Structural insights into IL-11-mediated signalling and human IL6ST variant-associated immunodeficiency.

IL-11 and IL-6 activate signalling via assembly of the cell surface receptor gp130; however, it is unclear how signals are transmitted across the membrane to instruct cellular responses. Here we solve the cryoEM structure of the IL-11 receptor recognition complex to discover how differences in gp130-binding interfaces may drive signalling outcomes. We explore how mutations in the IL6ST gene encoding for gp130, which cause severe immune deficiencies in humans, impair signalling without blocking cytokine binding. We use cryoEM to solve structures of both IL-11 and IL-6 complexes with a mutant form of gp130 associated with human disease. Together with molecular dynamics simulations, we show that the disease-associated variant led to an increase in flexibility including motion within the cytokine-binding core and increased distance between extracellular domains. However, these distances are minimized as the transmembrane helix exits the membrane, suggesting a stringency in geometry for signalling and dimmer switch mode of action.

Contact allergy in Swedish professional ice hockey players.

BACKGROUND: Professional ice hockey players may contract irritant and allergic contact dermatitis. AIMS: To investigate the presence of contact allergy (CA) in professional ice hockey players in Sweden. METHODS: Ten teams from the two top leagues were assessed for potential occupational exposure to sensitizers. Exactly 107 players were patch tested with an extended baseline series and a working series, in total 74 test preparations. The CA rates were compared between the ice hockey players and controls from the general population and dermatitis patients. RESULTS: One out of 4 players had at least one contact allergy. The most common sensitizers were Amerchol L 101, nickel and oxidized limonene. CA was as common in the ice hockey players as in dermatitis patients and significantly more common than in the general population. Fragrances and combined sensitizers in cosmetic products (fragrances + preservatives + emulsifier) were significantly more common in ice hockey players compared with the general population. CONCLUSION: The possible relationship between CA to fragrances and cosmetic products on the one hand and the presence of dermatitis on the other should be explored further.

Intraoperative dexamethasone and chronic postsurgical pain: a propensity score-matched analysis of a large trial.

BACKGROUND: Dexamethasone has been shown to reduce acute pain after surgery, but there is uncertainty as to its effects on chronic postsurgical pain (CPSP). We hypothesised that in patients undergoing major noncardiac surgery, a single intraoperative dose of dexamethasone increases the incidence of CPSP. METHODS: We devised a propensity score-matched analysis of the ENIGMA-II trial CPSP dataset, aiming to compare the incidence of CPSP in patients who had received dexamethasone or not 12 months after major noncardiac surgery. The primary outcome was the incidence of CPSP. We used propensity score matching and inverse probability weighting to balance baseline variables to estimate the average marginal effect of dexamethasone on patient outcomes, accounting for confounding to estimate the average treatment effect on those treated with dexamethasone. RESULTS: We analysed 2999 patients, of whom 116 of 973 (11.9%) receiving dexamethasone reported CPSP, and 380 of 2026 (18.8%) not receiving dexamethasone reported CPSP, unadjusted odds ratio 0.76 (95% confidence interval 0.78-1.00), P=0.052. After propensity score matching, CPSP occurred in 116 of 973 patients (12.2%) receiving dexamethasone and 380 of 2026 patients (13.8%) not receiving dexamethasone, adjusted risk ratio 0.88 (95% confidence interval 0.61-1.27), P=0.493. There was no difference between groups in quality of life or pain interference with daily activities, but 'least pain' (P=0.033) and 'pain right now' (P=0.034) were higher in the dexamethasone group. CONCLUSIONS: Dexamethasone does not increase the risk of chronic postsurgical pain after major noncardiac surgery. CLINICAL TRIAL REGISTRATION: Open Science Framework Registration DOI https://doi.org/10.17605/OSF.IO/ZDVB5.

Inflammation risk before cardiac surgery and the treatment effect of intraoperative dexamethasone.

Patients who exhibit high systemic inflammation after cardiac surgery may benefit most from pre-emptive anti-inflammatory treatments. In this secondary analysis (n = 813) of the randomised, double-blind Intraoperative High-Dose Dexamethasone for Cardiac Surgery trial, we set out to develop an inflammation risk prediction model and assess whether patients at higher risk benefit from a single intraoperative dose of dexamethasone (1 mg/kg). Inflammation risk before surgery was quantified from a linear regression model developed in the placebo arm, relating preoperatively available covariates to peak postoperative C-reactive protein. The primary endpoint was the interaction between inflammation risk and the peak postoperative C-reactive protein reduction associated with dexamethasone treatment. The impact of dexamethasone on the main clinical outcome (a composite of death, myocardial infarction, stroke, renal failure, or respiratory failure within 30 days) was also explored in relation to inflammation risk. Preoperatively available covariates explained a minority of peak postoperative C-reactive protein variation and were not suitable for clinical application (R2 = 0.058, P = 0.012); C-reactive protein before surgery (excluded above 10 mg/L) was the most predictive covariate (P < 0.001). The anti-inflammatory effect of dexamethasone increased as the inflammation risk increased (-0.689 mg/L per unit predicted peak C-reactive protein, P = 0.002 for interaction). No treatment-effect heterogeneity was detected for the main clinical outcome (P = 0.167 for interaction). Overall, risk predictions from a model of inflammation after cardiac surgery were associated with the degree of peak postoperative C-reactive protein reduction derived from dexamethasone treatment. Future work should explore the impact of this phenomenon on clinical outcomes in larger surgical populations.

Serum lidocaine (lignocaine) concentrations during prolonged perioperative infusion in patients undergoing breast cancer surgery: A secondary analysis of a randomised controlled trial.

Perioperative lidocaine (lignocaine) infusions are being employed with increasing frequency. The determinants of systemic lidocaine concentrations during prolonged administration are unclear. In the Long-term Outcomes after Lidocaine Infusions for PostOperative Pain (LOLIPOP) pilot trial, the impact of infusion duration and body size metrics on serum lidocaine concentrations was examined with regression models in 48 women undergoing breast cancer surgery. Lidocaine was delivered as an intravenous bolus (1.5 mg/kg) and infusion (2 mg/kg per h) intraoperatively, followed by a 12-h subcutaneous infusion (1.33 mg/kg per h) postoperatively. Dosing was based on total body weight. Wound infiltration with other long-acting local anaesthetics was permitted. Protein binding and pharmacogenomic data were also collected. Lidocaine concentrations (median (interquartile range) (range)) during prolonged administration were in the safe and potentially therapeutic range: post-anaesthesia care unit 2.16 (1.73-2.82) (1.12-6.06) µg/ml; ward 1.41 (1.22-1.75) (0.64-2.81) µg/ml. Concentrations increased non-linearly during the early intravenous phase of administration (mean rise 1.21 µg/ml per hour of infusion, P = 0.007) but reached a pseudo steady-state during the later subcutaneous phase. Higher dose rates received per kilogram of lean (P = 0.004), adjusted (P = 0.006) and ideal body weight (P = 0.009) were associated with higher steady-state concentrations. The lidocaine free fraction was unaffected by the presence of ropivacaine, and phenotypes linked to slow metabolism were infrequent. Serum lidocaine concentrations reached a pseudo steady-state during a 12-h postoperative infusion. Greater precision in steady-state concentrations can be achieved by dosing on lean body weight versus adjusted or ideal body weight (equivalent lean body weight doses: intravenous bolus 2.5 mg/kg; intravenous infusion 3.33 mg/kg per h; subcutaneous infusion 2.22 mg/kg per h.

Continence criteria of 193 618 patients after open, laparoscopic, and robot-assisted radical prostatectomy.

OBJECTIVES: To apply a new evidence-gathering methodology, called reverse systematic review (RSR), to analyse the influence of different continence classification criteria on urinary continence rates among open retropubic radical prostatectomy (RRP), laparoscopic RP (LRP) and robot-assisted RP (RARP). MATERIALS AND METHODS: A search was carried out in eight databases between 2000 and 2020 through systematic reviews (SRs) studies referring to RRP, LRP or RARP (80 SRs). All references used in these SRs were captured referring to 910 papers in an overall database called the 'EVIDENCE Database'. A total of 422 studies related to post-RP urinary continence were selected for the final analysis, totalling 782 reports referring to 193 618 patients. RESULTS: Overall, 206 (26.4%) reports for RRP, 243 (31.0%) reports for LRP, and 333 (42.6%) reports for RARP were found. Mean overall continence rates, respectively for RRP, LRP and RARP, were: 42%, 34% and 42% at 1 month; 62%, 64% and 65% at 3 months; 73, 77 and 79% at 6 months; and 81%, 85% and 86% at 12 months. The most used criterion was 'No pad' (53.3%), followed by 'Safety pad' (19.3%), 'Not described' (10.6%), and 'No leak' (9.9%). 'No pad' showed the lowest discrepancy in continence rates in each period compared to the overall average for each technique, demonstrating less ability to influence the final results favouring any of the techniques. CONCLUSION: The RSR demonstrated that the 'No pad' criterion was the most used in the literature and showed the lowest bias capable of influencing the results and favouring any of the techniques and is the fairest option for future comparisons.

Dynamics and Molecular Interactions of GPI-Anchored CD59.

CD59 is a GPI-anchored cell surface receptor that serves as a gatekeeper to controlling pore formation. It is the only membrane-bound inhibitor of the complement membrane attack complex (MAC), an immune pore that can damage human cells. While CD59 blocks MAC pores, the receptor is co-opted by bacterial pore-forming proteins to target human cells. Recent structures of CD59 in complexes with binding partners showed dramatic differences in the orientation of its ectodomain relative to the membrane. Here, we show how GPI-anchored CD59 can satisfy this diversity in binding modes. We present a PyLipID analysis of coarse-grain molecular dynamics simulations of a CD59-inhibited MAC to reveal residues of complement proteins (C6:Y285, C6:R407 C6:K412, C7:F224, C8ß:F202, C8ß:K326) that likely interact with lipids. Using modules of the MDAnalysis package to investigate atomistic simulations of GPI-anchored CD59, we discover properties of CD59 that encode the flexibility necessary to bind both complement proteins and bacterial virulence factors.

Variation in prescribing for the prevention of postoperative nausea, vomiting, and pain following abdominal surgery: A retrospective study.

Background and Aims: Adequate postoperative analgesia and prevention of post-op nausea and vomiting (PONV) are core components of modern day anaesthesia and peri-operative care. As well as contributing to overall morbidity, postoperative pain and PONV are frequently cited as one of the most unpleasant and distressing aspects of surgery for patients. Variation in healthcare delivery is known to exist but has often been poorly described. A first step to understanding the consequences of variation is to describe the extent of variation. We aimed to assess variation in pharmacological strategies to prevent postoperative pain, nausea and vomiting in patients undergoing elective major abdominal surgery at a tertiary hospital in Perth, Western Australia, over a three-month period. Methods: Retrospective cross-sectional study. Results: We observed considerable variation in prescribing of postoperative analgesia and PONV prophylaxis and suggest that despite adequate evidence based guidelines, they are often overlooked in practice. Conclusion: Measurement of the consequences of variation requires randomised clinical trials that evaluate differences in outcome and cost, associated with the strategies that exist within the spectrum of variation.

Dexamethasone and persistent wound pain: a prespecified analysis of the randomised Perioperative Administration of Dexamethasone and Infection (PADDI) trial.

BACKGROUND: Dexamethasone is commonly administered intraoperatively to prevent postoperative nausea and vomiting and is believed to have analgesic properties. It is unknown whether it has an impact on chronic wound pain. METHODS: In this prespecified embedded superiority substudy of the randomised PADDI trial, patients undergoing non-urgent noncardiac surgery received dexamethasone 8 mg or placebo intravenously after induction of anaesthesia, and were followed up for 6 months postoperatively. The primary outcome was the incidence of pain in the surgical wound at 6 months. Secondary outcomes included acute postoperative pain and correlates of chronic postsurgical pain. RESULTS: We included 8478 participants in the modified intention-to-treat population (4258 in the dexamethasone group and 4220 in the matched placebo group). The primary outcome occurred in 491 subjects (11.5%) in the dexamethasone arm and 404 (9.6%) subjects in the placebo arm (relative risk 1.2, 95% confidence interval 1.06-1.41, P=0.003). Maximum pain scores at rest and on movement in the first 3 postoperative days were lower in the dexamethasone group compared with the control group {median 5 (inter-quartile range [IQR] 3.0-8.0) vs 6 (IQR 3.0-8.0) and median 7 (IQR 5.0-9.0) vs 8 (IQR 6.0-9.0), P<0.001 for both}. Severity of postoperative pain was not predictive of chronic postsurgical pain. The severity of chronic postsurgical pain and the frequency of neuropathic features did not differ between treatment groups. CONCLUSION: Administration of dexamethasone 8 mg i.v. was associated with an increase in the risk of pain in the surgical wound 6 months after surgery. CLINICAL TRIAL REGISTRATION: ACTRN12614001226695.

Radical Prostatectomy Technique Dispute: Analyzing Over 1.35 Million Surgeries in 20 Years of History.

Systematic reviews (SR) produce the best evidence comparing open (RRP), laparoscopic (LRP), and robotic (RARP) radical prostatectomy (RP). However, the hyperfiltration of evidence generates very specific scenarios that reduce the power of extrapolation. To compare RP evidence regarding demographics using a new methodology called reverse systematic review (RSR). Between 2000 and 2020, 8 databases were searched for SR studies on RRP, LRP, or RARP. All references were captured and analyzed over time in 80 SR. Total of 1724 reports (nr = 752, 43.7% for RARP; nr = 559, 32.4% for RRP; nr = 413, 23.9% for LRP) described 1,353,485 patients (881,719, 65.1% RRP; 366,006, 27.0% RARP; 105,760, 7.8% LRP). Patients/center/year was higher in RARP compared to LRP and RRP, median 50.0, 40.0, and 36.66, respectively, P < .001. Surgeons per study was lesser in RARP and LRP compared to RRP, median 2.0, 2.0, and 6.0, respectively, P < .001. Study duration and follow-up in years was shorter in RARP compared to LRP and RRP, median 2.6, 3.0, and 4.0, respectively, P < .001. Cumulative RARP reports predominate in North America (55.7%, nr = 468) and Asia (47.8%, nr =129), while LRP predominate in Europe (42.3%, nr =230) and RRP in Oceania (45.1%, nr = 23). After 2010 all continents began to accumulate more patients in the robotic approach. Potential biases related to shorter follow-up, greater volume centers, and surgeons were identified favoring the RARP. Analyzing the context of the available evidence is essential to compare techniques. Influenced by economic and scientific interests, robotic surgery was developed in centers with a higher volume of surgeries, characterizing potential biases when comparing techniques in the clinical shared decision.

Structural basis for membrane attack complex inhibition by CD59.

CD59 is an abundant immuno-regulatory receptor that protects human cells from damage during complement activation. Here we show how the receptor binds complement proteins C8 and C9 at the membrane to prevent insertion and polymerization of membrane attack complex (MAC) pores. We present cryo-electron microscopy structures of two inhibited MAC precursors known as C5b8 and C5b9. We discover that in both complexes, CD59 binds the pore-forming ß-hairpins of C8 to form an intermolecular ß-sheet that prevents membrane perforation. While bound to C8, CD59 deflects the cascading C9 ß-hairpins, rerouting their trajectory into the membrane. Preventing insertion of C9 restricts structural transitions of subsequent monomers and indirectly halts MAC polymerization. We combine our structural data with cellular assays and molecular dynamics simulations to explain how the membrane environment impacts the dual roles of CD59 in controlling pore formation of MAC, and as a target of bacterial virulence factors which hijack CD59 to lyse human cells.

Dexamethasone and clinically significant postoperative nausea and vomiting: a prespecified substudy of the randomised perioperative administration of dexamethasone and infection (PADDI) trial.

BACKGROUND: Clinically significant postoperative nausea and vomiting (PONV) is a patient-reported outcome which reflects patient experience. Although dexamethasone prevents PONV, it is unknown what impact it has on this experience. METHODS: In this prespecified embedded superiority substudy of the randomised Perioperative Administration of Dexamethasone and Infection (PADDI) trial, patients undergoing non-urgent noncardiac surgery received dexamethasone 8 mg or placebo intravenously after induction of anaesthesia, and completed a validated PONV questionnaire. The primary outcome was the incidence of clinically significant PONV on day 1 or day 2 postoperatively. Secondary outcomes included the incidence of clinically significant PONV and severe PONV on days 1 and 2 considered separately. RESULTS: A total of 1466 participants were included, with 733 patients allocated to the dexamethasone arm and 733 to matched placebo. The primary outcome occurred in 52 patients (7.1%) in the dexamethasone arm and 66 (9%) patients in the placebo arm (relative risk [RR]=0.79; 95% confidence interval [CI], 0.56-1.11; P=0.18). Severe PONV occurred on day 2 in 27 patients (3.9%) in the dexamethasone arm and 47 patients (6.7%) in the placebo arm (RR=0.58; 95% CI, 0.37-0.92; P=0.02; number needed-to-treat (NNT)=36.7; 95% CI, 20-202). In the entire cohort of 8880 PADDI patients, lower nausea scores, less frequent administration of antiemetics, and fewer vomiting events were recorded by patients in the dexamethasone arm up to day 2 after surgery. CONCLUSIONS: Administration of dexamethasone 8 mg i.v. did not influence clinically significant PONV. Dexamethasone administration did, however, decrease the incidence and severity of PONV, and was associated with less frequent administration of antiemetic agents. CLINICAL TRIAL REGISTRATION: ACTRN12614001226695.

Postoperative anaemia and patient-centred outcomes after major abdominal surgery: a retrospective cohort study.

BACKGROUND: Compared with anaemia before surgery, the underlying pathogenesis and implications of postoperative anaemia are largely unknown. METHODS: This retrospective cohort study analysed prospective data obtained from 2983 adult patients across 47 centres enrolled in a clinical trial evaluating restrictive and liberal intravenous fluids. The primary endpoint was persistent disability or death up to 90 days after surgery. Secondary endpoints included major septic complications, hospital stay, and patient quality of recovery using a 15-item quality of recovery (QoR-15) score, hospital re-admissions, and disability-free survival up to 12 months after surgery. Anaemia and disability were defined according to the WHO definitions. Multivariable regression was used to adjust for baseline risk and surgery. RESULTS: A total of 2983 patients met inclusion criteria for this study, of which 78.5% (95% confidence interval [CI], 76.7-80.1%) had postoperative anaemia. Patients with postoperative anaemia had a higher adjusted risk of death or disability up to 90 days after surgery when compared with those without anaemia: 18.2% vs 9.2% (risk ratio [RR]=1.51; 95% CI, 1.10-2.07, P=0.011); lower QoR-15 scores on Day 3 and Day 30, 105 (95% CI, 87-119) vs 114 (95% CI, 99-128; P<0.001), and 130 (95% CI, 112-140) vs 139 (95% CI, 121-144; P<0.011), respectively; higher adjusted risk of a composite of mortality/septic complications, 2.01 (95% CI, 1.55-42.67; P<0.001); unplanned admission to ICU (RR=2.65; 95% CI, 1.65-4.23; P<0.001); and longer median (inter-quartile range [IQR]) hospital stays, 6.6 (4.4-12.4) vs 3.7 (2.5-6.5) days (P<0.001). CONCLUSIONS: Postoperative anaemia is common and is independently associated with poor outcomes after surgery. Optimal prevention and treatment strategies need to be investigated. CLINICAL TRIAL REGISTRATION: NCT04978285 (ClinicalTrials.gov).

Inclusion, characteristics, and outcomes of male and female participants in large international perioperative studies.

BACKGROUND: We compared baseline characteristics and outcomes and evaluated the subgroup effects of randomised interventions by sex in males and females in large international perioperative trials. METHODS: Nine randomised trials and two cohort studies recruiting adult patients, conducted between 1995 and 2020, were included. Baseline characteristics and outcomes common to six or more studies were evaluated. Regression models included terms for sex, study, and an interaction between the two. Comparing outcomes without adjustment for baseline characteristics represents the 'total effect' of sex on the outcome. RESULTS: Of 54 626 participants, 58% were male and 42% were female. Females were less likely to have ASA physical status ≥3 (56% vs 64%), to smoke (15% vs 23%), have coronary artery disease (21% vs 32%), or undergo vascular surgery (10% vs 23%). The pooled incidence of death was 1.6% in females and 1.8% in males (risk ratio [RR] 0.92; 95% confidence interval [CI]: 0.81-1.05; P=0.20), of myocardial infarction was 4.2% vs 4.5% (RR 0.92; 95% CI: 0.81-1.03; P=0.10), of stroke was 0.5% vs 0.6% (RR 1.03; 95% CI: 0.79-1.35; P=0.81), and of surgical site infection was 8.6% vs 8.3% (RR 1.03; 95% CI: 0.79-1.35; P=0.70). Treatment effects of three interventions demonstrated statistically significant effect modification by sex. CONCLUSIONS: Females were in the minority in all included studies. They were healthier than males, but outcomes were comparable. Further research is needed to understand the reasons for this discrepancy. CLINICAL TRIAL REGISTRATION: International Registry of Meta-Research (UID: IRMR_000011; 5 January 2021).

Incontinence after laparoscopic radical prostatectomy: a reverse systematic review

ABSTRACT Purpose: To report the prevalence of the definitions used to identify post-prostatectomy incontinence (PPI) after laparoscopic radical prostatectomy (LRP), and to compare the rates of PPI over time under different criteria. Materials and Methods: In the period from January 1, 2000, until December 31, 2017, we used a recently described methodology to perform evidence acquisition called reverse systematic review (RSR). The continence definition and rates were evaluated and compared at 1, 3, 6, 12, and >18 months post-operative. Moreover, the RSR showed the "natural history" of PPI after LRP. Results: We identified 353 review articles in the systematized search, 137 studies about PPI were selected for data collection, and finally were included 203 reports (nr) with 51.436 patients. The most used criterion of continence was No pad (nr=121; 59.6%), the second one was Safety pad (nr=57; 28.1%). A statistically significant difference between continence criteria was identified only at >18 months (p=0.044). From 2013 until the end of our analysis, the Safety pad and Others became the most reported. Conclusion: RSR revealed the "natural history" of PPI after the LRP technique, and showed that through time the Safety pad concept was mainly used. However, paradoxically, we demonstrated that the two most utilized criteria, Safety pad and No pad, had similar PPI outcomes. Further effort should be made to standardize the PPI denomination to evaluate, compare and discuss the urinary post-operatory function.

Aqueous Chlorination of D-Limonene.

Limonene (1-methyl-4-(1-methylethenyl)-cyclohexene) is one of the most widespread monocyclic terpenes, being both a natural and industrial compound. It is widely present in the environment, including in water supplies. Therefore, it may be subjected to aqueous chlorination at water treatment stations during drinking water preparation. Besides, being a component of numerous body care and cosmetic products, it may present at high levels in swimming pool waters and could also be subjected to aqueous chlorination. Laboratory experiments with aqueous chlorination of D-limonene demonstrated the prevalence of the conjugated electrophilic addition of HOCl molecule to the double bonds of the parent molecule as the primary reaction. The reaction obeys the Markovnikov rule, as the levels of the corresponding products were higher than those of the alternative ones. Fragmentation pattern in conditions of electron ionization enabled the assigning of the structures for four primary products. The major products of the chlorination are formed by the addition of two HOCl molecules to limonene. The reactions of electrophilic addition are usually accompanied by the reactions of elimination. Thus, the loss of water molecules from the products of various generations results in the reproduction of the double bond, which immediately reacts further. Thus, a cascade of addition-elimination reactions brings the most various isomeric polychlorinated species. At a ratio of limonene/active chlorine higher than 1:10, the final products of aqueous chlorination (haloforms) start forming, while brominated haloforms represent a notable portion of these products due to the presence of bromine impurities in the used NaOCl. It is worth mentioning that the bulk products of aqueous chlorination are less toxic in the bioluminescence test on V. fischeri than the parent limonene.

Testosterone kinetics on hypogonadal men under clomiphene.

OBJECTIVE: To evaluate total testosterone (TT) kinetics and its predictors 6 months after the discontinuation of clomiphene citrate (CC) in patients with hypogonadism. MATERIALS AND METHODS: Consecutive patients with normal testicles and male hypogonadism defined by TT < 300 ng/dl in the presence of signs or symptoms according to the previous consensus were prospectively evaluated in a urologic outpatient clinic by TT levels at baseline (T0), after a daily dose of 50 mg CC for 40 days (T1), and after the washout period of 6 months of CC discontinuation (T2). RESULTS: Among 75 patients, mean age 56.8 years, testosterone at T1 > 300 ng/dl was achieved by 69 (92%), 450-600 ng/dl by 32 (42.6%), and > 600 ng/dl by 27 (36.0%). 18 subjects (24%) maintained asymptomatic and TT levels over 300 ng/dl at T2. Age negatively related to testosterone response and T1 response > 810 ng/dl predicts a median gain of 166.5 ng/dl at 6 months of CC discontinuation. CONCLUSIONS: CC is a compelling option to treat male hypogonadism, although a chronic treatment is needed in most patients. About one in every four patients respond to a CC short trial to "reboot" the physiology. Further understanding of TT kinetics in these patients in the long term is warranted.

A survey of Circular Economy initiatives in Portuguese central public sector organisations: National outlook for implementation.

The Circular Economy (CE) is generally understood as an opportunity to transform the current unsustainable linear economic system by redesigning the way organisations provide goods and services rethinking how society consumes and uses those resources. In this context, the public sector is mainly recognised as an actor enabling the implementation of a sustainable CE through governmental interventions and policy initiatives. However, there is a lack of studies considering the public sector at an organisational level. CE in organisations includes a wide range of different practices that are important to examine in order to analyse the CE implementation process. Consequently, this study aims to characterise the current state of implementing circular practices and supporting strategies in central public sector organisations. To fulfil this aim, a questionnaire survey was sent to the organisations pertaining to the Portuguese Central Public Administration, as surveys are valuable tools to systematically collect information on various topics. The results demonstrate a relatively low level of implementation. Circular practices such as purchasing remanufactured or used items, using sharing platforms, increasing the efficiency of buildings, adopting green human resources and collaborative initiatives for circularity, and assessing and communicating about CE activities have presented low levels of adoption. At the same time, waste collection for recycling and dematerialisation practices showed good implementation levels. There is, thus, immense potential for further implementation of circularity in central public sector organisations in Portugal. This research contributes to deepening the understanding of the extent to which circular practices are embedded in public sector organisations and identifying the main implementation strengths and weaknesses. This research has the potential to help practitioners and researchers in the transition towards circularity in identifying circular opportunities in their organisations and in building a vision to further implement circularity in public sector organisations.

Incontinence after laparoscopic radical prostatectomy: a reverse systematic review.

PURPOSE: To report the prevalence of the definitions used to identify post-prostatectomy incontinence (PPI) after laparoscopic radical prostatectomy (LRP), and to compare the rates of PPI over time under different criteria. MATERIALS AND METHODS: In the period from January 1, 2000, until December 31, 2017, we used a recently described methodology to perform evidence acquisition called reverse systematic review (RSR). The continence definition and rates were evaluated and compared at 1, 3, 6, 12, and >18 months post-operative. Moreover, the RSR showed the "natural history" of PPI after LRP. RESULTS: We identified 353 review articles in the systematized search, 137 studies about PPI were selected for data collection, and finally were included 203 reports (nr) with 51.436 patients. The most used criterion of continence was No pad (nr=121; 59.6%), the second one was Safety pad (nr=57; 28.1%). A statistically significant difference between continence criteria was identified only at >18 months (p=0.044). From 2013 until the end of our analysis, the Safety pad and Others became the most reported. CONCLUSION: RSR revealed the "natural history" of PPI after the LRP technique, and showed that through time the Safety pad concept was mainly used. However, paradoxically, we demonstrated that the two most utilized criteria, Safety pad and No pad, had similar PPI outcomes. Further effort should be made to standardize the PPI denomination to evaluate, compare and discuss the urinary post-operatory function.

The impact of COVID-19 on cleft services in Great Britain & Northern Ireland.

INTRODUCTION: Cleft lip and/or palate is the most common craniofacial anomaly and occurs in 1 in 650 to 700 live births in the United Kingdom (UK). The majority of cleft surgery is elective, and as a result, almost all cleft surgery was suspended across the UK in March 2020 during the first national lockdown. The UK has centralised regional Cleft Services which all use the same agreed target-age standards for primary surgery including lip and palate repairs. The coronavirus disease-2019 (COVID-19) response has caused a delay in carrying out procedures. The severity of this delay depends on the impact of COVID-19 on local trusts and R-value within that region. As the country goes through the second and third wave, the impact could be long lasting, and we aimed to quantify it so that the data could be used to guide service prioritisation in the NHS and help future workforce planning. METHODS: An online survey was designed based on the cleft quality dashboard indicators and circulated nationally to all nine cleft regions in the UK. The survey was divided into three main headings: • Duration of suspended cleft services • Quantification of the impact on delayed in surgery/services • Changes needed to restart surgery/services RESULTS: We obtained a 60% response rate with five completed surveys from five out of nine regions. All regions reported that they suspended their cleft services in March 2020 around the time of the first wave and the first national lockdown. There has been an impact on delayed surgical and clinical interventions for cleft patients. Regions were affected differently with some on an exponential waiting list growth projection, whereas other teams are on track to recover from the backlog within 7-22 weeks. There has been an impact on the allied health professionals' services within the cleft multidisciplinary team. The cleft nurses' 24-h reviews, Speech And Language Therapy (SALT), and psychology maintained service delivery in some format. Patient-facing services such as audiology and dentistry were significantly disrupted and continue to experience delays due to reduced capacity. CONCLUSIONS: Various regions have seen a varied impact from COVID-19 on their services, from all cleft regions there seems to be an impact on achieving surgery within the national target age. The adverse effect of the COVID-19 impact is unlikely to be known for a few years to come; however, the data are a useful guide when supporting the allocation of resources within the healthcare setting. A prospective long-term study is required to assess the impact of COVID-19 on cleft surgery, follow-up, assess access to allied health professional MDT clinics, and long-term complications.