Biosimilars and access to biologic therapy in immune-mediated diseases.

BACKGROUND: The rise of biologic agents has been a major breakthrough in treating immune-mediated inflammatory diseases (IMIDs). However, their high cost underscores the need for strategies to optimize treatment efficiency. Biosimilars offer cost-effective alternatives to biologics. This study aimed to assess biosimilar drug availability's impact on biologic therapy access for IMIDs. RESEARCH DESIGN AND METHODS: A retrospective observational study in 15 Spanish hospitals analyzed IMID patients (arthropathies, inflammatory bowel disease and psoriasis) initiating biologic therapy with originator or biosimilar drugs (infliximab, etanercept, adalimumab). Time to availability and initiation of biologic therapy were assessed. RESULTS: 267 patients were included, with 58.4% starting on biosimilars. The mean time to availability of the biologic drugs in the hospitals was 15.9 ± 6.7 months, (20.0 ± 12.4 for originator and 11.8 ± 5.2 for biosimilars). Mean time to biologic treatment was 7.7 ± 9.0 years (8.6 ± 8.9 for originators and 7.0 ± 9.0 for biosimilars). Showing statistically significant differences among conditions. CONCLUSION: The emergence of biosimilar drugs has enhanced market competition and accelerated their adoption into hospitals' therapeutic regimens over original reference drugs. This has significantly improved access to biologic therapy for patients with IMIDs, evidenced by a notable 1.6-year reduction in access time for biosimilar drugs.

[Translated article] Real-world persistence with dolutegravir/lamivudine versus bictegravir/emtricitabine/tenofovir-alafenamide among persons with HIV.

OBJETIVES: The main objective was to compare the persistence between dolutegravir/lamivudine (DTG/3TC) and bictegravir/emtricitabine/tenofovir-alafenamide (BIC/FTC/TAF) and to analyze reasons for discontinuation. METHODS: We conducted a retrospective, non-interventional, descriptive, and longitudinal study. All human immunodeficiency virus (HIV) patients over 18 years treated with DTG/3TC or BIC/FTC/TAF in our center were included. Persistence after first year was compared using the χ2 test. Kaplan-Meier survival analysis was performed. RESULTS: Three hundred fifty-eight patients were included. 99.5% versus 90.99% of patients were persistent after the first year for DTG/3TC and BIC/FTC/TAF respectively (p=.001). Persistence with DGT/3TC was 1237 days (IC95% 1216-1258) and persistence with BIC/FTC/TAF was 986 days [(IC95% 950-1021); p<.001]. The difference was remained after adjusting for covariates with the cox regression model [HR=8.2 (IC95% 1.03-64.9), p=.047]. The main reasons for discontinuation for BIC/FTC/TAF were toxicity/tolerability. CONCLUSION: In our study, patients have a high persistence. Patients on DTG/3TC treatment are more persistent compared to BIC/FTC/TAF, although BIC/FTC/TAF have worse baseline characteristics. The main reason for discontinuation of BIC/FTC/TAF is tolerability/toxicity.

Healthcare service use for children with chronic complex diseases: A longitudinal six-year follow-up study.

PURPOSE: The objective was analysed the patterns use of healthcare services of this population and the influence of their clinical and sociodemographic characteristics. DESIGN AND METHODS: A six-year longitudinal follow-up study was performed to evaluate the annual healthcare resources use and clinical data among children with complex chronic diseases in Spain between 2015 and 2021. The sample trends in healthcare usage and the associated factors were analysed using ANCOVA and multivariable linear regression models. RESULTS: Patients had high attendance during the follow-up period, with >15 episodes year. This trend decreased over time, especially in children with oncological diseases compared with other diseases (F (16.75; 825.4) = 32.457; p < 0.001). A multivariable model showed that children with a greater number of comorbidities (ß = 0.17), shorter survival time (ß = -0.23), who had contact with the palliative care unit (ß = 0.16), and whose mothers had a higher professional occupation (ß = 0.14), had a greater use of the healthcare system. CONCLUSIONS: Children with a higher number of comorbidities and the use of medical devices made a greater frequentation of health services, showing a trend of decreasing use over time. Socioeconomic factors such as mothers' occupational status determine healthcare frequentation. These results suggest the existence of persistent gaps in care coordination sustained over time. PRACTICAL IMPLICATIONS: Systematized and coordinated models of care for this population should consider the presence of inequalities in health care use.

The impact of Aprepitant on Nausea and Vomiting following Laparoscopic Sleeve Gastrectomy: A Blinded Randomized Controlled Trial.

INTRODUCTION: Laparoscopic sleeve gastrectomy (LSG) is associated with postoperative nausea and vomiting (PONV). We aimed to compare the effects of aprepitant on the incidence of PONV after LSG. METHODS: In this double-blind, randomized controlled trial, the case group received the standard care regimen for PONV (dexamethasone 10 mg, ondansetron 4 mg, and metoclopramide 10 mg) plus prophylactic oral aprepitant 80 mg 1 h preoperatively. The control group received standard care plus a placebo. Comparative analyses using the Rhodes index were performed at 0, 6, 12, and 24 h postoperatively. RESULTS: A total of 400 patients (201 in the aprepitant group and 199 in the placebo group) underwent LSG. The groups were homogeneous. The aprepitant group experienced less PONV: early, 69 (34.3%) vs. 103 (51.7%), p ≤ 0.001; 6 h, 67 (33.3%) vs. 131 (65.8%), p ≤ 0.001; 12 h, 41 (20.4%) vs. 115 (57.8%), p ≤ 0.001; and 24 h, 22 (10.9%) vs. 67 (33.7%), p ≤ 0.001. Fewer patients in the aprepitant group vomited: early, 3 (1.5%) vs. 5 (2.5%), p = 0.020; 6 h, 6 (3%) vs. 18 (9%), p = 0.020; 12 h, 2 (1%) vs. 17 (8.5%), p = 0.006; and 24 h, 1 (0.5%) vs. 6 (3%), p = 0.040. Patients in the aprepitant group required less additional PONV medication: early, 61 (30.3%) vs. 86 (43.2), p = 0.008; 6 h, 7 (3.5%) vs. 34 (17%), p = 0.001; 12 h, 6 (3%) vs. 31 (15.6%), p ≤ 0.001; and 24 h, 5 (2.5%) vs. 11 (5.5%), p ≤ 0.001. CONCLUSIONS: Prophylactic aprepitant improved PONV between 0 h (early) and 24 h postoperatively in patients undergoing LSG.

Neuropathy of the suprascapular and axillary nerves in rotator cuff arthropathy: a prospective electrodiagnostic study.

PURPOSE: Prevalence of axillary (AN) and/or suprascapular (SSN) neuropathy in rotator cuff tear arthropathy (RCTA) is unknown. We aimed to prospectively evaluate for preoperative neurodiagnostic abnormalities in order to determine their prevalence, location, and influence on reverse shoulder arthroplasty (RSA) outcomes. METHODS: Patients who underwent RSA for RCTA were prospectively included. An electromyography and nerve conduction study were performed pre and post-surgery. Clinical situation: VAS, Relative Constant-Murley Score (rCMS) and ROM over a minimum of two years follow-up. RESULTS: Forty patients met the inclusion criteria; mean follow-up was 28.4 months (SD 4.4). Injuries in RCTA were present in 83.9% (77.4% in AN and 45.2% in SSN). There were no differences on preoperative VAS, ROM, and rCMS between patients with and without preoperative nerve injuries. Four acute postoperative neurological injuries were registered under chronic preoperative injuries. Six months after RSA, 69% of preoperative neuropathies had improved (82.14% chronic injuries and 77.7% disuse injuries). No differences in improvement between disuse and chronic injuries were found, but patients with preoperative neuropathy that had not improved at the postoperative electromyographic study at six months, scored worse on the VAS (1.44 vs 2.66; p .14) and rCMS (91.6 vs 89.04; p .27). CONCLUSIONS: The frequency of axillary and suprascapular neuropathies in RCTA is much higher than expected. Most of these injuries improve after surgery, with almost complete neurophysiological recovery and little functional impact on RSA. However, those patients with preoperative neuropathies and absence of neurophysiological improvement six months after surgery have lower functional results.

Physical and respiratory therapy in the critically ill patient with obesity: a narrative review.

Obesity has become increasingly prevalent in the intensive care unit, presenting a significant challenge for healthcare systems and professionals, including rehabilitation teams. Caring for critically ill patients with obesity involves addressing complex issues. Despite the well-established and safe practice of early mobilization during critical illness, in rehabilitation matters, the diverse clinical disturbances and scenarios within the obese patient population necessitate a comprehensive understanding. This includes recognizing the importance of metabolic support, both non-invasive and invasive ventilatory support, and their weaning processes as essential prerequisites. Physiotherapists, working collaboratively with a multidisciplinary team, play a crucial role in ensuring proper assessment and functional rehabilitation in the critical care setting. This review aims to provide critical insights into the key management and rehabilitation principles for obese patients in the intensive care unit.

Real-world persistence with dolutegravir/lamivudine versus bictegravir/emtricitabina/tenofovir-alafenamide among people with HIV. / Persistencia de los tratamientos con dolutegravir/lamivudina y bictegravir/emtricitabina/tenofovir-alafenamida en personas con VIH en la práctica real.

OBJETIVES: The main objective was to compare the persistence between dolutegravir/lamivudine (DTG/3TC) and bictegravir/emtricitabine/tenofovir-alafenamide (BIC/FTC/TAF) and to analyze reasons for discontinuation. METHODS: We conducted a retrospective, non-interventional, descriptive and longitudinal study. All human immunodeficiency virus (HIV) patients over 18 years treated with DTG/3TC or BIC/FTC/TAF in our center were included. Persistence after first year was compared using the χ2 test. Kaplan-Meier survival analysis was performed. RESULTS: Three hundred fifty-eight patients were included. 99.5% versus 90.99% of patients were persistent after the first year for DTG/3TC and BIC/FTC/TAF respectively (p = 0.001). Persistence with DGT/3TC was 1,237 days (IC95% 1,216-1,258) and persistence with BIC/FTC/TAF was 986 days ([IC95% 950-1,021]; p < 0.001). The difference was remained after adjusting for covariates with the cox regression model (HR= 8.2 [IC95% 1.03-64.9], p = 0.047). The main reasons for discontinuation for BIC/FTC/TAF were toxicity/tolerability. CONCLUSION: In our study patients had a high persistence. Patients on DTG/3TC treatment were more persistent compared to BIC/FTC/TAF, although BIC/FTC/TAF have worse baseline characteristics. The main reason for discontinuation of BIC/FTC/TAF was tolerability/toxicity.

Prolonged intensive care: muscular functional, and nutritional insights from the COVID-19 pandemic.

During the coronavirus disease 2019 (COVID-19) pandemic, clinical staff learned how to manage patients enduring extended stays in an intensive care unit (ICU). COVID-19 patients requiring critical care in an ICU face a high risk of experiencing prolonged intensive care (PIC). The use of invasive mechanical ventilation in individuals with severe acute respiratory distress syndrome can cause numerous complications that influence both short-term and long-term morbidity and mortality. Those risks underscore the importance of proactively addressing functional complications. Mitigating secondary complications unrelated to the primary pathology of admission is imperative in minimizing the risk of PIC. Therefore, incorporating strategies to do that into daily ICU practice for both COVID-19 patients and those critically ill from other conditions is significantly important.

Stratification of Colorectal Patients Based on Survival Analysis Shows the Value of Consensus Molecular Subtypes and Reveals the CBLL1 Gene as a Biomarker of CMS2 Tumours.

The consensus molecular subtypes (CMSs) classification of colorectal cancer (CRC) is a system for patient stratification that can be potentially applied to therapeutic decisions. Hakai (CBLL1) is an E3 ubiquitin-ligase that induces the ubiquitination and degradation of E-cadherin, inducing epithelial-to-mesenchymal transition (EMT), tumour progression and metastasis. Using bioinformatic methods, we have analysed CBLL1 expression on a large integrated cohort of primary tumour samples from CRC patients. The cohort included survival data and was divided into consensus molecular subtypes. Colon cancer tumourspheres were used to analyse the expression of stem cancer cells markers via RT-PCR and Western blotting. We show that CBLL1 gene expression is specifically associated with canonical subtype CMS2. WNT target genes LGR5 and c-MYC show a similar association with CMS2 as CBLL1. These mRNA levels are highly upregulated in cancer tumourspheres, while CBLL1 silencing shows a clear reduction in tumoursphere size and in stem cell biomarkers. Importantly, CMS2 patients with high CBLL1 expression displayed worse overall survival (OS), which is similar to that associated with CMS4 tumours. Our findings reveal CBLL1 as a specific biomarker for CMS2 and the potential of using CMS2 with high CBLL1 expression to stratify patients with poor OS.

p38γ MAPK delays myelination and remyelination and is abundant in multiple sclerosis lesions.

Multiple sclerosis is a chronic inflammatory disease in which disability results from the disruption of myelin and axons. During the initial stages of the disease, injured myelin is replaced by mature myelinating oligodendrocytes that differentiate from oligodendrocyte precursor cells. However, myelin repair fails in secondary and chronic progressive stages of the disease and with ageing, as the environment becomes progressively more hostile. This may be attributable to inhibitory molecules in the multiple sclerosis environment including activation of the p38MAPK family of kinases. We explored oligodendrocyte precursor cell differentiation and myelin repair using animals with conditional ablation of p38MAPKγ from oligodendrocyte precursors. We found that p38γMAPK ablation accelerated oligodendrocyte precursor cell differentiation and myelination. This resulted in an increase in both the total number of oligodendrocytes and the migration of progenitors ex vivo and faster remyelination in the cuprizone model of demyelination/remyelination. Consistent with its role as an inhibitor of myelination, p38γMAPK was significantly downregulated as oligodendrocyte precursor cells matured into oligodendrocytes. Notably, p38γMAPK was enriched in multiple sclerosis lesions from patients. Oligodendrocyte progenitors expressed high levels of p38γMAPK in areas of failed remyelination but did not express detectable levels of p38γMAPK in areas where remyelination was apparent. Our data suggest that p38γ could be targeted to improve myelin repair in multiple sclerosis.

Neumoencéfalo como complicación de bloqueo regional epidural por radiculopatía lumbosacra / Pneumocephalus as a Complication of Regional Epidural Block Due to Lumbosacral Radiculopathy

Introducción: El neumoencéfalo (sinonimia: aerocele o neumatocele intracerebral), se define como la presencia de gas dentro de cualquiera de los compartimentos intracraneales (intraventricular, intraparenquimatosa, subaracnoidea, subdural y epidural). Objetivo: Describir los hallazgos clínicos, estudios complementarios, conducta terapéutica y evolución de un caso con neumoencéfalo como complicación de bloqueo regional epidural por radiculopatía lumbosacra. Presentación de caso: Se presentó un paciente masculino de 57 años de edad que comenzó con un cuadro súbito de desorientación, excitabilidad psicomotriz y convulsiones tónico-clónicas, a partir de una inyección epidural de metilprednisolona como método analgésico. Conclusiones: El caso presentado exhibió manifestaciones neurológicas inespecíficas, la aparición súbita posterior al proceder invasivo hizo sospechar en un evento neurológico agudo o fenómeno tromboembólico. Los estudios complementarios como la tomografía axial computarizada craneal simple, permitió su diagnóstico para tener una conducta consecuente. El manejo conservador del neumoencéfalo como complicación del uso de anestesia epidural, constituyó una conducta terapéutica eficaz y repercutió en la satisfactoria evolución del paciente(AU)

Introduction: Pneumocephalus (synonym: aerocele or intracerebral pneumatocele), is defined as the presence of gas within any of the intracranial compartments (intraventricular, intraparenchymal, subarachnoid, subdural and epidural). Objective: To describe the clinical findings, complementary studies, therapeutic conduct and evolution of a case with pneumocephalus as a complication of regional epidural block due to lumbosacral radiculopathy Case presentation: A 57-year-old male patient was presented who began with a sudden episode of disorientation, psychomotor excitability and tonic-clonic seizures, following an epidural injection of methylprednisolone as an analgesic method. Conclusions: The case presented exhibited non-specific neurological manifestations, the sudden appearance after the invasive procedure raised suspicion of an acute neurological event or thromboembolic phenomenon. Complementary studies such as simple cranial computed axial tomography, allowed its diagnosis to have a consistent conduct. The conservative management of pneumocephalus as a complication of the use of epidural anesthesia constituted an effective therapeutic approach and had an impact on the patient's satisfactory evolution(AU)

In vitro assessment of ruminal biohydrogenation of polyunsaturated fatty acids in diets with different types and levels of protected fat and diverse sources of fibre.

The objective was to assess the in vitro rumen fermentation characteristics, methane production, and biohydrogenation of unsaturated fatty acids of diets with two protected fat (PF) sources from soybean or linseed oil, two levels of PF (0 and 6%) and two forage sources (canola silage (CS) or alfalfa hay (AH)) in a factorial 2x2x2 completely randomised design. Only fatty acids content at final incubation was affected (P<0.05) by triple interaction, where C18:2 was highest with AH plus 6% soybean PF (4.41mg/g DM), while C18:3 was with CS plus 6% linseed oil protected (1.98mg/g DM). C18:2 cis-9 trans-11 had high concentration (308 mg/g DM; P<0.05) with AH plus 6% PF regardless PF type, and C18:1 trans-11 was higher with 6% PF than without PF (13.41 vs 7.89 mg/g DM). Cumulative methane production was not affected by treatments (0.9973 ± 0.1549 mmol/g DM; P>0.05). Gas production and in vitro NDF digestibility were lower with 6% PF of linseed than soybean (160.88 vs 150.97 ml; and 69.28vs 62.89 %, respectively P<0.05). With linseed PF the NH3-N concentration was highest in CS than AH (41.27 vs 27.95 mg/dL; P<0.05) but IVDMD had the opposite result (78.54 vs 85.04). In conclusion, although methane production was not affected and in vitro digestibility and gas production were reduced with linseed PF, the concentration of C18:3 and C18:1 trans-11 was increased, which could improve the lipid profile of milk. The negative effects on digestibility were less with AH than of CS regardless of PF type and level.

SIKs Regulate HDAC7 Stabilization and Cytokine Recall in Late-Stage T Cell Effector Differentiation.

Understanding the mechanisms underlying the acquisition and maintenance of effector function during T cell differentiation is important to unraveling how these processes can be dysregulated in the context of disease and manipulated for therapeutic intervention. In this study, we report the identification of a previously unappreciated regulator of murine T cell differentiation through the evaluation of a previously unreported activity of the kinase inhibitor, BioE-1197. Specifically, we demonstrate that liver kinase B1 (LKB1)-mediated activation of salt-inducible kinases epigenetically regulates cytokine recall potential in effector CD8+ and Th1 cells. Evaluation of this phenotype revealed that salt-inducible kinase-mediated phosphorylation-dependent stabilization of histone deacetylase 7 (HDAC7) occurred during late-stage effector differentiation. HDAC7 stabilization increased nuclear HDAC7 levels, which correlated with total and cytokine loci-specific reductions in the activating transcription mark histone 3 lysine 27 acetylation (H3K27Ac). Accordingly, HDAC7 stabilization diminished transcriptional induction of cytokine genes upon restimulation. Inhibition of this pathway during differentiation produced effector T cells epigenetically poised for enhanced cytokine recall. This work identifies a previously unrecognized target for enhancing effector T cell functionality.

Genome-wide analysis of DNA-PK-bound MRN cleavage products supports a sequential model of DSB repair pathway choice.

The Mre11-Rad50-Nbs1 (MRN) complex recognizes and processes DNA double-strand breaks for homologous recombination by performing short-range removal of 5' strands. Endonucleolytic processing by MRN requires a stably bound protein at the break site-a role we postulate is played by DNA-dependent protein kinase (DNA-PK) in mammals. Here we interrogate sites of MRN-dependent processing by identifying sites of CtIP association and by sequencing DNA-PK-bound DNA fragments that are products of MRN cleavage. These intermediates are generated most efficiently when DNA-PK is catalytically blocked, yielding products within 200 bp of the break site, whereas DNA-PK products in the absence of kinase inhibition show greater dispersal. Use of light-activated Cas9 to induce breaks facilitates temporal resolution of DNA-PK and Mre11 binding, showing that both complexes bind to DNA ends before release of DNA-PK-bound products. These results support a sequential model of double-strand break repair involving collaborative interactions between homologous and non-homologous repair complexes.

Engineering a Pro-Osteogenic Secretome through the Transient Silencing of the Gene Encoding Secreted Frizzled Related Protein 1.

The evidence sustaining the regenerative properties of mesenchymal stem cells' (MSCs) secretome has prompted a paradigm change, where MSCs have shifted from being considered direct contributors to tissue regeneration toward being seen as cell factories for producing biotech medicines. We have previously designed a method to prime MSCs towards osteogenic differentiation by silencing the Wnt/ß-Catenin inhibitor Sfpr1. This approach produces a significant increase in bone formation in osteoporotic mice. In this current work, we set to investigate the contribution of the secretome from the MSCs where Sfrp1 has been silenced, to the positive effect seen on bone regeneration in vivo. The conditioned media (CM) of the murine MSCs line C3H10T1/2, where Sfrp1 has been transiently silenced (CM-Sfrp1), was found to induce, in vitro, an increase in the osteogenic differentiation of this same cell line, as well as a decrease of the expression of the Wnt inhibitor Dkk1 in murine osteocytes ex vivo. A reduction in the RANKL/OPG ratio was also detected ex vivo, suggesting a negative effect of CM-Sfrp1 on osteoclastogenesis. Moreover, this CM significantly increases the mineralization of human primary MSCs isolated from osteoportotic patients in vitro. Proteomic analysis identified enrichment of proteins involved in osteogenesis within the soluble and vesicular fractions of this secretome. Altogether, we demonstrate the pro-osteogenic potential of the secretome of MSCs primmed in this fashion, suggesting that this is a valid approach to enhance the osteo-regenerative properties of MSCs' secretome.

Comparative Analysis of Cell Mixtures Deconvolution and Gene Signatures Generated for Blood, Immune and Cancer Cells.

In the last two decades, many detailed full transcriptomic studies on complex biological samples have been published and included in large gene expression repositories. These studies primarily provide a bulk expression signal for each sample, including multiple cell-types mixed within the global signal. The cellular heterogeneity in these mixtures does not allow the activity of specific genes in specific cell types to be identified. Therefore, inferring relative cellular composition is a very powerful tool to achieve a more accurate molecular profiling of complex biological samples. In recent decades, computational techniques have been developed to solve this problem by applying deconvolution methods, designed to decompose cell mixtures into their cellular components and calculate the relative proportions of these elements. Some of them only calculate the cell proportions (supervised methods), while other deconvolution algorithms can also identify the gene signatures specific for each cell type (unsupervised methods). In these work, five deconvolution methods (CIBERSORT, FARDEEP, DECONICA, LINSEED and ABIS) were implemented and used to analyze blood and immune cells, and also cancer cells, in complex mixture samples (using three bulk expression datasets). Our study provides three analytical tools (corrplots, cell-signature plots and bar-mixture plots) that allow a thorough comparative analysis of the cell mixture data. The work indicates that CIBERSORT is a robust method optimized for the identification of immune cell-types, but not as efficient in the identification of cancer cells. We also found that LINSEED is a very powerful unsupervised method that provides precise and specific gene signatures for each of the main immune cell types tested: neutrophils and monocytes (of the myeloid lineage), B-cells, NK cells and T-cells (of the lymphoid lineage), and also for cancer cells.

Soft-robotic green sea turtle (Chelonia mydas) developed to replace animal experimentation provides new insight into their propulsive strategies.

Green sea turtles (Chelonia mydas) can swim up to 50 km per day while only consuming seagrass or microalgae. How the animal accomplishes this vast journey on such low energy intake points to the effectiveness of their swimming technique and is a testament to the power of evolution. Understanding the green sea turtle's ability to accomplish these journeys requires insight into their propulsive strategies. Conducting animal testing to uncover their propulsive strategies brings significant challenges: firstly, the ethical issues of conducting experiments on an endangered animal, and secondly, the animal may not even swim with its regular routine during the experiments. In this work, we develop a new soft-robotic sea turtle that reproduces the real animal's form and function to provide biomechanical insights without the need for invasive experimentation. We found that the green sea turtle may only produce propulsion for approximately 30% of the limb beat cycle, with the remaining 70% exploiting a power-preserving low-drag glide. Due to the animal's large mass and relatively low drag coefficient, losses in swim speed are minimal during the gliding stage. These findings may lead to the creation of a new generation of robotic systems for ocean exploration that use an optimised derivative of the sea turtle propulsive strategy.

Suprascapular nerve injury after reverse total shoulder arthroplasty: correlation with screw out of vault penetration and functional situation: prospective study.

BACKGROUND: Baseplate screws have been suggested as a possible cause of suprascapular neuropathy after reverse total shoulder arthroplasty. This study aims to investigate the association between screw penetration out of the vault, electromyographic study, and the clinical outcomes. METHODS: A total of 31 patients who underwent reverse total shoulder arthroplasty for cuff tear arthropathy were prospectively enrolled. They were followed up for a minimum of 24 months. All patients underwent computed tomography 6 months postoperatively to determine the extraosseous position of the screws (perforation of the second bone cortex and protrusion into the supra- or infraspinatus fossa). Electrodiagnostic evaluation was performed preoperatively and postoperatively to stablish any relation between cortex perforation of the screw and suprascapular nerve (SSN) injury. Clinical outcomes pre- and postoperatively (Constant score, ranges of motion, and visual analog scale) of patients with and without documented injury were recorded. RESULTS: A total of 14 patients (45.2%) had an abnormal preoperative SSN electrodiagnostic study (chronic or disuse injuries), and 6 patients (19.4%) had an abnormal postoperative study (acute injury). Of the 6 patients, 2 cases appeared over the pre-existing lesion and 4 appeared over an intact preoperative nerve, all of them affecting the infraspinatus branch of the SSN. Perforation of the second cortex was detected for 60% of superior screws and 40% of posterior screws. The mean lengths of the superior and posterior screws were 30 and 18.2 mm, respectively. Patients with screw perforation of the second cortex were assessed as having a high risk of nerve injury (40% vs. 9.5%). CONCLUSIONS: Preoperative SSN injuries do not have a significant clinical impact and do not predispose to an acute postoperative SSN lesion. The Constant score and visual analog scale score for patients with acute SSN injuries were not statistically different from those without SSN injury. The extraosseous position of the screw increases the probability of an SSN injury to 31%. This risk is higher with the posterior screw, which leads us to question whether it is really necessary to use it.

Meta-analysis of perioperative immunotherapy in renal cell carcinoma: Available, but the jury is still out.

INTRODUCTION: While surgical management of renal cell carcinoma (RCC) is curative for many patients, others may relapse and could benefit from adjuvant treatments. Immune checkpoint inhibitors (ICI) have been proposed as a potential adjuvant therapy for improving survival in these patients, but the benefit/risk ratio of ICI in the perioperative setting remains unclear. METHODS: A systematic review and a meta-analysis of phase III trials of perioperative ICI (anti PD1/PD-L1 alone or in combination with anti-CTLA4 agents) in RCC was conducted. RESULTS: The analysis included results from 4 phase III trials, comprising 3,407 patients. ICI did not show a significant increase in disease-free survival (Hazard Ratio [HR] 0.85; 95% confidence interval [CI] 0.69-1.04; p: 0.11) or overall survival [OS] (HR 0.73; 95% CI 0.40-1.34; p: 0.31). High-grade adverse events were more frequent in the immunotherapy arm (OR 2.65; 95% CI 1.53-4.59; p: <0.001), and high-grade treatment-related adverse events were 8 times more frequent in the experimental arm (OR: 8.07; 95% CI: 3.14-20.75; p: <0.001). Subgroup analyses showed statistically significant differences favoring the experimental arm in females (HR: 0.71; 95 CI 0.55-0.92; p: 0.009), in sarcomatoid differentiation (HR: 0.60 95% CI 0.41-0.89; p: 0.01), and PD-L1 positive tumors (HR HR: 0.74; 95% CI 0.61-0.90; p: 0.003). No significant effect was found in patients according to age, type of nephrectomy (radical vs. partial), and stage (M1 without evidence of disease vs. M0 patients). CONCLUSION: Our comprehensive meta-analysis generally suggests that immunotherapy does not confer a survival advantage in the perioperative setting for RCC, with the exception of one positive study. While the overall results are not statistically significant, individual patient factors and other variables may play a role in determining who benefits from immunotherapy. Therefore, despite the mixed findings, immunotherapy may still be a viable treatment option for certain patients, and further studies are needed to determine which patient subgroups would be most likely to benefit.