Focused ultrasound on the substantia nigra enables safe neurotensin-polyplex nanoparticle-mediated gene delivery to dopaminergic neurons intranasally and by blood circulation.

Neurotensin-polyplex nanoparticles provide efficient gene transfection of nigral dopaminergic neurons when intracerebrally injected in preclinical trials of Parkinson's disease because they do not cross the blood-brain barrier (BBB). Therefore, this study aimed to open BBB with focused ultrasound (FUS) on the substantia nigra to attain systemic and intranasal transfections and evaluate its detrimental effect in rats. Systemically injected Evans Blue showed that a two-pulse FUS opened the nigral BBB. Accordingly, 35 µL of neurotensin-polyplex nanoparticles encompassing the green fluorescent protein plasmid (79.6 nm mean size and + 1.3 mV Zeta-potential) caused its expression in tyrosine hydroxylase(+) cells (dopaminergic neurons) of both substantiae nigrae upon delivery via internal carotid artery, retro-orbital venous sinus, or nasal mucosa 30 min after FUS. The intracarotid delivery yielded the highest transgene expression, followed by intranasal and venous administration. However, FUS caused neuroinflammation displayed by infiltrated lymphocytes (positive to cluster of differentiation 45), activated microglia (positive to ionized calcium-binding adaptor molecule 1), neurotoxic A1 astrocytes (positive to glial fibrillary acidic protein and complement component 3), and neurotrophic A2 astrocytes (positive to glial fibrillary acidic protein and S100 calcium-binding protein A10), that ended 15 days after FUS. Dopaminergic neurons and axonal projections decreased but recuperated basal values on day 15 after transfection, correlating with a decrease and recovery of locomotor behavior. In conclusion, FUS caused transient neuroinflammation and reversible neuronal affection but allowed systemic and intranasal transfection of dopaminergic neurons in both substantiae nigrae. Therefore, FUS could advance neurotensin-polyplex nanotechnology to clinical trials for Parkinson's disease.

A realistic combined exposure scenario: effect of microplastics and atrazine on Piaractus mesopotamicus.

Microplastics, considered emerging environmental contaminants resulting from plastic degradation, are discovered in diverse aquatic ecosystems and can be unintentionally ingested by fish. Therefore, it is essential to characterize their interaction with other contaminants, such as agrochemicals, in aquatic environments. This study aimed to assess histological, enzymatic, and genotoxic biomarkers in juvenile pacú (Piaractus mesopotamicus) exposed to polyethylene (PE) microplastic particles and the herbicide atrazine, individually or combined, for 15 days. Four treatments were used: a negative control (CON), PE in the fish diet (0.1% w/w, FPE), atrazine through water (100 µg L-1, ATZ), and the mixture (ATZ+FPE). Results confirmed histological alterations in gills (edema and lamellar fusion) and liver (necrotic areas and congestion) of fish exposed to ATZ and ATZ+FPE. The number of goblet cells increased in the posterior intestine of fish under ATZ+FPE compared to CON and FPE. Enzyme activities (CAT, GST, AChE, and BChE) significantly increased in ATZ+FPE compared to CON. However, no genotoxic effect was demonstrated. These findings provide insights into the complex impacts of simultaneous exposure to atrazine and microplastics, emphasizing the need for continued research to guide effective environmental management strategies against these contaminants that represent a risk to aquatic organisms.

Novel implant design for comminuted posterior wall acetabular fractures.

BACKGROUND: In recent years, the medical community has witnessed a notable increase in high-energy traumatic injuries, leading to a surge in complex fracture patterns that challenge existing treatment methodologies. Among these, the posterior approach to acetabular fractures stands out for offering direct visualization of the retro-acetabular surface, with current fixation methods relying on 3.5 mm low-profile reconstruction plates and various other implants. Despite the effectiveness of these methods, there is a burgeoning demand for a singular, adaptable implant that not only streamlines the surgical process but also optimizes patient outcomes. METHODS: In an innovative approach to address this need, three-dimensional (3D) models of the posterior acetabular wall were meticulously crafted using AutoCAD® software. The chosen material for the implant was 316L surgical steel for its durability and strength. The design of the implant featured a low-profile mesh structure, which was instrumental in facilitating osteosynthesis. This design allowed for the placement of screws of varying lengths in multiple directions, ensuring the initial reconstruction of the joint in an anatomical position without hindering the placement of the definitive implant. The primary objective was to secure the fixation and stabilization of the fracture by specifically targeting the smaller bone fragments. A comparative analysis was then conducted between this novel plate and a conventional 316L surgical steel, seven-hole, 3.5 mm reconstruction plate through finite element analysis. RESULTS: The comparative analysis unveiled that both plates demonstrated comparable deformation capacities, with no significant differences in load-bearing capabilities observed. This finding suggests that the innovative plate can match the performance of traditional plates used in such surgeries. CONCLUSIONS: The finite element analysis revealed that the newly developed anatomical plate for posterior wall acetabular fractures meets the necessary physical and mechanical criteria for permanent implementation in patients with these fractures. This breakthrough represents a promising advancement that could simplify surgical procedures and potentially elevate patient outcomes. LEVEL OF EVIDENCE II: This study is classified as a Level II, diagnostic study.

Predictive Factors of Functional Outcomes and Quality of Life in Patients with Ankle Fractures: A Systematic Review.

Background: Evaluating the predictors of unfavorable outcomes in patients with ankle fractures is crucial for identifying high-risk patients and implementing personalized treatment strategies. This study aimed to analyze factors that influence quality of life in patients with ankle fractures. Methods: Four databases were consulted. The main outcomes were functionality and quality of life scales combined using the standard mean difference (SMD) (Review Manager 5.4). Results: Eight studies with 2486 patients were included. A significant correlation was found between female sex and worse functionality scores (beta 4.15, 95% CI 1.84-6.46). Additionally, older age was correlated with worse functionality scores (beta -0.24, 95% CI -0.29 to -0.19). Patients with diabetes or metabolic syndrome also had worse outcomes (SMD 0.27, 95% CI 0.18-0.36). High BMI and obesity were also associated with worse quality of life scores (beta 2.62, 95% CI 0.77-4.48). Smokers had greater disability in the analyzed scales (SMD 0.22, 95% CI 0.05-0.39). No significant differences were observed with respect to syndesmotic involvement. Conclusions: Age, sex, diabetes, high BMI, and smoking negatively impact functional outcomes and quality of life in patients with ankle fractures.

Ribociclib plus Endocrine Therapy in Early Breast Cancer.

BACKGROUND: Ribociclib has been shown to have a significant overall survival benefit in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Whether this benefit in advanced breast cancer extends to early breast cancer is unclear. METHODS: In this international, open-label, randomized, phase 3 trial, we randomly assigned patients with HR-positive, HER2-negative early breast cancer in a 1:1 ratio to receive ribociclib (at a dose of 400 mg per day for 3 weeks, followed by 1 week off, for 3 years) plus a nonsteroidal aromatase inhibitor (NSAI; letrozole at a dose of 2.5 mg per day or anastrozole at a dose of 1 mg per day for ≥5 years) or an NSAI alone. Premenopausal women and men also received goserelin every 28 days. Eligible patients had anatomical stage II or III breast cancer. Here we report the results of a prespecified interim analysis of invasive disease-free survival, the primary end point; other efficacy and safety results are also reported. Invasive disease-free survival was evaluated with the use of the Kaplan-Meier method. The statistical comparison was made with the use of a stratified log-rank test, with a protocol-specified stopping boundary of a one-sided P-value threshold of 0.0128 for superior efficacy. RESULTS: As of the data-cutoff date for this prespecified interim analysis (January 11, 2023), a total of 426 patients had had invasive disease, recurrence, or death. A significant invasive disease-free survival benefit was seen with ribociclib plus an NSAI as compared with an NSAI alone. At 3 years, invasive disease-free survival was 90.4% with ribociclib plus an NSAI and 87.1% with an NSAI alone (hazard ratio for invasive disease, recurrence, or death, 0.75; 95% confidence interval, 0.62 to 0.91; P = 0.003). Secondary end points - distant disease-free survival and recurrence-free survival - also favored ribociclib plus an NSAI. The 3-year regimen of ribociclib at a 400-mg starting dose plus an NSAI was not associated with any new safety signals. CONCLUSIONS: Ribociclib plus an NSAI significantly improved invasive disease-free survival among patients with HR-positive, HER2-negative stage II or III early breast cancer. (Funded by Novartis; NATALEE ClinicalTrials.gov number, NCT03701334.).

Geographic differences in lung cancer: focus on carcinogens, genetic predisposition, and molecular epidemiology.

Lung cancer poses a global health challenge and stands as the leading cause of cancer-related deaths worldwide. However, its incidence, mortality, and characteristics are not uniform across all regions worldwide. Understanding the factors contributing to this diversity is crucial in a prevalent disease where most cases are diagnosed in advanced stages. Hence, prevention and early diagnosis emerge as the most efficient strategies to enhance outcomes. In Western societies, tobacco consumption constitutes the primary risk factor for lung cancer, accounting for up to 90% of cases. In other geographic locations, different significant factors play a fundamental role in disease development, such as individual genetic predisposition, or exposure to other carcinogens such as radon gas, environmental pollution, occupational exposures, or specific infectious diseases. Comprehensive clinical and molecular characterization of lung cancer in recent decades has enabled us to distinguish different subtypes of lung cancer with distinct phenotypes, genotypes, immunogenicity, treatment responses, and survival rates. The ultimate goal is to prevent and individualize lung cancer management in each community and improve patient outcomes.

Disease-free survival as a surrogate for overall survival in HR+/HER2- early breast cancer: A correlation analysis.

BACKGROUND: Overall survival (OS) is a universally accepted measure of clinical benefit; however, prolonged follow-up is needed to observe sufficient events. Disease-free survival (DFS) has been widely adopted as a primary endpoint for early breast cancer (EBC) trials, as follow-up is comparatively shorter. Here, we present an analysis evaluating DFS as a surrogate for OS for adjuvant treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) EBC. METHODS: A systematic literature review which included randomized controlled trials (RCTs) with ≥80% of adult patients with HR+/HER2- EBC was conducted. The RCTs evaluated various systemic therapeutic categories; key inclusion criteria included reporting of DFS and OS hazard ratios (HRs) and mature OS data. Spearman rank correlation and weighted linear regression analyses evaluated DFS and OS HR correlation. A scenario analysis tested base-case analysis robustness, and a parallel analysis using patient-level data was conducted. RESULTS: The base case (N = 14 RCTs) showed an unweighted Spearman coefficient of 0.81 between OS and DFS (weighted: 0.81), with 84% of the variability in OS explained by DFS differences (R2 from weighted regression). The surrogate threshold effect (Burzykowski T, Buyse M. Pharm Stat. 2006;5:173-186) was 0.82 for DFS/OS HR. Scenario analysis (n = 9 RCTs), which excluded chemotherapy trials, and patient-level analysis using FACE trial data were consistent with the base-case analysis. CONCLUSIONS: These analyses support DFS as a reliable surrogate endpoint for OS in adjuvant HR+/HER2- EBC trials. Using DFS as a surrogate measure will permit timelier access to novel treatments for patients with HR+/HER2- EBC.

Assessing Knowledge, Competence, and Performance Following Web-Based Education on Early Breast Cancer Management: Health Care Professional Questionnaire Study and Anonymized Patient Records Analysis.

BACKGROUND: Web-based learning activities are key components of continuing medical education (CME) for health care professionals (HCPs). However, the published outcomes of web-based educational interventions for early breast cancer (EBC) are limited. OBJECTIVE: This study aims to objectively assess knowledge, competence, and performance among HCPs following participation in 2 EBC-focused CME activities and to identify the remaining educational gaps. METHODS: We developed 2 CME-accredited web-based educational activities addressing high-risk EBC, including integration of shared decision-making to optimize patient care (touchMDT) and stratification for early identification of high-risk patients and novel treatment strategies (touchPANEL DISCUSSION). Knowledge, competence, and performance were assessed before and after the activities against an expanded outcomes framework (levels 1-5) using self-reported questionnaires and an analysis of anonymized data extracted from patient records. RESULTS: Six months after the launch of the activity, 7047 and 8989 HCP participants engaged with touchMDT and touchPANEL DISCUSSION, respectively. The overall satisfaction was 82% (a total score of 20.6 out of 25) for the touchMDT and 88% (a total score of 21.9 out of 25) for the touchPANEL DISCUSSION. For the evaluation of knowledge and competence (50 respondents before the activity and 50 learners after the activity), there was a significant increase in the mean number of correctly answered questions from pre- to postactivity (touchMDT: median 4.0, IQR 3.0-5.0 to median 5.5, IQR 4.0-7.0; mean 4.00, SD 1.39 to mean 5.30, SD 1.56 and touchPANEL DISCUSSION: median 4.0, IQR 4.0-5.0 to median 6.0, IQR 5.0-7.0; mean 4.32, SD 1.30 to mean 5.88, SD 1.49; both P<.001). A significant improvement in self-reported performance (50 respondents before the activity and 50 learners after the activity) was observed in a combined analysis of both activities (median 3.0, IQR 2.0-3.0 to median 4.0, IQR 3.0-5.0; mean 2.82, SD 1.08 to mean 4.16, SD 1.45; P<.001). Patient record analysis (50 respondents before the activity and 50 learners after the activity) showed that the HCPs used a range of measures to determine EBC recurrence risk and revealed no significant differences in adjuvant therapies used before and after the activity (P=.97 and P>.99 for Ki-67 <20% and Ki-67 ≥20% tumors, respectively). The remaining educational gaps included strategies for implementing shared decision-making in clinical practice and the use of genetic and biomarker testing to guide treatment selection. CONCLUSIONS: Brief, web-based CME activities on EBC were associated with an improvement in HCP knowledge, competence, and self-reported performance and can help identify unmet needs to inform the design of future CME activities.

Elevated blood metal ion levels in patients undergoing instrumented spinal surgery: a systematic review and meta-analysis.

BACKGROUND CONTEXT: Elevated blood metal levels have been reported in patients after spinal surgery using metallic implants. Although some studies have suggested an association between heightened blood metal concentrations and potential adverse effects, estimates of the incidence of abnormal metal levels after spinal surgery have been inconsistent. PURPOSE: The aims of this systematic review and meta-analysis were to assess: (1) mean differences in blood metal ion levels between patients undergoing spinal fusion surgery and healthy controls, (2) odds of elevated blood metal ion levels after surgery compared to pre-surgery levels, and (3) pooled incidence of elevated blood metal ions overall and by metal type. STUDY DESIGN: Systematic review and meta-analysis. PATIENTS SAMPLE: The patient sample included 613 patients from 11 studies who underwent spinal surgery instrumentation. OUTCOME MEASURES: Blood metal ion concentrations and the incidence of patients with elevated metal levels compared with in those the control group. METHODS: A comprehensive search was conducted in PubMed, EMBASE, Scopus, and Cochrane Library to identify studies reporting blood metal ion levels after spinal fusion surgery. Mean differences (MD), odds ratios (OR), and incidence rates were pooled using random effects models. Heterogeneity was assessed using I2 statistics, and fixed-effects models were used if no heterogeneity was detected. Detailed statistical analysis was performed using the Review Manager version 5.4 software. RESULTS: The analysis included 11 studies, with a total of 613 patients. Mean blood metal ion levels were significantly higher after spinal fusion surgery (MD 0.56, 95% CI 0.17-0.96; I2=86%). Specifically, titanium levels were significantly elevated (MD 0.81, 95% CI 0.32-1.30; I2=47%). The odds of elevated blood metal ions were higher after surgery (OR 8.17, 95% CI 3.38-19.72; I2=41%), primarily driven by chromium (OR 23.50, 95% CI 5.56-99.31; I2=30%). The incidence of elevated chromium levels was found to be 66.98% (95% CI 42.31-91.65). CONCLUSION: In conclusion, blood metal ion levels, particularly titanium and chromium, were significantly increased after spinal fusion surgery compared to pre-surgery levels and healthy controls. Approximately 70% of the patients exhibited elevated blood levels of chromium and titanium.

The Best Current Research on Patellar Tendinopathy: A Review of Published Meta-Analyses.

Patellar tendinopathy is a frequent overuse injury in sports that can cause significant pain and disability. It requires evidence-based guidelines on effective prevention and management. However, optimal treatments remain uncertain. We aimed to analyze available meta-analyses to summarize treatment recommendations, compare therapeutic modalities, examine included trials, and offer methodological suggestions to improve future systematic reviews. Meta-analyses were systematically searched for in PubMed (PROSPERO: CRD42023457963). A total of 21 meta-analyses were included. The AMSTAR-2 scale assessed study quality, which was low, with only 23.8% of the meta-analyses being of moderate quality, and none were considered to be of high quality. Heterogeneous outcomes are reported. Multiple platelet-rich plasma (PRP) injections appear superior to eccentric exercises and provide lasting improvements compared to eccentric exercises when conservative treatments fail. Extracorporeal shockwave therapy (ESWT) also seems superior to non-operative options and similar to surgery for patellar tendinopathy in the long term. However, evidence for eccentric exercise efficacy remains unclear due to inconclusive findings. Preliminary findings also emerged for genetic risk factors and diagnostic methods but require further confirmation. This review reveals a lack of high-quality evidence on optimal patellar tendinopathy treatments. While PRP and ESWT show promise, limitations persist. Further rigorous meta-analyses and trials are needed to strengthen the evidence base and guide clinical practice. Methodological enhancements are proposed to improve future meta-analyses.

Incidence and risk factors of distal adjacent disc degeneration in adolescent idiopathic scoliosis patients undergoing fusion surgery: a systematic review and meta-analysis.

PURPOSE: The objective of this meta-analysis was to determine the incidence of disc degeneration in patients with surgically treated adolescent idiopathic scoliosis (AIS) and identify the associated risk factors. METHODS: PubMed, EMBASE, Scopus, and Cochrane Collaboration Library databases were searched. The outcomes of interest were the incidence of disc degeneration, SRS-22, and radiological risk factors. The lower instrumented vertebra (LIV) was also evaluated. Fixed effects were used if there was no evidence of heterogeneity. Statistical analysis was performed using Review Manager. RESULTS: A meta-analysis was conducted including nine studies with a total of 565 patients. The analysis revealed that the global incidence of intervertebral disc degeneration in patients with surgically treated AIS patients was 24.78% (95% CI 16.59-32.98%) 10 years after surgery, which significantly increased to 32.32% (95% CI 21.16-43.47% at an average of 13.8 years after surgery. Among patients with significant degenerative disc changes, the SRS-22 functional, self-image, and satisfaction domains showed significantly worse results (MD - 0.25, 95% CI - 0.44 to - 0.05; MD - 0.50, 95% CI - 0.75 to - 0.25; and MD - 0.34, 95% CI - 0.66 to - 0.03, respectively). Furthermore, instrumentation at or above the L3 level was associated with a lower incidence of intervertebral disc degeneration compared to instrumentation below the L3 level (OR 0.25, 95% CI 0.10-0.64). It was also found that the preoperative and final follow-up lumbar curve magnitudes (MD 8.11, 95% CI 3.82-12.41) as well as preoperative and final follow-up lumbar lordosis (MD 0.42, 95% CI - 3.81 to 4.65) were associated with adjacent disc degeneration. CONCLUSIONS: This meta-analysis demonstrated that the incidence of intervertebral disc degeneration significantly increased with long-term follow-up using fusion techniques, reaching up to 32% when patients were 28 years of age. Incomplete correction of deformity and fusion of levels below L3, were identified as negative prognostic factors. Furthermore, patients with disc degeneration showed worse functional outcomes.

Adhesion and Contact Aging of Acrylic Pressure-Sensitive Adhesives to Swollen Elastomers.

Fluid-infused (or swollen) elastomers are known for their antiadhesive properties. The presence of excess fluid at their surface is the main contributor to limiting contact formation and minimizing adhesion. Despite their potential, the mechanisms for adhesion and contact aging to fluid-infused elastomers are poorly understood beyond contact with a few materials (ice, biofilms, glass). This study reports on adhesion to a model fluid-infused elastomer, poly(dimethylsiloxane) (PDMS), swollen with silicone oil. The effects of oil saturation, contact time, and the opposing surface are investigated. Specifically, adhesion to two different adherents with comparable surface energies but drastically different mechanical properties is investigated: a glass surface and a soft viscoelastic acrylic pressure-sensitive adhesive film (PSA, modulus ∼25 kPa). Adhesion between the PSA and swollen PDMS [with 23% (w/w) silicone oil] retains up to 60% of its value compared to contact with unswollen (dry) PDMS. In contrast, adhesion to glass nearly vanishes in contact with the same swollen elastomer. Adhesion to the PSA also displays stronger contact aging than adhesion to glass. Contact aging with the PSA is comparable for dry and unsaturated PDMS. Moreover, load relaxation when the PSA is in contact with the PDMS does not correlate with contact aging for contact with the dry or unsaturated elastomer, suggesting that contact aging is likely caused by chain interpenetration and polymer reorganization within the contact region. Closer to full saturation of the PDMS with oil, adhesion to the PSA decreases significantly and shows a delay in the onset of contact aging that is weakly correlated to the poroelastic relaxation of the elastomer. Additional confocal imaging suggests that the presence of a layer of fluid trapped at the interface between the two solids could explain the delayed (and limited) contact aging to the oil-saturated PDMS.

Cadaveric biomechanical studies of ADDISC total lumbar disc prosthesis.

BACKGROUND: Most total disc replacements provide excessive mobility and not reproduce spinal kinematics, inducing zygapophyseal joint arthritic changes and chronic back pain. In cadaveric lumbosacral spines, we studied if a new lumbar disc prosthesis kinematics mimics the intact intervertebral disc. METHODS: In eight cold preserved cadaveric lumbosacral spines, we registered the movement ranges in flexion, extension, right and left lateral bending, and rotation in the intact status, post-discectomy, and after our prosthesis implantation, comparing them for each specimen. FINDINGS: Comparing the intact lumbosacral spine with the L4-L5 prosthesis implanted specimens, we saw statistically significant differences in lateral bending and right rotation but not in the full range of rotation. Analyzing segments, we also noticed statistically significant differences at L4-L5 in flexion-extension and rotation. On the other hand, the L4-L5 discectomy, compared to the baseline spine condition, showed a statistically significant mobility increase in flexion, extension, lateral bending, and axial rotation, with an abnormal instantaneous center of rotation, which destabilizes the segment partly due to anterior annulus surgical removal. Disc prosthesis implantation reversed these changes in instantaneous center of rotation, but the prosthesis failed to restore the initial range of motion due to the destabilization of the ligaments in the operated disc. INTERPRETATION: The ADDISC total disc replacement reproduces the intact disc kinematics and Instantaneous Center of Rotation, but the prosthesis fails to restore the initial range of motion due to ligament destabilization. More studies will be necessary to define a technique that restores the damaged ligaments when implanting the prosthesis.

Long-term patient-reported outcomes from monarchE: Abemaciclib plus endocrine therapy as adjuvant therapy for HR+, HER2-, node-positive, high-risk, early breast cancer.

BACKGROUND: In monarchE, abemaciclib demonstrated a sustained benefit in invasive disease-free survival and a tolerable safety profile at 42-months median follow-up. With no expected disease-related symptoms, therapies in the adjuvant setting should preserve quality of life (QoL). With all patients off abemaciclib, we report updated patient-reported outcomes (PROs) for the full 2-year treatment period and follow-up. METHODS: Patients completed PROs including FACT-B, FACT-ES, and FACIT-Fatigue at baseline, 3, 6, 12, 18, and 24 months during treatment, and 1, 6, and 12 months after treatment discontinuation. Mixed effects repeated measures model estimated changes from baseline within and between arms for QoL scales and individual items. Meaningful changes were prespecified and no statistical testing was performed. Frequencies of responses to items associated with relevant adverse events and treatment bother were summarized. RESULTS: At baseline, completion rates for PRO instruments were >96 %. Mean changes from baseline for all QoL scales were numerically similar within and between arms (ie, less than prespecified thresholds). The same was observed for all individual items, except diarrhea. Within abemaciclib arm, meaningful differences for diarrhea were observed at 3 and 6 months (mean increases of 1.19 and 1.03 points on 5-point scale, respectively). During treatment, most patients in both arms (69-78 %) reported being bothered "a little bit" or "not at all" by side effects. Overall, patterns for fatigue were similar between arms. During post-treatment follow-up, PROs in both arms were similar to baseline. CONCLUSION: PRO findings confirm a tolerable and reversible toxicity profile for abemaciclib. QoL was preserved with the addition of adjuvant abemaciclib to endocrine therapy, supporting its use in patients with HR+, HER2-, high-risk early breast cancer.

Systemic Treatment of Patients With Metastatic Breast Cancer: ASCO Resource-Stratified Guideline.

PURPOSE: To guide clinicians and policymakers in three global resource-constrained settings on treating patients with metastatic breast cancer (MBC) when Maximal setting-guideline recommended treatment is unavailable. METHODS: A multidisciplinary, multinational panel reviewed existing ASCO guidelines and conducted modified ADAPTE and formal consensus processes. RESULTS: Four published resource-agnostic guidelines were adapted for resource-constrained settings; informing two rounds of formal consensus; recommendations received ≥75% agreement. RECOMMENDATIONS: Clinicians should recommend treatment according to menopausal status, pathological and biomarker features when quality results are available. In first-line, for hormone receptor (HR)-positive MBC, when a non-steroidal aromatase inhibitor and CDK 4/6 inhibitor combination is unavailable, use hormonal therapy alone. For life-threatening disease, use single-agent chemotherapy or surgery for local control. For premenopausal patients, use ovarian suppression or ablation plus hormone therapy in Basic settings. For human epidermal growth factor receptor 2 (HER2)-positive MBC, if trastuzumab, pertuzumab, and chemotherapy are unavailable, use trastuzumab and chemotherapy; if unavailable, use chemotherapy. For HER2-positive, HR-positive MBC, use standard first-line therapy, or endocrine therapy if contraindications. For triple-negative MBC with unknown PD-L1 status, or if PD-L1-positive and immunotherapy unavailable, use single-agent chemotherapy. For germline BRCA1/2 mutation-positive MBC, if poly(ADP-ribose) polymerase inhibitor is unavailable, use hormonal therapy (HR-positive MBC) and chemotherapy (HR-negative MBC). In second-line, for HR-positive MBC, Enhanced setting recommendations depend on prior treatment; for Limited, use tamoxifen or chemotherapy. For HER2-positive MBC, if trastuzumab deruxtecan is unavailable, use trastuzumab emtansine; if unavailable, capecitabine and lapatinib; if unavailable, trastuzumab and/or chemotherapy (hormonal therapy alone for HR-positive MBC).Additional information is available at www.asco.org/resource-stratified-guidelines. It is ASCO's view that healthcare providers and system decision-makers should be guided by the recommendations for the highest stratum of resources available. The guideline is intended to complement but not replace local guidelines.

Assessing Biomechanical and Clinical Outcomes of an Elbow Orthosis Intervention in Youth Baseball: Preliminary Results.

Proper orthosis design may help youth baseball players develop safer pitching mechanics to prevent elbow injuries. This study evaluated the impact of a custom elbow orthosis on pitching biomechanics and adverse events. Ten 11-12-year-old players (mean age 11.5 years) from a regional league team were recruited. The inclusion criteria were at least two years of baseball experience. Six players were randomly assigned to the orthosis group, with four in the control group. Anthropometric data and baseline characteristics were recorded. A video analysis assessed elbow flexion angle during pitching at baseline and at 2 months. The frequency of orthosis wear was also tracked. Adverse events during twice-weekly practices were documented. Post-study surveys evaluated orthosis comfort, stability, and safety perceptions. In the orthosis group (n = 6), four participants showed improved elbow flexion angle, and two of the six participants showed almost no change. The overall median difference was 23.5°. In the control group (n = 4), three participants showed improvement, with a median improvement of 5.5°. Twelve adverse events, including pain, were reported by players not wearing orthoses, whereas no events occurred with orthosis use. Individual players in the control group or who did not wear the orthosis correctly experienced multiple episodes of pain from pitching over the study period. This preliminary study indicates a custom elbow orthosis can optimize pitching biomechanics and prevent adverse events in youth baseball players over the course of two months.

Impact of vitamin D deficiency on mortality in patients with hip fracture: A meta-analysis.

BACKGROUND: Vitamin D deficiency has been linked to numerous health issues, including an increased risk of hip fractures. This meta-analysis aimed to investigate the relationship between vitamin D deficiency and mortality in patients with hip fracture. To assess the impact of different levels of vitamin D deficiency on mortality in patients with hip fractures and examine the influence of potential confounding factors. METHODS: A systematic search of PubMed, EMBASE, Scopus, and Cochrane Collaboration Library was conducted, resulting in nine eligible cohort studies (n = 4409). Patients with hip fractures were categorized based on their vitamin D levels as severe, moderate, or insufficient. Mortality was the primary outcome measure in this study. Subgroup analyses were performed according to the follow-up time. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using a random-effects model in Review Manager 5.4. RESULTS: Nine studies, with a pool of 4409 patients, were included. Vitamin D insufficiency was significantly associated with increased mortality (OR 1.24, 95% CI 1.05-1.46; I2 = 4%). Severe deficiency also led to a significant increase in mortality (OR 2.08, 95% CI 1.09-3.97; I2 = 42%), whereas moderate deficiency did not show a significant effect (OR 1.06, 95% CI 0.79-1.44; I2 = 0%). Subgroup analysis revealed significant associations between vitamin D insufficiency and increased mortality at 1-year (OR 1.37, 95% CI 1.06-1.77) and 2-year follow-ups (OR 1.78, 95% CI 1.01-3.15). After adjusting for potential confounders, no significant increase in the mortality rate was observed. CONCLUSIONS: This meta-analysis suggests that vitamin D insufficiency and severe deficiency are associated with increased mortality in patients with hip fracture. However, after adjusting for confounding factors, this association was not statistically significant. Further research is necessary to understand the role of vitamin D deficiency in this population.

First-Line Ipatasertib, Atezolizumab, and Taxane Triplet for Metastatic Triple-Negative Breast Cancer: Clinical and Biomarker Results.

PURPOSE: To evaluate a triplet regimen combining immune checkpoint blockade, AKT pathway inhibition, and (nab-) paclitaxel as first-line therapy for locally advanced/metastatic triple-negative breast cancer (mTNBC). PATIENTS AND METHODS: The single-arm CO40151 phase Ib study (NCT03800836), the single-arm signal-seeking cohort of IPATunity130 (NCT03337724), and the randomized phase III IPATunity170 trial (NCT04177108) enrolled patients with previously untreated mTNBC. Triplet therapy comprised intravenous atezolizumab 840 mg (days 1 and 15), oral ipatasertib 400 mg/day (days 1-21), and intravenous paclitaxel 80 mg/m2 (or nab-paclitaxel 100 mg/m2; days 1, 8, and 15) every 28 days. Exploratory translational research aimed to elucidate mechanisms and molecular markers of sensitivity and resistance. RESULTS: Among 317 patients treated with the triplet, efficacy ranged across studies as follows: median progression-free survival (PFS) 5.4 to 7.4 months, objective response rate 44% to 63%, median duration of response 5.6 to 11.1 months, and median overall survival 15.7 to 28.3 months. The safety profile was consistent with the known toxicities of each agent. Grade ≥3 adverse events were more frequent with the triplet than with doublets or single-agent paclitaxel. Patients with PFS >10 months were characterized by NF1, CCND3, and PIK3CA alterations and increased immune pathway activity. PFS <5 months was associated with CDKN2A/CDKN2B/MTAP alterations and lower predicted phosphorylated AKT-S473 levels. CONCLUSIONS: In patients with mTNBC receiving an ipatasertib/atezolizumab/taxane triplet regimen, molecular characteristics may identify those with particularly favorable or unfavorable outcomes, potentially guiding future research efforts.

Ibero-Panamerican Federation of Periodontology Delphi study on the trends of periodontology and periodontics by the year 2030. A Latin American consensus.

BACKGROUND AND OBJECTIVE: As elsewhere in the world, the prevalence of periodontitis in stages I-II is high in the Latin American population, this scenario emphasizes the need for identification of urgent needs for allocating adequate resources to provide diagnosis, prevention, and treatment of these diseases. The aim of this Delphi study was to predict the trends in periodontology/periodontics in the Latin American region by the year 2030. METHODS: A steering committee and an advisory group of experts in periodontology/periodontics were selected from 16 countries. An open questionnaire of 60 questions was validated and used following the Delphi methodology. RESULTS: Two hundred and twenty-five experts from Latin America answered the two rounds of the questionnaire. Moderate to strong consensus was reached on 45 questions (75%). The prediction was that the prevalence of gingivitis and periodontitis in stages I and II will be maintained, the importance of the link with systemic diseases will increase, and the impact of prevention and periodontal treatment will also increase, mainly in the private sector. There was a strong consensus that plastic and regenerative surgical procedures will increase, as well as the demand for training in the specialty of periodontology. CONCLUSIONS: The present study has provided relevant and useful information on predictions in periodontology/periodontics in Latin America, with important level of consensus among experts. It has been predicted that periodontitis will still be a highly prevalent disease, and its links with other medical conditions should demand more attention by health authorities to develop adequate prevention and management policies and strategies.