Crystal structure and mechanistic studies of the PPM1D serine/threonine phosphatase catalytic domain.

Protein phosphatase 1D (PPM1D, Wip1) is induced by the tumor suppressor p53 during DNA damage response signaling and acts as an oncoprotein in several human cancers. Although PPM1D is a potential therapeutic target, insights into its atomic structure were challenging due to flexible regions unique to this family member. Here, we report the first crystal structure of the PPM1D catalytic domain to 1.8 Å resolution. The structure reveals the active site with two Mg2+ ions bound, similar to other structures. The flap subdomain and B-loop, which are crucial for substrate recognition and catalysis, were also resolved, with the flap forming two short helices and three short ß-strands that are followed by an irregular loop. Unexpectedly, a nitrogen-oxygen-sulfur bridge was identified in the catalytic domain. Molecular dynamics simulations and kinetic studies provided further mechanistic insights into the regulation of PPM1D catalytic activity. In particular, the kinetic experiments demonstrated a magnesium concentration-dependent lag in PPM1D attaining steady-state velocity, a feature of hysteretic enzymes that show slow transitions compared with catalytic turnover. All combined, these results advance the understanding of PPM1D function and will support the development of PPM1D-targeted therapeutics.

Systematic Review and Meta-analysis of the Impact of Surgeon-Physician Co-management Models on Short Term Outcomes for Vascular Surgery Inpatients.

OBJECTIVE: As the population ages, vascular surgeons are treating progressively older, multimorbid patients at risk of peri-operative complications. An embedded physician has been shown to improve outcomes in general and orthopaedic surgery. This systematic review and meta-analysis aimed to investigate the impact of surgeon-physician co-management models on morbidity and mortality rates in vascular inpatients. DATA SOURCES: PubMed, Scopus, Embase, conference abstract listings, and clinical trial registries. REVIEW METHODS: Studies comparing adult vascular surgery inpatients under co-management with standard of care were eligible. The relative risks (RRs) of death, medical complications, and 30 day re-admission between co-management and standard care were calculated. The effect of co-management on the mean length of stay was calculated using weighted means. Risk of bias was assessed using the Methodological Index for Non-Randomised Studies, and certainty assessment with the GRADE analysis tools. RESULTS: No randomised controlled trials were identified. Eight single institution studies between 2011 and 2020 with 7 410 patients were included. All studies were observational using before-after methodology. Studies were of high to moderate risk of bias, and outcomes were of very low GRADE certainty of evidence. Co-management was associated with a statistically significant lower relative risk of death (RR 0.64, 95% confidence interval [CI] 0.44 - 0.92; p = .02), cardiac complications (RR 0.47, 95% CI 0.25 - 0.87; p = .02), and infective complications (RR 0.49, 95% CI 0.35 - 0.67; p < .001) in vascular inpatients. No statistically significant differences in length of stay (standard mean difference -0.6 days, 95% CI -1.44 - 0.24 days; p = .16) and 30 day re-admission (RR 0.96, 95% CI 0.84 - 1.08; p = .49) were noted. CONCLUSION: Early results of physician and surgeon co-management for vascular surgery inpatients showed promising results from very low certainty data. Further well designed, prospective studies are needed to determine how to maximise the impact of physicians within a vascular service to improve patient outcomes while using hospital resources effectively.

Review of Mixed Arterial Venous Leg Ulcers (MAVLU) Disease in Contemporary Practice.

BACKGROUND: Mixed Arterial and Venous Leg Ulcers (MAVLU) are challenging. Clinical evidence specific to MAVLU management is scarce. We evaluated our recent experience with MAVLU patients and reviewed current data regarding MAVLU epidemiology, aetiology, diagnostic assessment and management options. METHODS: A prospective leg ulcer database was retrospectively interrogated to determine the prevalence and clinical outcome of MAVLU over 2-year period (2021-2022). The literature was reviewed to determine if optimal treatment strategies. RESULTS: 307 patients attended the ulcer clinic over a 2-year period. Most were venous leg ulcers (71%), 24% were arterial and 5% were MAVLU. The highest healing rate was in MAVLU (93%), followed by (74%) and (41%), in arterial and venous leg ulcer groups, respectively. CONCLUSION: Evidence-based guidelines for MAVLU remain lacking. Well-developed randomised controlled trials are warranted to guide current clinical practice.

Artificial intelligence in pediatric surgery.

Artificial intelligence (AI) is rapidly changing the landscape of medicine and is already being utilized in conjunction with medical diagnostics and imaging analysis. We hereby explore AI applications in surgery and examine its relevance to pediatric surgery, covering its evolution, current state, and promising future. The various fields of AI are explored including machine learning and applications to predictive analytics and decision support in surgery, computer vision and image analysis in preoperative planning, image segmentation, surgical navigation, and finally, natural language processing assist in expediting clinical documentation, identification of clinical indications, quality improvement, outcome research, and other types of automated data extraction. The purpose of this review is to familiarize the pediatric surgical community with the rise of AI and highlight the ongoing advancements and challenges in its adoption, including data privacy, regulatory considerations, and the imperative for interdisciplinary collaboration. We hope this review serves as a comprehensive guide to AI's transformative influence on surgery, demonstrating its potential to enhance pediatric surgical patient outcomes, improve precision, and usher in a new era of surgical excellence.

Syphilitic scleritis and episcleritis: A review.

Scleritis and episcleritis are rare, but potentially sight-threatening forms of syphilis. To provide a full description of this neglected subset of ocular syphilis, we evaluated the English literature for reports of syphilitic scleritis and episcleritis, recording the demographics, clinical characteristics, serological data, management practices, treatment responses, and visual outcomes. Previously published descriptions of 44 patients with syphilitic scleritis (50 eyes) and 9 patients with syphilitic episcleritis (14 eyes) were identified. The predominant type of scleritis was anterior scleritis, accounting for 92.9% of cases, with nodular anterior scleritis being the most frequent subtype at 58.1%. Almost one-quarter of patients were co-infected with human immunodeficiency virus (HIV). Initial misdiagnosis was common and led to delays in initiating treatment with appropriate antibiotics. Visual outcomes were often good in both scleritis and episcleritis, irrespective of HIV infection status, although complications including scleral thinning, keratitis, and uveitis, along with permanent visual loss and an association with neurosyphilis, were reported. Response to antibiotic treatment was typically rapid, often within 1 week. With the rising global incidence of syphilis, testing patients with scleritis or episcleritis for this infectious disease is important to ensure prompt diagnosis and treatment for best ocular and systemic outcomes.

Pharmacological Thromboprophylaxis for VTE Post-Endovenous Ablation of Varicose Veins: Network Meta-Analysis.

OBJECTIVE: Endovenous ablation has revolutionized treatment of varicose vein surgery but is associated with a risk of venous thromboembolism. There is no consensus regarding anticoagulation protocols for these patients. This network meta-analysis (NMA) aims to identify which anticoagulant is optimal in this cohort for clot prevention with minimal risk of adverse bleeding events. METHODS: Library databases were searched for studies where patients were treated with one or more anticoagulants following endovenous ablation for varicose veins. The methodological quality of included studies was quantified using the Risk of Bias (ROB) assessment tools. Findings were reported using the meta-analysis of observational studies in epidemiology (MOOSE) checklist. Statistical analysis was carried out using metainsight (rpackage). RESULTS: Observational data on just under 1500 patients prescribed post ablation anticoagulation (Rivaroxaban, Enoxaparin, Fondaparinux) were analyzed. Patient characteristics were comparable across the cohorts. 81 thrombotic and 40 minor bleeding events occurred in total. Overall rivaroxaban is found to be superior to the other agents. CONCLUSIONS: This NMA indicates that prophylactic rivaroxaban is the highest ranked anticoagulant for thromboprophylaxis in patients post endovenous ablation for varicose veins, with a low risk of adverse bleeding. The choice whether to anticoagulate these patients is likely to remain at the discretion of the treating clinician.

Single-session mechanical thrombectomy for iliofemoral deep vein thrombosis using a dual mechanism of action device combining basket and rotational thrombectomy.

OBJECTIVE: Interventional treatments for acute iliofemoral deep vein thrombosis (DVT) remain controversial after publication of the Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis (ATTRACT) study. Interventions have been shown to reduce post-thrombotic syndrome severity and improve quality of life in DVT patients, but have been accompanied by risk of major bleeding from thrombolytics. We describe thrombus removal using a novel combined basket-rotational thrombectomy device that minimizes the need for thrombolytics or repeat procedures. METHODS: The aim of this prospective, nonrandomized, multicenter, first-in-human study of 19 patients with acute iliofemoral DVT was to evaluate the safety and performance of the Pounce venous thrombectomy system ≤12 months after treatment. The primary performance end point was defined as procedural success through achievement of Society of Interventional Radiology (SIR) grade II lysis in treated vessels with freedom from procedural adverse events. Secondary end points included venous disease severity assessments using the Villalta scale and the Venous Clinical Severity Score, patient quality-of-life measurement using the Venous Insufficiency Epidemiological and Economic Study-Quality of Life questionnaire, and calf circumference measurements taken at baseline, 24 hours, and 1 month. RESULTS: The primary end point of complete or near-complete thrombus removal (Society of Interventional Radiology grade II or III) was achieved in all patients. All study device-related safety end points were met, with no major bleeding or device-related adverse events. Of the 19 patients treated, 16 (84.2%) did not receive thrombolytics during the procedure. Post-thrombotic syndrome (Villalta scale >4) was identified in 17 of 19 patients (89.5%) at baseline, 4 of 13 patients (30.8%) available for follow-up at 6 months, and 2 of 11 patients (18.2%) at 12 months. The median Venous Clinical Severity Score decreased (P < .001) from 8.5 (interquartile range [IQR], 7-10) at baseline to 4 (IQR, 2-4) at 1 month after the procedure and was similar at 6 months (2; IQR, 2-5) and 12 months (2; IQR, 1.5-3) after the procedure. The median Venous Insufficiency Epidemiological and Economic Study-Quality of Life questionnaire score improved (P < .001) by 39 from baseline (57; IQR, 53.5-74) to 1 month (96; IQR, 86-101) after the procedure, and remained high at 6 months (99; IQR, 75-103) and 12 months (98; IQR, 94.5-100). The median calf circumference decreased (P = .089) from 39 cm (IQR, 35-47.8 cm) at baseline to 36 cm (IQR, 32.5-40.5 cm) at 24 hours after the procedure and was 34.5 cm (IQR, 33.2-38.5 cm) at 1 month. CONCLUSIONS: The Pounce device is safe and effective for removal the of thrombus in patients with acute iliofemoral DVT. Initial results demonstrate improvements in venous disease severity and patient quality of life.

Influence of gender on clinical presentation, management practices and outcomes of ocular syphilis.

Ocular syphilis is a re-emerging inflammatory eye disease with a clear gender imbalance, disproportionately affecting men. We investigated the impact of gender on the presentation, management practices and clinical outcomes of this condition. Data generated from a study of patients consecutively diagnosed with ocular syphilis who attended a subspecialist uveitis service at one of four hospitals in Brazil over a 30-month period were disaggregated for analysis by gender. Two-hundred and fourteen eyes (161 men and 53 women) of 127 patients (96 men and 31 women) were included. Posterior uveitis was the most common presentation in both men and women (80.1% vs. 66.7%, p > 0.05), but men were significantly more likely to have vitritis as a feature of their disease (49.4% versus 28.8%, p = 0.019). Three eyes of women had nodular anterior scleritis (p = 0.015). Men were more likely to undergo a lumbar puncture to assess for neurosyphilis (71.9% vs. 51.6%, p = 0.048), but men and women undergoing a lumbar puncture were equally likely to have a cerebrospinal fluid abnormality (36.2% vs. 25.0%, p = 0.393). All patients were treated with aqueous penicillin G or ceftriaxone, and there was a trend towards more men receiving adjunctive systemic corticosteroid treatment as part of their management (65.2% vs. 46.7%, p = 0.071). There were no significant differences in the age of presentation, bilaterality of disease, anatomical classification of uveitis, initial or final visual acuity, and rates of ocular complications between men and women. Our findings indicate that ocular syphilis has comparable outcomes in men and women, but that there are differences in the type of ocular inflammation and management practices between the genders.

An improved in vivo method for atrioventricular node ablation via thoracotomy

The atrioventricular (AV) node is permanently damaged in approximately 3 percent of congenital heart surgery operations, requiring implantation of a permanent pacemaker. Improvements in pacemaker design and in alternative treatment modalities require an effective in vivo model of complete heart block (CHB) before testing can be performed in humans. Such a model should enable accurate, reliable, and detectable induction of the surgical pathology. Through our laboratory’s efforts in developing a tissue engineering therapy for CHB, we describe here an improved in vivo model for inducing chronic AV block. The method employs a right thoracotomy in the adult rabbit, from which the right atrial appendage may be retracted to expose an access channel for the AV node. A novel injection device was designed, which both physically restricts needle depth and provides electrical information via electrocardiogram interface. This combination of features provides real-time guidance to the researcher for confirming contact with the AV node, and documents its ablation upon formalin injection. While all animals tested could be induced to acute AV block, those with ECG guidance were more likely to maintain chronic heart block >12 h. Our model enables the researcher to reproduce both CHB and the associated peripheral fibrosis that would be present in an open congenital heart surgery, and which would inevitably impact the design and utility of a tissue engineered AV node replacement.

Winter storms over Canada

Various type of winter storms occur over Canada and produce major impacts on society. Canada is subjected to extra-tropical cyclones with all their embedded structures, as well as blizzards, mountain-induced storms, lake effect storms and polar lows. Many of these storms are accompanied by heavy precipitation in the form of snow or freezing precipitation, bitterly cold conditions, strong winds, and blowing snow. The occurrence and nature of these storms are discussed in this review article.(AU)

Health status and risk factors for dementia in the middle old in Trinidad: Findings from a nationally representative survey

Objective: To investigate self-reported health status and risk factors for dementia in middle old (75-84 years) individuals. Design and Methodology: This study used the validated 10/66 door- to-door interview protocols. All individuals (836 persons) 75-84 years old were approached. The modified 10/66 dementia algorithm produced output in 811 (97%). Dementia diagnosis was made according to 10/66 criteria from: (1) cognitive tests, the Community Screening Instrument for Dementia (CSI'D), (2) EURO-D depression scale (3) informant interview. Demographic data included information on accommodation, social network, level of impairment and instrumental activities of daily living. Data were analyzed using multilevel logistic regression models. Results: Of the 811 participants, 55% were females. The mean age was 78.9±6.3 years and dementia was present in 198 (24.4%). High level of education, professional employment and having no comorbidities were significant protective factors. In multivariate analyses those with stroke were nearly 5 times more likely (OR=4.81, 95% CI: 2.72, 8.53) to have dementia, and those with diabetes were 2.5 times (OR=2.55; 95% CI: 1.71-3.78) more likely to have dementia than those without these comorbities. Impairment in climbing stairs walking and sight was more common in the dementia group than the non-demented. Individuals with dementia were more likely to be unable to perform all seven instrumental activities of daily living (IADL) and were less active compared with their non-demented counterparts. Conclusion: In the middle old population in Trinidad having diabetes and stroke with varying levels of impairment as well as a sedentary lifestyle puts an individual at increased risk of dementia.

Socio-demographic and clinical determinants of dementia in the oldest old: National survey of ageing and cognition in Trinidad

Objective: To determine social and clinical factors associated with dementia in the oldest old (>85 years). Design and Methodology: A survey in a nationally representative sample of people aged 85 years and older using household enumeration was undertaken. Dementia status was ascertained using standardized interviews and algorithms from the 10/66 schedule. Information was also obtained on age, gender, level of education, ethnicity and previous occupation. Self-report on the presence of angina, heart disease, stroke, diabetes, high cholesterol, and hypertension was elicited and corroborated. Results: Of the participants 61.5% were females. The mean age was 89.0 years and dementia was present in 47.2 % persons. Dementia was significantly associated with age >95 (OR=2.02; 95%CI: 0.86- 4.69), female gender (OR=1.31; 95%CI: 0.85- 2.02), East Indian ethnicity (OR=1.45; 95%CI: 0.81-2.60), being widowed (OR=2.05; 95%CI: 0.59-7), Hindu religion (OR=2.10; 95%CI: 1.23- 3.58), history of working in the agricultural sector (OR=3.20; 95%CI: 1.59-6.48). Level of education (OR=0.14; 95%CI: 0.04-0.45), taking vitamins (OR=0.61; 95% CI: 0.37-0.97) and being of mixed ethnicity (African and East Indian) were protective factors. Of the self-reported disease conditions, those with greater than 3 medical co-morbidities were 2 times (OR=2.21; 95%CI: 0.48-9.94) more likely to have dementia than those with0-2 medical comorbidities. Dementia was not more likely to occur in diabetes (OR= 1.03; 95% CI: 0.65-1.64) and hypertension (OR= 0.67; 95% CI: 0.41-1.08). Conclusion: Our study, the first of its kind in Trinidad, supports more tailored policy and better planning of services for a rapidly expanding older population.