The KDM6A-KMT2D-p300 axis regulates susceptibility to diverse coronaviruses by mediating viral receptor expression.

Identification of host determinants of coronavirus infection informs mechanisms of pathogenesis and may provide novel therapeutic targets. Here, we demonstrate that the histone demethylase KDM6A promotes infection of diverse coronaviruses, including SARS-CoV, SARS-CoV-2, MERS-CoV and mouse hepatitis virus (MHV) in a demethylase activity-independent manner. Mechanistic studies reveal that KDM6A promotes viral entry by regulating expression of multiple coronavirus receptors, including ACE2, DPP4 and Ceacam1. Importantly, the TPR domain of KDM6A is required for recruitment of the histone methyltransferase KMT2D and histone deacetylase p300. Together this KDM6A-KMT2D-p300 complex localizes to the proximal and distal enhancers of ACE2 and regulates receptor expression. Notably, small molecule inhibition of p300 catalytic activity abrogates ACE2 and DPP4 expression and confers resistance to all major SARS-CoV-2 variants and MERS-CoV in primary human airway and intestinal epithelial cells. These data highlight the role for KDM6A-KMT2D-p300 complex activities in conferring diverse coronaviruses susceptibility and reveal a potential pan-coronavirus therapeutic target to combat current and emerging coronaviruses. One Sentence Summary: The KDM6A/KMT2D/EP300 axis promotes expression of multiple viral receptors and represents a potential drug target for diverse coronaviruses.

Cytoreductive surgery plus hyperthermic intraoperative peritoneal chemotherapy for people with peritoneal metastases from colorectal, ovarian or gastric origin: A systematic review of randomized controlled trials.

BACKGROUND: There is uncertainty in the relative benefits and harms of hyperthermic intraoperative peritoneal chemotherapy (HIPEC) when added to cytoreductive surgery (CRS) +/- systemic chemotherapy or systemic chemotherapy alone in people with peritoneal metastases from colorectal, gastric, or ovarian cancers. METHODS: We searched randomized controlled trials (RCTs) in the medical literature until April 14, 2022 and applied methods used for high-quality systematic reviews. FINDINGS: We included a total of eight RCTs (seven RCTs included in quantitative analysis as one RCT did not provide data in an analyzable format). All comparisons other than ovarian cancer contained only one trial. For gastric cancer, there is high uncertainty about the effect of CRS + HIPEC + systemic chemotherapy. For stage III or greater epithelial ovarian cancer undergoing interval cytoreductive surgery, CRS + HIPEC + systemic chemotherapy probably decreases all-cause mortality compared to CRS + systemic chemotherapy. For colorectal cancer, CRS + HIPEC + systemic chemotherapy probably results in little to no difference in all-cause mortality and may increase the serious adverse events proportions compared to CRS +/- systemic chemotherapy, but probably decreases all-cause mortality compared to fluorouracil-based systemic chemotherapy alone. INTERPRETATION: The role of CRS + HIPEC in gastric peritoneal metastases is uncertain. CRS + HIPEC should be standard of care in women with stage III or greater epithelial ovarian cancer undergoing interval CRS. CRS + systemic chemotherapy should be standard of care for people with colorectal peritoneal metastases, with HIPEC given only as part of a RCT focusing on subgroups and regimes. PROSPERO REGISTRATION: CRD42019130504.

Evaluation of multikinase inhibitor LDN193189 induced hepatotoxicity in teleost fish Poecilia latipinna.

Currently, scientists show keen interest in the drugs that inhibit multiple kinases, LDN193189, being an example. It combats certain cancers in vitro as well as in vivo, making it a prerequisite for researchers to study the toxic potential of this drug in animal models. As most of the drugs metabolized by liver cause hepatic injury, LDN193189-induced hepatotoxicity was examined using a teleost fish, Poecilia latipinna. As a prelude, calculation of LD50 showed a value of 95.22 mg/kg body weight and three doses were decided based on it for further evaluations. All these groups were tested for antioxidant enzyme levels and were significantly raised for mid- and high-dose group. Similar trend was recorded for ALP, AST, and ALT levels. Furthermore, some key indicators of drug metabolism in liver were tested for their expression in response to LDN193189 treatment. Among these, Cyt-C, CYP3A4, CYP1B1 and CYP1A1 were elevated in mid- and high dose, except CYP21A1, which declined remarkably. Moreover, histological profile of the liver reflected high degree of inflammation due to drug treatment, but this was found only at high dose. In summary, LDN193189, at 2.5 mg/kg body weight, did not cause any adverse hepatotoxicity, rendering it safe for use as an anti-proliferative agent - an activity for which it has already shown promising results in the same animal model. The low-dose group previously studied for its anti-proliferative property showed no adverse effect in liver, whereas the mid- and high dose induced moderate or severe hepatotoxicity in P. latipinna.

Inherent variations in the cellular events at the site of amputation orchestrate scar-free wound healing in the tail and scarred wound healing in the limb of lizard Hemidactylus flaviviridis.

Lizards are unique in having both-regeneration competent (tail) as well as non-regenerating appendages (limbs) in adults. They therefore present an appropriate model for comparing processes underlying regenerative repair and nonregenerative healing after amputation. In the current study, we use northern house gecko Hemidactylus flaviviridis to compare major cellular and molecular events following amputation of the limb and of the tail. Although the early response to injury in both cases comprises apoptosis, proliferation, and angiogenesis, the temporal distribution of these processes in each remained obscure. In this regard, observations were made on the anatomy and gene expression levels of key regulators of these processes during the healing phase of the tail and limb separately. It was revealed that cell proliferation markers like fibroblast growth factors were upregulated early in the healing tail, coinciding with the growing epithelium. The amputated limb, in contrast, showed weak expression of proliferation markers, limited only to fibroblasts in the later stage of healing. Additionally, apoptotic activity in the tail was limited to the very early phase of healing, as opposed to that in the limb, wherein high expression of caspase-3 was observed throughout the healing process. Early rise in VEGF-α expression reflected an early onset of angiogenesis in the tail, while it was seen to occur at a later stage in case of the limb. Moreover, the expression pattern of transforming growth factor beta members points toward a pro-fibrotic response being induced very early in the amputated limb. Collectively, these results explain why regenerating appendages are able to heal without scars and if we are to induce scar-free healing in nonregenerating limbs, what interventions can be envisaged. This is crucial to the field of regenerative medicine since it is the initial stages of repair following amputation, which decide whether the appendage will be restored or only covered with a scab.

Comprehensive Ryan White Assistance and Human Immunodeficiency Virus Clinical Outcomes: Retention in Care and Viral Suppression in a Medicaid Nonexpansion State.

Background: Knowledge gaps remain about how the Ryan White human immunodeficiency virus (HIV)/AIDS Program (RW) contributes to health outcomes. We examined the association between different RW service classes and retention in care (RiC) or viral suppression (VS). Methods: We identified Virginians engaged in any HIV care between 1 January and 31 December 2014. RW beneficiaries were classified by receipt of ≥1 service from 3 classes: Core medical, Support, and insurance and/or direct medication assistance through the AIDS Drug Assistance Program (ADAP). Receipt of all RW classes was defined as comprehensive assistance. We used multivariable logistic regression to compare the odds of RiC and of VS by comprehensive assistance and by RW classes alone and in combination. Results: Among 13104 individuals, 58% received any RW service and 17% comprehensive assistance. Comprehensive assistance is significantly associated with RiC (adjusted odds ratio [aOR], 8.8 [95% confidence interval {CI}, 7.2-10.8]) and viral suppression (aOR, 3.3 [95% CI, 2.9-3.8]). Receiving any 2 RW classes or Core alone is significantly associated with RiC and VS, with the strength of association decreasing as the number of classes decreases. Recipients of Support alone are significantly less likely to have VS (aOR, 0.75 [95% CI, .59-.96]). For ADAP recipients also receiving Core and/or Support, insurance assistance is significantly associated with VS compared to receiving direct medication only (aOR, 1.6 [95% CI, 1.3-1.9]); this relationship is not significant for those who receive ADAP alone. Conclusions: Receiving more classes of RW-funded services is associated with improved HIV outcomes. For some populations with insurance, RW-funded services may still be required for optimal health outcomes.

BMP signaling regulates the skeletal and connective tissue differentiation during caudal fin regeneration in sailfin molly (Poecilia latipinna).

Caudal fin regeneration in sailfin molly, Poecilia latipinna (Lesueur 1821) involves an initial wound healing stage, followed by blastema that is formed of fast proliferating cells. In order to replicate the lost fin, correct differentiation of the blastemal cells into various tissues is the prime essence. Among the molecular signals governing proper differentiation of blastemal cells, members of the bone morphogenetic protein (BMP) family are crucial. Herein, we investigated the specific effects of inhibition of BMP signaling using LDN193189 on skeletal and connective tissue formation in the regenerating tail fin of P. latipinna during early differentiation phase. It was observed that BMP inhibition leads to reduction in the length of regeneration, which can be correlated with compromised proliferation of blastemal cells. Decreased expression of cell proliferation marker like pcna together with reduced BrdU positive cells consolidate the above observation. Further, histological analysis revealed stunted progression of skeletal tissues and this correlated with the reduced expression of sox9, runx2 and dlx5, Osc and Osn genes in response to BMP inhibition. Also, defective bone patterning was observed due to BMP inhibition, which was associated with diminished levels of shh, ptc-1, gli2 and other BMP ligands. Moreover, histochemical analysis revealed that collagen, one of the most prominent components of connective tissue, was formed below par in treated fin tissues which was subsequently confirmed by biochemical and transcript level analyses. Overall our results highlight the importance of the BMP pathway in proper differentiation of skeletal and connective tissues during the differentiation stage of regenerating caudal fin.

Inhibition of BMP signaling reduces MMP-2 and MMP-9 expression and obstructs wound healing in regenerating fin of teleost fish Poecilia latipinna.

The tail fin of teleost fish responds to amputation by expressing few putative factors that promote scar-free wound healing, which paves the way for restoration of the lost part. Among the factors playing a role in this initial response, bone morphogenetic proteins (BMPs) are crucial. In the current study, we have analyzed the effect of BMP inhibition on wound healing in sailfin molly Poecilia latipinna. The study involved histological assessment of wound epithelium formation, an expression profile of proteins, and gelatinase activity as well as expression in response to BMP signal inhibition. LDN193189, a pharmacological inhibitor of BMP receptor, was administered to experimental fish. Our observations include incomplete wound healing and a significant reduction in the expression of a number of proteins as a result of LDN treatment at 24 h post-amputation. A pronounced effect was also seen on the gelatinases MMP-9 and MMP-2, which showed significantly reduced activities on a zymogram. Reduced expression of these MMPs after inhibitor treatment was also confirmed by western blot and real-time PCR analyses. In view of these results, we confirm that BMP signaling has a definitive role in the early stages of fin regeneration in P. latipinna. The effect of BMP inhibition is especially seen on the expression of MMP-9 and MMP-2, which are very important effectors of tissue remodeling immediately following amputation.

CHMP2A regulates broad immune cell-mediated antitumor activity in an immunocompetent in vivo head and neck squamous cell carcinoma model.

BACKGROUND: Natural killer (NK) cells are key effector cells of antitumor immunity. However, tumors can acquire resistance programs to escape NK cell-mediated immunosurveillance. Identifying mechanisms that mediate this resistance enables us to define approaches to improve immune-mediate antitumor activity. In previous studies from our group, a genome-wide CRISPR-Cas9 screen identified Charged Multivesicular Body Protein 2A (CHMP2A) as a novel mechanism that mediates tumor intrinsic resistance to NK cell activity. METHODS: Here, we use an immunocompetent mouse model to demonstrate that CHMP2A serves as a targetable regulator of not only NK cell-mediated immunity but also other immune cell populations. Using the recently characterized murine 4MOSC model system, a syngeneic, tobacco-signature murine head and neck squamous cell carcinoma model, we deleted mCHMP2A using CRISPR/Cas9-mediated knock-out (KO), following orthotopic transplantation into immunocompetent hosts. RESULTS: We found that mCHMP2A KO in 4MOSC1 cells leads to more potent NK-mediated tumor cell killing in vitro in these tumor cells. Moreover, following orthotopic transplantation, KO of mCHMP2A in 4MOSC1 cells, but not the more immune-resistant 4MOSC2 cells enables both T cells and NK cells to better mediate antitumor activity compared with wild type (WT) tumors. However, there was no difference in tumor development between WT and mCHMP2A KO 4MOSC1 or 4MOSC2 tumors when implanted in immunodeficient mice. Mechanistically, we find that mCHMP2A KO 4MOSC1 tumors transplanted into the immunocompetent mice had significantly increased CD4+T cells, CD8+T cells. NK cell, as well as fewer myeloid-derived suppressor cells (MDSC). CONCLUSIONS: Together, these studies demonstrate that CHMP2A is a targetable inhibitor of cellular antitumor immunity.

Virtual classroom proficiency-based progression for robotic surgery training (VROBOT): a randomised, prospective, cross-over, effectiveness study.

Robotic surgery training has lacked evidence-based standardisation. We aimed to determine the effectiveness of adjunctive interactive virtual classroom training (VCT) in concordance with the self-directed Fundamentals of Robotic Surgery (FRS) curriculum. The virtual classroom is comprised of a studio with multiple audio-visual inputs to which participants can connect remotely via the BARCO weConnect platform. Eleven novice surgical trainees were randomly allocated to two training groups (A and B). In week 1, both groups completed a robotic skills induction. In week 2, Group A received training with the FRS curriculum and adjunctive VCT; Group B only received access to the FRS curriculum. In week 3, the groups received the alternate intervention. The primary outcome was measured using the validated robotic-objective structured assessment of technical skills (R-OSAT) at the end of week 2 (time-point 1) and 3 (time-point 2). All participants completed the training curriculum and were included in the final analyses. At time-point 1, Group A achieved a statistically significant greater mean proficiency score compared to Group B (44.80 vs 35.33 points, p = 0.006). At time-point 2, there was no significant difference in mean proficiency score in Group A from time-point 1. In contrast, Group B, who received further adjunctive VCT showed significant improvement in mean proficiency by 9.67 points from time-point 1 (95% CI 5.18-14.15, p = 0.003). VCT is an effective, accessible training adjunct to self-directed robotic skills training. With the steep learning curve in robotic surgery training, VCT offers interactive, expert-led learning and can increase training effectiveness and accessibility.

De Novo Transcriptome Sequencing and Analysis of Differential Gene Expression among Various Stages of Tail Regeneration in Hemidactylus flaviviridis.

Across the animal kingdom, lizards are the only amniotes capable of regenerating their lost tail through epimorphosis. Of the many reptiles, the northern house gecko, Hemidactylus flaviviridis, is an excellent model system that is used for understanding the mechanism of epimorphic regeneration. A stage-specific transcriptome profile was generated in the current study following an autotomized tail with the HiSeq2500 platform. The reads obtained from de novo sequencing were filtered and high-quality reads were considered for gene ontology (GO) annotation and pathway analysis. Millions of reads were recorded for each stage upon de novo assembly. Up and down-regulated transcripts were categorized for early blastema (EBL), blastema (BL) and differentiation (DF) stages compared to the normal tail (NT) by differential gene expression analysis. The transcripts from developmentally significant pathways such as FGF, Wnt, Shh and TGF-ß/BMP were present during tail regeneration. Additionally, differential expression of transcripts was recorded from biological processes, namely inflammation, cell proliferation, apoptosis and cell migration. Overall, the study reveals the stage-wise transcriptome analysis in conjunction with cellular processes as well as molecular signaling pathways during lizard tail regeneration. The knowledge obtained from the data can be extrapolated to configure regenerative responses in other amniotes, including humans, upon loss of a complex organ.

The Impact of Same Gender Speed-Mentoring on Women's Perceptions of a Career in Surgery - A Prospective Cohort Study.

BACKGROUND: Mentoring is critically important for the personal and professional development of a surgeon. Early career stage mentoring by same-gender role models may help ameliorate the gender imbalance in surgery based on our understanding of barriers for women pursuing surgical careers. A novel method of establishing these relationships is speed mentoring. This study aims to examine the impact of a one-day speed-mentoring session with same gender mentors on a cohort's perceptions of a career in surgery. DESIGN: This prospective pre-post study compared attitudes and perceptions of a career in surgery before and after a speed-mentoring session with female surgeons. Mentees were assigned into groups of 1 or 2 and were paired with a female surgeon for 8 minutes. Each mentee group then rotated to another mentor for the same amount of time and this process continued for a total of twelve sessions. Mentees completed a 19-point questionnaire before and after the speed mentoring intervention. SETTING: This multicenter study included participants from across the United Kingdom. PARTICIPANTS: Inclusion criteria were female gender and medical student or foundation year doctor (internship year 1 or 2) status. Three hundred and forty participants participated in the intervention, 191 were included in the analysis. RESULTS: Following intervention, the percentage of participants who agreed that having a family would negatively impact a woman's surgical career progression significantly decreased from 46.6% to 23.0%. The percentage of participants who agreed that an "old boys' club" attitude exists in surgery also significantly decreased (73.8%-58.1%). The percentage of participants who agreed it was more difficult for a woman to succeed in her surgical career than a man significantly decreased (73.8%-64.9%). One hundred and eighty-three (96%) participants agreed that mentorship is important for career progression and 153 (71.2%) participants stated that they did not have someone who they considered a mentor. CONCLUSIONS: Conducting a speed mentoring program with same-gender role models significantly changed female medical students' and junior doctors' perceptions of women in surgery. The results suggest that such programs may be effective tools for facilitating mentor-mentee relationships and could be employed by surgical organizations to encourage a diverse uptake into surgery.

Surgical Field Quality in Trans-Nasal Endoscopic Surgeries Using Lignocaine Infusion and Dexmedetomidine Infusion. A Prospective Randomized Control Study.

Trans-nasal endoscopic surgery (TNES) is a helpful diagnostic and therapeutic modality in otorhinolaryngology surgeries and requires controlled hypotension for better visualization of the surgical field. Recent literature shows evidence of intravenous Lignocaine infusion to produce the controlled hypotension. The study aims to assess and compare the effects of Lignocaine (LIG) and Dexmedetomidine (DEX) infusion with respect to surgical field quality. 101 Consenting adult patients undergoing elective TNES were double-blinded, randomly allocated in one of the two groups and received either DEX infusion of 0.5ug/kg/hr (n = 51) or LIG infusion of 1.5 mg/kg/h (n = 50) after a loading dose. Surgical field score (SVF) as the primary outcome and secondary outcomes such as variations in hemodynamic parameters, the requirement for rescue agents and total blood loss were recorded. Both the groups were comparable with respect to patient demographics, total duration of anesthesia and surgery. SVF scores were significantly better in the LIG group during the first 105 min of the surgery (p < 0.05). In response to intubation, hemodynamic parameters were lower in LIG group. The requirement of other adjuvant drugs, total blood loss (166.40 ml vs. 251.17 ml) and extubation time were also significantly lower in the LIG group. The study concludes that intravenous Lignocaine gives a better surgical field in the first 105 min of surgery, comparable hemodynamics and decreased blood loss in patients undergoing TNES as compared to Dexmedetomidine infusion. Hence its role as an agent for controlled hypotension during TNES surgery is promising.

Virtual Interactive Surgical Skills Classroom: A Parallel-group, Non-inferiority, Adjudicator-blinded, Randomised Controlled Trial (VIRTUAL).

OBJECTIVE: This study evaluated the efficacy of virtual classroom training (VCT) in comparison to face-to-face training (FFT) and non-interactive computer-based learning (CBL) for basic surgical skills training. DESIGN: This was a parallel-group, non-inferiority, prospective randomised controlled trial with three intervention groups conducted in 2021. There were three intervention groups with allocation ratio 1:1:1. Outcome adjudicators were blinded to intervention assignment. Interventions consisted of 90-minute training sessions. VCT was delivered via the BARCO weConnect platform, FFT was provided in-person by expert instructors and CBL was carried out by participants independently. The primary outcome was post-intervention Objective Structured Assessment of Technical Skills score, adjudicated by two experts and adjusted for baseline proficiency. The assessed task was to place three interrupted sutures with hand-tied knots. SETTING: This multicentre study recruited from five medical schools in London. PARTICIPANTS: Inclusion criteria were medical student status and access to a personal computer and smartphone. One hundred fifty-nine eligible individuals applied online. Seventy-two participants were randomly selected and stratified by subjective and objective suturing experience prior to permuted block randomization. RESULTS: Twenty-four participants were allocated to each intervention, all were analysed per-protocol. The sample was 65.3% female with mean age 21.3 (SD 2.1). VCT was non-inferior to FFT (adjusted difference 0.44, 95% CI: -0.54 to 1.75, delta 0.675), VCT was superior to CBL (adjusted difference 1.69, 95% CI: 0.41-2.96) and FFT was superior to CBL (adjusted difference 1.25, 95% CI: 0.20-2.29). The costs per-attendee associated with VCT, FFT and CBL were £22.15, £39.69 and £16.33 respectively. Instructor hours used per student for VCT and FFT were 0.25 and 0.75, respectively. CONCLUSIONS: VCT provides greater accessibility and resource efficiency compared to FFT, with similar educational benefit. VCT has the potential to improve global availability and accessibility of surgical skills training.

Anesthetics or anesthetic techniques and cancer surgical outcomes: a possible link.

As of 2018 cancer is responsible for almost 9.6 million deaths annually and, with an aging population, the incidence of cancer is expected to continue to rise. Surgery is an important treatment modality for patients with solid organ cancers. It has been postulated that, due to potentially overlapping processes underlying the development of malignancy and the therapeutic pathways of various anesthetic agents, the choice of anesthetic type and method of administration may affect post-operative outcomes in patients with cancer. This is a literature review of the most recent evidence extracted from various databases including PubMed, EMBASE, and the Cochrane, as well as journals and book reference lists. The review highlights the pathophysiological processes underpinning cancer development and the molecular actions of anesthetic agents, pre-clinical and retrospective studies investigating cancer and anesthetics, as well as ongoing clinical trials. Overall, there are conflicting results regarding the impact of regional vs. general anesthesia on cancer recurrence, whilst the majority of data suggest a benefit of the use of intravenous propofol over inhalational volatile anesthetics. The biological changes associated with the surgical inflammatory response offer a unique opportunity to intervene to counteract any potentially cancer-promoting effects.

Site-specific variation in the activity of COX-2 alters the pattern of wound healing in the tail and limb of northern house gecko by differentially regulating the expression of local inflammatory mediators.

The role of COX-2 induced PGE2 in the site-specific regulation of inflammatory mediators that facilitate disparate wound healing in the tail and limb of a lizard was studied by analysing their levels during various stages of healing. The activity of COX-2 and concentration of PGE2 surged during the early healing phase of tail along with the parallel rise in EP4 receptor. PGE2-EP4 interaction is corelated to early resolution (by 3 dpa) of inflammation by rising the antiinflammatory mediator IL-10. This likely causes reduction in proinflammatory mediators viz., iNOS, TNF-α, IL-6, IL-17 and IL-22. Conversely, in the limb, COX-2 derived PGE2 likely causes rise in inflammation through EP2 receptor-based signalling, as all the proinflammatory mediators stay elevated through the course of healing (till 9 dpa), while expression of IL-10 is reduced. This study brings to light the novel roles of IL-17 and IL-22 in programming wound healing. As IL-17 reduces in tail, IL-22 behaves in reparative way, causing conducive environment for scar-free wound healing. On the contrary, synergic elevation of both IL-17 and Il-22 form a micro-niche suitable for scarred wound healing in limb, thus obliterating its regenerative potential.

Virtual Interactive Surgical Skills Classroom: Protocol for a Parallel-Group, Noninferiority, Adjudicator-Blinded, Randomized Controlled Trial (VIRTUAL).

BACKGROUND: Traditional face-to-face training (FFT) for basic surgical skills is inaccessible and resource-intensive. Noninteractive computer-based learning is more economical but less educationally beneficial. Virtual classroom training (VCT) is a novel method that permits distanced interactive expert instruction. VCT may optimize resources and increase accessibility. OBJECTIVE: We aim to investigate whether VCT is superior to computer-based learning and noninferior to FFT in improving proficiency in basic surgical skills. METHODS: This is a protocol for a parallel-group, noninferiority, randomized controlled trial. A sample of 72 undergraduates will be recruited from 5 medical schools in London. Participants will be stratified by subjective and objective suturing experience level and allocated to 3 intervention groups at a 1:1:1 ratio. VCT will be delivered using the BARCO weConnect software, and FFT will be provided by expert instructors. Optimal student-to-teacher ratios of 12:1 for VCT and 4:1 for FFT will be maintained. The assessed task will be interrupted suturing with hand-tied knots. RESULTS: The primary outcome will be the postintervention Objective Structured Assessment of Technical Skills score, adjudicated by 2 experts blinded to the study and adjusted for baseline proficiency. The noninferiority margin (δ) will be defined using historical data. CONCLUSIONS: This study will serve as a comprehensive appraisal of the suitability of virtual basic surgical skills classroom training as an alternative to FFT. Our findings will assist the development and implementation of further resource-efficient, accessible, virtual basic surgical skills training programs during the COVID-19 pandemic and in the future. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number ISRCTN12448098; https://www.isrctn.com/ISRCTN12448098. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/28671.

Salvage Versus Primary Robot-assisted Radical Prostatectomy: A Propensity-matched Comparative Effectiveness Study from a High-volume Tertiary Centre.

BACKGROUND: Salvage robot-assisted radical prostatectomy (sRARP) is a potential treatment option for locally recurrent prostate cancer (PCa) after nonsurgical primary treatment. There are minimal data comparing outcomes between propensity-matched sRARP and primary robot-assisted radical prostatectomy (RARP). OBJECTIVE: The primary objective is to compare perioperative, oncological, and functional outcomes of sRARP with primary RARP, and the secondary is to compare outcomes between sRARP after whole and focal gland therapy. DESIGN SETTING AND PARTICIPANTS: A 1:1 propensity-matched comparison was carried out of 135 sRARP cases with primary RARP cases from a cohort of 3852 consecutive patients from a high-volume tertiary centre. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Perioperative, oncological, and functional outcomes including complication rates, positive surgical margins, biochemical recurrence (BCR), continence, and erectile dysfunction (ED) were retrospectively collected. RESULTS AND LIMITATIONS: There were no significant differences in patient characteristics between sRARP and primary RARP groups. In the salvage and primary groups, median (interquartile range) follow-up periods were 521 (304-951) and 638 (394-951) d, grade III-V Clavien-Dindo complication rates were 1.5% and 0% (p = 0.310), BCR rates were 31.9% and 14.1% (p < 0.001) at the last follow-up, pad-free continence rates were 78.8% and 84.3% at 2 yr (p = 0.337), and ED rates were 94.8% and 76.3% (p < 0.001), respectively. Comparing the whole and focal gland groups, BCR rates were 36.7% and 29.1% (p = 0.687) at follow-up, pad-free continence rates were 53.1% and 89.3% at 2 yr (p < 0.001), and ED rates were 98% and 93% (p = 0.214), respectively. CONCLUSIONS: Salvage RARP has similar perioperative outcomes to primary RARP with inferior potency rates. Post-focal therapy sRARP has similar recurrence and continence rates to primary RARP. Post-whole gland therapy, complication, and recurrence rates are higher, and there is a higher risk of urinary incontinence. PATIENT SUMMARY: We report the largest propensity-matched comparison of salvage robot-assisted radical prostatectomy (RARP) after focal and whole gland therapy. Salvage RARP is a feasible procedure for the treatment of locally recurrent prostate cancer in high-volume centres; however, patients should be counselled appropriately as to the different outcomes.