Clinical Benefit Research Articles

Prognostic value of 24-hour cultivation of peritoneal fluid to distinguish complicated from uncomplicated acute appendicitis: a prospective cohort study.

The distinction between complicated and uncomplicated acute appendicitis (AA) is important as it guides postoperative antibiotic treatment. A diagnosis based on intraoperative findings is imprecise and standard cultivation of peritoneal fluid is generally time-consuming with little clinical benefit. The aim of this study was to examine if cultivation of peritoneal fluid in acute appendicitis could reliably detect bacteria within 24h. Patients older than 18 years undergoing laparoscopic appendectomy were prospectively enrolled at two surgical departments after informed consent was obtained. Periappendicular fluid was collected prior to appendectomy and sent for cultivation. Sensitivity, specificity and positive and negative predictive values were calculated with 95% confidence intervals (CIs) using 72-hour cultivation results as the gold standard. Patients with complicated AA as determined by the surgeon, received a three-day course of oral antibiotics. Postoperative infectious complications within 30 days after surgery were registered. From July 2020 to January 2021, 101 patients were included. The intraoperative diagnosis was complicated AA in 34 cases. Of these patients, six (17.6%) had bacteria cultured within 24h after surgery, leading to a sensitivity of 60% and a specificity of 100%. The positive and negative predictive values were 1.00 and 0.96, respectively. Seven patients developed a postoperative infection (five superficial wound infections and two intra-abdominal abscess). In all cases with a positive cultivation result, the intraoperative diagnosis was complicated appendicitis and a postoperative course of antibiotics prescribed. Twenty-four-hour cultivation of the peritoneal fluid in acute appendicitis is a valid indicator for peritoneal bacterial contamination. Randomized studies are necessary to determine if this approach is suitable for targeting postoperative antibiotic treatment as a means to prevent overtreatment without increasing the risk of infectious complications.

Vitrectomy as an Adjunct to Treat-and-Extend Anti-VEGF Injections for Diabetic Macular Edema: The Vitrectomy in Diabetic Macular Oedema (VIDEO) Randomized Clinical Trial.

There are reported benefits from vitrectomy for diabetic macular edema (DME); however, data precede anti-vascular endothelial growth therapy (VEGF) therapy, supporting a need to assess the current role of vitrectomy. To determine rates of recruitment and efficacy outcomes of vitrectomy plus internal limiting membrane (ILM) peeling adjunctive to treat-and-extend (T&E) anti-VEGF injections for diabetic macular edema (DME). This was a single-masked, multicenter randomized clinical trial at 21 sites in the United Kingdom from June 2018 to January 2021, evaluating single eyes of treatment-naive patients with symptomatic vision loss from DME for less than 1 year. Inclusion criteria were best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study letter score greater than 35 (approximate Snellen equivalent, 20/200 or better) and central subfield thickness (CST) greater than 350 μm after 3 monthly intravitreal injections of ranibizumab or aflibercept. Data analysis was performed in July 2023. Patients were randomized 1:1 into vitrectomy plus standard care or standard care alone and further stratified into groups with vs without vitreomacular interface abnormality. Both groups received a T&E anti-VEGF injection regimen with aflibercept, 2 mg, or ranibizumab, 0.5 mg. The vitrectomy group additionally underwent pars plana vitrectomy with epiretinal membrane or ILM peel within 1 month of randomization. Rate of recruitment and distance BCVA. Secondary outcome measures were CST, change in BCVA and CST, number of injections, rate of completed follow-up, and withdrawal rate. Over 32 months, 47 of a planned 100 patients were enrolled; 42 (89%; mean [SD] age, 63 [11] years; 26 [62%] male) completed 12-month follow-up visits. Baseline characteristics appeared comparable between the control (n = 23; mean [SD] age, 66 [10] years) and vitrectomy (n = 24; mean [SD] age, 62 [12] years) groups. No difference in 12-month BCVA was noted between groups, with a 12-month median (IQR) BCVA letter score of 73 (65-77) letters (Snellen equivalent, 20/40) in the control group vs 77 (67-81) letters (Snellen equivalent, 20/32) in the vitrectomy group (difference, 4 letters; 95% CI, -8 to 2; P = .24). There was no difference in BCVA change from baseline (median [IQR], -1 [-3 to 2] letters for the control group vs -2 [-8 to 2] letters for the vitrectomy group; difference, 1 letter; 95% CI, -5 to 7; P = .85). No difference was found in CST changes (median [IQR], -94 [-122 to 9] μm for the control group vs -32 [-48 to 25] μm for the vitrectomy group; difference, 62 μm; 95% CI, -110 to 11; P = .11). Enrollment goals could not be attained. However, with 47 participants, evidence did not support a clinical benefit of vitrectomy plus ILM peeling as an adjunct to a T&E regimen of anti-VEGF therapy for DME. isrctn.org Identifier: ISRCTN59902040.

Carboplatin desensitization in the era of target therapies: still worthwhile?

Unresectable pediatric low-grade gliomas (LGG) usually need adjuvant therapy, and carboplatin hypersensitivity reaction (HR) commonly leads to premature treatment cessation of a standard chemotherapy regimen. In the molecular era, advances in understanding tumor genetic characteristics allowed the development of targeted therapies for this group of tumors; however, cost-effectiveness assessment of treatments, especially in low-income countries, is crucial. The aim is to describe the results of carboplatin desensitization protocol in a single center in a middle-income country. Prospective analysis of children with LGG submitted to carboplatin desensitization from December 2017 to June 2020 with follow-up until April 2024. Nine patients were included. The mean age was 11years. Five patients were male. Seven had optic pathway and two cervicomedullary location. Six had histologic diagnosis and four molecular analyses. The incidence of carboplatin reactions during the study period was 39.1%. Six patients underwent skin prick test, three with positive results. The first HR occurred, on average, around the 9th cycle of treatment. All patients had cutaneous symptoms, and five out of nine had anaphylaxis as the first reaction. 77.7% of the patients completed the protocol, and the clinical benefit rate (stable disease and partial response) was 88.8%. Six patients further required other lines of therapy. Monthly, the total cost for carboplatin was $409.09, and for target therapies (dabrafenib plus trametinib), $4929.28 to $5548.57. Our study presented an interesting and cost-effective option where desensitization allowed children with HR to be treated with first-line therapy, avoiding the discontinuation of an effective treatment.

Prevalence of problematic pharmaceutical opioid use in patients with chronic non-cancer pain: A systematic review and meta-analysis.

Chronic non-cancer pain (CNCP) is one of the most common causes of disability globally. Opioid prescribing to treat CNCP remains widespread, despite limited evidence of long-term clinical benefit and evidence of harm such as problematic pharmaceutical opioid use (POU) and overdose. The study aimed to measure the prevalence of POU in CNCP patients treated with opioid analgesics. A comprehensive systematic literature review and meta-analysis was undertaken using MEDLINE, Embase and PsycINFO databases from inception to 27 January 2021. We included studies from all settings with participants aged ≥ 12 with non-cancer pain of ≥ 3months duration, treated with opioid analgesics. We excluded case-control studies, as they cannot be used to generate prevalence estimates. POU was defined using four categories: dependence and opioid use disorder (D&OUD), signs and symptoms of D&OUD (S&S), aberrant behaviour (AB) and at risk of D&OUD. We used a random-effects multi-level meta-analytical model. We evaluated inconsistency using the I2 statistic and explored heterogeneity using subgroup analyses and meta-regressions. A total of 148 studies were included with > 4.3 million participants; 1% of studies were classified as high risk of bias. The pooled prevalence was 9.3% [95% confidence interval (CI) = 5.7-14.8%; I2= 99.9%] for D&OUD, 29.6% (95% CI = 22.1-38.3%, I2= 99.3%) for S&S and 22% (95% CI = 17.4-27.3%, I2= 99.8%) for AB. The prevalence of those at risk of D&OUD was 12.4% (95% CI = 4.3-30.7%, I2 = 99.6%). Prevalence was affected by study setting, study design and diagnostic tool. Due to the high heterogeneity, the findings should be interpreted with caution. Problematic pharmaceutical opioid use appears to be common in chronic pain patients treated with opioid analgesics,with nearly one in 10 experiencing dependence and opioid use disorder, one in three showing signs and symptoms of dependence and opioid use disorder and one in five showing aberrant behaviour.

Anti-Cytokine Active Immunotherapy Based on Supramolecular Peptides for Alleviating IL-1β-Mediated Inflammation.

IL-1β is a principal proinflammatory cytokine underlying multiple local and systemic chronic inflammatory conditions including psoriasis, rheumatoid arthritis, inflammatory bowel disease, and type 2 diabetes. Passive immunotherapies and biologic drugs targeting IL-1β, while offering significant clinical benefit, nevertheless have limitations such as significant non-response rates, induction of anti-drug antibodies, and high costs. Here, an active immunotherapy raising antibody responses against IL-1β employing self-assembling peptide nanofibers is described. The nanofibers contain defined quantities of B-cell epitopes from IL-1β and exogenous T helper epitopes and employ the Q11 self-assembling peptide platform. Without adjuvant, the nanofibers raised durable anti-IL-1β antibody responses that inhibit IL-1β activity in vitro and in vivo. In a mouse model of imiquimod-induced psoriasis, prophylactic immunizations with the nanofibers diminished symptoms of epidermal thickening. This therapeutic effect is associated with biasing the immune response toward an anti-inflammatory IgG1/Th2 phenotype and a lowered expression of proinflammatory genes in the skin. Further, anti-IL-1β nanofibers induced therapeutic immunosuppressive CD62L+ Treg cells. This technology represents a potential alternative for passive immunotherapies and other biologics for treating chronic inflammatory conditions.

Regorafenib-related erythrocytosis in metastatic extra-gastrointestinal stromal tumor: a case report

IntroductionRegorafenib is an oral multi-targeted tyrosine kinase inhibitor (TKI) indicated for the treatment of various tumor types, including metastatic gastrointestinal stromal tumors (GIST), as a third-line systemic therapy. Erythrocytosis, which is characterized by an increase in erythrocyte count, hemoglobin, and hematocrit levels, has been described as a side effect of some antiangiogenic TKIs but has never been associated with regorafenib administration.Case presentationAn extra-GIST was diagnosed in a 58-year-old woman after she underwent surgery to remove a pelvic mass. Three years later, systemic therapy with imatinib was started due to pelvic disease recurrence. However, after six months, due to disease progression, we prescribed sunitinib, which the patient received for four years. Regorafenib was initiated in June 2019, and after six months, we noted an increase in the erythrocytes’ count and hemoglobin (Hb) levels. Given that the patient had clinical benefit and hematocrit was within normal range, we only monitored the blood cell count and continued to give regorafenib at the same dose. The drug was then stopped for over six weeks due to hospitalization for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and Hb levels returned to normal. Therefore, we decided to restart regorafenib at a lower dose. However, Hb levels rose again in conjunction with increased hematocrit, resulting in the need for multiple phlebotomies. We attempted to restart regorafenib every other day, but it was unsuccessful, so we stopped it permanently in May 2023, and all values returned to normal.ConclusionRegorafenib may cause secondary erythrocytosis that could not be dose-related, as this case report suggests. Secondary erythrocytosis might be a marker of TKI efficacy, given the patient’s prolonged clinical benefit during regorafenib treatment (48 months). In patients receiving regorafenib, monitoring blood count as well as any symptoms associated with erythrocytosis may be suggested.

The clinical significance of endoplasmic reticulum stress related genes in non-small cell lung cancer and analysis of single nucleotide polymorphism for CAV1

In recent years, protein homeostasis imbalance caused by endoplasmic reticulum stress has become a major hallmark of cancer. Studies have shown that endoplasmic reticulum stress is closely related to the occurrence, development, and drug resistance of non-small cell lung cancer, however, the role of various endoplasmic reticulum stress-related genes in non-small cell lung cancer is still unclear. In this study, we established an endoplasmic reticulum stress scores based on the Cancer Genome Atlas for non-small cell lung cancer to reflect patient features and predict prognosis. Survival analysis showed significant differences in overall survival among non-small cell lung cancer patients with different endoplasmic reticulum stress scores. In addition, endoplasmic reticulum stress scores was significantly correlated with the clinical features of non-small cell lung cancer patients, and can be served as an independent prognostic indicator. A nomogram based on endoplasmic reticulum stress scores indicated a certain clinical net benefit, while ssGSEA analysis demonstrated that there was a certain immunosuppressive microenvironment in high endoplasmic reticulum stress scores. Gene Set Enrichment Analysis showed that scores was associated with cancer pathways and metabolism. Finally, weighted gene co-expression network analysis displayed that CAV1 was closely related to the occurrence of non-small cell lung cancer. Therefore, in order to further analyze the role of this gene, Chinese non-smoking females were selected as the research subjects to investigate the relationship between CAV1 rs3779514 and susceptibility and prognosis of non-small cell lung cancer. The results showed that the mutation of rs3779514 significantly reduced the risk of non-small cell lung cancer in Chinese non-smoking females, but no prognostic effect was found. In summary, we proposed an endoplasmic reticulum stress scores, which was an independent prognostic factor and indicated immune characteristics in the microenvironment of non-small cell lung cancer. We also validated the relationship between single nucleotide polymorphism locus of core genes and susceptibility to non-small cell lung cancer.

Radiomics nomogram based on CT radiomics features and clinical factors for prediction of Ki-67 expression and prognosis in clear cell renal cell carcinoma: a two-center study

ObjectivesTo develop and validate a radiomics nomogram combining radiomics features and clinical factors for preoperative evaluation of Ki-67 expression status and prognostic prediction in clear cell renal cell carcinoma (ccRCC).MethodsTwo medical centers of 185 ccRCC patients were included, and each of them formed a training group (n = 130) and a validation group (n = 55). The independent predictor of Ki-67 expression status was identified by univariate and multivariate regression, and radiomics features were extracted from the preoperative CT images. The maximum relevance minimum redundancy (mRMR) and the least absolute shrinkage and selection operator algorithm (LASSO) were used to identify the radiomics features that were most relevant for high Ki-67 expression. Subsequently, clinical model, radiomics signature (RS), and radiomics nomogram were established. The performance for prediction of Ki-67 expression status was validated using area under curve (AUC), calibration curve, Delong test, decision curve analysis (DCA). Prognostic prediction was assessed by survival curve and concordance index (C-index).ResultsTumour size was the only independent predictor of Ki-67 expression status. Five radiomics features were finally identified to construct the RS (AUC: training group, 0.821; validation group, 0.799). The radiomics nomogram achieved a higher AUC (training group, 0.841; validation group, 0.814) and clinical net benefit. Besides, the radiomics nomogram provided a highest C-index (training group, 0.841; validation group, 0.820) in predicting prognosis for ccRCC patients.ConclusionsThe radiomics nomogram can accurately predict the Ki-67 expression status and exhibit a great capacity for prognostic prediction in patients with ccRCC and may provide value for tailoring personalized treatment strategies and facilitating comprehensive clinical monitoring for ccRCC patients.

Examining breast cancer screening recommendations in Canada: The projected resource impact of screening among women aged 40-49.

To quantify the resource use of revising breast cancer screening guidelines to include average-risk women aged 40-49 years across Canada from 2024 to 2043 using a validated microsimulation model. OncoSim-Breast microsimulation platform was used to simulate the entire Canadian population in 2015-2051. We compared resource use between current screening guidelines (biennial screening ages 50-74) and alternate screening scenarios, which included annual and biennial screening for ages 40-49 and ages 45-49, followed by biennial screening ages 50-74. We estimated absolute and relative differences in number of screens, abnormal screening recalls without cancer, total and negative biopsies, screen-detected cancers, stage of diagnosis, and breast cancer deaths averted. Compared with current guidelines in Canada, the most intensive screening scenario (annual screening ages 40-49) would result in 13.3% increases in the number of screens and abnormal screening recalls without cancer whereas the least intensive scenario (biennial screening ages 45-49) would result in a 3.4% increase in number of screens and 3.8% increase in number of abnormal screening recalls without cancer. More intensive screening would be associated with fewer stage II, III, and IV diagnoses, and more breast cancer deaths averted. Revising breast cancer screening in Canada to include average-risk women aged 40-49 would detect cancers earlier leading to fewer breast cancer deaths. To realize this potential clinical benefit, a considerable increase in screening resources would be required in terms of number of screens and screen follow-ups. Further economic analyses are required to fully understand cost and budget implications.

Focused ultrasound therapy for Alzheimer’s disease: exploring the potential for targeted amyloid disaggregation

IntroductionAlzheimer’s disease, a progressive neurodegenerative disorder, is marked by beta-amyloid plaque accumulation and cognitive decline. The limited efficacy and significant side effects of anti-amyloid monoclonal antibody therapies have prompted exploration into innovative treatments like focused ultrasound therapy. Focused ultrasound shows promise as a non-invasive technique for disrupting the blood–brain barrier, potentially enhancing drug delivery directly to the brain and improving the penetration of existing therapeutic agents.MethodsThis systematic review was conducted using PubMed and Embase databases, focusing on studies published in the last ten years that examined the use of low–intensity focused ultrasound for blood–brain barrier disruption in Alzheimer’s disease. The search strategy encompassed terms related to Alzheimer’s disease, focused ultrasound, and the blood–brain barrier. Studies were selected based on predefined inclusion and exclusion criteria. The quality of included studies was assessed using the Oxford Centre for Evidence-Based Medicine Levels of Evidence framework.ResultsTwelve studies were analyzed, the results of which suggested that low intensity focused ultrasound when combined with microbubbles may safely and transiently disrupt the blood–brain barrier. These studies, primarily early-phase and observational, highlight the potential feasibility of focused ultrasound in facilitating drug delivery to the brain for the treatment of Alzheimer’s disease. Notably, one study reported positive impacts on cognitive tests, suggesting potential direct therapeutic effects of focused ultrasound beyond blood–brain barrier disruption.ConclusionThe results of the included studies indicate the use of focused ultrasound in Alzheimer’s disease treatment might be safe and effective in transiently opening the blood–brain barrier. Although current evidence is promising, further research is needed to establish generalizability. Future studies should also aim to further elucidate the mechanisms of action of low-intensity focused ultrasound as well as microbubbles for blood–brain barrier opening and explore potential clinical benefits beyond blood–brain barrier opening such as impacts on cognitive outcomes. Future studies should also aim for greater participant diversity to ensure findings are applicable across the full spectrum of Alzheimer’s disease patients.

Effectiveness of preventive intervention programmes aiming to improve oral health in children who have undergone caries-related dental extractions: a rapid review.

To determine the effectiveness of preventive interventions in children who have undergone caries-related dental extractions. Rapid review across five databases (CENTRAL, Ovid Medline, Embase, Web of Science and Scopus). Quality was assessed using the Risk of Bias 2 tool. Five studies were included, all randomised controlled trials involving pre-and/or post-extractions activity. Three studies involved oral health education (computer game, motivational interviewing, visual aids), one delivered clinical prevention (fissure sealants), and one an enhanced prevention programme combining additional health education and a clinical intervention (fluoride varnish). Retention was mixed (55%-80% in the intervention groups). Of the three studies measuring caries, all reported less caries development in the test group. However, only a study involving a dental nurse-delivered structured conversation, informed by motivational interviewing, showed an improvement in oral health. Two studies reporting on plaque and gingival bleeding had conflicting results. A study reporting on subsequent dental attendance did not demonstrate a clear improvement. Few published studies have explored prevention-based interventions in high caries-risk children requiring dental extractions. Whilst evidence of clinical benefit of preventive interventions in this population is limited, the potential use of contemporary behaviour change techniques appears promising. There is an urgent need for more high-quality longer-term trials using contemporary methodologies.

Is It the Best Option? Robotic Surgery for Endometriosis

Endometriosis is a chronic condition affecting approximately 10% of women of reproductive age, leading to significant physical and emotional stress. Treatments include medical management and surgical interventions, with laparoscopic surgery being the gold standard for removing endometrial tissue. The advent of robotic-assisted laparoscopic surgery (RALS) has enabled more complex procedures to be performed minimally invasively, increasing its use in high-difficulty surgeries. Developed in the late 20th century, systems like the Da Vinci Surgical System have revolutionized surgery by enhancing precision, dexterity, and visualization. The latest models, including the Da Vinci Xi and SP, offer advanced features such as enhanced arm mobility, fluorescence imaging, and single-port capabilities. Comparative studies of RALS and conventional laparoscopy (LPS) for endometriosis show mixed results. While some studies indicate no significant differences in complications or recovery outcomes, others highlight longer operative times and hospital stays for RALS. Despite these drawbacks, RALS is not inferior to LPS overall. The clinical benefits of RALS include greater precision and accuracy, reduced surgeon fatigue, and a faster learning curve, facilitated by advanced ergonomic and control systems. However, the high costs and extensive infrastructure requirements limit the accessibility and availability of robotic surgery, particularly in smaller or rural hospitals. The absence of tactile feedback remains a challenge, though upcoming advancements aim to address this. Continued research and development are essential to make robotic surgery more cost-effective and broadly accessible, ensuring its benefits can reach a wider patient population. This abstract encapsulates the key aspects of robotic surgery’s development, comparative studies with conventional methods, and its clinical benefits and limitations, highlighting the need for ongoing improvements and research.

45 INTerpath-004: A phase 2, randomized, double-blind study of pembrolizumab with V940 (mRNA-4157) or placebo in the adjuvant treatment of renal cell carcinoma

Abstract Background The PD-1 inhibitor pembrolizumab is approved as monotherapy for the adjuvant treatment of patients with renal cell carcinoma (RCC) who are at increased risk of recurrence following nephrectomy or nephrectomy and resection of metastatic lesions based on results from the phase 3 KEYNOTE-564 trial. Novel combination strategies could provide further clinical benefit in the adjuvant setting. V940 (mRNA-4157) is an individualized neoantigen therapy that is hypothesized to increase the antitumor activity of T cells and enhance the activity of pembrolizumab. V940 plus pembrolizumab showed improved clinical outcomes for stage III/IV melanoma compared with pembrolizumab alone in the phase 2b KEYNOTE-942 study. INTerpath-004 is a global, multicenter, randomized, double-blind, phase 2 trial (NCT06307431) designed to evaluate the efficacy and safety of adjuvant pembrolizumab with V940 or placebo in patients with RCC who have undergone nephrectomy. Methods Eligible patients are adults with histologically or cytologically confirmed RCC with clear cell or papillary histology (intermediate-high risk [pT2 Gr4, N0, M0 or pT3 Gr3/4, N0, M0], high-risk [pT4, N0, M0 or pT any stage, N1, M0], or M1 NED [solid, isolated, soft tissue metastases that can be completely resected at the time of nephrectomy or ≤2 years from nephrectomy]) with or without sarcomatoid features. Patients must have undergone nephrectomy and/or metastasectomy ≤12 weeks prior to randomization and be tumor-free as assessed by investigator. Patients must not have received prior systemic therapy ≤4 weeks or radiotherapy ≤2 weeks prior to randomization. Approximately 272 patients will be randomly assigned 1:1 to receive pembrolizumab 400 mg intravenously every 6 weeks for up to 9 cycles in combination with either V940 1 mg or placebo intramuscularly every 3 weeks for up to 9 doses or treatment discontinuation due to unacceptable toxicity, disease recurrence, patient withdrawal, or investigator decision. Randomization will be stratified by histology (clear cell vs papillary) and disease risk (intermediate-high vs high vs M1 NED). Imaging assessments (computed tomography or magnetic resonance imagery) will be performed every 12 weeks through year 2, every 16 weeks in years 3-5, and every 24 weeks in year 6 and beyond. The primary endpoint is disease-free survival by investigator assessment. Secondary endpoints include distant metastasis-free survival, overall survival, and safety parameters including adverse events (AEs), laboratory test results, and vital signs. AEs will be monitored throughout the study and for 30 days after the last dose of treatment (90 for serious AEs) and graded per National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Efficacy will be assessed in all randomly assigned patients, and safety will be assessed in all patients who received ≥1 dose of study intervention. Recruitment is ongoing.

Hypothyroidism in Older Adults: A Concise Review of the Recent Literature

Abstract Introduction Hypothyroidism (HypoT) is a common condition whose prevalence varies according to regional and ethnic factors, dietary iodine, gender, and age. The symptoms of HypoT are generally nonspecific, with considerable overlap with other conditions. These symptoms are not useful for diagnosing HypoT, and a thyroid function test is required for a final diagnosis. Materials and methods We aimed to provide an overview of the recent global literature on HypoT in older adults. A narrative, nonsystematic review of the international literature from a single major medical online database (PubMed) for the past 5 years was performed. The relevant literature was narrated in a concise thematic account. Results Most studies and expert opinions reiterated the benefit of replacement therapy in younger and middle-aged individuals. A good volume of literature also considered the interplay between thyroid hormones and (1) cardiovascular function and risk factors, (2) cognitive function, (3) mental health, and (4) quality of life. Most workers are cognizant of the important difference in normal ranges of thyroid-stimulating hormone (TSH) and the consequent TSH targets in older adults compared to younger age groups. Extra care is recommended for the initiation and titration of thyroid hormone replacement therapy to avoid cardiovascular and skeletal adverse effects of relative overtreatment. Conclusion While clinical benefit is evident in patients under age 65 with overt and subclinical HypoT who are treated with levothyroxine, treatment may be harmful in older adults with subclinical HypoT. The 97th percentile of TSH distribution is 7.5 mIU/L for patients over age 80. Hence, TSH goals should be individualized in older adults to achieve any possible benefit and avoid unnecessary harm.

Camera-based near-infrared autofluorescence versus visual identification in total thyroidectomy for parathyroid function preservation: Systematic review and meta-analysis of randomized clinical trials.

Hypocalcemia is the most common postoperative complication of total thyroidectomy. Near-infrared autofluorescence (NIRAF) technology is a surgical adjunct that has been increasingly utilized with the aim of preventing postoperative hypocalcemia, but its clinical benefits have not yet been firmly established. The aim of this study was to assess the clinical benefit of utilizing NIRAF technology in patients undergoing total thyroidectomy. A systematic review and meta-analysis of randomized clinical trials was performed according to PRISMA guidelines. Seven randomized clinical trials with 1437 patients (318 males, 22.13%) undergoing total thyroidectomy were included for analysis. Risk of postoperative hypocalcemia was reduced in the NIRAF arm (RR, 0.65; 95%CI, 0.50-0.84). Use of NIRAF was also associated with a reduction in the risk of permanent parathyroid dysfunction (RR, 0.46; 95%CI, 0.22-0.95) and inadvertent parathyroid gland resection (RR, 0.40; 95%CI, 0.26-0.60). We present a systematic review and meta-analysis of randomized clinical trials examining the impact of NIRAF technology on preservation of parathyroid function. Our results suggest that use of camera-based NIRAF technology reduces the risk of postoperative hypocalcemia, permanent parathyroid dysfunction, and inadvertent parathyroid gland resection.

The potential effect of romosozumab on perioperative management for instrumentation surgery.

Age-related changes in bone health increase the risk for complications in elderly patients undergoing orthopedic surgery. Osteoporosis is a key therapeutic target that needs to be addressed to ensure successful instrumentation surgery. The effectiveness of pharmacological interventions in orthopedic surgery, particularly the new drug romosozumab, is still unknown. We aim to evaluate the effect of 3-month romosozumab treatment on biomechanical parameters related to spinal instrumentation surgery, using the Quantitative Computed Tomography (QCT)-based Finite Element Method (FEM). This open-labeled, prospective study included 81 patients aged 60 to 90 years, who met the osteoporosis criteria and were scheduled for either romosozumab or eldecalcitol treatment. Patients were assessed using blood samples, dual-energy absorptiometry (DXA), and QCT. Biomechanical parameters were evaluated using FEM at baseline and 3 months post-treatment. The primary endpoints were biomechanical parameters at 3 months, while secondary endpoints included changes in regional volumetric bone mineral density around the pedicle (P-vBMD) and vertebral body (V-vBMD). Romosozumab treatment led to significant gains in P-vBMD, and V-vBMD compared to eldecalcitol at 3 months. Notably, the romosozumab group showed greater improvements in all biomechanical parameters estimated by FEM at 3 months compared to the eldecalcitol group. Romosozumab significantly increased the regional vBMD as well as biomechanical parameters, potentially offering clinical benefits in reducing post-operative complications in patients with osteoporosis undergoing orthopedic instrumentation surgery. This study highlights the novel advantages of romosozumab treatment and advocates further research on its effectiveness in perioperative management.

Dapagliflozin Enhances Arterial and Venous Compliance During Exercise in Heart Failure With Preserved Ejection Fraction: Insights From the Cardiac and Metabolic Effects of Dapagliflozin in Heart Failure With Preserved Ejection Fraction Trial.

Systemic arterial compliance and venous capacitance are typically impaired in patients with heart failure with preserved ejection fraction (HFpEF), contributing to hemodynamic congestion with stress. Sodium-glucose cotransporter-2 inhibitors reduce hemodynamic congestion and improve clinical outcomes in patients with HFpEF, but the mechanisms remain unclear. This study tested the hypothesis that Dapagliflozin would improve systemic arterial compliance and venous capacitance during exercise in patients with HFpEF. In this secondary analysis from the Cardiac and Metabolic Effects of Dapagliflozin in Heart Failure With Preserved Ejection Fraction Trial, 37 patients with HFpEF (mean age 68 ± 9 years, women 65%) underwent invasive hemodynamic exercise testing with simultaneous echocardiography at baseline and following treatment for 24 weeks with Dapagliflozin or placebo. Radial artery pressure (BP) was measured continuously using a fluid-filled catheter with transformation to aortic pressure, central hemodynamics were measured using high-fidelity micromanometers, and stressed blood volume was estimated from hemodynamic indices fit to a comprehensive cardiovascular model. There was no statistically significant effect of Dapagliflozin on resting BP, but Dapagliflozin reduced systolic BP during peak exercise (estimated treatment difference [ETD], -18.8 mm Hg [95% CI, -33.9 to -3.7] P=0.016). Reduction in BP was related to improved exertional total arterial compliance (ETD, 0.06 mL/mm Hg/m2 [95% CI, 0.003-0.11] P=0.039) and aortic root characteristic impedance (ETD, -2.6 mm Hg/mL*sec [95% CI: -5.1 to -0.03] P=0.048), with no significant effect on systemic vascular resistance. Dapagliflozin reduced estimated stressed blood volume at rest and during peak exercise (ETD, -292 mm Hg [95% CI, -530 to -53] P=0.018), and improved venous capacitance evidenced by a decline in ratio of estimated stressed blood volume to total blood volume (ETD, -7.3% [95% CI, -13.3 to -1.3] P=0.020). Each of these effects of Dapagliflozin at peak exercise were also observed during matched 20W exercise intensity. Improvements in total arterial compliance and estimated stressed blood volume were correlated with decreases in body weight, and reduction in systolic BP with treatment was correlated with the change in estimated stressed blood volume during exercise (r=0.40, P=0.019). Decreases in BP were correlated with reduction in pulmonary capillary wedge pressure during exercise (r=0.56, P<0.001). In patients with HFpEF, treatment with Dapagliflozin improved systemic arterial compliance and venous capacitance during exercise, while reducing aortic characteristic impedance, suggesting a reduction in arterial wall stiffness. These vascular effects may partially explain the clinical benefits with sodium-glucose cotransporter-2 inhibitors in HFpEF. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04730947.

Impact of p53-associated acute myeloid leukemia hallmarks on metabolism and the immune environment

Acute myeloid leukemia (AML), an aggressive malignancy of hematopoietic stem cells, is characterized by the blockade of cell differentiation, uncontrolled proliferation, and cell expansion that impairs healthy hematopoiesis and results in pancytopenia and susceptibility to infections. Several genetic and chromosomal aberrations play a role in AML and influence patient outcomes. TP53 is a key tumor suppressor gene involved in a variety of cell features, such as cell-cycle regulation, genome stability, proliferation, differentiation, stem-cell homeostasis, apoptosis, metabolism, senescence, and the repair of DNA damage in response to cellular stress. In AML, TP53 alterations occur in 5%–12% of de novo AML cases. These mutations form an important molecular subgroup, and patients with these mutations have the worst prognosis and shortest overall survival among patients with AML, even when treated with aggressive chemotherapy and allogeneic stem cell transplant. The frequency of TP53-mutations increases in relapsed and recurrent AML and is associated with chemoresistance. Progress in AML genetics and biology has brought the novel therapies, however, the clinical benefit of these agents for patients whose disease is driven by TP53 mutations remains largely unexplored. This review focuses on the molecular characteristics of TP53-mutated disease; the impact of TP53 on selected hallmarks of leukemia, particularly metabolic rewiring and immune evasion, the clinical importance of TP53 mutations; and the current progress in the development of preclinical and clinical therapeutic strategies to treat TP53-mutated disease.

Functional genetic variants and susceptibility and prediction of gestational diabetes mellitus

The aetiological mechanism of gestational diabetes mellitus (GDM) has still not been fully understood. The aim of this study was to explore the associations between functional genetic variants screened from a genome-wide association study (GWAS) and GDM risk among 554 GDM patients and 641 healthy controls in China. Functional analysis of single nucleotide polymorphisms (SNPs) positively associated with GDM was further performed. Univariate regression and multivariate logistic regression analyses were used to screen clinical risk factors, and a predictive nomogram model was established. After adjusting for age and prepregnancy BMI, rs9283638 was significantly associated with GDM susceptibility (P < 0.05). Moreover, an obvious interaction between rs9283638 and clinical variables was detected (Pinteraction < 0.05). Functional analysis confirmed that rs9283638 can regulate not only target gene transcription factor binding, but it also regulates the mRNA levels of SAMD7 (P < 0.05). The nomogram model constructed with the factors of age, FPG, 1hPG, 2hPG, HbA1c, TG and rs9283638 revealed an area under the ROC curve of 0.920 (95% CI 0.902–0.939). Decision curve analysis (DCA) suggested that the model had greater net clinical benefit. Conclusively, genetic variants can alter women's susceptibility to GDM by affecting the transcription of target genes. The predictive nomogram model constructed based on genetic and clinical variables can effectively distinguish individuals with different GDM risk factors.

Brain modulation after exergaming training in advanced forms of Parkinson’s disease: a randomized controlled study

BackgroundPhysical activity combined with virtual reality and exergaming has emerged as a new technique to improve engagement and provide clinical benefit for gait and balance disorders in people with Parkinson’s disease (PD).ObjectiveTo investigate the effects of a training protocol using a home-based exergaming system on brain volume and resting-state functional connectivity (rs-FC) in persons with PD.MethodsA single blind randomized controlled trial was conducted in people with PD with gait and/or balance disorders. The experimental (active) group performed 18 training sessions at home by playing a custom-designed exergame with full body movements, standing in front of a RGB-D Kinect® motion sensor, while the control group played using the computer keyboard. Both groups received the same training program. Clinical scales, gait recordings, and brain MRI were performed before and after training. We assessed the effects of both training on both the grey matter volumes (GVM) and rs-FC, within and between groups.ResultsTwenty-three patients were enrolled and randomly assigned to either the active (n = 11) or control (n = 12) training groups. Comparing pre- to post-training, the active group showed significant improvements in gait and balance disorders, with decreased rs-FC between the sensorimotor, attentional and basal ganglia networks, but with an increase between the cerebellar and basal ganglia networks. In contrast, the control group showed no significant changes, and rs-FC significantly decreased in the mesolimbic and visuospatial cerebellar and basal ganglia networks. Post-training, the rs-FC was greater in the active relative to the control group between the basal ganglia, motor cortical and cerebellar areas, and bilaterally between the insula and the inferior temporal lobe. Conversely, rs FC was lower in the active relative to the control group between the pedunculopontine nucleus and cerebellar areas, between the temporal inferior lobes and the right thalamus, between the left putamen and dorsolateral prefrontal cortex, and within the default mode network.ConclusionsFull-body movement training using a customized exergame induced brain rs-FC changes within the sensorimotor, attentional and cerebellar networks in people with PD. Further research is needed to comprehensively understand the neurophysiological effects of such training approaches.Trial registration ClinicalTrials.gov NCT03560089.