have been reported, but no overview is available. Therefore, we performed an extensive literature search to provide a comprehensive overview of gene mutations associated with porto-sinusoidal vascular disorder. We identified 34 genes and one chromosomal abnormality associated with porto-sinusoidal vascular disorder in the literature, and we describe here one additional gene mutation (TBL1XR1 mutation, leading to Pierpont syndrome). These gene mutations are associated either with extrahepatic organ involvement as part of syndromes (Adams Oliver, telomere biology disorders, retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations, immune deficiencies, cystic fibrosis, cystinosis, Williams Beuren, Turner, Pierpont) or with isolated porto-sinusoidal vascular disorder (KCNN3, DGUOK, FOPV, GIMAP5, FCHSD1, TRMT5, HRG gene mutations). Most of the cases were revealed by signs or complications of portal hypertension. When analysing the cell types in which these genes are expressed, we found that these genes are predominantly expressed in immune cells, suggesting that these cells may play a more important role in the development of porto-sinusoidal vascular disorder than previously thought. In addition, pathway analyses suggested that there may be 2 types of porto-sinusoidal vascular disorder associated with gene mutations: those resulting directly from morphogenetic abnormalities and those secondary to immune changes.

Long-Term Differential Effects of Gastric Bypass and Sleeve Gastrectomy on Bone Mineral Density.

Context: The association of obesity with bone fragility fractures is complex and non-linear. Despite good efficacy on weight loss, bariatric surgery (BS) is also associated with bone loss. However, we lack information on risk factors of the long-term deleterious effects of BS on the skeleton. Objective: We aimed to assess the factors associated with low bone mineral density (BMD) performed a long time after Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG). Methods: This cross-sectional study involved patients at a long distance from their BS that underwent dual-energy x-ray absorptiometry (DXA) with biological factors (vitamins, micronutrients, bone and inflammation biomarkers). Simple and multiple linear models (stepwise and parsimony approach) were developed. Results: A total of 131 patients (91 RYGB, 40 SG) underwent DXA (51.8 ± 11.08 years, 87.8% women). At a mean of 6.8 ± 3.7 years after surgery, the mean weight loss was -28.6 ± 9.6%, and only 6 patients (5.7%) had a T-score less than or equal to -2.5. On univariate analysis, BMD was lower in the RYGB than in the SG group (P < .001) at all sites, despite similar fat and fat-free mass and weight loss. Serum parathyroid hormone and phosphate levels were higher in RYGB than SG patients. A total of 10.1% of patients showed vascular calcifications. On multivariable analysis, BMD remained different between surgery groups after adjustment for age, body mass index, ethnicity, and sex. The model-adjusted R 2 values were 0.451 for the total hip; 0.462 the femoral neck, and 0.191 the lumbar spine for the inflammation model; 0.458, 0.462, and 0.254, respectively, for the bone marker model; and 0.372, 0.396, and 0.142 for the vitamin model. Serum zinc, ferritin, and uric acid levels were the markers associated with BMD to a low extent. Conclusion: BMD differed depending on the BS procedure. A few biological markers may be associated weakly with BMD well after the surgery.

Division of the iliac vessels in the anterior intrapelvic approach to acetabular fracture.

INTRODUCTION: The modified Stoppa approach is gradually becoming the gold standard in pelvic ring and acetabulum surgery. One of the potential intraoperative complications is vascular injury. The aim of this study was to identify the level of division of common iliac vessels with respect to a bone landmark, their inter-individual variability and their correlation with morphological criteria. MATERIAL AND METHODS: This was a single-center continuous retrospective study of patients who had preoperative CT angiography for pelvic fracture between February 2017 and May 2018. The level of arterial and venous division and the angle of vein division were measured bilaterally for each patient from the most antero-inferior part of the sacroiliac joint on multiplanar reconstruction and standardized analysis. Relationships with morphological data (age, gender, BMI, height), anterior column fracture and deep venous thrombosis were analyzed. RESULTS: The right arterial division level was 50±16mm (-2.35; 96) from the landmark and the left arterial division level 44±14mm (0; 80). The right venous division level was 30±12mm (-9; 75) and the left venous division level 30±13mm (-5; 66). The right venous bifurcation angle was 65±18° (22; 119) and the left venous bifurcation angle 68±17° (18; 117). The arterial division level was significantly higher on the right side (p=0.007). There were no significant correlations with morphological data. CONCLUSION: The great inter-individual variability of iliac vessels should prompt analysis of their morphology on routine imaging when planning pelvic surgery using the modified Stoppa approach, in order to anticipate the risk of bleeding. LEVEL OF EVIDENCE: IV; cases series.

Multi-ancestry polygenic risk scores for venous thromboembolism.

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality, with large disparities in incidence rates between Black and White Americans. Polygenic risk scores (PRSs) limited to variants discovered in genome-wide association studies in European-ancestry samples can identify European-ancestry individuals at high risk of VTE. However, there is limited evidence on whether high-dimensional PRS constructed using more sophisticated methods and more diverse training data can enhance the predictive ability and their utility across diverse populations. We developed PRSs for VTE using summary statistics from the International Network against Venous Thrombosis (INVENT) consortium genome-wide association studies meta-analyses of European- (71 771 cases and 1 059 740 controls) and African-ancestry samples (7482 cases and 129 975 controls). We used LDpred2 and PRS-CSx to construct ancestry-specific and multi-ancestry PRSs and evaluated their performance in an independent European- (6781 cases and 103 016 controls) and African-ancestry sample (1385 cases and 12 569 controls). Multi-ancestry PRSs with weights tuned in European-ancestry samples slightly outperformed ancestry-specific PRSs in European-ancestry test samples (e.g. the area under the receiver operating curve [AUC] was 0.609 for PRS-CSx_combinedEUR and 0.608 for PRS-CSxEUR [P = 0.00029]). Multi-ancestry PRSs with weights tuned in African-ancestry samples also outperformed ancestry-specific PRSs in African-ancestry test samples (PRS-CSxAFR: AUC = 0.58, PRS-CSx_combined AFR: AUC = 0.59), although this difference was not statistically significant (P = 0.34). The highest fifth percentile of the best-performing PRS was associated with 1.9-fold and 1.68-fold increased risk for VTE among European- and African-ancestry subjects, respectively, relative to those in the middle stratum. These findings suggest that the multi-ancestry PRS might be used to improve performance across diverse populations to identify individuals at highest risk for VTE.

Plasma levels of complement components C5 and C9 are associated with thrombin generation.

BACKGROUND: The thrombin generation assay (TGA) evaluates the potential of plasma to generate thrombin over time, providing a global picture of an individual's hemostatic balance. OBJECTIVES: This study aimed to identify novel biological determinants of thrombin generation using a multiomics approach. METHODS: Associations between TGA parameters and plasma levels of 377 antibodies targeting 236 candidate proteins for cardiovascular risk were tested using multiple linear regression analysis in 770 individuals with venous thrombosis from the Marseille Thrombosis Association (MARTHA) study. Proteins associated with at least 3 TGA parameters were selected for validation in an independent population of 536 healthy individuals (Etablissement Français du Sang Alpes-Méditerranée [EFS-AM]). Proteins with strongest associations in both groups underwent additional genetic analyses and in vitro experiments. RESULTS: Eighteen proteins were associated (P < 1.33 × 10⁻4) with at least 3 TGA parameters in MARTHA, among which 13 demonstrated a similar pattern of associations in EFS-AM. Complement proteins C5 and C9 had the strongest associations in both groups. Ex vivo supplementation of platelet-poor plasma with purified C9 protein had a significant dose-dependent effect on TGA parameters. No effect was observed with purified C5. Several single nucleotide polymorphisms associated with C5 and C9 plasma levels were identified, with the strongest association for the C5 missense variant rs17611, which was associated with a decrease in C5 levels, endogenous thrombin potential, and peak in MARTHA. No association of this variant with TGA parameters was observed in EFS-AM. CONCLUSION: This study identified complement proteins C5 and C9 as potential determinants of thrombin generation. Further studies are warranted to establish causality and elucidate the underlying mechanisms.

Real-world outcomes of lobectomy, segmentectomy and wedge resection for the treatment of stage c-IA lung carcinoma.

OBJECTIVES: To determine safety and survival outcomes associated with lobectomy, segmentectomy and wedge resection for early-stage lung cancer by quiring the French population-based registry EPIdemiology in THORacic surgery (EPITHOR). METHODS: Retrospective analysis of 19 452 patients with stage c IA lung carcinoma who underwent lobectomy, segmentectomy or wedge resection between 2016 and 2022 with curative-intent. Main outcome measures were 90-day mortality and 5-year overall survival estimates. Proportional hazards regression and propensity score matching were used to adjust outcomes for key patient, tumour and practice environment factors. RESULTS: The treatment distribution was 72.2% for lobectomy, 21.5% for segmentectomy and 6.3% for wedge. Unadjusted 90-day mortality rates were 1.6%, 1.2% and 1.1%, respectively (P = 0.10). Unadjusted 5-year overall survival estimates were 80%, 78% and 70%, with significant inter-group survival curves differences (P < 0.0001). Multivariable proportional hazards regression showed that wedge was associated with worse overall survival [adjusted hazard ratio (AHR), 1.23 (95% confidence interval 1.03-1.47); P = 0.021] compared with lobectomy, while no significant difference was disclosed when comparing segmentectomy to lobectomy (1.08 [0.97-1.20]; P = 0.162). The three-way propensity score analyses confirmed similar 90-day mortality rate for wedge resection and segmentectomy compared with lobectomy (hazard ratio: 0.43; 95% confidence interval 0.16-1.11; P = 0.081 and 0.99; 0.48-2.10; P = 0.998, respectively), but poorer overall survival (1.45; 1.13-1.86; P = 0.003 and 1.31; 1-1.71; P = 0.048, respectively). CONCLUSIONS: Wedge resection was associated with comparable 90-day mortality but lower overall survival when compared to lobectomy. Overall, all types of sublobar resections may not offer equivalent oncologic effectiveness in real-world settings.

Step-up approach for the treatment of infected necrotising pancreatitis: real life data from a single-centre experience with long-term follow-up.

BACKGROUND: About 20% of patients with acute pancreatitis develop a necrotising form with a worse prognosis due to frequent appearance of organ failure(s) and/or infection of necrosis. Aims of the present study was to evaluate the "step up" approach treatment of infected necrosis in terms of: feasibility, success in resolving infection, morbidity of procedures, risk factors associated with death and long-term sequels. METHODS: In this observational retrospective monocentric study in the real life, necrotizing acute pancreatitis at the stage of infected walled-off necrosis were treated as follow: first step with drainage (radiologic and/or endoscopic-ultrasound-guided with lumen apposing metal stent); in case of failure, minimally invasive necrosectomy sessions(s) by endoscopy through the stent and/or via retroperitoneal surgery (step 2); If necessary open surgery as a third step. Efficacy was assessed upon to a composite clinical-biological criterion: resolution of organ failure(s), decrease of at least two of clinico-biological criteria among fever, CRP serum level, and leucocytes count). RESULTS: Forty-one consecutive patients were treated. The step-up strategy: (i) was feasible in 100% of cases; (ii) allowed the infection to be resolved in 33 patients (80.5%); (iii) Morbidity was mild and rapidly resolutive; (iv) the mortality rate at 6 months was of 19.5% (significant factors: SIRS and one or more organ failure(s) at admission, fungal infection, size of the largest collection ≥ 16 cm). During the follow-up (median 72 months): 27% of patients developed an exocrine pancreatic insufficiency, 45% developed or worsened a previous diabetes, 24% had pancreatic fistula and one parietal hernia. CONCLUSIONS: Beside a very good feasibility, the step-up approach for treatment of infected necrotizing pancreatitis in the real life displays a clinico-biological efficacy in 80% of cases with acceptable morbidity, mortality and long-term sequels regarding the severity of the disease.

A robust clustering strategy for stratification unveils unique patient subgroups in acutely decompensated cirrhosis.

BACKGROUND: Patient heterogeneity poses significant challenges for managing individuals and designing clinical trials, especially in complex diseases. Existing classifications rely on outcome-predicting scores, potentially overlooking crucial elements contributing to heterogeneity without necessarily impacting prognosis. METHODS: To address patient heterogeneity, we developed ClustALL, a computational pipeline that simultaneously faces diverse clinical data challenges like mixed types, missing values, and collinearity. ClustALL enables the unsupervised identification of patient stratifications while filtering for stratifications that are robust against minor variations in the population (population-based) and against limited adjustments in the algorithm's parameters (parameter-based). RESULTS: Applied to a European cohort of patients with acutely decompensated cirrhosis (n = 766), ClustALL identified five robust stratifications, using only data at hospital admission. All stratifications included markers of impaired liver function and number of organ dysfunction or failure, and most included precipitating events. When focusing on one of these stratifications, patients were categorized into three clusters characterized by typical clinical features; notably, the 3-cluster stratification showed a prognostic value. Re-assessment of patient stratification during follow-up delineated patients' outcomes, with further improvement of the prognostic value of the stratification. We validated these findings in an independent prospective multicentre cohort of patients from Latin America (n = 580). CONCLUSIONS: By applying ClustALL to patients with acutely decompensated cirrhosis, we identified three patient clusters. Following these clusters over time offers insights that could guide future clinical trial design. ClustALL is a novel and robust stratification method capable of addressing the multiple challenges of patient stratification in most complex diseases.

Genome-wide investigation of exogenous female hormones, genetic variation, and venous thromboembolism risk.

BACKGROUND: Increased risk of venous thromboembolism (VTE) is a life-threatening side effect for users of oral contraceptives (OCs) or hormone therapy (HT). OBJECTIVES: To investigate the potential for genetic predisposition to VTE in OC or HT users, we conducted a gene-by-environment case-only meta-analysis of genome-wide association studies (GWAS). METHODS: Use or nonuse of OCs (7 studies) or HT (8 studies) at the time of the VTE event was determined by pharmacy records or self-report. A synergy index (SI) was modeled for each variant in each study and submultiplicative/supramultiplicative gene-by-environment interactions were estimated. The SI parameters were first meta-analyzed across OC and HT studies and subsequently meta-analyzed to obtain an overall estimate. The primary analysis was agnostic GWAS and interrogated all imputed genotypes using a P value threshold of <5.0 × 10-8; secondary analyses were candidate-based. RESULTS: The VTE case-only OC meta-analysis included 2895 OC users and 6607 nonusers; the case-only HT meta-analysis included 2434 HT users and 12 793 nonusers. In primary GWAS meta-analyses, no variant reached genome-wide significance, but the smallest P value approached statistical significance: rs9386463 (P = 5.03 × 10-8). We tested associations for 138 candidate variants and identified 2 that exceeded statistical significance (0.05/138 = 3.62 × 10-4): F5 rs6025 (P = 1.87 × 10-5; SI, 1.29; previously observed) and F11 rs2036914 (P = 2.0 × 10-4; SI, 0.91; new observation). CONCLUSION: The candidate variant approach to identify submultiplictive/supramultiplicative associations between genetic variation and OC and HT use identified a new association with common genetic variation in F11, while the agnostic interrogations did not yield new discoveries.

Development of a Semi-Automated Approach for the Quantification of Neuronal Cells in the Spiral Ganglion of the Whole Implanted Gerbil Cochlea, Acquired by Light-Sheet Microscopy.

INTRODUCTION: Assessing cochlear implantation's impact on cell loss and preventing post-implant cochlear damage are key areas of focus for hearing preservation research. The preservation of auditory neuronal and sensory neural hearing cells has a positive impact on auditory perception after implantation. This study aimed to provide details on a semi-automated spiral ganglion neuronal cell counting method, developed using whole implanted gerbil cochlea acquisitions with light-sheet microscopy. METHODS: Mongolian gerbils underwent right cochlear implantation with an electrode array whose silicone was loaded with dexamethasone or not and were euthanized 10 weeks after implantation. The cochleae were prepared according to a 29-day protocol, with the electrode array in place. Light-sheet microscopy was used for acquisition, and Imaris software was employed for three-dimensional analysis of the cochleas and semi-automatic quantification of spiral ganglion cells. The imaJ software was used for the manual quantification of these cells. RESULTS: Six cochleae were acquired by light-sheet microscopy, allowing good identification of cells. There was no significant difference between the mean number of spiral ganglion cells obtained by manual and semi-automatic counting (p = 0.25). CONCLUSION: Light-sheet microscopy provided complete visualization of the spiral ganglion and cell identification. The semi-automated counting method developed using Imaris software tools proved reliable and efficient and could be applied to a larger sample to assess post-cochlear implant cell damage and the efficacy of protective drugs delivered to the inner ear.

Genotype-by-genotype interkingdom cross-talk between symbiotic nitrogen fixing Sinorhizobium meliloti strains and Trichoderma species.

In the understanding of the molecular interaction between plants and their microbiome, a key point is to identify simplified models of the microbiome including relevant bacterial and fungal partners which could also be effective in plant growth promotion. Here, as proof-of-concept, we aim to identify the possible molecular interactions between symbiotic nitrogen-fixing rhizobia and soil fungi (Trichoderma spp.), hence shed light on synergistic roles rhizospheric fungi could have in the biology of symbiotic nitrogen fixation bacteria. We selected 4 strains of the model rhizobium Sinorhizobium meliloti and 4 Trichoderma species (T. velutinum, T. tomentosum, T. gamsii and T. harzianum). In an experimental scheme of 4 ×4 strains x species combinations, we investigated the rhizobia physiological and transcriptomic responses elicited by fungal spent media, as well as spent media effects on rhizobia-host legume plant (alfalfa, Medicago sativa L.) symbiosis. Fungal spent media had large effects on rhizobia, specific for each fungal species and rhizobial strains combination, indicating a generalized rhizobia genotype x fungal genotype interaction, including synergistic, neutral and antagonistic effects on alfalfa symbiotic phenotypes. Differential expression of a high number of genes was shown in rhizobia strains with up to 25% of total genes differentially expressed upon treatment of cultures with fungal spent media. Percentages over total genes and type of genes differentially expressed changed according to both fungal species and rhizobial strain. To support the hypothesis of a relevant rhizobia genotype x fungal genotype interaction, a nested Likelihood Ratio Test indicated that the model considering the fungus-rhizobium interaction explained 23.4% of differentially expressed genes. Our results provide insights into molecular interactions involving nitrogen-fixing rhizobia and rhizospheric fungi, highlighting the panoply of genes and genotypic interactions (fungus, rhizobium, host plant) which may concur to plant symbiosis.

Wheat dwarfing reshapes plant and fungal development in arbuscular mycorrhizal symbiosis.

The introduction of Reduced height (Rht) dwarfing genes into elite wheat varieties has contributed to enhanced yield gain in high input agrosystems by preventing lodging. Yet, how modern selection for dwarfing has affected symbiosis remains poorly documented. In this study, we evaluated the response of both the plant and the arbuscular mycorrhizal fungus to plant genetic variation at a major Quantitative Trait Locus called QTL 4B2, known to harbor a Rht dwarfing gene, when forming the symbiosis. We used twelve inbred genotypes derived from a diversity base broadened durum wheat Evolutionary Pre-breeding Population and genotyped with a high-throughput Single Nucleotide Polymorphism (SNP) genotyping array. In a microcosm setup segregating roots and the extra-radical mycelium, each wheat genotype was grown with or without the presence of Rhizophagus irregularis. To characterize arbuscular mycorrhizal symbiosis, we assessed hyphal density, root colonization, spore production, and plant biomass. Additionally, we split the variation of these variables due either to genotypes or to the Rht dwarfing genes alone. The fungus exhibited greater development in the roots of Dwarf plants compared to non-Dwarf plants, showing increases of 27%, 37% and 51% in root colonization, arbuscules, and vesicles, respectively. In addition, the biomass of the extra-radical fungal structures increased by around 31% in Dwarf plants. The biomass of plant roots decreased by about 43% in mycorrhizal Dwarf plants. Interestingly, extraradical hyphal production was found to be partly genetically determined with no significant effect of Rht, as for plant biomasses. In contrast, variations in root colonization, arbuscules and extraradical spore production were explained by Rht dwarfing genes. Finally, when mycorrhizal, Dwarf plants had significantly lower total P content, pointing towards a less beneficial symbiosis for the plant and increased profit for the fungus. These results highlight the effect of Rht dwarfing genes on both root and fungal development. This calls for further research into the molecular mechanisms governing these effects, as well as changes in plant physiology, and their implications for fostering arbuscular mycorrhizal symbiosis in sustainable agrosystems.