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The pampas of South America represent one of the most productive lands for agriculture in the world, and consequently this activity has expanded throughout the region, especially in Argentina. In this context, native fauna faces various risks associated with agriculture, with exposure to pesticides being one of the most dangerous and deadly. Assessing the impact of pesticides on wildlife becomes fundamental and the use of sentinel species emerges as an important tool to monitor environmental health. In this study, we determined pesticide levels in the burrowing owl Athene cunicularia nesting in both rural and urban areas of the argentinean pampas. We used a multiple scale approach to evaluate the influence of land-uses (urban, crops, and grazing fields) at the nesting site on the contaminant load of A. cunicularia individuals, and assessed the potential use of this owl as a sentinel species. From March 2018 to January 2020, A. cunicularia feathers were collected at their nest sites in one urban and two rural areas. These samples were analyzed for the presence of contaminants, including chlorpyrifos and 18 organochlorine pesticides. All the compounds analyzed were detected in A. cunicularia samples. The chlorpyrifos showed the highest frequency of occurrence and concentration, thus denoting the exposure of owls to current-use pesticides. ∑DDTs showed the highest occurrence among organochlorines, followed by ∑HCHs > ∑Endosulfans > ∑Heptachlors > ∑Drins = ∑Chlordanes > methoxychlor. Principal Component Analysis showed that most of the compounds found in A. cunicularia samples showed a positive association with grazing fields, suggesting that exposure to contaminants does not depend on specific habitat use at the local scale, but probably the regional scale. Our results evidenced the exposure of A. cunicularia individuals to past and current-use pesticides in the pampas of Argentina, and indicate that this owl would be useful as a sentinel species., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Myosin heavy chain 7 ( MYH7 )-related myopathies ( MYH7 -RMs) are a group of muscle disorders linked to pathogenic variants in the MYH7 gene, encoding the slow/beta-cardiac myosin heavy chain, which is highly expressed in skeletal muscle and heart. The phenotype is heterogeneous including distal, predominantly axial or scapuloperoneal myopathies with variable cardiac involvement., Methods: We retrospectively analysed the clinical, muscle MRI, genetic and myopathological features of 57 MYH7 patients. Patients received a thorough neurological (n=57, 100%), cardiac (n=51, 89%) and respiratory (n=45, 79%) assessment. Muscle imaging findings and muscle biopsies were reappraised in 19 (33%) and 27 (47%) patients, respectively., Results: We identified three phenotypes with varying degrees of overlap: distal myopathy (70%), scapuloperoneal (23%) and axial with peculiar cervical spine rigidity called the 'sphinx' phenotype (7%). 14% of patients had either dilated cardiomyopathy, hypertrophic cardiomyopathy or left ventricular non-compaction cardiomyopathy. 31% of patients had prominent respiratory involvement, including all patients with the 'sphinx' phenotype. Muscle MRI showed involvement of tibialis anterior, followed by quadriceps, and erector spinae in patients with axial phenotype. Cores represented the most common myopathological lesion. We report 26 pathogenic variants of MYH7 gene, 9 of which are novel., Conclusions: MYH7 -RMs have a large phenotypic spectrum, including distal, scapuloperoneal or axial weakness, and variable cardiac and respiratory involvement. Tibialis anterior is constantly and precociously affected both clinically and on muscle imaging. Cores represent the most common myopathological lesion. Our detailed description of MYH7 -RMs should improve their recognition and management., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

While Coronavirus disease 2019 (COVID-19) vaccines have proven to be both effective and generally safe, rare but severe adverse events following immunization (AEFIs) are described. Autoantibodies to platelet factor-4 are associated with catastrophic thrombotic AEFIs, but comprehensive investigations of other autoantibodies are lacking. We aimed to detect and describe autoantibodies targeting coagulation-related proteins in a population-wide cohort (SWEDEGENE) including AEFIs attributed to COVID-19 vaccines in Sweden. Subjects were recruited from December 2020 to October 2022 and were stratified based on diagnosis and COVID-19 exposure. Screening was carried out in two phases, with a multiplex bead-based assay in the first subset (until September 2021) and with targeted assays for the second (until October 2022). Positivity was defined based on absolute, relative, and biological/technical thresholds. Patients with coagulation-related AEFIs were older and the Vaxzevria vaccine was overrepresented in this group. Two cases had antiphospholipid antibodies but none had PF4 antibodies. We identified six positives for protein S autoantibodies. Protein S concentrations were negatively correlated with autoantibody response in patients with immunoreactivity and functional analysis revealed low protein S activity in three subjects. Our population-wide analysis reveals cases with autoantibodies against protein S which possibly underlie coagulopathic AEFIs., (© 2024. The Author(s).)

Introduction: Traditionally, radical prostatectomy (RP) has been considered a contraindication to minimally invasive inguinal hernia repair. Purpose of this systematic review was to examine the current evidence and outcomes of minimally invasive inguinal hernia repair after RP., Materials and Methods: Web of Science, PubMed, and EMBASE data sets were consulted. Laparoscopic transabdominal preperitoneal repair (TAPP), robotic TAPP (r-TAPP), and totally extraperitoneal (TEP) repair were included., Results: Overall, 4655 patients (16 studies) undergoing TAPP, r-TAPP, and TEP inguinal hernia repair after RP were included. The age of the patients ranged from 35 to 85 years. Open (49.1%), laparoscopic (7.4%), and robotic (43.5%) RP were described. Primary unilateral hernia repair was detailed in 96.3% of patients while 2.8% of patients were operated for recurrence. The pooled prevalence of intraoperative complication was 0.7% (95% CI 0.2-3.4%). Bladder injury and epigastric vessels bleeding were reported. The pooled prevalence of conversion to open was 0.8% (95% CI 0.3-1.7%). The estimated pooled prevalence of seroma, hematoma, and surgical site infection was 3.2% (95% CI 1.9-5.9%), 1.7% (95% CI 0.9-3.1%), and 0.3% (95% CI = 0.1-0.9%), respectively. The median follow-up was 18 months (range 8-48). The pooled prevalence of hernia recurrence and chronic pain were 1.1% (95% CI 0.1-3.1%) and 1.9% (95% CI 0.9-4.1%), respectively., Conclusions: Minimally invasive inguinal hernia repair seems feasible, safe, and effective for the treatment of inguinal hernia after RP. Prostatectomy should not be necessarily considered a contraindication to minimally invasive inguinal hernia repair., (© 2024. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Background: The mainstay of treatment for early-stage follicular lymphoma is local radiotherapy, with a possible role for anti-CD20 monoclonal antibody (mAb). We aimed to evaluate the effect of these treatments using a measurable residual disease (MRD)-driven approach., Methods: This prospective, multicentre, phase 2 trial was conducted at 27 centres of the Fondazione Italiana Linfomi (FIL) in Italy. Eligible participants were adults (≥18 years) with newly diagnosed, histologically confirmed follicular lymphoma (stage I or II; grade I-IIIa). Patients were initially treated with 24 Gy involved-field radiotherapy over 12 days; those who were MRD-positive after radiotherapy or during follow-up received eight intravenous doses (1000 mg per dose; one dose per week) of the anti-CD20 mAb ofatumumab. The primary endpoint was the proportion of patients who were MRD-positive after involved-field radiotherapy and became MRD-negative after ofatumumab treatment. Patients were included in the primary endpoint analysis population if they were positive for BCL2::IGH rearrangement at enrolment in peripheral blood or bone marrow samples. MRD positivity was defined as the persistence of BCL2::IGH rearrangement in peripheral blood or bone marrow, assessed centrally by laboratories of the FIL MRD Network. The trial was registered with EudraCT, 2012-001676-11., Findings: Between May 2, 2015, and June 1, 2018, we enrolled 110 participants, of whom 106 (96%) were eligible and received involved-field radiotherapy. Of these, 105 (99%) were White, one (1%) was Black, 50 (47%) were male, and 56 (53%) were female. Of 105 participants in whom BCL2::IGH status was evaluable, 32 (30%) had a detectable BCL2::IGH rearrangement at baseline. After radiotherapy, 12 (40%) of 30 patients reached MRD-negative status, which was long-lasting (at least 36 or 42 months) in three (25%). In those who were MRD-positive after radiotherapy, ofatumumab induced MRD-negativity in 23 (92%; 95% CI 74-99) of 25 evaluable patients. After a median follow-up of 46·1 months (IQR 42·8-50·8), 14 (61%) of these 23 patients remain in complete response and are MRD-negative. The most common grade 3-4 adverse events were infusion-related reactions, observed in four patients., Interpretation: Local radiotherapy is frequently not associated with the eradication of follicular lymphoma. An MRD-driven, anti-CD20 monoclonal antibody consolidation enables molecular remission to be reached in almost all patients and is associated with a reduced incidence of relapse over time. A clinical advantage of an MRD-driven consolidation is therefore suggested., Funding: AIRC Foundation for Cancer Research in Italy, Novartis International, and GlaxoSmithKline., Competing Interests: Declaration of interests AP reports support for the study from Novartis and AIRC 5 × 1000; payment or honoraria for lectures or presentations from Takeda Pharmaceuticals, Roche, Janssen Pharmaceuticals, and BeiGene; payment for expert testimony from Takeda Pharmaceuticals and Roche; support for attending meetings and/or travel from Takeda Pharmaceuticals, Roche, Janssen Pharmaceuticals, BeiGene, Pfizer, and AbbVie; and participation on a data safety monitoring board or advisory board for Takeda Pharmaceuticals, Roche, and Janssen Pharmaceuticals. SL reports payment or honoraria for lectures or presentations from Roche, BeiGene, Regeneron Pharmaceuticals, and Kite Pharma; support for attending meetings and/or travel from Roche and BeiGene; and participation on a data safety monitoring board or advisory board from Roche, Regeneron Pharmaceuticals, Miltenyi Biomedicine, Takeda Pharmaceuticals, Sobi, and Incyte. GG reports consulting fees from AbbVie, AstraZeneca, BeiGene, Incyte, Lilly, and Johnson & Johnson and payment or honoraria for lectures or presentations from AbbVie, AstraZeneca, BeiGene, Incyte, Lilly, Johnson & Johnson, and Hikma Pharmaceuticals. PC received consulting fees from AbbVie, ADC Therapeutics, Amgen, BeiGene, Celgene, Daiichi Sankyo, Eli Lilly, Gilead/Kite, GSK, Incyte, Janssen Pharmaceuticals, Jazz Pharma, Novartis, Pfizer, Roche, Sanofi, Sobi, and Takeda Pharmaceuticals and payment for lectures from AbbVie, Amgen, Celgene, Gilead/Kite, Incyte, Janssen Pharmaceuticals, Jazz Pharma, Novartis, Roche, Sanofi, Sobi, and Takeda Pharmaceuticals. LA received consulting fees from Roche, Janssen-Cilag, Verastem Oncology, Incyte, EUSA Pharma, Celgene/Bristol Myers Squibb, Kite/Gilead, ADC Therapeutics, and Novartis and payment or honoraria for lectures or presentations from EUSA Pharma and Novartis. ML received grants or contracts from Roche, BeiGene, ADC Therapeutics, and Janssen Pharmaceuticals and consulting fees and/or payment or honoraria from AbbVie, Amgen, ADC Therapeutics, Sobi, BeiGene, Bristol Myers Squibb, EUSA Pharma, Gilead/Kite, Novartis, Incyte, Janssen Pharmaceuticals, Jazz Pharma, Lilly, Regeneron Pharmaceuticals, Roche, Ellipses Pharma, GSK, and Istituto Gentili. IDG received payment or honoraria for lectures or presentations from Takeda Pharmaceuticals, Janssen Pharmaceuticals, Roche, and AstraZeneca; support for attending meetings and/or travel from Takeda Pharmaceuticals, Janssen Pharmaceuticals, Roche, and AstraZeneca; and support for participation on a data safety monitoring board or advisory board from Takeda Pharmaceuticals and Roche. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: In military flight operations, during flights, fighter pilots constantly work under hyperoxic breathing conditions with supplemental oxygen in varying hypobaric environments. These conditions are suspected to cause oxidative stress to neuronal organ tissues. For civilian flight operations, the Federal Aviation Administration (FAA) also recommends supplemental oxygen for flying under hypobaric conditions equivalent to higher than 3048 m altitude, and has made it mandatory for conditions equivalent to more than 3657 m altitude., Aim: We hypothesized that hypobaric-hyperoxic civilian commercial and private flight conditions with supplemental oxygen in a flight simulation in a hypobaric chamber at 2500 m and 4500 m equivalent altitude would cause significant oxidative stress in healthy individuals., Methods: Twelve healthy, COVID-19-vaccinated (third portion of vaccination 15 months before study onset) subjects (six male, six female, mean age 35.7 years) from a larger cohort were selected to perform a 3 h flight simulation in a hypobaric chamber with increasing supplemental oxygen levels (35%, 50%, 60%, and 100% fraction of inspired oxygen, FiO 2 , via venturi valve-equipped face mask), switching back and forth between simulated altitudes of 2500 m and 4500 m. Arterial blood pressure and oxygen saturation were constantly measured via radial catheter and blood samples for blood gases taken from the catheter at each altitude and oxygen level. Additional blood samples from the arterial catheter at baseline and 60% oxygen at both altitudes were centrifuged inside the chamber and the serum was frozen instantly at -21 °C for later analysis of the oxidative stress markers malondialdehyde low-density lipoprotein (M-LDL) and glutathione-peroxidase 1 (GPX1) via the ELISA test., Results: Eleven subjects finished the study without adverse events. Whereas the partial pressure of oxygen (PO 2 ) levels increased in the mean with increasing oxygen levels from baseline 96.2 mm mercury (mmHg) to 160.9 mmHg at 2500 m altitude and 60% FiO 2 and 113.2 mmHg at 4500 m altitude and 60% FiO 2 , there was no significant increase in both oxidative markers from baseline to 60% FiO 2 at these simulated altitudes. Some individuals had a slight increase, whereas some showed no increase at all or even a slight decrease. A moderate correlation (Pearson correlation coefficient 0.55) existed between subject age and glutathione peroxidase levels at 60% FiO 2 at 4500 m altitude., Conclusion: Supplemental oxygen of 60% FiO 2 in a flight simulation, compared to flying in cabin pressure levels equivalent to 2500 m-4500 m altitude, does not lead to a significant increase or decrease in the oxidative stress markers M-LDL and GPX1 in the serum of arterial blood.

Background: Severe postoperative complications (SPCs) may occur after curative esophagectomy for cancer and are associated with prolonged hospital stay, augmented costs, and increased in-hospital mortality. However, the effect of SPCs on survival after esophagectomy is uncertain., Aim: To assess the impact of severe postoperative complications (SPCs) on long-term survival following curative esophagectomy for cancer, we conducted a systematic search of PubMed, MEDLINE, Scopus, and Web of Science databases up to December 2023. The included studies examined the relationship between SPCs and survival outcomes, defining SPCs as Clavien-Dindo grade > 3. The primary outcome measure was long-term overall survival (OS). We used restricted mean survival time difference (RMSTD) and 95% confidence intervals (CIs) to calculate pooled effect sizes. Additionally, we applied the GRADE methodology to evaluate the certainty of the evidence., Results: Ten studies (2181 patients) were included. SPCs were reported in 651 (29.8%) patients. The RMSTD overall survival analysis shows that at 60-month follow-up, patients experiencing SPCs lived for 8.6 months (95% Cis -12.5, -4.7; p < 0.001) less, on average, compared with no-SPC patients. No differences were found for 60-month follow-up disease-free survival (-4.6 months, 95% CIs -11.9, 1.9; p = 0.17) and cancer-specific survival (-6.8 months, 95% CIs -11.9, 1.7; p = 0.21). The GRADE certainty of this evidence ranged from low to very low., Conclusions: This study suggests a statistically significant detrimental effect of SPCs on OS in patients undergoing curative esophagectomy for cancer. Also, a clinical trend toward reduced CSS and DFS was perceived.

To date, little is known about the usefulness of ultra-high frequency ultrasound (UHF-US, 50-70 MHz) in clinical practice for the diagnosis of dysimmune neuropathies. We present a prospective study aimed at comparing UHF-US alterations of nerves and fascicles in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), distal CIDP (d-CIDP) and anti-MAG neuropathy and their relationships with clinical and electrodiagnostic (EDX) features. 28 patients were included (twelve CIDP, 6 d-CIDP and 10 anti-MAG) and ten healthy controls. Each patient underwent neurological examination, EDX and UHF-US study of median and ulnar nerves bilaterally. UHF-US was reliable in differentiating immune neuropathies from controls when using mean and/or segmental nerve and/or fascicle cross-sectional area (CSA); furthermore, fascicle ratio (fascicle/nerve CSA) was a reliable factor for differentiating d-CIDP from other types of polyneuropathies. The fascicle CSA appears to be more increased in CIDP and its variant than in anti-MAG neuropathy. UHF-US offers information beyond simple nerve CSA and allows for a better characterization of the different forms of dysimmune neuropathies., (© 2024. The Author(s).)

Type I interferons act as gatekeepers against viral infection, and autoantibodies that neutralize these signaling molecules have been associated with COVID-19 severity and adverse reactions to the live-attenuated yellow fever vaccine. On this background, we sought to examine whether autoantibodies against type I interferons were associated with adverse events following COVID-19 vaccination. Our nationwide analysis suggests that type I interferon autoantibodies were not associated with adverse events after mRNA or viral-vector COVID-19 vaccines., (© 2024. The Author(s).)

Background: Genome-wide association studies (GWAS) have identified genetic variants linked to fat metabolism and related traits, but rarely pinpoint causative variants. This limitation arises from GWAS not considering functional implications of noncoding variants that can affect transcription factor binding and potentially regulate gene expression. The aim of this study is to investigate a candidate noncoding functional variant within a genetic locus flagged by a GWAS SNP associated with non-alcoholic fatty liver disease (NAFLD), a condition characterized by liver fat accumulation in non-alcohol consumers., Methods: CRISPR-Cas9 gene editing in HepG2 cells was used to modify the regulatory element containing the candidate functional variant linked to NAFLD. Global gene expression in mutant cells was assessed through RT-qPCR and targeted transcriptomics. A phenotypic assay measured lipid droplet accumulation in the CRISPR-Cas9 mutants., Results: The candidate functional variant, rs2294510, closely linked to the NAFLD-associated GWAS SNP rs11206226, resided in a regulatory element within the DIO1 gene's promoter region. Altering this element resulted in changes in transcription factor binding sites and differential expression of candidate target genes like DIO1, TMEM59, DHCR24, and LDLRAD1, potentially influencing the NAFLD phenotype. Mutant HepG2 cells exhibited increased lipid accumulation, a hallmark of NAFLD, along with reduced LDL-C, HDL-C and elevated triglycerides., Conclusions: This comprehensive approach, that combines genome editing, transcriptomics, and phenotypic assays identified the DIO1 promoter region as a potential enhancer. Its activity could regulate multiple genes involved in the NAFLD phenotype or contribute to defining a polygenic risk score for enhanced risk assessment in NAFLD patients., (© 2024. The Author(s).)

Background: Debate exists concerning the impact of D2 vs. D1 lymphadenectomy on long-term oncological outcomes after gastrectomy for cancer., Methods: PubMed, MEDLINE, Scopus, and Web of Science were searched and randomized controlled trials (RCTs) analyzing the effect of D2 vs. D1 on survival were included. Overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS) were assessed. Restricted mean survival time difference (RMSTD) and 95% confidence intervals (CI) were used as effect size measures., Results: Five RCTs (1653 patients) were included. Overall, 805 (48.7%) underwent D2 lymphadenectomy. The RMSTD OS analysis shows that at 60-month follow-up, D2 patients lived 1.8 months (95% CI -4.2, 0.7; p = 0.14) longer on average compared to D1 patients. Similarly, 60-month CSS (1.2 months, 95% CI -3.9, 5.7; p = 0.72) and DFS (0.8 months, 95% CI -1.7, 3.4; p = 0.53) tended to be improved for D2 vs. D1 lymphadenectomy., Conclusions: Compared to D1, D2 lymphadenectomy is associated with a clinical trend toward improved OS, CSS, and DFS at 60-month follow-up.

River widening, defined as a lateral expansion of the channel, is a critical process that maintains fluvial ecosystems and is part of the regular functioning of rivers. However, in areas with high population density, channel widening can cause damage during floods. Therefore, for effective flood risk management it is essential to identify river reaches where abrupt channel widening may occur. Despite numerous efforts to predict channel widening, most studies have been limited to single rivers and single flood events, which may not be representative of other conditions. Moreover, a multi-catchment scale approach that covers various settings and flood magnitudes has been lacking. In this study, we fill this gap by compiling a large database comprising 1564 river reaches in several mountain regions in Europe affected by floods of varying magnitudes in the last six decades. By applying a meta-analysis, we aimed to identify the types of floods responsible for more extensive widening, the river reach types where intense widening is more likely to occur, and the hydraulic and morphological variables that explain widening and can aid in predicting widening. Our analysis revealed seven groups of reaches with significantly different responses to floods regarding width ratios (i.e., the ratio between channel width after and before a flood). Among these groups, the river reaches located in the Mediterranean region and affected by extreme floods triggered by short and intense precipitation events showed significantly larger widening than other river reaches in other regions. Additionally, the meta-analysis confirmed valley confinement as a critical morphological variable that controls channel widening but showed that it is not the only controlling factor. We proposed new statistical models to identify river reaches prone to widening, estimate potential channel width after a flood, and compute upper bound width ratios. These findings can inform flood hazard evaluations and the design of mitigation measures., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Different techniques have been described for esophagojejunostomy (EJ) during laparoscopic total gastrectomy (LTG) for gastric cancer. Linear stapled techniques include overlap (OL) and functional end-to-end anastomosis (FEEA) while single staple technique (SST), hemi-double staple technique (HDST), and OrVil® are circular stapled approaches. Nowadays, the choice among techniques for EJ depends on operating surgeon personal preference., Purpose: To compare short-term outcomes of different EJ techniques during LTG., Methods: Systematic review and network meta-analysis. OL, FEEA, SST, HDST, and OrVil® were compared. Primary outcomes were anastomotic leak (AL) and stenosis (AS). Risk ratio (RR) and weighted mean difference (WMD) were used as pooled effect size measures, whereas 95% credible intervals (CrI) were used to measure relative inference., Results: Overall, 3177 patients (20 studies) were included. The technique for EJ was SST (n = 1026; 32.9%), OL (n = 826; 26.5%), FEEA (n = 752; 24.1%), OrVil® (n = 317; 10.1%), and HDST (n = 196; 6.4%). AL was comparable for OL vs. FEEA (RR = 0.82; 95% CrI 0.47-1.49), OL vs. SST (RR = 0.55; 95% CrI 0.27-1.21), OL vs. OrVil® (RR = 0.54; 95% CrI 0.32-1.22), and OL vs. HDST (RR = 0.65; 95% CrI 0.28-1.63). Similarly, AS was similar for OL vs. FEEA (RR = 0.46; 95% CrI 0.18-1.28), OL vs. SST (RR = 0.89; 95% CrI 0.39-2.15), OL vs. OrVil® (RR = 0.36; 95% CrI 0.14-1.02), and OL vs. HDST (RR = 0.61; 95% CrI 0.31-1.21). Anastomotic bleeding, time to soft diet resumption, pulmonary complications, hospital length of stay, and mortality were comparable while operative time was reduced for FEEA., Conclusions: This network meta-analysis shows similar postoperative AL and AS risk when comparing OL, FEEA, SST, HDST, and OrVil® techniques. Similarly, no differences were found for anastomotic bleeding, operative time, soft diet resumption, pulmonary complications, hospital length of stay and 30-day mortality., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Incisional hernia (IH) represents an important complication after surgery. Prophylactic mesh reinforcement (PMR) with different mesh locations [onlay (OL), retromuscular (RM), preperitoneal (PP), and intraperitoneal (IP)] has been described to possibly reduce the risk of postoperative IH. However, data reporting the 'ideal' mesh location are sparse. The aim of this study was to evaluate the optimal mesh location for IH prevention during elective laparotomy., Methods: Systematic review and network meta-analysis of randomized controlled trials (RCTs). OL, RM, PP, IP, and no mesh (NM) were compared. The primary aim was postoperative IH. Risk ratio (RR) and weighted mean difference (WMD) were used as pooled effect size measures, whereas 95% credible intervals (CrI) were used to assess relative inference., Results: Fourteen RCTs (2332 patients) were included. Overall, 1052 (45.1%) had no mesh (NM) while 1280 (54.9%) underwent PMR stratified in IP ( n =344 pts), PP ( n =52 pts), RM ( n =463 pts), and OL ( n =421 pts) placement. Follow-up ranged from 12 months to 67 months. RM (RR=0.34; 95% CrI: 0.10-0.81) and OL (RR=0.15; 95% CrI: 0.044-0.35) were associated with significantly reduced IH RR compared to NM. A tendency toward reduced IH RR was noticed for PP versus NM (RR=0.16; 95% CrI: 0.018-1.01), while no differences were found for IP versus NM (RR=0.59; 95% CrI: 0.19-1.81). Seroma, hematoma, surgical site infection, 90-day mortality, operative time and hospital length of stay were comparable among treatments., Conclusions: RM or OL mesh placement seems associated with reduced IH RR compared to NM. PP location appears promising; however, future studies are warranted to corroborate this preliminary indication., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Incisional hernia (IH) is a common complication after abdominal surgery. Prevention of IH is matter of intense research. Prophylactic mesh reinforcement (PMR) has been shown to be promising in the minimization of IH risk after elective midline laparotomy., Methods: Systematic review and meta-analysis of randomized controlled trials (RCTs) comparing PMR vs. primary suture closure (PSC). Risk ratio (RR) and standardized mean difference (MD) were used as pooled effect size measures whereas 95% confidence intervals (95%CI) were used to assess relative inference., Results: Fourteen RCTs (2332 patients) were included. Overall, 1280 (54.9%) underwent PMR while 1052 (45.1%) PSC. Postoperative follow-up ranged from 12 to 67 months. The incidence of IH was reduced for PMR vs. PSC (13.4% vs. 27.5%). The estimated pooled IH RR for PMR vs. PSC is 0.38 (95% CI 0.24-0.58; p < 0.001). Stratified subgroup analysis according to mesh location shows a risk reduction for intraperitoneal (RR = 0.65; 95% CI 0.48-0.89), preperitoneal (RR = 0.18; 95% CI 0.04-0.81), retromuscular (RR = 0.47; 95% CI 0.24-0.92) and onlay (RR = 0.24; 95% CI 0.12-0.51) compared to PSC. The seroma RR was higher for PMR (RR = 2.05; p = 0.0008). No differences were found for hematoma (RR = 1.49; p = 0.34), surgical site infection (SSI) (RR = 1.17; p = 0.38), operative time (OT) (MD = 0.27; p = 0.413), and hospital length of stay (HLOS) (MD = -0.03; p = 0.237)., Conclusions: PMR seems effective in reducing the risk of IH after elective midline laparotomy compared to PSC in the medium-term follow-up. While the risk of postoperative seroma appears higher for PMR, hematoma, SSI, HLOS and OT seems comparable., (© 2022. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Minimal/measurable residual disease (MRD) monitoring is progressively changing the management of hematologic malignancies. The possibility of detecting the persistence/reappearance of disease in patients in apparent clinical remission offers a refined risk stratification and a treatment decision making tool. Several molecular techniques are employed to monitor MRD, from conventional real-time quantitative polymerase chain reaction (RQ-PCR) to next generation sequencing and digital droplet PCR (ddPCR), in different tissues or compartments through the detection of fusion genes, immunoglobulin and T-cell receptor gene rearrangements or disease-specific mutations. RQ-PCR is still the gold standard for MRD analysis despite some limitations. ddPCR, considered the third-generation PCR, yields a direct, absolute, and accurate detection and quantification of low-abundance nucleic acids. In the setting of MRD monitoring it carries the major advantage of not requiring a reference standard curve built with the diagnostic sample dilution and of allowing to reduce the number of samples below the quantitative range. At present, the broad use of ddPCR to monitor MRD in the clinical practice is limited by the lack of international guidelines. Its application within clinical trials is nonetheless progressively growing both in acute lymphoblastic leukemia as well as in chronic lymphocytic leukemia and non-Hodgkin lymphomas. The aim of this review is to summarize the accumulating data on the use of ddPCR for MRD monitoring in chronic lymphoid malignancies and to highlight how this new technique is likely to enter into the clinical practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Assanto, Del Giudice, Della Starza, Soscia, Cavalli, Cola, Bellomarino, Di Trani, Guarini and Foà.)

Circulating tumor DNA (ctDNA) has become the most investigated analyte in blood. It is shed from the tumor into the circulation and represents a subset of the total cell-free DNA (cfDNA) pool released into the peripheral blood. In order to define if ctDNA could represent a useful tool to monitor hematologic malignancies, we analyzed 81 plasma samples from patients affected by different diseases. The results showed that: (i) the comparison between two different extraction methods Qiagen (Hilden, Germany) and Promega (Madison, WI) showed no significant differences in cfDNA yield, though the first recovered higher amounts of larger DNA fragments; (ii) cfDNA concentrations showed a notable inter-patient variability and differed among diseases: acute lymphoblastic leukemia and chronic myeloid leukemia released higher amounts of cfDNA than chronic lymphocytic leukemia, and diffuse large B-cell lymphoma released higher cfDNA quantities than localized and advanced follicular lymphoma; (iii) focusing on the tumor fraction of cfDNA, the quantity of ctDNA released was insufficient for an adequate target quantification for minimal residual disease monitoring; (iv) an amplification system proved to be free of analytical biases and efficient in increasing ctDNA amounts at diagnosis and in follow-up samples as shown by droplet digital PCR target quantification. The protocol has been validated by quality control rounds involving external laboratories. To conclusively document the feasibility of a ctDNA-based monitoring of patients with hematologic malignancies, more post-treatment samples need to be evaluated. This will open new possibilities for ctDNA use in the clinical practice., (© 2022 John Wiley & Sons Ltd.)

Background: Anastomotic leak (AL) is a feared complication after colorectal surgery. Prompt diagnosis and treatment are crucial. C-reactive protein (CRP) and procalcitonin (PCT) have been proposed as early AL indicators. The aim of this systematic review was to evaluate the CRP and CPT predictive values for early AL diagnosis after colorectal surgery., Methods: Systematic literature search to identify studies evaluating the diagnostic accuracy of postoperative CRP and CPT for AL. A Bayesian meta-analysis was carried out using a random-effects model and pooled predictive parameters to determine postoperative CRP and PCT cut-off values at different postoperative days (POD)., Results: Twenty-five studies (11,144 patients) were included. The pooled prevalence of AL was 8% (95 CI 7-9%), and the median time to diagnosis was 6.9 days (range 3-10). The derived POD3, POD4 and POD5 CRP cut-off were 15.9 mg/dl, 11.4 mg/dl and 10.9 mg/dl respectively. The diagnostic accuracy was comparable with a pooled area under the curve (AUC) of 0.80 (95% CIs 0.23-0.85), 0.84 (95% CIs 0.18-0.86) and 0.84 (95% CIs 0.18-0.89) respectively. Negative likelihood ratios (LR-) showed moderate evidence to rule out AL on POD 3 (LR- 0.29), POD4 (LR- 0.24) and POD5 (LR- 0.26). The derived POD3 and POD5 CPT cut-off were 0.75 ng/ml (AUC = 0.84) and 0.9 ng/ml (AUC = 0.92) respectively. The pooled POD5 negative LR (-0.18) showed moderate evidence to rule out AL., Conclusions: In the setting of colorectal surgery, CRP and CPT serum concentrations lower than the derived cut-offs on POD3-POD5, may be useful to rule out AL thus possibly identifying patients at low risk for AL development., (© 2022. The Society for Surgery of the Alimentary Tract.)

Objective: To determine the impact of tumor characteristics and treatment approach on (1) local recurrence, (2) scoliosis development, and (3) patient-reported quality of life in children with sarcoma of the chest wall., Summary of Background Data: Children with chest wall sarcoma require multimodal therapy including chemotherapy, surgery, and/or radiation. Despite aggressive therapy which places them at risk for functional impairment and scoliosis, these patients are also at significant risk for local recurrence., Methods: A multi-institutional review of 175 children (median age 13 years) with chest wall sarcoma treated at seventeen Pediatric Surgical Oncology Research Collaborative institutions between 2008 and 2017 was performed. Patient-reported quality of life was assessed prospectively using PROMIS surveys., Results: The most common diagnoses were Ewing sarcoma (67%) and osteosarcoma (9%). Surgical resection was performed in 85% and radiation in 55%. A median of 2 ribs were resected (interquartile range = 1-3), and number of ribs resected did not correlate with margin status ( P = 0.36). Local recurrence occurred in 23% and margin status was the only predictive factor(HR 2.24, P = 0.039). With a median follow-up of 5 years, 13% developed scoliosis (median Cobb angle 26) and 5% required corrective spine surgery. Scoliosis was associated with posteriorrib resection (HR 8.43; P= 0.003) and increased number of ribs resected (HR 1.78; P = 0.02). Overall, patient-reported quality of life is not impaired after chest wall tumor resection., Conclusions: Local recurrence occurs in one-quarter of children with chest wall sarcoma and is independent of tumor type. Scoliosis occurs in 13% of patients, but patient-reported quality of life is excellent., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Paraesophageal hiatal hernia (PEH) is characterized by protrusion of intra-abdominal organs into the posterior mediastinum. Respiratory symptoms and reduced pulmonary function have been described as possibly related to lung compression., Objective: To assess the effect of laparoscopic Toupet fundoplication (LTF) for PEH repair on pulmonary function, measured with pulmonary function tests (PFTs), and respiratory symptoms., Methods: Retrospective, single-center, cohort study (November 2015-2020). All patients that completed pre- and postoperative (12 months) PFTs assessment were included. The gastroesophageal reflux disease health-related quality of life (GERD-HRQL), reflux symptom index (RSI) and short form-36 (SF-36) were used., Results: Overall, 71 patients were included. The median age was 67.1 years and the majority were females (78.8%). Baseline PFTs were within normal limits in 91% of patients. At 12 month follow-up, total lung capacity (TLC) (4.77 vs. 5.07 L; p = 0.0251), vital capacity (VC) (2.97 vs. 3.31 L; p = 0.0065), forced expiratory volume in one second (FEV1) (2.07 vs. 2.44 L; p < 0.001) and forced vital capacity (FVC) (2.78 vs. 3.19 L; p < 0.001) were significantly improved. No significant differences were found for diffusing capacity of lung for carbon monoxide (DLCO) (17.09 vs. 17.24; p = 0.734), and FEV1/FVC (0.77 vs. 0.77; p = 0.967). Interestingly, improvements were more pronounced in patients with large PEH (type IIIb and IV). At 12 month follow-up, both gastrointestinal and respiratory symptoms were significantly improved and 94% of patients were satisfied with the operation. The GERD-HRQL (18.1 ± 7.9 vs. 4.01 ± 2.4; p = 0.001), RSI (37.8 ± 9.7 vs. 10.6 ± 8.9; p < 0.001) and all SF-36 items were improved., Conclusions: LTF for the treatment of PEH is safe and seems to be effective up to 12 month follow-up with improved lung volumes, spirometry values, quality of life, gastrointestinal and respiratory symptoms., (© 2022. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Environmental and genetic factors cause defects in pancreatic islets driving type 2 diabetes (T2D) together with the progression of multi-tissue insulin resistance. Mass spectrometry proteomics on samples from five key metabolic tissues of a cross-sectional cohort of 43 multi-organ donors provides deep coverage of their proteomes. Enrichment analysis of Gene Ontology terms provides a tissue-specific map of altered biological processes across healthy, prediabetes (PD), and T2D subjects. We find widespread alterations in several relevant biological pathways, including increase in hemostasis in pancreatic islets of PD, increase in the complement cascade in liver and pancreatic islets of PD, and elevation in cholesterol biosynthesis in liver of T2D. Our findings point to inflammatory, immune, and vascular alterations in pancreatic islets in PD that are hypotheses to be tested for potential contributions to hormonal perturbations such as impaired insulin and increased glucagon production. This multi-tissue proteomic map suggests tissue-specific metabolic dysregulations in T2D., Competing Interests: Declaration of interests C.K. is an employee of AstraZeneca. J.W.E. has received research grants and honoraria from AstraZeneca. The other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: While vascularized lymph node transplant (VLNT) has gained popularity, there are a lack of prospective long-term studies and standardized outcomes. The purpose of this study was to evaluate the safety and efficacy of VLNT using all available outcome measures., Methods: This was a prospective study on all consecutive patients who underwent VLNT. Outcomes were assessed with 2 patient-reported outcome metrics, limb volume, bioimpedance, need for compression, and incidence of cellulitis., Results: There were 89 patients with the following donor sites: omentum (73%), axilla (13%), supraclavicular (7%), groin (3.5%). The mean follow-up was 23.7±12 months. There was a significant improvement at 2 years postoperatively across all outcome measures: 28.4% improvement in the Lymphedema Life Impact Scale, 20% average reduction in limb volume, 27.5% improvement in bioimpedance score, 93% reduction in cellulitis, and 34% of patients no longer required compression. Complications were transient and low without any donor site lymphedema., Conclusions: VLNT is a safe and effective treatment for lymphedema with significant benefits fully manifesting at 2 years postoperatively. Omentum does not have any donor site lymphedema risk making it an attractive first choice., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Aim: A follow-up genome-wide association study (GWAS) in an extended cohort of rheumatoid arthritis (RA) patients starting low-dose methotrexate (MTX) treatment was performed to identify further genetic variants associated with alanine aminotransferase (ALT) elevation. Patients & methods: A GWAS was performed on 346 RA patients. Two outcomes within the first 6 months of MTX treatment were assessed: ALT >1.5-times the upper level of normal (ULN) and maximum level of ALT. Results: SPATA9 (rs72783407) was significantly associated with maximum level of ALT (p = 2.58 × 10 -8 ) and PLCG2 (rs60427389) was tentatively associated with ALT >1.5 × ULN. Conclusion: Associations with SNPs in genes related to male fertility ( SPATA9 ) and inflammatory processes ( PLCG2 ) were identified.

Background: Different methods have been described for laparoscopic hiatoplasty and hiatus hernia (HH) repair. All techniques are not standardized and the choice to reinforce or not the hiatus with a mesh is left to the operating surgeon's preference. Hiatal surface area (HSA) has been described as an attempt at standardization; in case the area is > 4 cm 2 , a mesh is used to reinforce the repair., Objective: The aim of this study was to describe a new patient-tailored algorithm (PTA), compare its performance in predicting crura mesh buttressing to HSA, and analyze outcomes., Methods: Retrospective, single-center, descriptive study (September 2018-September 2021). Adult patients (≥ 18 years old) who underwent laparoscopic HH repair. Outcomes and quality of life measured with the disease-specific gastroesophageal reflux disease health-related quality of life (GERD-HRQL) and reflux symptom index (RSI) were analyzed., Results: Fifty patients that underwent laparoscopic hiatoplasty and Toupet fundoplication were included. The median age was 61 years (range 32-83) and the median BMI was 26.7 (range 17-36). According to the PTA, 27 patients (54%) underwent simple suture repair while crural mesh buttressing with Phasix-ST® was used in 23 (46%). According to the HSA, the median hiatus area was 4.7 cm 2 while 26 patients had an HSA greater than 4 cm 2 . The overall concordance rate between PTA and HSA was 94% (47/50). The median hospital stay was 1.9 days (range 1-8) and the 90-day complication rate was 4%. The median follow-up was 18.6 months (range 1-35). Hernia recurrence was diagnosed in 6%. Postoperative dysphagia occurred in one patient (2%). The GERD-HRQL (p < 0.001) and RSI (p = 0.001) were significantly improved., Conclusions: The application of PTA for cruroplasty standardization in the setting of HH repair seems effective. While concordance with HSA is high, the PTA seems easier and promptly available in the operative theater with a potential increase in procedure standardization, reproducibility, and teaching., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Digital droplet PCR (ddPCR) is an implementation of conventional PCR, with the potential of overcoming some limitations of real-time quantitative PCR (RQ-PCR). To evaluate if ddPCR may improve the quantification of disease levels and refine patients' risk stratification, 116 samples at four time points from 44 (35 B-lineage and 9 T-lineage) adult Philadelphia-negative acute lymphoblastic leukemia patients enrolled in the GIMEMA LAL1913 protocol were analyzed by RQ-PCR and ddPCR. A concordance rate between RQ-PCR and ddPCR of 79% (P < 0.0001) was observed; discordances were identified in 21% of samples, with the majority being RQ-PCR-negative (NEG) or positive not quantifiable (PNQ). ddPCR significantly reduced the proportion of PNQ samples-2.6% versus 14% (P = 0.003)-and allowed disease quantifiability in 6.6% of RQ-PCR-NEG, increasing minimal residual disease quantification in 14% of samples. Forty-seven samples were also investigated by next-generation sequencing, which confirmed the ddPCR results in samples classified as RQ-PCR-PNQ or NEG. By reclassifying samples on the basis of the ddPCR results, a better event-free survival stratification of patients was observed compared to RQ-PCR; indeed, ddPCR captured more true-quantifiable samples, with five relapses occurring in three patients who resulted RQ-PCR-PNQ/NEG but proved ddPCR positive quantifiable. At variance, no relapses were recorded in patients whose follow-up samples were RQ-PCR-PNQ but reclassified as ddPCR-NEG. A broader application of ddPCR in acute lymphoblastic leukemia clinical trials will help to improve patients' stratification., (Copyright © 2022 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Purpose: Staple line reinforcement (SLR) during laparoscopic sleeve gastrectomy (LSG) is controversial. The purpose of this study was to perform a comprehensive evaluation of the most commonly utilized techniques for SLR., Materials and Methods: Network meta-analysis of randomized controlled trials (RCTs) to compare no reinforcement (NR), suture oversewing (SR), glue reinforcement (GR), bioabsorbable staple line reinforcement (Gore® Seamguard®) (GoR), and clips reinforcement (CR). Risk Ratio (RR), weighted mean difference (WMD), and 95% credible intervals (CrI) were used as pooled effect size measures., Results: Overall, 3994 patients (17 RCTs) were included. Of those, 1641 (41.1%) underwent NR, 1507 (37.7%) SR, 689 (17.2%) GR, 107 (2.7%) GoR, and 50 (1.3%) CR. SR was associated with a significantly reduced risk of bleeding (RR=0.51; 95% CrI 0.31-0.88), staple line leak (RR=0.56; 95% CrI 0.32-0.99), and overall complications (RR=0.50; 95% CrI 0.30-0.88) compared to NR while no differences were found vs. GR, GoR, and CR. Operative time was significantly longer for SR (WMD=16.2; 95% CrI 10.8-21.7), GR (WMD=15.0; 95% CrI 7.7-22.4), and GoR (WMD=15.5; 95% CrI 5.6-25.4) compared to NR. Among treatments, there were no significant differences for surgical site infection (SSI), sleeve stenosis, reoperation, hospital length of stay, and 30-day mortality., Conclusions: SR seems associated with a reduced risk of bleeding, leak, and overall complications compared to NR while no differences were found vs. GR, GoR, and CR. Data regarding GoR and CR are limited while further trials reporting outcomes for these techniques are warranted., (© 2022. The Author(s).)

DNA methylation is a central epigenetic mark that has diverse roles in gene regulation, development, and maintenance of genome integrity. 5 methyl cytosine (5mC) can be interrogated at base resolution in single cells by using bisulfite sequencing (scWGBS). Several different scWGBS strategies have been described in recent years to study DNA methylation in single cells. However, there remain limitations with respect to cost-efficiency and yield. Herein, we present a new development in the field of scWGBS library preparation; single cell Splinted Ligation Adapter Tagging (scSPLAT). scSPLAT employs a pooling strategy to facilitate sample preparation at a higher scale and throughput than previously possible. We demonstrate the accuracy and robustness of the method by generating data from 225 single K562 cells and from 309 single liver nuclei and compare scSPLAT against other scWGBS methods., (© 2022. The Author(s).)

Background: Different surgical variations have been described for laparoscopic crural repair however, the technique is not standardized and left to the surgeons' preference., Objective: The purpose of this study is to describe a standardized "patient tailored" approach for laparoscopic posterior cruroplasty in the setting of elective hiatal hernia repair., Methods: Retrospective single-center study was conducted (November 2015 to November 2019). The technical aspects of a standardized "patient tailored" laparoscopic posterior crural repair are described. Perioperative outcomes and patients' quality of life, measured with the disease specific Gastro-Esophageal Reflux Disease Health-Related Quality of Life (GERD-HRQL) and generic Short Form-36 (SF-36), were analyzed., Results: One hundred and forty-one patients were treated for symptomatic hiatal hernia according to the described "patient tailored" concept. Overall, 102 (72.3%) patients underwent simple suture repair while simple suture repair buttressed with biosynthetic resorbable U shaped mesh [Phasix ST ® -Bard] was used in 39 (27.7%) patients. Toupet fundoplication was fashioned in all patients. The median operative time was 131 min (IQR 55-240). No intraoperative complications or conversion to open surgery occurred. The median postoperative stay was 1.8 days (range 1-7). The overall postoperative complication rate was 4.2%. The median follow-up was 21 months (IQR range 1-34) with 102 patients having a minimum follow-up of 6 months. Recurrent hernia was diagnosed in three patients (2.1%), but none required reoperation. No mesh-related complications occurred. Compared to baseline, the median GERD-HRQL (p = 0.003) and all SF-36 items (p < 0.001) were significantly improved., Conclusion: The application of a standardized "patient tailored" concept for laparoscopic posterior cruroplasty seems safe and effective in the medium-term follow-up with promising perioperative outcomes and quality of life improvement. This approach may be valuable to assure procedure reproducibility, standardization, and to uniformly interpret the outcomes., (© 2020. Springer-Verlag France SAS, part of Springer Nature.)

Background: In the setting of esophageal squamous cell carcinoma, controversy exists regarding the optimal extent of lymphadenectomy, while conclusive evidence regarding the advantages of 3-field versus 2-field lymphadenectomy remains controversial. The purpose of the present meta-analysis was to investigate the effect of 3-field lymphadenectomy versus 2-field lymphadenectomy on overall survival., Methods: Systematic review and meta-analyses were computed to compare 3-field lymphadenectomy versus 2-field lymphadenectomy in the setting of esophageal squamous cell carcinoma. Risk ratio, weighted mean difference, hazard ratio, and restricted mean survival time difference were used as pooled effect size measures., Results: Fourteen studies (3,431 patients) were included. Overall, 1,664 (48.8%) patients underwent 3-field lymphadenectomy, and 1,767 (51.5%) underwent 2-field lymphadenectomy. Three-field lymphadenectomy was associated with a significantly improved 5-year overall survival (hazard ratio: 0.80; 95% confidence interval 0.71-0.90; P < .001). The restricted mean survival time difference showed a statistically significant difference between 3-field lymphadenectomy versus 2-field lymphadenectomy up to 48 months (1.6 months; P = .04), however, no significant differences were found at 60-month follow-up (1.2 months; P = .14). No significant differences were found in term of postoperative mortality, anastomotic leak, pulmonary complications, chylothorax, and recurrent nerve palsy., Conclusion: For resectable esophageal squamous cell carcinoma, 3-field lymphadenectomy seems associated with a slight trend toward improved 5-year overall survival; however, its clinical benefit remains limited., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The choice of the best reconstruction technique after distal gastrectomy (DG) remains controversial and still not defined. The purpose was to perform a comprehensive evaluation within the major type of intestinal reconstruction after DG for gastric cancer., Methods: Systematic review and network meta-analyses of randomized controlled trials (RCTs) to compare Billroth I (BI), Billroth II (BII), Billroth II Braun (BII Braun), Roux-en-Y (RY), and Uncut Roux-en-Y (URY). Risk ratio (RR) and weighted mean difference (WMD) were used as pooled effect size measures while 95% credible intervals (CrI) were used to assess relative inference., Results: Ten RCTs (1456 patients) were included. Of these, 448 (33.7%) underwent BI, 220 (15.1%) BII, 114 BII Braun (7.8%), 533 (36.6%) RY, and 141 URY (9.6%). No significant differences were found among treatments for 30-day mortality, anastomotic leak, anastomotic stricture, and overall complications. At 12-month follow-up, RY was associated with a significantly reduced risk of remnant gastritis compared to BI (RR=0.56; 95% Crl 0.35-0.76) and BII reconstruction (RR=0.47; 95% Crl 0.22-0.97). Similarly, despite the lack of statistical significance, RY seems associated with a trend toward reduced endoscopically proven esophagitis compared to BI (RR=0.58; 95% Crl 0.24-1.51) and bile reflux compared to BI (RR=0.48; 95% Crl 0.17-1.41), BII (RR=0.74; 95% Crl 0.20-2.81), and BII Braun (RR=0.65; 95% Crl 0.30-1.43)., Conclusions: This network meta-analysis shows that there are five main options for intestinal anastomosis after DG. All techniques seem equally safe with comparable anastomotic leak, anastomotic stricture, overall morbidity, and short-term outcomes. In the short-term follow-up (12 months), RY seems associated with a reduced risk of remnant gastritis and a trend toward a reduced risk of bile reflux and esophagitis., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Hernia recurrence after laparoscopic repair is a perplexing problem. In an effort to reduce anatomical and clinical recurrences, different type of meshes have been used to bolster the esophageal hiatus., Objective: The aim of this study was to assess safety, medium-term efficacy, and quality of life improvement after laparoscopic repair of hiatal hernia reinforced with a biosynthetic absorbable mesh (Phasix-ST ® )., Methods: Observational single-center retrospective single-arm cohort study (November 2015-February 2021). We included all adult patients (> 18 years old) who underwent laparoscopic paraesophageal hernia repair with Phasix-ST ® mesh and Toupet fundoplication., Results: Sixty-eight patients were included. The median postoperative stay was 3.2 days (range 2-9) and the postoperative complication rate was 11.7%. The median follow-up time was 27 months (range 1-53). No mesh-related complications were detected. Hernia recurrence was diagnosed in six patients (8.8%). The recurrence-free probability at 34 months was 0.89 (95% CI 0.807-0.988) while at 60 months was 0.86 (95% CI 0.76-0.97). Hernia recurrences were mostly observed between 21 and 36 months after the operation. None of the patients required surgical revision and all were managed with PPI. Postoperative dysphagia requiring endoscopic balloon dilatation occurred in 2.9% of patients. Compared to baseline, both the GERD-HRQL (15.2 ± 6.2 vs. 3.2 ± 3.1; p = 0.026) and all SF-36 items were significantly improved (p < 0.001)., Conclusions: Laparoscopic crura augmentation with Phasix-ST ® mesh combined with a Toupet fundoplication is safe and seems effective in the medium-term follow-up. Phasix-ST ® crural reinforcement resulted in low hernia recurrence rate with a sustained symptoms and quality of life improvement., (© 2021. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Background: Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common myopathies in adults, displaying a progressive, frequently asymmetric involvement of a typical muscles' pattern. FSHD is associated with epigenetic derepression of the polymorphic D4Z4 repeat on chromosome 4q, leading to DUX4 retrogene toxic expression in skeletal muscles. Identifying biomarkers that correlate with disease severity would facilitate clinical management and assess potential FSHD therapeutics' efficacy., Objectives: This study purpose was to analyze serum cytokines to identify potential biomarkers in a large cohort of adult patients with FSHD., Methods: We retrospectively measured the levels of 20 pro-inflammatory and regulatory cytokines in sera from 100 genetically confirmed adult FSHD1 patients. Associations between cytokine concentrations and various clinical scores were investigated. We then measured serum and muscle interleukin 6 (IL-6) levels in a validated FSHD-like mouse model, ranging in severity and DUX4 expression., Results: IL-6 was identified as the only cytokine with a concentration correlating with several clinical severity and functional scores, including Clinical Severity Score, Manual Muscle Testing sum score, Brooke and Vignos scores. Further, FSHD patients displayed overall IL-6 levels more than twice high as control, and patients with milder phenotypes exhibited lower IL-6 serum concentration than those with severe muscular weakness. Lastly, an FSHD-like mouse model analysis confirmed that IL-6 levels positively correlate with disease severity and DUX4 expression., Conclusions: Serum IL-6, therefore, shows promise as a serum biomarker of FSHD severity in a large cohort of FSHD1 adult patients.

Comprehensive genomic studies have delineated key driver mutations linked to disease progression for most cancers. However, corresponding transcriptional changes remain largely elusive because of the bias associated with cross-study analysis. Here, we overcome these hurdles and generate a comprehensive prostate cancer transcriptome atlas that describes the roadmap to tumor progression in a qualitative and quantitative manner. Most cancers follow a uniform trajectory characterized by upregulation of polycomb-repressive-complex-2, G2-M checkpoints, and M2 macrophage polarization. Using patient-derived xenograft models, we functionally validate our observations and add single-cell resolution. Thereby, we show that tumor progression occurs through transcriptional adaption rather than a selection of pre-existing cancer cell clusters. Moreover, we determine at the single-cell level how inhibition of EZH2 - the top upregulated gene along the trajectory - reverts tumor progression and macrophage polarization. Finally, a user-friendly web-resource is provided enabling the investigation of dynamic transcriptional perturbations linked to disease progression., (© 2021. The Author(s).)

Background: Despite the advent of innovative surgical platforms and operative techniques, a definitive indication of the best surgical option for the treatment of unilateral primary inguinal hernia remains unsettled. Purpose was to perform an updated and comprehensive evaluation within the major approaches to inguinal hernia., Methods: Systematic review and network meta-analyses of randomized controlled trials (RCTs) compare Lichtenstein tension-free repair, laparoscopic transabdominal preperitoneal (TAPP) repair, and totally extraperitoneal repair (TEP). Risk ratio (RR) and weighted mean difference (WMD) were used as pooled effect size measures, whereas 95% credible intervals (CrI) were used to assess relative inference., Results: Thirty-five RCTs (7777 patients) were included. Overall, 3496 (44.9%) underwent Lichtenstein, 1269 (16.3%) TAPP, and 3012 (38.8%) TEP repair. The Visual Analogue Scale (VAS) was significantly lower for minimally invasive repair at <12 hours, 24 hours, and 48 hours. Postoperative chronic pain [TAPP vs Lichtenstein (RR = 0.36; 95% CrI 0.15-0.81) and TEP vs Lichtenstein (RR = 0.36; 95% CrI 0.21-0.54)] and return to work/activities [TAPP vs Lichtenstein (WMD = -3.3; 95% CrI -4.9 to -1.8) and TEP vs Lichtenstein (WMD = -3.6; 95% CrI -4.9 to -2.4)] were significantly reduced for minimally invasive approaches. Wound hematoma and infection were significantly reduced for minimally invasive approaches, whereas no differences were found for seroma, hernia recurrence, and hospital length of stay., Conclusions: Minimally invasive TAPP and TEP repair seem associated with significantly reduced early postoperative pain, return to work/activities, chronic pain, hematoma, and wound infection compared to the Lichtenstein tension-free repair. Hernia recurrence, seroma, and hospital length of stay seem similar across treatments., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The magnetic sphincter augmentation (MSA) device has become a common option for the treatment of gastroesophageal reflux disease (GERD). Knowledge of MSA-related complications, indications for removal, and techniques are puzzled. With this study, we aimed to evaluate indications, techniques for removal, surgical approach, and outcomes with MSA removal., Methods: This is an observational singe-center study. Patients were followed up regularly with endoscopy, pH monitoring, and assessed for specific gastroesophageal reflux disease health-related quality of life (GERD-HRQL) and generic short-form 36 (SF-36) quality of life., Results: Five patients underwent MSA explant. Four patients were males and the median age was 47 years (range 44-55). Heartburn, epigastric/chest pain, and dysphagia were commonly reported. The median implant duration was 46 months (range 31-72). A laparoscopic approach was adopted in all patients. Intraoperative findings included normal anatomy (40%), herniation in the mediastinum (40%), and erosion (20%). The most common anti-reflux procedures were Dor (n = 2), Toupet (n = 2), and anterior partial fundoplication (n = 1). The median operative time was 145 min (range 60-185), and the median hospital length of stay was 4 days (range 3-6). The median postoperative follow-up was 41 months (range 12-51). At the last follow-up, 80% of patients were off PPI; the GERD-HRQL and SF-36 questionnaire were improved with DeMeester score and esophageal acid exposure normalization., Conclusion: The MSA device can be safely explanted through a single-stage laparoscopic procedure. Tailoring a fundoplication, according to preoperative patient symptoms and intraoperative findings, seems feasible and safe with a promising trend toward improved symptoms and quality of life., (© 2021. The Author(s).)

Aim: To identify novel genetic variants predisposing to elevation of Alanine aminotransferase (ALT) in rheumatoid arthritis (RA) patients after initiation of methotrexate (MTX) treatment. Patients & methods: We performed genome-wide association studies in 198 RA patients starting MTX. Outcomes were maximum level of ALT and ALT >1.5-times the upper level of normal within the first 6 months of treatment. Results: RAVER2 (rs72675408) was significantly associated with maximum level of ALT (p = 4.36 × 10 -8 ). This variant is in linkage disequilibrium with rs72675451, which is associated with differential expression of JAK1 and RAVER2 . Conclusion: We found an association between ALT elevation and genetic variants that may regulate the expression of JAK1 and RAVER2 . JAK1 encodes a janus kinase involved in the pathogenesis of RA.

Type 2 diabetes (T2D) is characterized by pathophysiological alterations in lipid metabolism. One strategy to understand the molecular mechanisms behind these abnormalities is to identify cis -regulatory elements (CREs) located in chromatin-accessible regions of the genome that regulate key genes. In this study we integrated assay for transposase-accessible chromatin followed by sequencing (ATAC-seq) data, widely used to decode chromatin accessibility, with multi-omics data and publicly available CRE databases to identify candidate CREs associated with T2D for further experimental validations. We performed high-sensitive ATAC-seq in nine human liver samples from normal and T2D donors, and identified a set of differentially accessible regions (DARs). We identified seven DARs including a candidate enhancer for the ACOT1 gene that regulates the balance of acyl-CoA and free fatty acids (FFAs) in the cytoplasm. The relevance of ACOT1 regulation in T2D was supported by the analysis of transcriptomics and proteomics data in liver tissue. Long-chain acyl-CoA thioesterases (ACOTs) are a group of enzymes that hydrolyze acyl-CoA esters to FFAs and coenzyme A. ACOTs have been associated with regulation of triglyceride levels, fatty acid oxidation, mitochondrial function, and insulin signaling, linking their regulation to the pathogenesis of T2D. Our strategy integrating chromatin accessibility with DNA binding and other types of omics provides novel insights on the role of genetic regulation in T2D and is extendable to other complex multifactorial diseases.

Purpose: To examine the updated evidence on safety, effectiveness, and outcomes of the totally extraperitoneal (TEP) versus the laparoscopic transabdominal preperitoneal (TAPP) repair and to explore the timely tendency variations favoring one treatment over another., Methods: Systematic review and trial sequential analysis (TSA) of randomized controlled trials (RCTs). MEDLINE, Scopus, Web of Science, Cochrane Central Library, and ClinicalTrials.gov were consulted. Risk Ratio (RR), weighted mean difference (WMD), and 95% confidence intervals (CI) were used as pooled effect size measures., Results: Fifteen RCTs were included (1359 patients). Of these, 702 (51.6%) underwent TAPP and 657 (48.4%) TEP repair. The age of the patients ranged from 18 to 92 years and 87.9% were males. The estimated pooled RR for hernia recurrence (RR = 0.83; 95% CI 0.35-1.96) and chronic pain (RR = 1.51; 95% CI 0.54-4.22) were similar for TEP vs. TAPP. The TSA shows a cumulative z-curve without crossing the monitoring boundaries line (Z = 1.96), thus supporting true negative results while the information size was calculated as adequate for both outcomes. No significant differences were found in term of early postoperative pain, operative time, wound-related complications, hospital length of stay, return to work/daily activities, and costs., Conclusions: TEP and TAPP repair seems comparable in terms of postoperative hernia recurrence and chronic pain. The cumulative evidence and information size are sufficient to provide a conclusive evidence on recurrence and chronic pain. Similar trials or meta-analyses seem unlikely to show diverse results and should be discouraged., (© 2021. The Author(s).)

Mutations in the MATR3 gene are associated to distal myopathy with vocal cord and pharyngeal weakness (VCPDM), as well as familiar and sporadic motor neuron disease. To date, 12 VCPDM families from the United States, Germany, Japan, Bulgary, and France have been described in the literature. Here we report an Italian family with a propositus of a 40-year-old woman presenting progressive bilateral foot drop, rhinolalia, and distal muscular atrophy, without clinical signs of motor neuron affection. Her father, deceased some years before, presented a similar distal myopathy phenotype, while her 20-year-old son is asymptomatic. Myopathic changes with vacuolization were observed in muscle biopsy from the propositus. These results, together with the peculiar clinical picture, lead to MATR3 gene sequencing, which revealed a heterozygous p.S85C mutation in the propositus. The same mutation was found in her son. Over a 5-year follow-up, progression is mild in the propositus, while her son remains asymptomatic. Clinical, radiological, and pathological data of our propositus are presented and compared to previously reported cases of VCPDM. VCPDM turns out to be a quite homogenous phenotype of late-onset myopathy associated to p.S85C mutation in MATR3 gene. MATR3 -related pathology, encompassing myopathy and motor neuron disease, represents an illustrative example of multisystem proteinopathy (MSP), such as other diseases associated to mutations in VCP, HNRNPA2B1, HNRNPA1 , and SQSTM1 genes. The present report contributes to a further characterization of this still poorly understood pathology and points out the diagnostic utility of muscle biopsy in challenging cases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cavalli, Cardani, Renna, Toffetti, Villa and Meola.)

Background: The role of minimally invasive surgery for the treatment of early and locally advanced gastric cancer remains controversial. The purpose of this study was to perform a comprehensive evaluation of major surgical approaches for operable distal gastric cancer., Methods: Systematic review and network meta-analyses of randomized controlled trials were performed to compare open distal gastrectomy, laparoscopic-assisted distal gastrectomy, and robotic distal gastrectomy. Risk ratio, weighted mean difference, and 95% credible intervals were used as pooled effect size measures., Results: Seventeen randomized controlled trials (5,909 patients) were included. Overall, 2,776 (46.8%) underwent open distal gastrectomy, 2,964 (50.1%) laparoscopic-assisted distal gastrectomy, and 141 (3.1%) robotic distal gastrectomy. Among these 3 groups, there were no significant differences in 30-day mortality, anastomotic leak, and overall complications. Compared to open distal gastrectomy, laparoscopic-assisted distal gastrectomy was associated with significantly reduced intraoperative blood loss, early postoperative pain, time to first flatus, and hospital length of stay. Similarly, robotic distal gastrectomy was associated with significantly reduced blood loss and time to first flatus compared to open distal gastrectomy. No differences were found in the total number of harvested lymph nodes, tumor-free resection margins, 5-year overall, and disease-free survival. The subgroup analysis in locally advanced gastric cancer showed trends toward reduced blood loss, time to first flatus, and hospital length of stay with minimally invasive approaches but similar overall and disease-free survival., Conclusion: Laparoscopic-assisted distal gastrectomy and robotic distal gastrectomy performed by well-trained experienced surgeons, even in the setting of locally advanced gastric cancer, seem associated with improved short-term outcomes with similar overall and disease-free survival compared with open distal gastrectomy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: The anatomy of the esophageal hiatus is altered during esophagogastric surgery with an increased risk of postoperative hiatus hernia (HH). The purpose of this article was to examine the current evidence on the surgical management and outcomes associated with HH after esophagogastric surgery for cancer., Materials and Methods: Systematic review and meta-analysis. Web of Science, PubMed, and EMBASE data sets were consulted., Results: Twenty-seven studies were included for a total of 404 patients requiring surgical treatment for HH after esophagogastric surgery. The age of the patients ranged from 35 to 85 years, and the majority were males (82.3%). Abdominal pain, nausea/vomiting, and dyspnea were the commonly reported symptoms. An emergency repair was required in 51.5%, while a minimally invasive repair was performed in 48.5%. Simple suture cruroplasty and mesh reinforced repair were performed in 65% and 35% of patients, respectively. The duration between the index procedure and HH repair ranged from 3 to 144 months, with the majority (67%) occurring within 24 months. The estimated pooled prevalence rates of pulmonary complications, anastomotic leak, overall morbidity, and mortality were 14.1% (95% CI = 8.0-22.0%), 1.4% (95% CI = 0.8-2.2%), 35% (95% CI = 20.0-54.0%), and 5.0% (95% CI = 3.0-8.0%), respectively. The postoperative follow-up ranged from 1 to 110 months (mean = 24) and the pooled prevalence of HH recurrence was 16% (95% CI = 13.0-21.6%)., Conclusions: Current evidence reporting data for HH after esophagogastric surgery is narrow. The overall postoperative pulmonary complications, overall morbidity, and mortality are 14%, 35%, and 5%, respectively. Additional studies are required to define indications and treatment algorithm and evaluate the best technique for crural repair at the index operation in an attempt to minimize the risk of HH., (© 2021. The Author(s).)

The stearoyl-CoA desaturase 1 (SCD1) gene at 10q24.31 encodes the rate limiting enzyme SCD1 that catalyzes the biosynthesis of monounsaturated fatty acids (MUFAs) from saturated fatty acids (SFAs). Dysregulated SCD1 activity has been observed in many human diseases including non-alcoholic fatty liver disease (NAFLD), obesity, hypertension, hyperlipidemia, metabolic syndrome and several types of cancer. HNF4A is a central regulator of glucose and lipid metabolism and previous studies suggested that it is deeply involved in regulating the SCD1 activity in the liver. However, the underlying mechanisms on whether and how SCD1 is regulated by HNF4A have not been explored in detail. In this study, we found that HNF4A regulates SCD1 expression by directly binding to the key regulatory regions in the SCD1 locus. Knocking down of HNF4A significantly downregulated the expression of SCD1. Variants rs55710213 and rs56334587 in intron 5 of SCD1 directly reside in a canonical HNF4A binding site. The GG haplotype of rs55710213 and rs56334587 is associated with decreased SCD1 activity by disrupting the binding of HNF4A, which further decreased the enhancer activity and SCD1 expression. In conclusion, our study demonstrated that SCD1 is directly regulated by HNF4A, which may be helpful in the understanding of the altered metabolic pathways in many diseases associated with dysregulated SCD1 or HNF4A or both., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Diastasis recti abdominis (DRA) or rectus diastasis is an acquired condition in which the rectus muscles are separated by an abnormal distance along their length, but with no fascia defect. To data there is no consensus about risk factors for DRA. The aim of this article is to critically review the literature about prevalence and risk factor of DRA., Method: A total of 13 papers were identified., Results: The real prevalence of DRA is unknown because the prevalence rate varies with measurement method, measurement site and judgment criteria, but it is certainly an extremely frequent condition. Numbers of parity, BMI, diabetes are the most plausible risk factors. We identified a new anatomical variation in cadaveric dissection and in abdominal CT image evaluation: along the semilunar line the internal oblique aponeurosis could join the rectus sheath with only a posterior layer, so without a double layer (anterior and posterior) as usually described. We conducted a retrospective review of abdominal CT images and the presence of the posterior insertion only could be considered as a risk factor for DRA., Conclusion: Further studies with large sample size, including nulliparous, primiparous, pluriparous and men too, are necessary for identify the real prevalence., (© 2021. The Author(s).)

Recent studies suggested that dysregulated YY1 plays a pivotal role in many liver diseases. To obtain a detailed view of genes and pathways regulated by YY1 in the liver, we carried out RNA sequencing in HepG2 cells after YY1 knockdown. A rigid set of 2,081 differentially expressed genes was identified by comparing the YY1-knockdown samples (n = 8) with the control samples (n = 14). YY1 knockdown significantly decreased the expression of several key transcription factors and their coactivators in lipid metabolism. This is illustrated by YY1 regulating PPARA expression through binding to its promoter and enhancer regions. Our study further suggest that down-regulation of the key transcription factors together with YY1 knockdown significantly decreased the cooperation between YY1 and these transcription factors at various regulatory regions, which are important in regulating the expression of genes in hepatic lipid metabolism. This was supported by the finding that the expression of SCD and ELOVL6 , encoding key enzymes in lipogenesis, were regulated by the cooperation between YY1 and PPARA/RXRA complex over their promoters., (© 2021 Pan et al.)