The association between sodium glucose cotransporter-2 inhibitors vs dipeptidyl peptidase-4 inhibitors and renal outcomes in people discharged from hospital with type 2 diabetes: A population-based cohort study.

BACKGROUND: We investigated the association between post-hospital discharge use of sodium glucose cotransporter-2 inhibitors (SGLT-2is) compared to dipeptidyl peptidase-4 inhibitors (DPP-4is) and the incidence of hospitalization for acute renal failure (ARF) and chronic kidney disease (CKD) in people with type 2 diabetes. METHODS: We conducted a retrospective cohort study using linked hospital and prescription data. Our cohort included people aged ≥30 years with type 2 diabetes discharged from a hospital in Victoria, Australia, from December 2013 to June 2018. We compared new users of SGLT-2is with new users of DPP-4is following discharge. People were followed from first dispensing of a SGLT-2i or DPP-4i to a subsequent hospital admission for ARF or CKD. We used competing risk models with inverse probability of treatment weighting (IPTW) to estimate subhazard ratios. RESULTS: In total, 9620 people initiated SGLT-2is and 9962 initiated DPP-4is. The incidence rate of ARF was 12.3 per 1000 person-years (median years of follow-up [interquartile range [IQR] 1.4 [0.7-2.2]) among SGLT-2i initiators and 18.9 per 1000 person-years (median years of follow-up [IQR] 1.7 [0.8-2.6]) among DPP-4i initiators (adjusted subhazard ratio with IPTW 0.78; 95% confidence interval [CI] 0.70-0.86). The incidence rate of CKD was 6.0 per 1000 person-years (median years of follow-up [IQR] 1.4 [0.7-2.2]) among SGLT-2i initiators and 8.9 per 1000 person-years (median years of follow-up [IQR] 1.7 [0.8-2.6]) among DPP-4i initiators (adjusted subhazard ratio with IPTW 0.83; 95% CI 0.73-0.94). CONCLUSIONS: Real-world data support using SGLT-2is over DPP-4is for preventing acute and chronic renal events in people with type 2 diabetes.

Sex as a risk factor regarding presbyopia in the rhesus monkey.

PURPOSE: To determine the effect of sex as a risk factor regarding presbyopia. METHODS: Maximum accommodation was pharmacologically induced (40% cabachol corneal iontophoresis) in 97 rhesus monkeys (49 males and 48 females) ranging in age from 8 to 36 years old. Accommodation was measured by Hartinger coincidence refractometry. RESULTS: Accommodative amplitude measured refractometrically decreased with age, and the rate of change was not different between males and females (p = 0.827). CONCLUSIONS: Presbyopia is essentially sex neutral, and no one is spared. There may be modest variations between different populations for various reasons, but essentially it is monotonously predictable. At present there is no biological therapeutic.

Disruption of the pro-oncogenic c-RAF-PDE8A complex represents a differentiated approach to treating KRAS-c-RAF dependent PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is considered the third leading cause of cancer mortality in the western world, offering advanced stage patients with few viable treatment options. Consequently, there remains an urgent unmet need to develop novel therapeutic strategies that can effectively inhibit pro-oncogenic molecular targets underpinning PDACs pathogenesis and progression. One such target is c-RAF, a downstream effector of RAS that is considered essential for the oncogenic growth and survival of mutant RAS-driven cancers (including KRASMT PDAC). Herein, we demonstrate how a novel cell-penetrating peptide disruptor (DRx-170) of the c-RAF-PDE8A protein-protein interaction (PPI) represents a differentiated approach to exploiting the c-RAF-cAMP/PKA signaling axes and treating KRAS-c-RAF dependent PDAC. Through disrupting the c-RAF-PDE8A protein complex, DRx-170 promotes the inactivation of c-RAF through an allosteric mechanism, dependent upon inactivating PKA phosphorylation. DRx-170 inhibits cell proliferation, adhesion and migration of a KRASMT PDAC cell line (PANC1), independent of ERK1/2 activity. Moreover, combining DRx-170 with afatinib significantly enhances PANC1 growth inhibition in both 2D and 3D cellular models. DRx-170 sensitivity appears to correlate with c-RAF dependency. This proof-of-concept study supports the development of DRx-170 as a novel and differentiated strategy for targeting c-RAF activity in KRAS-c-RAF dependent PDAC.

Results of Response-Guided Therapy with Pegylated Interferon Alpha 2a in Chronic Hepatitis B and D.

Pegylated interferon alpha 2a continues to be used for the treatment of chronic hepatitis D. The reported on-treatment virologic response varies between 17 and 47%, with relapses in more than 50% of these patients. No stopping rules have been defined, and the duration of the treatment is not clearly established, but it should be between 48 and 96 weeks. In total, 76 patients with compensated liver disease treated with peg-interferon according to the Romanian National protocol for the treatment of hepatitis D were retrospectively included. The duration of treatment was up to 96 weeks, with the following stopping rules: less than a 2 log HDV RNA decrease by week 24 and less than a 1 log decrease every 6 months afterwards. Six months after stopping the treatment, it can be restarted for unlimited cycles. The inclusion criteria were aged above 18, HBs Ag-positive, HDV RNA detectable, ALT above ULN and/or liver fibrosis at least F1 at liver biopsy, or Fibrotest and/or Fibroscan higher than 7 KPa and/or inflammation at least A1 at liver biopsy or Fibrotest. We monitored our patients for a total period of 4 years (including those that repeated the cycle). After the first 6 months of treatment, 27 patients (35.5%) had a greater than 2 log HDV RNA decrease, 19 of them achieving undetectable HDV RNA. Seventeen patients (22.3%) had undetectable HDV RNA 24 weeks after stopping 96 weeks of treatment, and none relapsed in the following 2 years. Of these 17 patients, 6 were cirrhotic, and 4 had F3. Undetectable HDV RNA at 24 weeks was the only parameter that predicted a long-term suppression of HDV RNA. In 49 patients, the treatment was stopped after 6 months according to protocol, but it was restarted 6 months later. Five of these patients finished a 48-week course of treatment; none achieved undetectable HDV RNA. During the first course of therapy, 45 patients had at least one moderate adverse reaction to treatment. In one patient, the treatment was stopped due to a serious adverse event (osteomyelitis). Treatment doses had to be reduced in 29 patients. The virologic response at week 24 can select the patients who will benefit from continuing the treatment from those who should be changed to another type of medication when available.

Macrophage memories of early-life injury drive neonatal nociceptive priming.

The developing peripheral nervous and immune systems are functionally distinct from those of adults. These systems are vulnerable to early-life injury, which influences outcomes related to nociception following subsequent injury later in life (i.e., "neonatal nociceptive priming"). The underpinnings of this phenomenon are unclear, although previous work indicates that macrophages are trained by inflammation and injury. Our findings show that macrophages are both necessary and partially sufficient to drive neonatal nociceptive priming, possibly due to a long-lasting remodeling in chromatin structure. The p75 neurotrophic factor receptor is an important effector in regulating neonatal nociceptive priming through modulation of the inflammatory profile of rodent and human macrophages. This "pain memory" is long lasting in females and can be transferred to a naive host to alter sex-specific pain-related behaviors. This study reveals a mechanism by which acute, neonatal post-surgical pain drives a peripheral immune-related predisposition to persistent pain following a subsequent injury.

Existing Psychiatric Diagnoses Among Breast Cancer Patients Interact with Outcomes After Autologous and Implant-Based Bilateral Breast Reconstruction: A Propensity Score Matched Analysis.

BACKGROUND: Breast reconstruction is an integral postoncologic procedure that has been associated with improved mental health and psychological outcomes. The possible interaction between existing psychiatric diagnoses hospital courses and postoperative complications warrants further exploration. METHODS: Bilateral breast reconstruction patients were identified from the 2016 to 2018 Healthcare Cost and Utilization Project-National Inpatient Sample (HCUP - NIS). Number and type of psychiatric diagnoses within the cohort were then evaluated using a host of ICD-10 codes. A propensity score analysis was applied to control for confounding variables such as demographics, existing comorbidities, and hospital characteristics. A binary logistic regression model was then used to identify the prediction value of psychiatric diagnosis and its interaction with modality of reconstruction for objective outcomes like length of hospital stay, treatment charge, and postoperative complications. RESULTS: A total of 10,114 patients were identified as the final cohort of breast reconstruction patients. 2621 (25.9%) patients possessed an average of 1.4 ± 0.6 existing psychiatric diagnoses. Presence of at least 1 psychiatric diagnosis was a strong predictor alone for extended length of stay (OR: 1.34, 95% CI: 1.28-1.41, P < .001) and occurrence of postoperative complications (OR: 1.31, 95% CI: 1.21-1.41, P < .001). Psychiatric diagnosis displayed a significant interaction with modality of breast reconstruction and conferred a lower increase in risk of extended length of stay in autologous reconstruction when compared to implant-based reconstruction (OR: 0.80, 95% CI: 0.72-0.89, P < .001). CONCLUSION: Existing psychiatric diagnoses were shown to strongly predict and modulate risk of adverse postoperative outcomes depending on modality of reconstruction.

Impact of Tricuspid Regurgitation on Outcomes After Transcatheter Mitral Valve Replacement.

Development of functional tricuspid regurgitation (TR) because of chronic mitral disease and subsequent heart failure is common. However, the effect of TR on clinical outcomes after transcatheter mitral valve replacement (TMVR) remains unclear. We aimed to evaluate the impact of baseline TR on outcomes after TMVR. This was a single-center, retrospective analysis of patients who received valve-in-valve or valve-in-ring TMVR between 2012 and 2022. Patients were categorized into none/mild TR and moderate/severe TR based on baseline echocardiography. The primary outcome was 3 years all-cause death and the secondary outcomes were in-hospital events. Of the 135 patients who underwent TMVR, 64 (47%) exhibited none/mild TR at baseline, whereas 71 (53%) demonstrated moderate/severe TR. There were no significant differences in in-hospital events between the groups. At 3 years, the moderate/severe TR group exhibited a significantly increased risk of all-cause death (adjusted hazard ratio 3.37, 95% confidence interval 1.35 to 8.41, p = 0.009). When patients with baseline moderate/severe TR were stratified by echocardiography at 30 days into improved (36%) and nonimproved (64%) TR groups, although limited by small sample size, there was no significant difference in 3-year all-cause mortality (p = 0.48). In conclusion, this study investigating the impact of baseline TR on clinical outcomes revealed that moderate/severe TR is prevalent in those who underwent TMVR and is an independent predictor of 3-year all-cause mortality. Earlier mitral valve intervention before the development of significant TR may play a pivotal role in improving outcomes after TMVR.

Clonal hematopoiesis in people with advanced HIV and associated inflammatory syndromes.

People with HIV (PWH) have a higher age-adjusted mortality due to chronic immune activation and age-related comorbidities. PWH also have higher rates of clonal hematopoiesis (CH) than age-matched non-HIV cohorts, however, risk factors influencing the development and expansion of CH in PWH remain incompletely explored. We investigated the relationship between CH, immune biomarkers, and HIV-associated risk factors (CD4, CD8 T-cells, nadir CD4 count, opportunistic infections [OIs], and immune reconstitution inflammatory syndrome [IRIS]) in a diverse cohort of 197-PWH with median age of 42-years, using a 56-gene panel. Seventy-nine percent had a CD4 nadir < 200, 58.9% had prior OIs, and 34.5% had a history of IRIS. The prevalence of CH was high (27.4%), even in younger individuals, and CD8 T-cells and nadir CD4 counts strongly associated with CH after controlling for age. A history of IRIS was associated with CH in a subgroup analysis of ≥ 35-years-old patients. Inflammatory biomarkers were higher in CH carriers compared to non-carriers supporting a dysregulated immune state. These findings suggest PWH with low nadir CD4 and/or inflammatory complications may be at high risk of CH regardless of age and represent a high-risk group that could benefit from risk reduction and potentially targeted immunomodulation.

Factors Associated With Episode of Care Adverse Events After Humerus Nonunion Repair.

BACKGROUND: Humeral nonunions have devastating negative effects on patients' upper extremity function and health-related quality of life. The objective of this study was to identify factors independently associated with 30-day complication, hospital readmission, and reoperation after surgical treatment of humeral nonunions. MATERIALS AND METHODS: A retrospective case-control study was performed using the American College of Surgeons National Surgical Quality Improvement Program database by querying the Current Procedural Terminology codes for patients who underwent humeral nonunion repair from 2011 to 2020. The study outcomes were 30-day complication, hospital readmission, and reoperation. RESULTS: Of the 1306 patients in our cohort, 135 patients (10%) developed a complication, 66 patients (5%) were readmitted to the hospital, and 44 patients (3%) underwent reoperation during the 30-day postoperative period. Multivariable logistic regression analysis showed that older age, longer operative time, partially dependent functional status, congestive heart failure, bleeding disorder, and contaminated wound classification were associated with 30-day complication after humeral nonunion repair. Older age and disseminated cancer were associated with 30-day reoperation after humeral nonunion repair. Disseminated cancer was associated with 30-day readmission after humeral nonunion repair. CONCLUSION: Using a large database over a recent 10-year period, we identified demographic and comorbid factors independently associated with episode of care adverse events after humeral nonunion repair. Patients 50 years or older had approximately three times the incidence of complications, readmissions, and reoperations in the first month after humeral nonunion repair compared with patients younger than 50 years. Our findings are relevant for preoperative risk stratification and counseling. [Orthopedics. 202x;4x(x):xx-xx.].

Non-endothelial expression of Endomucin in the mouse and human choroid.

Endomucin (EMCN) is a 261 AA transmembrane glycoprotein that is highly expressed by venous and capillary endothelial cells where it plays a role in VEGF-mediated angiogenesis and regulation of immune cell recruitment. However, it is better known as a histological marker, where it has become widespread due to the commercial availability of high-quality antibodies that work under a wide range of conditions and in many tissues. The specificity of EMCN staining has been well-validated in retinal vessels, but while it has been used extensively as a marker in other tissues of the eye, including the choroid, the pattern of expression has not been described in detail. Here, in addition to endothelial expression in the choriocapillaris and deeper vascular layers, we characterize a population of EMCN-positive perivascular cells in the mouse choroid that did not co-localize with cells expressing other endothelial markers such as PECAM1 or PODXL. To confirm that these cells represented a new population of EMCN-expressing stromal cells, we then performed single cell RNA sequencing in choroids from adult wild-type mice. Analysis of this new dataset confirmed that, in addition to endothelial cells, Emcn mRNA expression was present in choroidal pericytes and a subset of fibroblasts, but not vascular smooth muscle cells. Besides Emcn , no known endothelial gene expression was detected in these cell populations, confirming that they did not represent endothelial-stromal doublets, a common technical artifact in single cell RNA seq datasets. Instead, choroidal Emcn -expressing fibroblasts exhibited high levels of chemokine and interferon signaling genes, while Emcn -negative fibroblasts were enriched in genes encoding extracellular matrix proteins. Emcn expressing fibroblasts were also detected in published datasets from mouse brain and human choroid, suggesting that stromal Emcn expression was not unique to the choroid and was evolutionarily conserved. Together, these findings highlight unique fibroblast and pericyte populations in the choroid and provide new context for the role of EMCN in angiogenesis and immune cell recruitment.

Morphometric Analysis of the Thymic Epithelial Cell (TEC) Network Using Integrated and Orthogonal Digital Pathology Approaches.

The thymus, a central primary lymphoid organ of the immune system, plays a key role in T cell development. Surprisingly, the thymus is quite neglected with regards to standardized pathology approaches and practices for assessing structure and function. Most studies use multispectral flow cytometry to define the dynamic composition of the thymus at the cell population level, but they are limited by lack of contextual insight. This knowledge gap hinders our understanding of various thymic conditions and pathologies, particularly how they affect thymic architecture, and subsequently, immune competence. Here, we introduce a digital pathology pipeline to address these challenges. Our approach can be coupled to analytical algorithms and utilizes rationalized morphometric assessments of thymic tissue, ranging from tissue-wide down to microanatomical and ultrastructural levels. This pipeline enables the quantitative assessment of putative changes and adaptations of thymic structure to stimuli, offering valuable insights into the pathophysiology of thymic disorders. This versatile pipeline can be applied to a wide range of conditions that may directly or indirectly affect thymic structure, ranging from various cytotoxic stimuli inducing acute thymic involution to autoimmune diseases, such as myasthenia gravis. Here, we demonstrate applicability of the method in a mouse model of age-dependent thymic involution, both by confirming established knowledge, and by providing novel insights on intrathymic remodeling in the aged thymus. Our orthogonal pipeline, with its high versatility and depth of analysis, promises to be a valuable and practical toolset for both basic and translational immunology laboratories investigating thymic function and disease.

The Relationship Between Preoperative International Normalized Ratio and Postoperative Major Bleeding in Total Shoulder Arthroplasty.

INTRODUCTION: This study aimed to assess the relationship between preoperative international normalized ratio (INR) levels and major postoperative bleeding events after total shoulder arthroplasty (TSA). METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried for TSA from 2011 to 2020. A final cohort of 2405 patients with INR within 2 days of surgery were included. Patients were stratified into four groups: INR ≤ 1.0, 1.0 < INR ≤ 1.25, 1.25< INR ≤ 1.5, and INR > 1.5. The primary outcome was bleeding requiring transfusion within 72 hours, and secondary outcome variables included complication, revision surgery, readmission, and hospital stay duration. Multivariable logistic and linear regression analyses adjusted for relevant comorbidities were done. RESULTS: Of the 2,405 patients, 48% had INR ≤ 1.0, 44% had INR > 1.0 to 1.25, 7% had INR > 1.25 to 1.5, and 1% had INR > 1.5. In the adjusted model, 1.0 < INR ≤ 1.25 (OR 1.7, 95% CI 1.176 to 2.459), 1.25 < INR ≤ 1.5 (OR 2.508, 95% CI 1.454 to 4.325), and INR > 1.5 (OR 3.200, 95% CI 1.233 to 8.302) were associated with higher risks of bleeding compared with INR ≤ 1.0. DISCUSSION: The risks of thromboembolism and bleeding lie along a continuum, with higher preoperative INR levels conferring higher postoperative bleeding risks after TSA. Clinicians should use a patient-centered, multidisciplinary approach to balance competing risks.

HIV risk behaviour, viraemia, and transmission across HIV cascade stages including low-level viremia: Analysis of 14 cross-sectional population-based HIV Impact Assessment surveys in sub-Saharan Africa.

As antiretroviral treatment (ART) coverage for people living with HIV (PLHIV) increases, HIV programmes require up-to-date information about evolving HIV risk behaviour and transmission risk, including those with low-level viremia (LLV; >50 to ≤1000 copies/mL), to guide prevention priorities. We aimed to assess differences in sexual risk behaviours, distribution of viral load (VL) and proportion of transmission across PLHIV subgroups. We analysed data from Population-based HIV Impact Assessment surveys in 14 sub-Saharan African countries during 2015-2019. We estimated adjusted prevalence ratios (aPR) of self-reported HIV high-risk behaviour (multiple partners and condomless sex) across cascade stages via generalised estimation equations. We modelled the proportions of transmission from each subgroup using relative self-reported sexual risk, a Hill function for transmission rate by VL, and proportions within cascade stages from surveys and UNAIDS country estimates for 2010-2020. Compared to PLHIV with undetectable VL (≤50 copies/mL), undiagnosed PLHIV (aPR women: 1.28 [95% CI: 1.08-1.52]; men: 1.61 [1.33-1.95]) and men diagnosed but untreated (2.06 [1.52-2.78]) were more likely to self-report high-risk sex. High-risk behaviour was not significantly associated with LLV. Mean VL was similar among undiagnosed, diagnosed but untreated, and on ART but non-suppressed sub-groups. Across surveys, undiagnosed and diagnosed but untreated contributed most to transmission (40-91% and 1-41%, respectively), with less than 1% from those with LLV. Between 2010 and 2020, the proportion of transmission from individuals on ART but non-suppressed increased. In settings with high ART coverage, effective HIV testing, ART linkage, and retention remain priorities to reduce HIV transmission. Persons with LLV are an increasing share of PLHIV but their contribution to HIV transmission was small. Improving suppression among PLHIV on ART with VL ≥1000 copies/mL will become increasingly important.

The Significance of Subjective Mechanical Symptoms in Rotator Cuff Pathology.

BACKGROUND: The presence of subjective mechanical symptoms, such as clicking or popping, is common in patients presenting for shoulder pain and dysfunction, with unclear clinical significance. The primary objective of this study was to assess whether subjective mechanical symptoms in the affected shoulder were associated with full-thickness rotator cuff tearing in a consecutive, prospective cohort of patients undergoing shoulder magnetic resonance imaging (MRI) for suspected rotator cuff pathology. METHODS: A prospective cohort study was performed of 100 consecutive patients with suspected rotator cuff tendinopathy and/or tearing who underwent shoulder MRI. The presence of subjective shoulder mechanical symptoms, including clicking or popping, was documented prior to MRI. Indications for MRI included weakness on isolated testing of rotator cuff muscle(s) or symptoms refractory to conservative treatment including at least a 6-week course of physical therapy. The primary outcome variable was the presence of full-thickness rotator cuff tearing; secondary outcome variables included any (full-thickness or partial-thickness) rotator cuff tearing and biceps long head subluxation. Radiographic parameters, including critical shoulder angle, Goutallier grade, tear retraction, and tear size were quantified. One patient was lost to follow-up, and 99 patients completed MRI imaging. RESULTS: In our cohort, 60% of patients reported subjective mechanical symptoms in the affected shoulder. Full-thickness rotator cuff tearing was identified in 42% of patients, any rotator cuff tearing in 69% of patients, and biceps long head subluxation in 14% of patients. Subjective mechanical symptoms were not associated with full-thickness rotator cuff tearing, any rotator cuff tearing, biceps long head subluxation, critical shoulder angle, Goutallier grade, tear size, or tear retraction. Older age was associated with full-thickness and any rotator cuff tearing. As a diagnostic test for full-thickness rotator cuff tearing, subjective shoulder mechanical symptoms has a sensitivity of 64%, a specificity of 44%, and Youden's index of 0.08, consistent with poor diagnostic accuracy. CONCLUSIONS: Subjective mechanical symptoms in the affected shoulder are a common complaint in patients with suspected rotator cuff pathology. Patients may be reassured that a sensation of clicking or popping alone does not necessarily entail structural shoulder derangement.

Assessment and management of exaggerated blood pressure response to standing and orthostatic hypertension: consensus statement by the European Society of Hypertension Working Group on Blood Pressure Monitoring and Cardiovascular Variability.

Recent evidence suggests that an exaggerated blood pressure (BP) response to standing (ERTS) is associated with an increased risk of adverse outcomes, both in young and old individuals. In addition, ERTS has been shown to be an independent predictor of masked hypertension. In the vast majority of studies reporting on the prognostic value of orthostatic hypertension (OHT), the definition was based only on systolic office BP measurements. This consensus statement provides recommendations on the assessment and management of individuals with ERTS and/or OHT. ERTS is defined as an orthostatic increase in SBP at least 20 mmHg and OHT as an ERTS with standing SBP at least 140 mmHg. This statement recommends a standardized methodology to assess ERTS, by considering body and arm position, and the number and timing of BP measurements. ERTS/OHT should be confirmed in a second visit, to account for its limited reproducibility. The second assessment should evaluate BP changes from the supine to the standing posture. Ambulatory BP monitoring is recommended in most individuals with ERTS/OHT, especially if they have high-normal seated office BP. Implementation of lifestyle changes and close follow-up are recommended in individuals with ERTS/OHT. Whether specific antihypertensive treatment should be administered in hypertensive patients with ERTS/OHT is unknown. Thus, they should be managed as any other hypertensive patient. Standardized standing BP measurement should be implemented in future epidemiological and interventional studies.

Experience of X-linked hypophosphatemic rickets in the Gulf Cooperation Council countries: case series.

Summary: X-linked hypophosphatemic rickets (XLH), the most prevalent form of inherited hypophosphatemic rickets, is caused by loss-of-function mutations in the gene encoding phosphate-regulating endopeptidase homolog, X-linked (PHEX). This case series presents 14 cases of XLH from Gulf Cooperation Council (GCC) countries. The patients' medical history, biochemical and radiological investigative findings, as well as treatment responses and side effects from both conventional and burosumab therapy, are described. Cases were aged 2-40 years at diagnosis. There were two male cases and 12 female cases. All cases were treated with conventional therapy which resulted in a lack of improvement in or worsening of the clinical signs and symptoms of rickets or biochemical parameters. Side effects of conventional therapy included nausea, diarrhea, abdominal pain, nephrocalcinosis, and hyperparathyroidism, which affected the patients' quality of life and adherence to treatment. In the 10 patients treated with burosumab, there was a marked improvement in the biochemical markers of rickets, with a mean increase in serum phosphate of +0.56 mmol/L and tubular maximum phosphate reabsorption (TmP) to glomerular filtration rate (GFR) ratio (TmP/GFR) of +0.39 mmol/L at 12 months compared to baseline. Furthermore, a mean decrease in serum alkaline phosphatase (ALP) of -80.80 IU/L and parathyroid hormone (PTH) of -63.61 pmol/L at 12 months compared to baseline was observed in these patients. Additionally, patients treated with burosumab reported reduced pain, muscle weakness, and fatigue as well as the ability to lead more physically active lives with no significant side effects of treatment. Learning points: Conventional therapy resulted in a suboptimal response, with a lack of improvement of clinical signs and symptoms. Side effects of conventional therapy included nausea, diarrhea, abdominal pain, nephrocalcinosis, and hyperparathyroidism, which affected the patients' quality of life and adherence to treatment. Burosumab demonstrated marked improvements in the biochemical markers of rickets, in addition to reducing pain, muscle weakness, and fatigue. There were no significant side effects associated with burosumab therapy.

Characteristics and validation of pediatric extremity vascular trauma in dedicated pediatric and adult trauma centers: A scoping review protocol.

OBJECTIVES: Pediatric extremity vascular injuries constitute a rare yet serious entity that can lead to serious complications especially if left untreated or become late diagnosed. In our scoping review, we sought to evaluate different characteristics and outcomes of pediatric and combined adult trauma centers in the management of pediatric extremity vascular injury. METHODS: We sought to analyze various characteristics and parameters that differentiate a dedicated pediatric and a combined pediatric adult trauma center in terms of effectiveness and quality of care in the acute setting and to describe special features and characteristics of an acute vascular disease that constitute pediatric population unique from the aspect of diagnosis and management. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping reviews guidelines to conduct the study. RESULTS: The search identified 8815 records in title using MeSH terms from PubMed/MEDLINE database among which twelve studies reporting a total of 2124 pediatric patients with vascular extremity injuries were included for analysis. Incidence of pediatric extremity vascular injury was 0.5%. Upper extremity injuries were the most frequent presenting in 63% of cases followed by lower extremity injuries in 37% of cases. Blunt injuries were marginally more common than penetrating injuries (58% versus 42%). In-hospital mortality and morbidity ranged from 13.2% to 0.9% and 13% to 30% respectively. Limb-salvage rates were high, ranging from 92% to 99%. Furthermore, there are no clearly defined clinical guidelines involving the mode of imaging and diagnosis, the surgical specialties involved and the competency of nursing or medical staff overall. CONCLUSIONS: Dedicated children trauma centers theoretically represent the optimal path for acute pediatric trauma admission, especially in complex trauma necessitating vascular reconstruction. However, in the current setting of rapidly increasing health costs and economic crisis worldwide, regional or resource-related factors make this option rather unavailable. In any case, it is imperative the clinicians have a high index of suspicion when confronting with these types of injuries because early diagnosis is highly related with reduced morbidity and superior outcomes.

Is the robotic revolution stunting surgical skills?

This perspective piece aims to examine the impact of the growing utilization of robotic platforms in general and minimally invasive surgery on surgical trainee experience, skill level, and comfort in performing general surgical and minimally invasive procedures following completion of training. We review current literature and explore the application of robotic surgery to surgical training, where minimum case thresholds and breadth distribution are well defined, and where development of surgical technique is historically gained through delicate tissue handling with haptic feedback rather than relying on visual feedback alone. We call for careful consideration as to how best to incorporate robotics in surgical training in order to embrace technological advances without endangering the surgical proficiency of the surgeons of tomorrow. Key message: The large-scale incorporation of robotics into general and minimally invasive surgical training is something that most, if not all, trainees must grapple with in today's world, and the proportion of robotics is increasing. This shift may significantly negatively affect trainees in terms of surgical skill upon completion of training and must be approached with an appropriate degree of concern and thoughtfulness so as to protect the surgeons of tomorrow.

Atrial Fibrillation Screening During Routine Automated Office, Home, and Ambulatory Blood Pressure Measurement: A Diagnostic Test Accuracy Systematic Review and Meta-Analysis.

BACKGROUND: Atrial fibrillation (AF) is often asymptomatic and undiagnosed. As AF and hypertension often coexist, opportunistic AF detection during routine automated blood pressure (BP) measurement appears to be an attractive screening method. METHODS: A systematic literature search was conducted to identify studies assessing the diagnostic test accuracy of office, home, or 24-hour ambulatory BP measuring devices with AF detection algorithms versus reference electrocardiography. Analyses were performed per participant (AF status based on several BP readings; most office/home devices) or per reading (AF status based on individual readings; all ambulatory devices). A meta-analysis stratified by device type (office/home/ambulatory) was conducted to calculate pooled measures of diagnostic accuracy. Sensitivity/meta-regression analyses were also performed. RESULTS: Among 3096 records initially retrieved, 23 diagnostic test accuracy studies were included. Data derived from 11 093 individuals (weighted age 69 years, males 56%, hypertensives 79%, diabetics 24%, and AF prevalence 17%) indicated a pooled sensitivity 0.97 (95% CI, 0.92-0.99), specificity 0.93 (95% CI, 0.90-0.95), and accuracy 0.93 (95% CI, 0.89-0.95), with generally consistent results using office, home, or ambulatory BP devices (slightly lower specificity with the latter). The positive and negative predictive values were 0.70 (95% CI, 0.60-0.80) and 0.99 (95% CI, 0.98-1.00), respectively. Sensitivity analyses indicated lower specificity in studies implementing reading versus participant analyses. Most studies presented a low risk of bias and minor applicability concerns. CONCLUSIONS: There is considerable and consistent evidence suggesting high diagnostic accuracy of AF detection algorithms implemented in automated BP monitors during routine BP measurements in and out of the office. AF diagnosis requires verification (electrocardiography) before treatment is administered.

Nivolumab plus cabozantinib versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended follow-up from the phase III randomised CheckMate 9ER trial.

BACKGROUND: Nivolumab plus cabozantinib (NIVO + CABO) was approved for first-line treatment of advanced renal cell carcinoma (aRCC) based on superiority versus sunitinib (SUN) in the phase III CheckMate 9ER trial (18.1 months median survival follow-up per database lock date); efficacy benefit was maintained with an extended 32.9 months of median survival follow-up. We report updated efficacy and safety after 44.0 months of median survival follow-up in intent-to-treat (ITT) patients and additional subgroup analyses, including outcomes by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk score. PATIENTS AND METHODS: Patients with treatment-naïve aRCC received NIVO 240 mg every 2 weeks plus CABO 40 mg once daily or SUN 50 mg for 4 weeks (6-week cycles), until disease progression/unacceptable toxicity (maximum NIVO treatment, 2 years). Primary endpoint was progression-free survival (PFS) per blinded independent central review (BICR). Secondary endpoints were overall survival (OS), objective response rate (ORR) per BICR, and safety and tolerability. RESULTS: Overall, 323 patients were randomised to NIVO + CABO and 328 to SUN. Median PFS was improved with NIVO + CABO versus SUN [16.6 versus 8.4 months; hazard ratio (HR) 0.59; 95% confidence interval (CI) 0.49-0.71]; median OS favoured NIVO + CABO versus SUN (49.5 versus 35.5 months; HR 0.70; 95% CI 0.56-0.87). ORR (95% CI) was higher with NIVO + CABO versus SUN [56% (50% to 62%) versus 28% (23% to 33%)]; 13% versus 5% of patients achieved complete response, and median duration of response was 22.1 months versus 16.1 months, respectively. PFS and OS favoured NIVO + CABO over SUN across intermediate, poor and intermediate/poor IMDC risk subgroups; higher ORR and complete response rates were seen with NIVO + CABO versus SUN regardless of IMDC risk subgroup. Any-grade (grade ≥3) treatment-related adverse events occurred in 97% (67%) versus 93% (55%) of patients treated with NIVO + CABO versus SUN. CONCLUSIONS: After extended follow-up, NIVO + CABO maintained survival and response benefits; safety remained consistent with previous follow-ups. These results continue to support NIVO + CABO as a first-line treatment for aRCC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03141177.