Microglial TNFα orchestrates protein phosphorylation in the cortex during the sleep period and controls homeostatic sleep.

Sleep intensity is adjusted by the length of previous awake time, and under tight homeostatic control by protein phosphorylation. Here, we establish microglia as a new cellular component of the sleep homeostasis circuit. Using quantitative phosphoproteomics of the mouse frontal cortex, we demonstrate that microglia-specific deletion of TNFα perturbs thousands of phosphorylation sites during the sleep period. Substrates of microglial TNFα comprise sleep-related kinases such as MAPKs and MARKs, and numerous synaptic proteins, including a subset whose phosphorylation status encodes sleep need and determines sleep duration. As a result, microglial TNFα loss attenuates the build-up of sleep need, as measured by electroencephalogram slow-wave activity and prevents immediate compensation for loss of sleep. Our data suggest that microglia control sleep homeostasis by releasing TNFα which acts on neuronal circuitry through dynamic control of phosphorylation.

Heterotypic Amyloid ß interactions facilitate amyloid assembly and modify amyloid structure.

It is still unclear why pathological amyloid deposition initiates in specific brain regions or why some cells or tissues are more susceptible than others. Amyloid deposition is determined by the self-assembly of short protein segments called aggregation-prone regions (APRs) that favour cross-ß structure. Here, we investigated whether Aß amyloid assembly can be modified by heterotypic interactions between Aß APRs and short homologous segments in otherwise unrelated human proteins. Mining existing proteomics data of Aß plaques from AD patients revealed an enrichment in proteins that harbour such homologous sequences to the Aß APRs, suggesting heterotypic amyloid interactions may occur in patients. We identified homologous APRs from such proteins and show that they can modify Aß assembly kinetics, fibril morphology and deposition pattern in vitro. Moreover, we found three of these proteins upon transient expression in an Aß reporter cell line promote Aß amyloid aggregation. Strikingly, we did not find a bias towards heterotypic interactions in plaques from AD mouse models where Aß self-aggregation is observed. Based on these data, we propose that heterotypic APR interactions may play a hitherto unrealized role in amyloid-deposition diseases.

Embracing the future-is artificial intelligence already better? A comparative study of artificial intelligence performance in diagnostic accuracy and decision-making.

BACKGROUND AND PURPOSE: The integration of artificial intelligence (AI) in healthcare has the potential to revolutionize patient care and clinical decision-making. This study aimed to explore the reliability of large language models in neurology by comparing the performance of an AI chatbot with neurologists in diagnostic accuracy and decision-making. METHODS: A cross-sectional observational study was conducted. A pool of clinical cases from the American Academy of Neurology's Question of the Day application was used as the basis for the study. The AI chatbot used was ChatGPT, based on GPT-3.5. The results were then compared to neurology peers who also answered the questions-a mean of 1500 neurologists/neurology residents. RESULTS: The study included 188 questions across 22 different categories. The AI chatbot demonstrated a mean success rate of 71.3% in providing correct answers, with varying levels of proficiency across different neurology categories. Compared to neurology peers, the AI chatbot performed at a similar level, with a mean success rate of 69.2% amongst peers. Additionally, the AI chatbot achieved a correct diagnosis in 85.0% of cases and it provided an adequate justification for its correct responses in 96.1%. CONCLUSIONS: The study highlights the potential of AI, particularly large language models, in assisting with clinical reasoning and decision-making in neurology and emphasizes the importance of AI as a complementary tool to human expertise. Future advancements and refinements are needed to enhance the AI chatbot's performance and broaden its application across various medical specialties.

Rigorous pH measurement in non-aqueous solution: measurement method and reference values in ethanol.

The recently introduced unified pH ([Formula: see text]) concept enables rigorous pH measurements in non-aqueous and mixed media while at the same time maintaining comparability to the conventional aqueous pH scale. However, its practical application is hindered by a shortage of reference [Formula: see text] values. In order to improve this situation, the European Metrology Research Project (EMPIR) UnipHied ("Realisation of a UnipHied pH scale") launched an interlaboratory comparison among highly experienced electrochemistry expert laboratories to assign the first such reference [Formula: see text] values by adopting an extensive statistical treatment of the reported measurement data: to phosphate buffer in water-ethanol mixture (50 wt% of ethanol) and ammonium formate buffer in pure ethanol. Two different measurement setups - one capable of being easily adopted in industrial applications - have been used to demonstrate the robustness of [Formula: see text] measurement. This is an important step towards wider adoption of the [Formula: see text] concept in practice, like liquid chromatography, biofuels analysis and electrocatalysis.

"Submarine-Shaped" Radial Forearm Flap for Simultaneous Reconstruction of Oral and Lower Lip Defects".

BACKGROUND: Reconstruction of the oral cavity commonly results in trismus and lip incompetence. AIM AND OBJECTIVES: In this study, we aim to describe an innovative design of a radial forearm free flap for resurfacing bilateral buccal defects and simultaneous functional lower lip reconstruction in a single stage. MATERIALS AND METHODS: Between January 2010 and December 2019, 6 males underwent simultaneous buccal and lower lip reconstruction with a radial forearm free flap. The mean age of the patients was 57.3 years (range, 50-68 years). The defects were caused by trismus release and due to previous treatments. The mean size of the defects was 17.9 cm in length and 3.25 cm in width. Flaps were harvested, including the proximal perforators of the radial vessels, and the inset began in the buccal area opposite the anastomosis side. RESULTS: Flap size ranged from 16 to 21 × 2 to 4 cm. The recipient vessels used were the superficial temporal (4) and facial (2). All flaps survived. Lip infection was seen in 2 cases and managed conservatively. The mean follow-up was 19.2 months (range, 12-28 months). The mean increase in the interincisal distance was 10.7 mm. Oral continence was good in all patients. Speech intelligibility was considered total in 4 patients and partial in the remaining 2. CONCLUSION: The radial forearm flap constitutes an option for simultaneous lower lip reconstruction and resurfacing of bilateral buccal areas after trismus release. The procedure provides a thin and pliable reconstruction using only 1 donor site and 1 set of recipient vessels.

Nuclear import of the DSCAM-cytoplasmic domain drives signaling capable of inhibiting synapse formation.

DSCAM and DSCAML1 are immunoglobulin and cell adhesion-type receptors serving important neurodevelopmental functions including control of axon growth, branching, neurite self-avoidance, and neuronal cell death. The signal transduction mechanisms or effectors of DSCAM receptors, however, remain poorly characterized. We used a human ORFeome library to perform a high-throughput screen in mammalian cells and identified novel cytoplasmic signaling effector candidates including the Down syndrome kinase Dyrk1a, STAT3, USP21, and SH2D2A. Unexpectedly, we also found that the intracellular domains (ICDs) of DSCAM and DSCAML1 specifically and directly interact with IPO5, a nuclear import protein of the importin beta family, via a conserved nuclear localization signal. The DSCAM ICD is released by γ-secretase-dependent cleavage, and both the DSCAM and DSCAML1 ICDs efficiently translocate to the nucleus. Furthermore, RNA sequencing confirms that expression of the DSCAM as well as the DSCAML1 ICDs alone can profoundly alter the expression of genes associated with neuronal differentiation and apoptosis, as well as synapse formation and function. Gain-of-function experiments using primary cortical neurons show that increasing the levels of either the DSCAM or the DSCAML1 ICD leads to an impairment of neurite growth. Strikingly, increased expression of either full-length DSCAM or the DSCAM ICD, but not the DSCAML1 ICD, significantly decreases synapse numbers in primary hippocampal neurons. Taken together, we identified a novel membrane-to-nucleus signaling mechanism by which DSCAM receptors can alter the expression of regulators of neuronal differentiation and synapse formation and function. Considering that chromosomal duplications lead to increased DSCAM expression in trisomy 21, our findings may help uncover novel mechanisms contributing to intellectual disability in Down syndrome.

Predicting Prosthetic Mobility at Discharge From Rehabilitation Following Major Amputation in Vascular Surgery.

OBJECTIVE: This study aimed to construct a decision aid to estimate the likelihood of independence with a prosthesis following rehabilitation for limb loss secondary to advanced ischaemia (acute or chronic limb threatening ischaemia) or diabetic foot disease (DFD). A secondary aim was to determine whether prosthetic independence is a surrogate marker of long term survival. METHODS: A retrospective cohort study of a prospectively maintained database of unilateral amputations due to ischaemia or DFD entering rehabilitation between 2007 and 2020 was performed. Predictors of independent prosthetic mobility (IPM) were used in construction of the IPM prediction model, which underwent bootstrap internal and criterion validation through correlation with predictors of other measures of function: Timed Up and Go (TUG) and two minute walk test. Kaplan-Meier and Cox regression analyses were performed to address the secondary aim. RESULTS: Of the 771 patients included, only 49.9% of amputees achieved IPM. Independent negative predictors of IPM were age > 75 years, female sex, higher amputation level, active malignancy, cerebrovascular disease, end stage renal disease, and cognitive impairment. The model yielded high discrimination (C statistic 0.778), and internal validation was demonstrated with bootstrapping (C statistic 0.778), confirming no over optimism. There was a strong correlation between IPM, TUG, and two minute distance and their predictors, confirming strong criterion validity. The IPM group had a median survival of 93.7 (80.7, 105) months, whereas the non-IPM group fared worse with a median survival of 56.6 (48.5, 66.7) months (p < .001). CONCLUSION: An internally validated decision aid for estimating the likelihood of independence with a prosthesis after major amputation was constructed. A strong association between female sex and poorer prosthetic mobility was observed. Prosthetic function was shown to be a surrogate marker of long term survival. Future research will involve external validation studies to confirm the generalisability of the decision aid in clinical practice.

Predictors for adverse events following intravesical botulinum toxin injections in men.

INTRODUCTION: Intravesical botulinum toxin A (BTX-A) has been long established as treatment for overactive bladder and neurogenic bladder dysfunction. However, most published data are reported among a female cohort. Adverse events such as intermittent self-catheterization (ISC) and urinary tract infections (UTIs) play a large role in discontinuation of therapy. There is currently limited information regarding predictive factors to appropriately counsel male patients. MATERIALS AND METHODS: We retrospectively collected data on male patients undergoing their first intravesical BTX-A therapy from January 2016 to July 2021 in two high-volume centers. Data included demographics, past medical and surgical history, and urodynamic parameters. Patients were excluded if they had a long-term catheter or ISC before initiation of therapy. RESULTS: A total of 69 men were included in the study with a median age of 66 years. There were 18 patients with neurogenic bladder dysfunction. Thirty men had urge incontinence secondary to radical prostatectomy or bladder outflow surgery. Overall rates of ISC were 43.5%. Predictors for ISC included a baseline postvoid residual (PVR) ≥ 50 mL (odds ratio [OR]: 4.2, 95% confidence interval [CI]: 1.36-13.03, p = 0.01), BTX-A dose >100 units (OR: 4.2, 95% CI: 1.36-13.0, p = 0.01). Stress urinary incontinence was protective against ISC (OR: 0.20, 95% CI: 0.04-1.00, p = 0.049) as well as history of prostatectomy/bladder outflow obstruction (BOO) surgery (OR: 0.16, 95% CI: 0.05-0.47, p < 0.001). A multivariable logistic regression model with these factors yielded a c-statistic of 0.80 (optimism-adjusted = 0.75). An enlarged prostate was the only predictor for UTI among our male cohort (OR: 8.0, 95% CI: 2.03-31.5, p = 0.003). CONCLUSIONS: This is the first study assessing risk factors of adverse events among men following BTX-A injection. High PVR and BTX-A dose of >100U were predictors of requiring ISC after BTX-A. Stress incontinence, previous radical prostatectomy, and BOO surgery were all protective against needing ISC post-BTX-A. An enlarged prostate was associated with development of UTI. These factors can be used to assist in counseling male patients regarding their risk of ISC and UTI.

Interrelationship between muscle fitness in childhood and bone mineral density in adulthood: mediation analysis of muscle fitness in adulthood.

BACKGROUND: This study was aimed to examine the relationship between muscular fitness indicators in childhood and areal bone mineral density (aBMD) in adulthood and to verify whether the relationship is mediated by performance on muscular fitness indicators in adulthood. METHODS: A sample of 138 healthy adults (69 males; 22.3 years) were followed after a previous assessment at the age of 7-10 years. Stature, body mass and muscular fitness indicators (handgrip strength, standing long jump and sit-ups tests) were assessed in childhood and adulthood. Additionally, total body, upper limbs, lower limbs, right femoral neck and lumbar spine aBMD was assessed in adulthood using dual X-ray absorptiometry. Analysis included descriptive statistics; t-test or Mann-Whitney U-test for comparison between males and females, multiple linear regression for the prediction aBMD from muscular fitness indicators in childhood, mediation analysis of the respective muscular fitness indicators in adulthood and the relationship between muscular fitness indicators in childhood and aBMD. RESULTS: Males were stronger compared to females regarding muscular fitness indicators in childhood and adulthood, and presented higher mean values for aBMD in adulthood, except for lumbar spine (p < 0.05). Regression analysis revealed that some muscular fitness indicators in childhood showed significant positive relationship with bone health indicators in adulthood, such as: handgrip strength and total body aBMD (ß = 0.005; R2 = 0.35; p = 0.040) and upper limbs aBMD (ß = 0.005; R2 = 0.55; p = 0.019); and sit-ups test was a significant predictors of lumbar spine BMD (ß = 0.003; R2 = 0.06; p = 0.039). Mediation analysis pointed out the following: adulthood handgrip strength mediated relationships between childhood handgrip strength and total aBMD (indirect effect (IE) = 0.0025; 95%CI = 0.0005-0.0048), and upper limbs aBMD (IE = 0.0040; 95%CI = 0.0017-0.0069). CONCLUSIONS: Muscular fitness indicators in childhood showed significant relationship with bone health indicators in adulthood and the sit-ups test in childhood had direct effect on lumbar spine aBMD in adulthood. Adulthood handgrip strength mediated the relationship between childhood handgrip strength and total body and upper limb aBMD, pointing out that muscular fitness in childhood may be a aBMD determinant in adulthood, especially when higher muscle fitness performance is maintained in adulthood.

Intra-observer reproducibility and inter-observer agreement of Fels skeletal age assessments among male tennis players 8-16 years.

BACKGROUND: Skeletal age (SA) is an estimate of biological maturity status that is commonly used in sport-related medical examinations. This study considered intra-observer reproducibility and inter-observer agreement of SA assessments among male tennis players. METHODS: SA was assessed with the Fels method in 97 male tennis players with chronological ages (CA) spanning 8.7-16.8 years. Radiographs were evaluated by two independent trained observers. Based on the difference between SA and CA, players were classified as late, average or early maturing; if a player was skeletally mature, he was noted as such as an SA is not assigned. RESULTS: The magnitude of intra-individual differences between repeated SA assessments were d = 0.008 year (observer A) and d = 0.001 year (observer B); the respective coefficients of variation were 1.11% and 1.75%. Inter-observer mean differences were negligible (t = 1.252, p = 0.210) and the intra-class correlation coefficient was nearly perfect (ICC = 0.995). Concordance of classifications of players by maturity status between observers was 90%. CONCLUSION: Fels SA assessments were highly reproducible and showed an acceptable level of inter-observer agreement between trained examiners. Classifications of players by skeletal maturity status based on assessments of the two observers were highly concordant, though not 100%. The results highlight the importance of experienced observers in skeletal maturity assessments.

Association between statin-use and mobility and long-term survival after major lower limb amputation.

AIM: The aim of this study was to determine if there is an association between statin-use and prosthetic mobility and long-term survival in patients receiving rehabilitation after major amputation for lower limb arterial disease. METHODS: A retrospective analysis of prospectively maintained data (2008-2020) from a centre for rehabilitation was performed. Patients were grouped by statin-use status and sub-grouped by the combination of statin and antithrombotic drugs (antiplatelets or anticoagulants). Outcomes were prosthetic mobility (SIGAM score, timed-up-go and 2-min walking distance) and long-term survival. Regression, Kaplan-Meier and Cox-proportional hazard analyses were performed to test associations adjusted to confounders. RESULTS: Of 771 patients, 499 (64.7%) were on a statin before amputation or prescribed a statin peri-operatively. Rate of statin-use was significantly lower among female (53.3%) compared to male (68.2%) patients, P < 0.001. Statin-use was associated with significantly better prosthetic independence (53.1% vs 44.1%, P = 0.017), timed-up-go (mean difference of 4 s, P = 0.04) and long-term survival HR 0.59 (0.48-0.72, P < 0.001). Significance persisted after adjusting for confounding factors and in subgroup analyses. The combination of statin with antiplatelet was associated with the most superior survival, HR 0.51 (0.40-0.65, P < 0.001). Sensitivity analysis (exclusion of non-users of prosthesis) showed that statin-use remained a significant indicator of longer survival, maximally when combined with antiplatelet use HR 0.52 (0.39-0.68, P < 0.001). CONCLUSIONS: Statin-use is associated with better mobility and long-term survival in rehabilitees after limb loss, particularly when used in combination with antiplatelets. Significantly lower rates of statin-use were observed in female patients. Further research is warranted on gender disparities in statin-use and causality in their association with improved mobility and survival.

Microsurgical Reconstruction of Extensive Lower Lip Defects: An Algorithm for Free Flap Selection and Functional Outcomes.

BACKGROUND: Large defects of the lower lip pose a difficult challenge for any reconstructive surgeon. When there is limited local tissue available to resurface the defects, free flaps are the preferred option. AIM AND OBJECTIVES: We reported our experience in the reconstruction of extensive lower lip defects. The authors propose a new algorithm for microsurgical technique selection and assessment of the functional outcomes obtained. MATERIALS AND METHODS: A retrospective review of all microsurgical reconstructions of extensive lower lip defects by the senior author for 10 years was performed. The functional outcomes assessed included speech, feeding, and oral continence. Patients were stratified according to their status of simultaneous mandible resection (none, marginal, segmental). RESULTS: Fifty-one patients were included in this study. Almost all patients (96.1%) achieved intelligible speech. Only 1 patient experienced severe drooling. Most patients could eat a solid or soft diet (72.5%). Mandible resection was associated with the worst feeding outcomes. CONCLUSIONS: Microsurgical reconstruction of extensive lip defects is safe and provides good results. Free flap selection should take into account the location of the defect, the resected structures, and the body mass index of the patient. Feeding status seems to be inversely correlated with the amount of mandibular resection.

Direct peroral cholangioscopy with conventional upper gastrointestinal endoscope.

An 83-year-old male with a history of Whipple procedure (pancreatoduodenectomy) due to pancreatic cancer, underwent endoscopic retrograde colangiopancreatography (ERCP) for acute cholangitis. Because of the altered anatomy, an upper gastrointestinal endoscope was used. Severe stricture of the hepaticojejunal anastomosis was found. The anastomotic stricture was dilated with a 12mm through-the-scope (TTS) balloon under fluoroscopy and direct visualization. Right and left ducts were explored with Dormia basket and balloon, with extraction of bile duct stones and pus. Cholangioscopy with upper gastrointestinal endoscope was performed and residual cholesterol stones were identified in branches of the left hepatic duct and these were removed with the stone extraction balloon under endoscopic visualization. Ciprofloxacin was administered for 5 days and post interventional course was uneventful. Direct peroral colangioscopy using a conventional endoscope provides high quality endoscopic imaging, enabling access to virtual chromoendoscopy and the 2.8 mm diameter working channel allows for interventional procedures. This strategy is useful and economical, helping confirm clearance of common bile duct stones, while allowing extraction of any residual stones. New, cost effective scopes for peroral cholangioscopy are needed to improve the safety and success rate.

Refractory benign esophageal strictures - Cut or dilate?

A 67-year-old male patient with long term gastroesophageal reflux disease (GERD) on double dose proton pump inhibitors, presented with dysphagia for soft foods. He underwent upper gastrointestinal (UGI) endoscopy which revealed a severe regular stricture at the level of the esophagogastric junction with a residual luminal orifice measuring 2 mm. Biopsies at the site of the stricture ruled out malignancy and were suggestive of peptic etiology. The patient underwent twelve endoscopic dilatation sessions, 11 of them with Savary-Guillard bougies and 1 with TTS balloon, up to a maximal diameter of 18 mm, with only partial relief of dysphagia symptoms. Due to the persistence of the stricture and dysphagia symptoms, incisional therapy was performed in two endoscopic sessions at the site of the stricture was performed with a Mori´s knife parallel to the longitudinal axis of the esophagus in a radial manner in all of the quadrants. There were no adverse events. On follow-up, 2 months later after the last session, the patient had a significant improvement and did not have any dysphagia symptoms. UGI endoscopy revealed minimal residual narrowing at the site of the previous stricture in the distal esophagus. He remains asymptomatic after 6 months follow-up.

Nautical astrology: a forgotten early modern tradition.

While the link between navigation and astronomy is quite evident and its history has been extensively explored, the prognosticatory element included in astronomical knowledge has been almost completely left out. In the early modern world, the science of the stars also included prognostication known today as astrology. Together with astronomical learning, navigation also included astrology as a means to predict the success of a journey. This connection, however, has never been adequately researched. This paper makes the first broad study of the tradition of astrology in navigation as well as its role in early modern globalization. It shows how astrological doctrine had its own tools for nautical prognostication. These could be used when dealing with the uncertainty of reaching the desired destination, to inquire about the condition of a loved one, or an important cargo. It was widely used, both in time and geographical context, by navigators and cosmographers for weather forecasting and elections for the start of a successful voyage.

SorCS1-mediated sorting in dendrites maintains neurexin axonal surface polarization required for synaptic function.

The pre- and postsynaptic membranes comprising the synaptic junction differ in protein composition. The membrane trafficking mechanisms by which neurons control surface polarization of synaptic receptors remain poorly understood. The sorting receptor Sortilin-related CNS expressed 1 (SorCS1) is a critical regulator of trafficking of neuronal receptors, including the presynaptic adhesion molecule neurexin (Nrxn), an essential synaptic organizer. Here, we show that SorCS1 maintains a balance between axonal and dendritic Nrxn surface levels in the same neuron. Newly synthesized Nrxn1α traffics to the dendritic surface, where it is endocytosed. Endosomal SorCS1 interacts with the Rab11 GTPase effector Rab11 family-interacting protein 5 (Rab11FIP5)/Rab11 interacting protein (Rip11) to facilitate the transition of internalized Nrxn1α from early to recycling endosomes and bias Nrxn1α surface polarization towards the axon. In the absence of SorCS1, Nrxn1α accumulates in early endosomes and mispolarizes to the dendritic surface, impairing presynaptic differentiation and function. Thus, SorCS1-mediated sorting in dendritic endosomes controls Nrxn axonal surface polarization required for proper synapse development and function.

Air-Depleted and Solvent-Impregnated Cork Powder as a New Natural and Sustainable Fining Agent for Removal of 2,4,6-Trichloroanisole (TCA) from Red Wines.

Trichloroanisole (TCA) in wine results in a sensory defect called "cork taint", a significant problem for the wine industry. Wines can become contaminated by TCA absorption from the atmosphere through contaminated wood barrels, cork stoppers, and wood pallets. Air-depleted solvent-impregnated (ADSI) cork powder (CP) was used to mitigate TCA in wines. The ADSI CP (0.25 g/L) removed 91% of TCA (6 ng/L levels), resulting in an olfactory activity value of 0.14. A Freundlich isotherm described ADSI CP TCA adsorption with irreversible adsorption and a KF = 33.37. ADSI CP application had no significant impact on the phenolic profile and chromatic characteristics of red wine. Using headspace sampling with re-equilibration, an average reduction in the volatile abundance of 29 ± 15%, 31 ± 19%, and 37 ± 24% was observed for the 0.10, 0.25, and 0.50 g/L ADSI CP, respectively. The alkyl esters and acids were the most affected. The impact observed was much lower when using headspace sampling without re-equilibration. Isoamyl acetate, ethyl hexanoate, ethyl hexanoate, and ethyl decanoate abundances were not significantly different from the control wine and 0.25 g/L ADSI CP application. Thus, ADSI CP can be a new sustainable fining agent to remove this "off-flavor" from wine, with a reduced impact on the wine characteristics.

Venous Size Discrepancy Is a Critical Factor When Using Superficial Temporal Vessels as Recipient Vessels for Free Flaps.

BACKGROUND: Superficial temporal vessels have been used successfully as recipient vessels for head and neck reconstruction. This study evaluates the impact of several treatment variables on flap failure and take-back rate when using these recipient vessels. METHODS: We conducted a retrospective study of all microsurgical reconstructions using superficial temporal vessels as recipient vessels in a period of 10 years. Variables collected included previous treatments (radiotherapy, chemotherapy, neck dissection, free flap reconstruction), type of flaps used (soft tissue, osteocutaneous), and vessel size discrepancy between donor and recipient vessels. RESULTS: A total of 132 patients were included in the study. The flap success rate was 98.5%. The take-back rate was 10.6%. The most frequent reason for take-back was venous congestion secondary to thrombosis. None of the studied variables was associated with flap failure. Reconstructions using osteocutaneous flaps and vein diameter discrepancy (ratio ≥ 2:1) had significantly higher take-back rates. CONCLUSION: Flaps with a significant size discrepancy between donor and recipient veins (ratio ≥ 2:1) and fibula flaps (compared with soft tissue flaps) were associated with a higher risk of take-back. It is crucial to minimize venous engorgement during flap harvest and anastomosis, and limit vein redundancy during flap in-setting.

Is the Toxicity of Salvage Prostatectomy Related to the Primary Prostate Cancer Therapy Received?

PURPOSE: To compare the toxicity profile and oncological outcome of salvage radical prostatectomy following focal therapy versus salvage radical prostatectomy after radiation therapies (external beam radiation therapy or brachytherapy). MATERIALS AND METHODS: Data concerning all men undergoing salvage radical prostatectomy for recurrent prostate cancer after either focal therapy, external beam radiation therapy or brachytherapy were retrospectively collected from 4 high volume surgical centers. The primary outcome measure of the study was toxicity of salvage radical prostatectomy characterized by any 30-day postoperative Clavien-Dindo complication rate, 12-month continence rate and 12-month potency rate. The secondary outcome was oncological outcome after salvage radical prostatectomy including positive margin rate and 12-month biochemical recurrence rate. Biochemical recurrence was estimated using Kaplan-Meier methods and significant differences were calculated using a log rank test. Median followup was 29.5 months. RESULTS: Between April 2007 and September 2018, 185 patients underwent salvage radical prostatectomy of whom 95 had salvage radical prostatectomy after focal therapy and 90 had salvage radical prostatectomy after radiation therapy (external beam radiation therapy or brachytherapy). Salvage radical prostatectomy after radiation therapy was associated with a significantly higher 30-day Clavien-Dindo I-IV complication rate (34% vs 5%, p <0.001). At 12 months following surgery, patients undergoing salvage radical prostatectomy after focal therapy had significantly better continence (83% pad-free vs 49%) while potency outcomes were similar (14% vs 11%). Men undergoing salvage radical prostatectomy after radiation therapy had a significantly higher stage and grade of disease together with a higher positive surgical margin rate (37% vs 13%, p=0.001). The 3-year biochemical recurrence after focal therapy was 35% compared to 32% after radiation therapy (p=0.76). In multivariable analysis, men undergoing salvage radical prostatectomy after focal therapy experienced a higher risk of biochemical recurrence (HR 0.36, 95% CI 0.16-0.82, p=0.02). CONCLUSIONS: This multicenter study demonstrates the toxicity of salvage radical prostatectomy in terms of perioperative complications and long-term urinary continence recovery is dependent on initial primary prostate cancer therapy received with men undergoing salvage radical prostatectomy after focal therapy experiencing lower postoperative complication rates and better urinary continence outcomes.

Outcomes of the RAFT trial: robotic surgery after focal therapy.

OBJECTIVES: To report toxicity of treatment observed in men participating in the Robotic surgery After Focal Therapy (RAFT) clinical trial. PATIENTS AND METHODS: Men were eligible for this prospective single group interventional study if they had histologically confirmed recurrent/residual prostate adenocarcinoma following primary FT. The short-form Expanded Prostate Cancer Index Composite (EPIC-26) measured prior to salvage robotic prostatectomy (S-RARP) and 3-monthly post-operatively together with Clavien-Dindo complications (I-IV). Secondary outcomes included biochemical recurrence-free survival (BCFS) following surgery and need for salvage treatment after surgery. This study is registered with ClinicalTrials.gov NCT03011606. RESULTS: Twenty-four men were recruited between February 2016 and September 2018. 1 patient withdrew from the trial after consenting and before S-RARP. 23 men completed 12-month post S-RARP follow-up. Median EPIC-26 urinary continence scores initially deteriorated after 3 months (82.4 vs 100) but there was no statistically significant difference from baseline at 12 months (100 vs 100, P = 0.31). Median lower urinary tract symptom scores improved after 12 months compared to baseline (93.8 vs 87.5, P = 0.01). At 12 months, 19/23 (83%) were pad-free and 22/23 (96%) required 0/1 pads. Median sexual function subscale scores deteriorated and remained low at 12 months (22.2 vs 58.3, P < 0.001). Utilising a minimally important difference of nine points, at 12 months after surgery 17/23 (74%) reported urinary continence to be 'better' or 'not different' to pre-operative baseline. The corresponding figure for sexual function (utilising a minimally important difference of 12 points) was 7/23 (30%). There was no statistically significant difference on median bowel/hormonal subscale scores. Only a single patient had a post-operative complication (Clavien-Dindo Grade I). BCFS at 12 months after surgery was 82.6% (95% confidence interval [CI]: 60.1-93.1%) while 4/23 (17%) received salvage radiation. CONCLUSIONS: The RAFT clinical trial suggests toxicity of surgery after FT is low, with good urinary function outcomes, albeit sexual function deteriorated overall. Oncological outcomes at 12 months appear acceptable.