Early fate decision for mitochondrially encoded proteins by a molecular triage.

Folding of newly synthesized proteins poses challenges for a functional proteome. Dedicated protein quality control (PQC) systems either promote the folding of nascent polypeptides at ribosomes or, if this fails, ensure their degradation. Although well studied for cytosolic protein biogenesis, it is not understood how these processes work for mitochondrially encoded proteins, key subunits of the oxidative phosphorylation (OXPHOS) system. Here, we identify dedicated hubs in proximity to mitoribosomal tunnel exits coordinating mitochondrial protein biogenesis and quality control. Conserved prohibitin (PHB)/m-AAA protease supercomplexes and the availability of assembly chaperones determine the fate of newly synthesized proteins by molecular triaging. The localization of these competing activities in the vicinity of the mitoribosomal tunnel exit allows for a prompt decision on whether newly synthesized proteins are fed into OXPHOS assembly or are degraded.

Identifying attacks in the Russia-Ukraine conflict using seismic array data.

Seismometers are generally used by the research community to study local or distant earthquakes, but seismograms also contain critical observations from regional1,2 and global explosions3, which can be used to better understand conflicts and identify potential breaches of international law. Although seismic, infrasound and hydroacoustic technology is used by the International Monitoring System4 to monitor nuclear explosions as part of the Comprehensive Nuclear-Test-Ban Treaty, the detection and location of lower-yield military attacks requires a network of sensors much closer to the source of the explosions. Obtaining comprehensive and objective data that can be used to effectively monitor an active conflict zone therefore remains a substantial challenge. Here we show how seismic waves generated by explosions in northern Ukraine and recorded by a local network of seismometers can be used to automatically identify individual attacks in close to real time, providing an unprecedented view of an active conflict zone. Between February and November 2022, we observed more than 1,200 explosions from the Kyiv, Zhytomyr and Chernihiv provinces, providing accurate origin times, locations and magnitudes. We identify a range of seismoacoustic signals associated with various types of military attack, with the resulting catalogue of explosions far exceeding the number of publicly reported attacks. Our results demonstrate that seismic data can be an effective tool for objective monitoring of a continuing conflict, providing invaluable information about potential breaches of international law.

Molecular Connectivity of Mitochondrial Gene Expression and OXPHOS Biogenesis.

Mitochondria contain their own gene expression systems, including membrane-bound ribosomes dedicated to synthesizing a few hydrophobic subunits of the oxidative phosphorylation (OXPHOS) complexes. We used a proximity-dependent biotinylation technique, BioID, coupled with mass spectrometry to delineate in baker's yeast a comprehensive network of factors involved in biogenesis of mitochondrial encoded proteins. This mitochondrial gene expression network (MiGENet) encompasses proteins involved in transcription, RNA processing, translation, or protein biogenesis. Our analyses indicate the spatial organization of these processes, thereby revealing basic mechanistic principles and the proteins populating strategically important sites. For example, newly synthesized proteins are directly handed over to ribosomal tunnel exit-bound factors that mediate membrane insertion, co-factor acquisition, or their mounting into OXPHOS complexes in a special early assembly hub. Collectively, the data reveal the connectivity of mitochondrial gene expression, reflecting a unique tailoring of the mitochondrial gene expression system.

The functional significance of mitochondrial respiratory chain supercomplexes.

The mitochondrial respiratory chain (MRC) is a key energy transducer in eukaryotic cells. Four respiratory chain complexes cooperate in the transfer of electrons derived from various metabolic pathways to molecular oxygen, thereby establishing an electrochemical gradient over the inner mitochondrial membrane that powers ATP synthesis. This electron transport relies on mobile electron carries that functionally connect the complexes. While the individual complexes can operate independently, they are in situ organized into large assemblies termed respiratory supercomplexes. Recent structural and functional studies have provided some answers to the question of whether the supercomplex organization confers an advantage for cellular energy conversion. However, the jury is still out, regarding the universality of these claims. In this review, we discuss the current knowledge on the functional significance of MRC supercomplexes, highlight experimental limitations, and suggest potential new strategies to overcome these obstacles.

Parameters predicting postoperative pain and quality of life after hemorrhoidectomy: follow-up results from a prospective multicenter randomized trial.

PURPOSE: Pain and reduced quality of life (QoL) are major subjects of interest after surgery for hemorrhoids. The aim of this study was to find predictive parameters for postoperative pain and QoL after hemorrhoidectomy. METHODS: This is a follow-up analysis of data derived from a multicenter randomized controlled trial including 770 patients, which examines the usefulness of tamponade after hemorrhoidectomy. Different pre-, intra-, and postoperative parameters were correlated with pain level assessed by NRS and QoL by the EuroQuol. RESULTS: At univariate analysis, relevant (NRS > 5/10 pts.) early pain within 48 h after surgery was associated with young age (≤ 40 years, p = 0.0072), use of a tamponade (p < 0.0001), relevant preoperative pain (p = 0.0017), pudendal block (p < 0.0001), and duration of surgery (p = 0.0149). At multivariate analysis, not using a pudendal block (OR 2.64), younger age (OR 1.55), use of a tamponade (OR 1.70), and relevant preoperative pain (OR 1.56) were significantly associated with relevant early postoperative pain. Relevant pain on day 7 was significantly associated only with relevant early pain (OR 3.13, p < 0.001). QoL overall remained at the same level. However, n = 229 (33%) patients presented an improvement of QoL and n = 245 (36%) an aggravation. Improvement was associated with a reduction of pain levels after surgery (p < 0.0001) and analgesia with opioids (p < 0.0001). CONCLUSION: Early relevant pain affects younger patients but can be prevented by avoiding tamponades and using a pudendal block. Relevant pain after 1 week is associated only with early pain. Relief in preexisting pain and opioids improve QoL. TRIAL REGISTRATION: DRKS00011590 12 April 2017.

Hepatic blood flow regulation but not oxygen extraction capability is impaired in prolonged experimental abdominal sepsis.

Impaired oxygen utilization has been proposed to play a significant role in sepsis-induced liver dysfunction, but its magnitude and temporal course during prolonged resuscitation is controversial. The aim of this study is to evaluate the capability of the liver to increase oxygen extraction in sepsis during repeated acute portal vein blood flow reduction. Twenty anesthetized and mechanically ventilated pigs with hepatic hemodynamic monitoring were randomized to fecal peritonitis or controls (n = 10, each). After 8-h untreated sepsis, the animals were resuscitated for three days. The ability to increase hepatic O2 extraction was evaluated by repeated, acute decreases in hepatic oxygen delivery (Do2) via reduction of portal flow. Blood samples for liver function and liver biopsies were obtained repeatedly. Although liver function tests, ATP content, and Do2 remained unaltered, there were signs of liver injury in blood samples and overt liver cell necrosis in biopsies. With acute portal vein occlusion, hepatic Do2 decreased more in septic animals compared with controls [max. decrease: 1.66 ± 0.68 mL/min/kg in sepsis vs. 1.19 ± 0.42 mL/min/kg in controls; portal venous flow (Qpv) reduction-sepsis interaction: P = 0.028]. Hepatic arterial buffer response (HABR) was impaired but recovered after 3-day resuscitation, whereas hepatic oxygen extraction increased similarly during the procedures in both groups (max. increase: 0.27 ± 0.13 in sepsis vs. 0.18 ± 0.09 in controls; all P > 0.05). Our data indicate maintained capacity of the liver to acutely increase O2 extraction, whereas blood flow regulation is transiently impaired with the potential to contribute to liver injury in sepsis.NEW & NOTEWORTHY The capacity to acutely increase hepatic O2 extraction with portal flow reduction is maintained in sepsis with accompanying liver injury, but hepatic blood flow regulation is impaired.

Respiratory supercomplexes enhance electron transport by decreasing cytochrome c diffusion distance.

Respiratory chains are crucial for cellular energy conversion and consist of multi-subunit complexes that can assemble into supercomplexes. These structures have been intensively characterized in various organisms, but their physiological roles remain unclear. Here, we elucidate their function by leveraging a high-resolution structural model of yeast respiratory supercomplexes that allowed us to inhibit supercomplex formation by mutation of key residues in the interaction interface. Analyses of a mutant defective in supercomplex formation, which still contains fully functional individual complexes, show that the lack of supercomplex assembly delays the diffusion of cytochrome c between the separated complexes, thus reducing electron transfer efficiency. Consequently, competitive cellular fitness is severely reduced in the absence of supercomplex formation and can be restored by overexpression of cytochrome c. In sum, our results establish how respiratory supercomplexes increase the efficiency of cellular energy conversion, thereby providing an evolutionary advantage for aerobic organisms.

Mesh fixation to fascia during incisional hernia repair results in increased prevalence of pain at long-term follow up: a multicenter propensity score matched prospective observational study.

BACKGROUND: Patient-reported outcomes such as postoperative pain are critical for the evaluation of outcomes after incisional hernia repair. The aim of this study is to determine the long-term impact of mesh fixation on postoperative pain in patients operated by open and laparoscopic technique. METHODS: A multicenter prospective observational cohort study was conducted from September 2011 until March 2016 in nine hospitals across Switzerland. Patients undergoing elective incisional hernia repair were included in this study and stratified by either laparoscopic or open surgical technique. Propensity score matching was applied to balance the differences in baseline characteristics between the treatment groups. Clinical follow-up was conducted 3, 12 and 36 months postoperatively to detect hernia recurrence, postoperative pain and complications. RESULTS: Three-hundred-sixty-one patients were included into the study. No significant differences in hernia recurrence and pain at 3, 12 and 36 months postoperatively were observed when comparing the laparoscopic with the open treatment group. Mesh fixation by sutures to fascia versus other mesh fixation led to significantly more pain at 36 months postoperatively (32.8% vs 15.7%, p = 0.025). CONCLUSIONS: At long-term follow-up, no difference in pain was identified between open and laparoscopic incisional hernia repair. Mesh fixation by sutures to fascia was identified to be associated with increased pain 36 months after surgery. Omitting mesh fixation by sutures to the fascia may reduce long-term postoperative pain after hernia repair.

Tumour budding and CD8+ T cells: 'attackers' and 'defenders' in rectal cancer with and without neoadjuvant chemoradiotherapy.

AIM: Tumour budding ('attacker') and CD8+ T cells ('defender') are recognised as important parameters for risk stratification in colon cancers and, combined, may have an even stronger clinical impact. Here, we determine the value of tumour budding and CD8+ in rectal cancer patients treated with/without neoadjuvant therapy. METHODS AND RESULTS: Using digital scans of all tumour slides/case, we analysed CD8+ T cell counts in two patient cohorts: 45 neoadjuvantly treated and 47 primarily surgically treated (totalling n = 543 slides) after double-staining of the surgical resection specimen for pan-cytokeratin and CD8+ . Tumour buds in hot-spots were manually counted (area = 0.785 mm2 ) and CD8+ T cell counts were analysed separately both in tumour budding hot-spots and the densest CD8+ regions throughout the tumour. In neoadjuvantly treated patients, only tumour budding and not CD8+ T cells was associated with tumour features, including more advanced ypT (P = 0.0062), venous invasion (P = 0.002), lymphatic invasion (P = 0.0003) and perineural invasion (P = 0.0017), as well as higher American Joint Committee on Cancer (AJCC) tumour regression score (P = 0.0035), indicating less tumour response. Overall survival was also worse in patients with high-grade budding in univariate analysis only. In contrast, all three variables, namely tumour budding (P = 0.0347), CD8+ T cells in budding hot-spots (P = 0.0382) and CD8+ T cells in the densest areas (P = 0.0117) were also associated with worse (budding) and better (CD8) survival time in the multivariate setting. CONCLUSION: In rectal cancer, tumour budding has clinical relevance in both primarily surgically treated patients and in those with neoadjuvantly treated patients, where it characterises highly aggressive residual disease. CD8+ T cell counts appear not to have prognostic relevance in the neoadjuvant context.

LARS is Associated with Lower Anastomoses, but not with the Transanal Approach in Patients Undergoing Rectal Cancer Resection.

BACKGROUND: Low anterior resection syndrome (LARS) is a defecation disorder that frequently occurs after a low anterior resection (LAR) with a total mesorectal excision (TME). The transanal (ta) TME for low rectal pathologies could potentially overcome some of the difficulties encountered with the abdominal approach in a narrow pelvis. However, the impact of the transanal approach on functional outcomes remains unknown. Here, we investigated the effect of the taTME approach on functional outcomes by comparing LARS scores between the LAR and taTME approaches in patients with colorectal cancer. METHODS: We conducted a retrospective cohort study including 80 patients (n = 40 LAR-TME, n = 40 taTME) with rectal adenocarcinoma. We reviewed medical charts to obtain LARS scores 6 months after the rectal resection or a reversal of the protective ileostomy. RESULTS: At the 6-month follow-up, 80% of patients exhibited LARS symptoms (44% minor LARS and 36% major LARS). LARS scores were not significantly associated with the T-stage, N-stage, or neo-adjuvant radiotherapy. The mean distance of the anastomosis from the anal verge was 4.0 ± 2.0 cm. The taTME group had significantly lower anastomoses compared with the LAR-TME group (median 4.0 cm [IQR1.8] vs. median 5.0 cm [IQR 2.0], p < 0.001). Univariable analysis revealed significantly higher LARS scores in the taTME group compared with the LAR-TME group (median LARS scores: 29 vs. 25, p = 0.040). However, multivariable regression analysis, adjusting for neo-adjuvant treatment, anastomosis distance from the anal verge, anastomotic leak rate, and body mass index, revealed no significant effect of taTME on the LARS score (adjusted regression coefficient: - 2.147, 95%CI: - 2.130 to 6.169, p = 0.359). We also found a significant correlation between LARS scores and the distance of the anastomosis from the anal verge (regression coefficient: - 1.145, 95%CI: - 2.149 to - 1.141, p = 0.026). CONCLUSION: Fifty percentage of patients in this cohort exhibited some LARS symptoms after a mid- or low-rectal cancer resection. As previously described, LARS scores were negatively correlated with the distance of the anastomosis from the anal verge. TaTME was after adjustment for the height of the anastomosis not associated with higher LARS at 6 months when compared with LAR-TME.

[Feminizing Genital Gender-affirmative Surgery in Centralized and Decentralized Health Care Settings - The Hamburg TransCare study]. / Interdisziplinär integriert oder dezentral verteilt? Versorgungssettings im Kontext feminisierender Genitaloperationen ­ Studienprotokoll zur Hamburger TransCare-Studie.

BACKGROUND: Gender Dysphoria (GD, formerly known as transsexualism) describes distress and impairment in an individual caused by the incongruence between the experienced gender and the sex assigned at birth (Gender Incongruence: GI). Transgender health care focusses on gender-affirmative treatments (e. g., hormone therapy) and associated needs (e. g., psychotherapy). Moreover, genital surgery is considered an effective treatment to reduce GI/GD and improve mental health and quality of life. Interdisciplinary cooperation between the associated medical facilities is regarded as evidence-based health care. OBJECTIVES: To date, THC is delivered in zwei different health care settings: interdisciplinary and centralized from one medical institution vs. decentralized, spread over several medical institutions. In Germany, individuals with GI/GD access health care mostly in decentralized structures. The consequences of feminizing genital surgery carried out in centralized and decentralized health care structures in terms of quality and effectiveness have not been investigated so far. The goal of the TransCare study is to prospectively examine individuals with GI/GD seeking feminizing genital surgery regarding demographics and clinical characteristics as well as to analyze the influence of centralized and decentralized health care settings on the psychosocial and clinical outcome. MATERIALS AND METHODS: To recruit a valid and comprehensive sample, participants were questioned prospectively. RESULTS: The results of the study should help gain new insights into the influence of centralized and decentralized health care settings carrying out feminizing genital surgery on psychosocial and clinical outcomes for the patients. CONCLUSION: Based on the TransCare study, we suggest that health care should be improved according to individual patient needs.

[Transgender health and healthcare during the COVID­19 pandemic: a cross-sectional online survey in German-speaking countries]. / Gesundheit und Gesundheitsversorgung von trans Personen während der COVID­19-Pandemie: Eine Online-Querschnittstudie in deutschsprachigen Ländern.

BACKGROUND AND OBJECTIVE: Since spring of 2020, the COVID­19 pandemic has disrupted our day-to-day lives and led to negative consequences in various areas of life, including mental and physical wellbeing. In this article, we take a closer look at the situation of trans people, who - due to experiences with discrimination and marginalization as well as their specific health-related interests - could be characterized by a particular vulnerability. METHODS: Using an online cross-sectional survey, which we designed collaboratively with experts from the trans community, we investigated the mental and physical health of trans people from German-speaking countries and their access to trans-related healthcare during the COVID­19 pandemic in the period from 1 May 2020 to 31 January 2021. RESULTS: Since the beginning of the COVID­19 pandemic, trans people have experienced barriers in access to gender-affirming treatments, mental health services, and COVID­19-related medical care. At the same time, trans people reported being affected by chronic diseases disproportionately more often than the general population, including those leading to a higher risk for poorer outcomes of a COVID­19 infection. Moreover, the participants reported being exposed to many risk factors associated with higher mental distress (e.g., having a chronic illness, belonging to a minority based on a non-heterosexual orientation, or having a low income). DISCUSSION: The results of this survey indicate that prior vulnerabilities with regards to health problems and the restricted access to an informed and qualified transgender healthcare were exacerbated by the COVID­19 pandemic.

[Smarter Medicine: From the Diagnosis to the Intervention in General and Visceral Surgery]. / Smarter Medicine in der Viszeralchirurgie.

Smarter Medicine: From the Diagnosis to the Intervention in General and Visceral Surgery Abstract. More is not always a plus. With this slogan, in smarter medicine it is a principle to make a decision together. In general surgery diagnostic or therapeutic interventions have the potential to harm the patient. The admission to the emergency room of a young patient with abdominal pain does not necessarily require a computed tomography. A potential acute appendicitis without typical clinical and laboratory findings could potentially be unmasked by watchful waiting, or even a nonessential operation could be avoided. Possibly, acute cholecystitis or some forms of hollow organ perforation could be treated solely with antibiotics. Is it feasible to treat an acute severe diverticulitis with antibiotics only? In addition, if a colon resection is necessary, could a direct anastomosis be made, and a second operation be avoided? Are there thyroid nodules that do not need removal? The management of diseases in the surgical domain are evaluated with evidence-based medicine in the focus of smarter medicine and newly reconsidered.

Defense mechanisms to increasing back pressure for hepatic oxygen transport and venous return in porcine fecal peritonitis.

High central venous pressure (CVP) acutely decreases venous return. How this affects hepatic oxygen transport in sepsis remains unclear. The aim of this study was to evaluate the effects of repeated increases in CVP via standard nursing procedures (NPs) on hepato-splanchnic and renal oxygen transport in a prolonged porcine sepsis model. Twenty anesthetized and mechanically ventilated pigs with regional hemodynamics monitored were randomized to fecal peritonitis or controls (n = 10 pigs/group). Resuscitation was started after 8 h of observation and continued for 3 days. NPs were performed at baseline and 8 h, 32 h, 56 h, and 72 h after resuscitation started. NPs increased CVP by 4-7 mmHg in both groups. In controls, this was associated with less decrease in hepatic arterial (Qha; 62 ± 70 mL/min) than portal venous flow (Qpv; 364 ± 151 mL/min). Portal venous oxygen content and hepatic O2 delivery (Do2) and consumption (V̇o2) decreased by 11 ± 6 mL/dL and 0.9 ± 0.3 and 0.4 ± 0.3 mL·min-1·kg-1, respectively. In septic animals, hepatic Do2 decreased more in response to increasing CVP (1.5 ± 0.9 mL·min-1·kg-1), which was attributable to a larger fall in both Qha (88 ± 66 ml/min) and portal O2 content (14 ± 10 mL/dL, all P < 0.05). This resulted in numerically lower hepatic V̇o2 since O2 extraction did not increase significantly. In control conditions, a smaller decrease in Qha compared with Qpv helped to limit the reduction in hepatic V̇o2 in response to acute CVP increase. In sepsis, the contribution of Qha to maintain hepatic Do2 was reduced, which jeopardized hepatic V̇o2 further. Renal arterial flow was similarly affected by CVP increase as Qha.NEW & NOTEWORTHY Sepsis impairs intrinsic mechanisms to attenuate effects of increasing back pressure on hepatic oxygen transport.

Being Trans Without Medical Transition: Exploring Characteristics of Trans Individuals from Germany Not Seeking Gender-Affirmative Medical Interventions.

Until recently, trans persons were expected to align their sex characteristics as much as possible with the opposite sex. Today, research and health care, as well as the diagnostic criteria from DSM-5 and ICD-11, reflect a broader understanding of trans individuals. It encompasses diverse identities and treatment requests, including trans individuals not wanting or having decided against gender-affirmative medical interventions (GAMI). The present study explored this insufficiently studied group by (1) reviewing the existing literature regarding trans individuals not seeking GAMI and by (2) exploring their demographic and trans-related characteristics in a non-clinical online convenience sample from Germany. The literature review found one large survey with a single question on trans individuals not seeking GAMI. Beyond that, only community literature addressed the topic. The analyzed sample consisted of 415 trans participants, of whom 220 were assigned female at birth (AFAB) and 195 were assigned male at birth (AMAB). Fourteen (3.4%) reported neither previous nor planned GAMI (AFAB = 9, AMAB = 5). Trans individuals not seeking GAMI were significantly older and more often reported to identify with a non-binary gender. The two interdependent, central reasons for refusing GAMI were the avoidance of transition-related suffering and the lack of necessity for treatment. The diversification of gender, as reflected in the increasing visibility of non-binary or genderqueer gender identities, seems to go hand in hand with a diversification of transition-related treatment, including the option not to seek GAMI.

Effectiveness of terlipressin for prevention of complications after major liver resection - A randomized placebo-controlled trial.

BACKGROUND: Elevated portal pressure in response to major liver resection is associated with impaired liver regeneration and increased postoperative complications. Terlipressin, a splanchnic vasoconstrictor used for treatment of hepatorenal syndrome, was tested for reduction of complications and renal protection after liver resection. METHODS: A randomized double-blinded placebo-controlled trial including patients undergoing elective major liver resection was performed. Terlipressin was administered to patients in the intervention group for five days. The primary outcome parameter was the incidence of a clinical composite endpoint of following liver specific complications 6 weeks after surgery: liver failure, ascites, bile leakage, intra-abdominal abscess and operative mortality. Postoperative kidney function was assessed as a secondary endpoint. RESULTS: 150 patients (mean age 63.4 years, 73.3% male) were included. No difference was found in the composite endpoint between the placebo and intervention group (32.8% versus 30.8%, relative risk 1.066, 95%CI 0.643 to 1.769, p = 0.85). Patients receiving terlipressin showed a significant lower decrease in postoperative estimated glomerular filtration rate compared to placebo (two way ANOVA, p = 0.005). CONCLUSION: Perioperative administration of terlipressin during major liver surgery did not affect a composite endpoint of liver specific complications, but significantly protected from postoperative deterioration of kidney function compared to placebo. CLINICALTRIALS. GOV IDENTIFIER: NCT01921985.

[Update: Management of colonic diverticulitis]. / Update zum Management der Divertikulitis.

Update: Management of colonic diverticulitis Abstract. Several classification systems exist for diverticulosis and diverticulitis. We preferably use the "Classification of Diverticular Disease" (CDD) to grade the severity of disease. This classification is based on imaging by CT scan or ultrasound. The CDD system divides patients into categories with a common therapeutic strategy. Acute uncomplicated diverticulitis is treated by oral or intravenous antibiotics. For the majority of patients with uncomplicated diverticulitis, antibiotic therapy might be omitted in favor of a solely symptomatic therapy. Acute diverticulitis complicated by a relevant abscess or a perforation is treated by interventional drainage or surgical therapy. Resection with primary anastomosis replaces more and more resection with end colostomy (Hartmann's procedure). For patients with sepsis, the concept of damage control surgery has been introduced. The indication for elective surgery after conservative treatment of diverticulitis shall be dictated by the degree of the patient's symptoms, rather than the number of conservatively treated episodes of diverticulitis. Persisting complications, as fistulas and stenosis, represent an indication for elective colonic resection.

Portal hyperperfusion after major liver resection and associated sinusoidal damage is a therapeutic target to protect the remnant liver.

Extended liver resection results in loss of a large fraction of the hepatic vascular bed, thereby causing abrupt alterations in perfusion of the remnant liver. Mechanisms of hemodynamic adaptation and associated changes in oxygen metabolism after liver resection and the effect of mechanical portal blood flow reduction were assessed. A pig model (n = 16) of extended partial hepatectomy was established that included continuous observation for 24 h under general anesthesia. Pigs were randomly separated into two groups, one with a portal flow reduction of 70% compared with preoperative values, and the other as a control (n = 8, each). In controls, portal flow [mean (SD)] increased from 74 (8) mL·min-1·100 g-1 preoperatively to 240 (48) mL·min-1·100 g-1 at 6 h after resection (P < 0.001). Hepatic arterial buffer response was abolished after resection. Oxygen uptake per unit liver mass increased from 4.0 (1.1) mL·min-1·100 g-1 preoperatively to 7.7 (1.7) mL·min-1·100 g-1 8 h after resection (P = 0.004). Despite this increase in relative oxygen uptake, total hepatic oxygen consumption (V̇o2) was not maintained, and markers of hypoxia and anaerobic metabolism were significantly increased in hepatocytes after resection. Reduced postoperative portal flow was associated with significantly decreased levels of aspartate aminotransferase and bilirubin and increased hepatic clearance of indocyanine green. In conclusion, major liver resection was associated with persistent portal hyperperfusion, loss of the hepatic arterial buffer response, decreased total hepatic V̇o2 and with increased anaerobic metabolism. Portal flow modulation by partial portal vein occlusion attenuated liver injury after extended liver resection.NEW & NOTEWORTHY Because of continuous monitoring, the experiments allow precise observation of the influence of liver resection on systemic and local abdominal hemodynamic alterations and oxygen metabolism. Major liver resection is associated with significant and persistent portal hyperperfusion and loss of hepatic arterial buffer response. The correlation of portal hyperperfusion and parameters of liver injury and dysfunction offers a novel therapeutic option to attenuate liver injury after extended liver resection.

Perioperative von Willebrand factor dynamics are associated with liver regeneration and predict outcome after liver resection.

von Willebrand Factor (vWF) was found to mediate platelet influx during the early phase of liver regeneration in mice. Furthermore, increased vWF-antigen (vWF-Ag) levels were shown to be predictive for outcome of patients with chronic liver disease. Accordingly, we aimed to assess the relevance of perioperative vWF-Ag dynamics in terms of liver regeneration and clinical outcome in patients undergoing liver resection (LR). Accordingly, we observed that vWF-Ag and its activity-estimated by ristocetin cofactor measurement-increased immediately after induction of liver regeneration and was associated with platelet accumulation within the liver. However, a significant vWF-Ag burst was only observed in patients with unaffected postoperative liver regeneration. E-selectin, as an established marker for endothelial cell activation, was found to correlate with vWF-Ag in the liver vein after induction of liver regeneration (R = 0.535, P = 0.022). Preoperative vWF-Ag levels significantly predicted postoperative liver dysfunction (LD; N = 95; area under the curve, 0.725; P = 0.009). Furthermore, a cutoff of vWF-Ag ≥182% was defined to identify patients with a higher risk for postoperative LD or morbidity. This was confirmed within an independent mulitcenter validation cohort (N = 133). Ultimately, multivariable analysis revealed that vWF-Ag was an independent predictor of postoperative LD and morbidity. CONCLUSION: Within this study, we were able to provide evidence that an initial vWF burst is required to allow for adequate platelet accumulation and concomitant liver regeneration post-LR and might be abolished as a consequence of intrahepatic endothelial cell dysfunction. We were further able to reveal and validate the potential of preoperative vWF-antigen levels to predict poor postoperative outcome in patients undergoing LR. Despite the pathophysiological relevance of our findings, vWF-Ag seems to be a valuable tool for preoperative risk assessment in patients undergoing LR. (Hepatology 2018;67:1516-1530).

Prevalence of Sexual Dysfunctions in Transgender Persons: Results from the ENIGI Follow-Up Study.

INTRODUCTION: Studies about sexual functioning in trans persons have mainly focused on sexual functioning after genital gender-affirming surgery, have had small sample sizes, and have not explored the broad range of possible sexual dysfunctions. Measuring sexual functioning in trans persons during transitioning is important to determine the kind of care trans persons may need in order to regain their sexual health. AIM: The first aim of the present study was to explore the prevalence of sexual function disturbances and dysfunctions (with distress) in trans women and trans men 4 to 6 years after initial clinical entry. The second aim was to compare the prevalence of sexual dysfunctions among the various treatment trajectories and between trans persons with or without further genital treatment intentions. METHODS: An online follow-up questionnaire was filled out by 518 trans persons (307 identifying predominantly feminine, 211 identifying predominantly masculine) as a part of the European Network for the Investigation of Gender Incongruence initiative. All participants had their initial clinical appointments in gender clinics in Ghent, Amsterdam, or Hamburg. MAIN OUTCOME MEASURE: The main outcome measures were the prevalence of sexual dysfunctions and medical treatment data, measured via self-report items. RESULTS: The most frequent sexual dysfunctions experienced by trans women and trans men were difficulties initiating and seeking sexual contact (26% and 32%, respectively) and difficulties achieving an orgasm (29% and 15%, respectively). Compared with trans women after hormone treatment and non-genital surgery, trans women after vaginoplasty less often experienced arousal difficulties, sexual aversion, and low sexual desire. Compared with trans men without medical treatment, trans men after a phalloplasty experienced sexual aversion and low sexual desire less often. No significant differences were found between participants with or without further genital treatment intentions. CLINICAL IMPLICATIONS: Clinicians should consider sexual counseling after medical treatments, paying particular attention to potential social and psychological barriers to the sexual health of their patients. STRENGTHS & LIMITATIONS: This study included all trans persons irrespective of treatment decisions, and focused on a broad range of potential sexual difficulties taking the distress criteria into account. Limitations include the cross-sectional design, the limited power for the comparison of treatment groups and the absence of validated questionnaires about sexual functioning for transgender persons. CONCLUSION: Sexual dysfunctions among trans men and women were very common among the various treatment groups and were unrelated to intentions to have further genital treatment. Although medical treatment may be helpful or even essential to developing good sexual health, a significant group of trans persons experienced sexual dysfunctions after genital surgery. Kerckhof ME, Kreukels BPC, Nieder TO, et al. Prevalence of Sexual Dysfunctions in Transgender Persons: Results from the ENIGI Follow-Up Study. J Sex Med 2019; 16:2018-2019.