Clinical Evidence Research Articles

Clinical application and challenges of thermal vapor lung volume reduction

There are major clinical challenges in the management of chronic obstructive pulmonary disease (COPD). Recent studies suggest that thermal vapor lung volume reduction may be an important interventional method in the treatment of emphysema phenotype of COPD. In this article, we reviewed and summarized the research and development, the current situation of clinical application, and the clinical challenges of thermal vapor lung volume reduction, to provide further clinical evidence for the standardized application of thermal vapor lung volume reduction.

Short Bowel Syndrome Is Not a Contraindication for Kidney Transplantation

ABSTRACTBackgroundShort bowel syndrome (SBS) is a malabsorptive condition that develops as a result of massive resection of the small intestine and causes morbidities such as chronic diarrhea, dehydration attacks, parenteral nutrition (PN) dependence, and recurrent infections. Kidney transplantation in this patient group may be complicated by aforementioned morbidities, as well as the absorption problems of immunosuppressive drugs.MethodsWe report the first pediatric patient (18‐month‐old male) with SBS secondary to volvulus who underwent a successful living related kidney transplantation with a primary diagnosis of autosomal recessive polycystic kidney disease and had a successful 4‐year follow‐up without intestinal transplantation.ResultsTacrolimus, mycophenolate mofetil (MMF), and prednisolone were administered for maintenance of immunosuppression after transplantation. The patient reached therapeutic trough levels of tacrolimus with usual doses. The 4‐year renal survival was excellent without a clinical evidence of rejection, despite long‐term necessity of PN and intravenous fluids.ConclusionsKidney transplantation should not be avoided in patients with SBS solely because of concerns about the effectiveness of immunosuppressive therapy. Prednisolone, tacrolimus, and MMF combination was effective in our case, and these drugs can be considered as first‐line agents in these patients.

Nonsurgical Endodontic Retreatment of a Cystic Apical Lesion Associated with Root Resorption: A Promising Approach

This case report highlights the successful management of a cystic apical lesion associated with root resorption through nonsurgical endodontic retreatment, utilizing calcium-enriched mixture (CEM) cement as an obturating biomaterial. A 35-year-old woman presented with mild discomfort in the mandibular right first molar (#46), with radiographic evidence of a well-defined radiolucent lesion at the apex of the mesial root. The tooth had a history of previous failed endodontic treatment with poor root canal obturation, indicating internal root resorption. Nonsurgical endodontic retreatment was performed, and the canals were filled/sealed with CEM cement. Follow-up radiographs showed a gradual reduction in the size of the cystic lesion. At 54 months, complete bone healing of the cystic apical lesion was evident. This case report provides clinical evidence supporting the potential efficacy of nonsurgical endodontic retreatment using CEM cement in managing certain cystic apical lesions, offering a promising alternative to traditional surgical enucleation, even in cases with inflammatory root resorption. Further research is needed to validate the long-term efficacy of this approach in larger patient populations.

Placental Extracts, Proteins, and Hydrolyzed Proteins as Active Ingredients in Cosmetic Preparations for Hair Loss: A Systematic Review of Available Clinical Evidence

Placentae and their derivatives have been used in both traditional and modern medicine, as well as in cosmetic sciences. Although hair loss is frequently mentioned among problems for which the placenta is supposed to be a remedy, the evidence seems rather scarce. The aim of this study was to highlight the clinical evidence for the efficacy of placenta products against baldness and hair loss. Methods: This systematic review was performed according to PRISMA and PICO guidelines. Database searches were conducted in PubMed, Google Scholar and Scopus. Results: Among the 2922 articles retrieved by the query, only 3 previously published clinical trials on placental products were identified. One study was a randomized controlled trial, in which the efficacy of a bovine placenta hair tonic was found to be comparable to that of minoxidil 2% in women with androgenic alopecia. Another controlled study showed that a porcine placenta extract significantly accelerated the regrowth of shaved hair in healthy people. The third study was an uncontrolled trial of a hair shampoo and tonic containing equine placental growth factor in women with postpartum telogen effluvium with unclear and difficult-to-interpret results. Due to the design and methodology of these studies, the level of evidence as assessed with the GRADE method was low for the first study and very low for the other two. Conclusions: The very limited scientific evidence available to date appears, overall, to indicate the efficacy of placental products in both inhibiting hair loss and stimulating hair growth. Unfortunately, the number of clinical studies published to date is very limited. Further, carefully designed, randomized controlled trials of well-defined placental products are needed to definitively address the question of the value of the placenta and its derivatives in hair loss.

Pharmacogenetic testing: current state of the issue

Aim. The purpose of this work is to emphasize the importance and practical benefits of pharmacogenetics in medicine, demonstrating how the integration of pharmacogenetics into clinical practice can improve treatment outcomes and enhance the safety of therapies. Pharmacogenetics is a rapidly developing branch of pharmacology that studies how genetic variation affects an individual’s response to drugs. By understanding these genetic differences, healthcare providers can tailor drug therapy to maximize efficacy and minimize adverse drug reactions. The field aims to move away from the traditional one-size-fits-all approach and instead personalize medical treatment based on a person’s genetic makeup. The ability to predict a person’s response to medication based on their genetic profile has profound implications. For example, pharmacogenetic testing can identify patients at risk for life-threatening adverse drug reactions, such as drug-induced liver injury. This proactive approach can prevent adverse events, improving patient safety and the overall quality of care. In addition, pharmacogenetics aids in the development of new drugs by identifying genetic markers associated with drug responses, optimizing the drug development process, and reducing the time and costs associated with bringing new drugs to market. Key advances in pharmacogenetics include the identification of genetic polymorphisms in enzymes, such as cytochrome P450, that affect drug metabolism, thereby influencing both safety and efficacy. Pharmacogenetic testing allows doctors to predict the best drug and dosage for a patient, improving treatment outcomes and reducing the risk of adverse drug events. Despite its potential, the integration of pharmacogenetics into clinical practice faces challenges, including a lack of reliable clinical evidence, inadequate physician education, and the need for a comprehensive health IT infrastructure to support the use of genetic data. Ethical and legal issues, such as patient privacy and the risk of genetic discrimination, also present significant obstacles. However, continued research, the development of genetic testing technologies, and interdisciplinary collaborations are paving the way for more widespread adoption of pharmacogenetics, which promises to significantly improve patient care and healthcare efficiency. Key resources such as PharmGKB, CPIC, and the NIH provide valuable information and guidance for clinicians, researchers, and students, helping bridge the gap between genetics research and clinical application. Conclusions. Pharmacogenetics represents a significant advancement in personalized medicine, offering the potential to tailor drug therapies to individual genetic profiles. Although the field has made substantial progress, challenges remain in the form of insufficient clinical evidence, implementation barriers, and ethical concerns. Continued research and collaboration among stakeholders are essential to fully realize the benefits of pharmacogenetic testing in clinical practice.

Epigenetic Effects of Natural Products in Inflammatory Diseases: Recent Findings

ABSTRACTInflammation is an essential step for the etiology of multiple diseases. Clinically, due to the limitations of current drugs for the treatment of inflammatory diseases, such as serious side effects and expensive costs, it is urgent to explore novel mechanisms and medicines. Natural products have received extensive attention recently because of their multi‐component and multi‐target characteristics. Epigenetic modifications are crucial pathophysiological targets for developing innovative therapies for pharmacological interventions. Investigations examining how natural products improving inflammation through epigenetic modifications are emerging. This review state that natural products relieve inflammation via regulating the gene transcription levels through chromosome structure regulated by histone acetylation levels and the addition or deletion of methyl groups on DNA duplex. They could also exert anti‐inflammatory effects by modulating the proteins in typical inflammatory signaling pathways by ubiquitin‐related degradation and the effect of glycolysis derived free glycosyls. Studies on epigenetic modifications have the potential to facilitate the development of natural products as therapeutic agents. Future research directed at better understanding of how natural products modulate inflammatory processes through less studied epigenetic modifications including neddylation, SUMOylation, palmitoylation and lactylation, may provide new implications. Meanwhile, higher quality preclinical studies and more powerful clinical evidence are still needed to firmly establish the clinical efficacy of the natural products. Trial Registration: ClinicalTrials.gov Identifier: NCT01764204; ClinicalTrials.gov Identifier: NCT05845931; ClinicalTrials.gov Identifier: NCT04657926; ClinicalTrials.gov Identifier: NCT02330276

Anti‐saccade can be used as a screening tool for early cognitive impairment: a correlation study based on anti‐saccade parameters and cognitive function

AbstractBackgroundEye movement tasks, especially anti‐saccade tasks, have been used to assess cognitive function in patients with neuropsychiatric disorders. Although it has been shown that individuals with cognitive impairment perform worse on anti‐saccades tasks, there is a lack of systematic evaluation of the sensitivity of parameters of anti‐saccades to assess different subtypes of cognitive impairment.MethodsA total of 158 participants were enrolled in this study, consisting of 66 men and 92 women, with an average age of 50.2 ± 10 years. The comparison of pro‐saccade reaction time, anti‐saccade reaction time, and error rates in the saccade task between individuals with cognitive impairments and a normal group was conducted. Furthermore, we systematically analyzed the correlations between the performance in neurological function tests (Mini‐Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Stroop) and these anti‐saccade parameters. Especially, the correlation between these parameters and cognitive function in different domains of the MoCA task were also evaluated.ResultsThe pro‐saccade reaction time, anti‐saccade reaction time and error rate were negatively correlated with the MMSE and MoCA scores (P < 0.001), and positively correlated with the time used in Stroop tasks. Among them, the error rate had the strongest correlation with the performance of MMSE, MoCA and Stroop tasks (MoCA: P < 0.0001, r2 = −0.608; MMSE: P < 0.0001, r2 = −0.344; Stroop: P < 0.0001, r2 = 0.455). Among the seven cognitive domains examined by the MoCA task, error rates had relatively high correlations with visuospatial/executive (P < 0.0001, r2 = −0.4660) and delayed recall (P < 0.0001, r2 = −0.4228) compared to naming, language (P = 0.0004, r2 = −0.0788), attention (P = 0.0004, r2 = −0.0780), abstraction (P < 0.0001, r2 = −0.1515), orientation (P < 0.0001, r2 = −0.1075). Moreover, pro‐saccade reaction time, anti‐saccade reaction time and error rate of people with high MoCA scores were significantly higher than those of people with low MoCA scores, which can be used to identify people with mild cognitive impairment.ConclusionsOur study's results provide valuable clinical evidence supporting the effectiveness of anti‐saccades in assessing cognitive impairment, which is beneficial for screening and timely clinical intervention in individuals with specific cognitive impairment.

Sensitive Detection of Gynecological Cancer Recurrence Using Circulating Tumor DNA and Digital PCR: A Comparative Study with Serum Biochemical Markers

Early detection of recurrences in gynecological cancers is crucial for women’s health. Circulating tumor DNA (ctDNA) analysis through liquid biopsy offers a promising approach for monitoring disease progression and identifying relapses. This study investigated the utility of digital Polymerase Chain Reaction (dPCR) for ctDNA detection in three gynecological cancer patients with clinically confirmed relapses during a two-year post-surgical follow-up. Patient-specific tumor mutations were identified through whole-exome sequencing (WES) and confirmed via Sanger sequencing. dPCR probes targeting these mutations were used to quantify the ctDNA levels in plasma samples collected throughout the follow-up period, and the findings were compared with standard serum biochemical markers. In two patients, persistent positive dPCR signals for the selected mutations were detected after tumor removal, with ctDNA levels progressively increasing even after post-surgical chemotherapy. Notably, dPCR identified elevated ctDNA levels before an increase in the cancer antigen 125 (CA125) biochemical marker was observed. In the third patient, no ctDNA signals from the two selected mutations were detected despite clinical evidence of recurrence, suggesting the emergence of new mutations. While this study highlights the promise of dPCR for early recurrence detection in gynecological cancers, it also underscores the critical need for comprehensive mutation panels to overcome the inherent challenges posed by tumor heterogeneity and the emergence of new mutations during disease progression.

Synopsis of the 2023 U.S. Department of VA and U.S. DoD Clinical Practice Guideline for the Management of Pregnancy

ABSTRACT Introduction This Clinical Practical Guideline provides recommendations based on a systematic review of the evidence to address critical decision points in the management of pregnancy. The guideline is intended to improve patient outcomes and local management of patients who are pregnant. This CPG is based on a systematic review of both clinical and epidemiological evidence and was developed by a panel of multidisciplinary experts. The Work Group provides clear and comprehensive evidence-based recommendations incorporating current information and practices targeting practitioners throughout the DoD and VA Health Care systems. The guideline is intended to improve patient outcomes and local management of patients who are pregnant. This CPG does not address every aspect of routine pregnancy care and is not intended to be a comprehensive guide to all care needed in pregnancy. It also addresses some clinically important and generally accepted standards of pregnancy care interventions that do not have sufficient high-quality evidence to support standalone recommendations. Additionally, it highlights emerging topics that have the potential to impact pregnancy care in the future and identifies gaps in the literature that warrant further research. Materials and Methods The development of all VA/DoD guidelines is directed by the Evidence-Based Practice Guideline Work Group and adheres to the standards for trustworthy guidelines that were set by the National Academy of Medicine. A patient focus group was convened to assess important aspects of treatment for patients and to gain information about patient values and preferences. The Lewin Group, a contracted third party with expertise in CPG development, facilitated meetings and the development of key questions using the population, intervention, comparison, outcome, timing, and setting format. Consensus was achieved among the Work Group through an iterative process involving discussions on conference calls and in person during the recommendation development meeting. An independent third party, ECRI, conducted the systematic evidence review, which the guideline Work Group then used to develop recommendations using the Grading of Recommendations Assessment, Development and Evaluation system (7-9). The search methods and results are detailed in the full guideline. Results This CPG provides 28 clinical practice recommendations that cover selected topics that the Work Group deemed had high priority need for evidence-based standards. The recommendations are divided into 3 main categories: routine care, complicated obstetrics, and mental health. An algorithm delineating recommended interventions and appropriate timing of these interventions over the course of the pregnancy and postpartum period was also created. Conclusion The CPG is not intended to define standards of care nor address all care needed in pregnancy; it does provide comprehensive guidance for routine pregnancy care. It aligns with the VA and DOD’s goal of providing care that is consistent in quality and utilization of resources in efforts to reduce errors and inappropriate variations in practices. In total, the Work Group identified 71 items needing further study, including areas requiring stronger evidence to support current recommendations and newer topics that will guide future guideline development.

Patient considerations when using ritlecitinib for alopecia areata in adolescents: Guidance for the clinicians

Background: Alopecia areata (AA) is an autoimmune disease characterized by non-scarring hair loss that can affect children, adolescents, and adults. Ritlecitinib, an orally administered Janus kinase (JAK) 3/tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family inhibitor, is the first and currently the only treatment approved by the United States Food and Drug Administration for adolescents (aged 12-17 years) with severe AA. Summary: The ALLEGRO Phase 2b–3 trial demonstrated that 25% and 50% of adolescents with a Severity of Alopecia Tool (SALT) score ≥50 at baseline achieved a SALT score ≤20 at week 24 and week 48 after receiving 50mg ritlecitinib daily, respectively. The most common adverse events were headache, acne, and nasopharyngitis in adolescents. This review summarizes the mechanism of action, clinical trial evidence on efficacy and safety profile, factors associated with treatment response to JAK inhibitors for AA, and vaccination considerations for adolescents. Key Messages: This review aims to facilitate the risk-benefit assessment and shared decision-making between clinicians and patients and provide clinical considerations and management recommendations for ritlecitinib use in adolescents with AA.

The cellular and molecular mechanisms mediating the protective effects of sodium-glucose linked transporter 2 inhibitors against metabolic dysfunction-associated fatty liver disease.

Metabolic dysfunction-associated fatty liver disease (MAFLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is a common, highly heterogeneous condition that affects about a quarter of the world's population, with no approved drug therapy. Current evidence from preclinical research and a number of small clinical trials indicates that SGLT2 inhibitors could also be effective for MAFLD. MAFLD is associated with a higher risk of chronic liver disease and multiple extrahepatic events, especially cardiovascular disease (CVD) and chronic kidney disease (CKD). MAFLD is considered a more appropriate terminology than NAFLD because it captures the complex bidirectional interplay between fatty liver and metabolic dysfunctions associated with disease progression, such as obesity and type 2 diabetes mellitus (T2DM). SGLT2 inhibitors are antidiabetic drugs that block glucose reabsorption in the kidney proximal tubule. In this article, we reviewed current clinical evidence supporting the potential use of SGLT2 inhibitors as a drug therapy for MAFLD and discussed the possible cellular and molecular mechanisms involved. We also reviewed the clinical benefits of SGLT2 inhibitors against MAFLD-related comorbidities, especially CVD, CKD and cardiovascular-kidney-metabolic syndrome (CKM). The broad beneficial effects of SGLT2 inhibitors support their use, likely in combination with other drugs, as a therapy for MAFLD.

The vague language use scale: Clinical utility and psychometrics from adults with traumatic brain injury.

Pragmatic communication difficulties encompass many distinct behaviours, including the use of vague and/or insufficient language, a common characteristic following traumatic brain injury (TBI) that negatively impacts psychosocial outcomes. Existing assessments evaluate pragmatic communication broadly, often with only one or two items capturing each behaviour, thus limiting sensitivity and precision to variations within each behaviour. Given that greater nuance is needed to detect subtle pragmatic communication differences and investigate underlying cognitive mechanisms, a more refined measure is critical to improve psychosocial outcomes. The Vague scale was developed to address those needs. To provide preliminary evidence supporting the novel Vague language use (Vague) scale's reliability, validity and clinical utility. The Vague scale rates each discourse sample utterance for vague language use on a 3-point scale; the measure's Vague score represents the mean of utterance-level ratings. Using the Vague scale, two raters naïve to diagnosis evaluated Cinderella narratives of 46 adults with severe TBI and 46 controls with no brain injury, providing reliability, construct validity and classification accuracy evidence. Vague scores were also compared to other clinical measures to gather criterion-related validity evidence. Interrater agreement across all transcripts was moderate. Construct validity was supported by expected group differences and criterion validation, including significant relationships with increased violations of Grice's maxim of quantity and measures of lexical variation; significant relationships with psychosocial outcomes, supporting clinical utility; and nonsignificant relationships with measures of syntax and overall pragmatic communication. Classification accuracy expectedly did not support using Vague scores in isolation for diagnosis, due to unacceptable sensitivity (0.696). Evidence supported the Vague scores' psychometric properties. Thus, the Vague scale shows promise as a measure of one distinct pragmatic communication behaviour: vague language use. Future research should apply the Vague scale to determine its sensitivity in individuals with subtle social communication challenges (e.g., mild TBI), explore its utility with more naturalistic discourse samples as part of a pragmatic communication battery, longitudinally examine changes in Vague scores, and investigate cognitive mechanisms underlying this specific pragmatic communication behaviour. What is already known on this subject Use of vague language is common following traumatic brain injury (TBI) and may contribute to negative psychosocial outcomes related to employment and relationships. However, existing measures of vague language lack sensitivity and precision, limiting their utility for identifying subtle performance variations or determining the cognitive mechanisms underlying this specific pragmatic communication behaviour. What this study adds to existing knowledge The current study gathered promising reliability, validity and clinical utility evidence to support using the novel Vague language use (Vague) scale, which was developed to address these limitations. Based on complex (Cinderella) stories of adults with and without TBI, Vague scores demonstrated moderate interrater agreement and promising construct validity based on expected group differences and criterion validation, including moderate associations with related constructs and weak associations with unrelated constructs. Because pragmatic communication profiles post-TBI can vary, classification accuracy expectedly indicated that Vague scores should not be used alone to identify communication differences post-TBI. What are the clinical implications of this work? Vague scores show promise for documenting clients' use of vague language and planning intervention to address associated discourse-level challenges. Future research should investigate applying the Vague scale to naturalistic discourse samples (1) as part of a battery that sensitively and precisely identifies pragmatic communication differences and (2) as a tool for investigating cognitive mechanisms underlying vague language use, with the goal of improving interventions that support pragmatic communication and enhance psychosocial outcomes.

Early and Late Intrinsic Hand Muscle Reinnervation After End-to-Side AIN to Ulnar Motor Nerve Transfer.

The "supercharge" end-to-side (SETS) anterior-interosseous-nerve (AIN) to ulnar-motor nerve transfer is used to improve intrinsic muscle recovery in cases of severe ulnar nerve compression or proximal axonotmetic injuries. Previous work has found differing intrinsic muscle recovery after this transfer. The objectives of this study were to examine the patterns of recovery in first dorsal interossei (FDI) and abductor digiti minimi (ADM) and the impact of AIN transfer to a specific fascicular location on the ulnar-motor nerve. A retrospective review of one fellowship-trained surgeon's consecutive patients at a single center from December 2019 to September 2021 was conducted. Patients who had an AIN to ulnar-motor nerve transfer for any indication were included and were excluded if they had less than 9 months follow-up. Seventeen patients were included (88% male, mean age 55 ± 14 years). At early follow-up, compound muscle action potential amplitudes for ADM and FDI did not increase. Compound muscle action potential amplitude for ADM significantly increased at late follow-up (P < .01). Average British Medical Research Council (BMRC) strength increased at early follow-up for FDI (P < .05), but not ADM. The proportion of patients with BMRC ≥ 3 increased for FDI (P < .01) and ADM (P < .05) at late follow-up. Volar-ulnar AIN insertion position did not have a clear effect on outcomes. The SETS AIN to ulnar-motor nerve transfer demonstrates clinical and electrophysiologic evidence of intrinsic muscle recovery and reinnervation, with differing recovery of outcomes. The role of specific fascicular targeting is still unclear and required further examination as does the mechanism behind differing intrinsic recovering.

Curating genomic disease-gene relationships with Gene2Phenotype (G2P)

Genetically determined disorders are highly heterogenous in clinical presentation and underlying molecular mechanism. The evidence underpinning these conditions in the peer-reviewed literature requires robust critical evaluation for diagnostic use. Here, we present a structured curation process for Gene2Phenotype (G2P). This draws on multiple lines of clinical, bioinformatic and functional evidence. The process utilises and extends existing terminologies, allows for precise definition of the molecular basis of disease, and confidence levels to be attributed to a given gene-disease assertion. In-depth disease curation using this process will prove useful in applications including in diagnostics, research and development of targeted therapeutics. G2P: www.ebi.ac.uk/gene2phenotype.

Cost-Effectiveness of Radiofrequency Renal Denervation for Uncontrolled Hypertension in Japan.

Radiofrequency renal denervation (RF RDN) is a novel therapy for uncontrolled hypertension. In the recent sham-controlled SPYRAL HTN-ON MED study, office-based systolic blood pressure (oSBP) and nighttime BP were reduced significantly. This study examined the cost-effectiveness of RF RDN in the context of the Japanese healthcare system based on this latest clinical evidence. Clinical events, costs, and quality-adjusted life-years (QALYs) were projected using a decision-analytic Markov model adjusted to Japanese incidence data. Risk reduction in clinical events from changes in oSBP was calculated based on a published meta-regression of 47 trials of intentional hypertension treatment. Demographics and results from the SPYRAL HTN-ON MED trial (oSBP effect size -4.9mmHg vs. sham) were utilized in the base case analysis. Additional scenarios were explored including the potential added benefit of improved night-time control. Costs were sourced from claims data and published literature. The incremental cost-effectiveness ratio (ICER) was evaluated against a cost-effectiveness threshold of ¥5000000 per QALY gained. RF RDN was projected to reduce clinical events (10-year relative risks: 0.80 for stroke, 0.88 for myocardial infarction, and 0.75 for heart failure). Over lifetime, RF RDN added 0.36 QALYs at the incremental cost of ¥923723, resulting in an ICER of ¥2565236 per QALY gained. Under the assumption of added night-time benefit, the ICER decreased to ¥2155895 per QALY. Cost-effectiveness findings were robust across all tested scenarios. The findings of this model-based analysis suggest that RF RDN can provide meaningful clinical event reductions and is a cost-effective treatment option in the Japanese healthcare system.

Unveiling tomorrow: Carbonic anhydrase activators and inhibitors pioneering new frontiers in Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder and a principal basis of dementia in the elderly population globally. Recently, human carbonic anhydrases (hCAs, EC 4.2.1.1) were demonstrated as possible new targets for treating AD. hCAs are vital for maintaining pH balance and performing other physiological processes as they catalyze the reversible hydration of carbon dioxide to bicarbonate and a proton. Current research indicates that hCA plays a role in brain functions critical for transmitting neural signals. Activation of carbonic anhydrase (CA) has emerged as a promising avenue in addressing memory loss and cognitive issues. Conversely, the exploration of CA inhibition represents a novel frontier in this field. By enhancing glial fitness and cerebrovascular health and blocking amyloid-β (Aβ)-induced mitochondrial dysfunction pathways, cytochrome C (CytC) release, caspase 9 activation, and H2O2 generation in neurons, CA inhibitors improve cognition and lessen the pathology caused by Aβ. Recent research has pushed hCAs into the spotlight as critical players in AD pathogenesis and precise therapeutic targets. The captivating dilemma of choosing between hCA inhibitors and activators looms large, as inhibitors reduce Aβ aggregation and improve cerebral blood flow, while activators enhance cerebrovascular functions and restore pH balance. The current review sheds light on the clinical evidence for hCAs and the roles of inhibitors and activators in AD. Additionally, this review offers a fascinating outlook on the data that may aid medicinal chemists in designing and developing new leads that are more effective and selective for upcoming in vitro and in vivo studies, allowing for the discovery and introduction of novel drug candidates for the treatment of AD to the market and into the clinical pipeline.

Predictive values of four nutritional indices for adverse outcomes in patients with hypertension.

Malnutrition, evaluated by nutritional indices, is reportedly related to a poor prognosis in patients with hypertension. However, clinical evidence on which index is more suitable for predicting a kidney prognosis is limited, and it has not been evaluated in hypertension. The aim of the present study was to investigate and compare the predictive values of four nutritional indices: Geriatric Nutritional Risk Index (GNRI); Prognostic Nutrition Index (PNI); Triglycerides × Total cholesterol × Body weight Index (TCBI); and the controlling nutritional status (CONUT) score. A retrospective, cohort study of 1255 hypertensive patients under care in the Fukushima Cohort Study was conducted. The primary outcome was kidney events, defined as a combination of a 50% decline in eGFR from baseline and renal failure requiring dialysis therapy or kidney transplantation. Kaplan-Meier analyses and multivariate Cox regression analyses were conducted to examine associations between the four nutritional indices and kidney events. The area under the curve (AUC) values of the receiver-operating characteristic curves were also examined to compare the predictive values of these nutritional indices. Lower GNRI, lower PNI, and higher CONUT score were significantly related to a higher risk of kidney events. GNRI (AUC = 0.729, 95% confidence interval 0.681-0.777) and PNI (AUC = 0.710, 95% confidence interval 0.665-0.756) had significantly higher AUCs for kidney events than the TCBI and CONUT score. GNRI and PNI showed greater predictive values for kidney events than other nutritional indices in patients with hypertension.

Capturing Hydrophilic Chemotherapeutics Agents Into siRNA-Encapsulated Vesicle-Like Nanoparticles for Convenient ICB-Chemo Combination Therapy.

Clinical evidence has demonstrated that combining immune checkpoint blockade (ICB) therapy with chemotherapy significantly improves response rates to ICB therapy and therapeutic efficacy in various tumor types. However, a convenient method for achieving synergistic ICB therapy and chemotherapy with precise co-delivery of both agents is still highly desirable. In this study, a strategy for co-delivering small interfering RNA (siRNA) encapsulated in vesicle-like nanoparticles (VNPsiRNA) and chemotherapeutic drugs is aimed to develop. It is discovered that the hydrophilic chemotherapeutic drug mitoxantrone hydrochloride (MTO·2HCl) can be captured into VNPsiRNA. The resulting VNPsiRNACpMTO can simultaneously block immune checkpoints via RNA silencing and induce chemotherapeutic effects on tumor cells. The mechanism of MTO·2HCl is elucidates, captures, and demonstrates the superior therapeutic effect of VNPsiRNACpMTO through chemo-immunotherapy. This strategy can also be extended to deliver other hydrochloride anticancer drugs, such as doxorubicin hydrochloride (DOX·HCl), for achieving synergistic combination therapy. This study provides a facile strategy for enhancing combined ICB and chemotherapy via co-delivering siRNA and chemotherapeutic drugs, offering a promising approach to cancer treatment.

Insights From the ISASS Webinar Series on Current and Emerging Techniques in Endoscopic Spine Surgery | Part 1: Polytomous Rasch Analysis of Surgeon Endorsement of Endoscopic Discectomy/Foraminotomy, Interbody Fusion, and Importance of Patient Feedback During Surgery.

The International Society for the Advancement of Spine Surgery hosted the first of a series of 4 webinars on endoscopic spine surgery techniques, focusing on end§oscopic discectomy, foraminotomy, instrumented endoscopic fusion, standalone lumbar interbody fusion with innovative materials, and the role of patient feedback in awake procedures. This series aims to share knowledge and discuss the complexities and clinical evidence of modern endoscopic spine surgery. To analyze the level of surgeon endorsement for the presented endoscopic spine surgery techniques before and after the webinar, utilizing polytomous Rasch analysis, and to evaluate the potential for these insights to inform clinical guideline recommendations. A survey was available to 1311 potential respondents during the Zoom webinar, collecting data on surgeon endorsements using a Likert scale. The polytomous Rasch model was employed to analyze responses, considering the complexity of decisions against surgeon expertise, developing a logarithmic measurement scale, allowing objective statistical analysis of categorical variables, highlighting incongruent or out-of-order items vs congruent and in-order items, and driving improvement in clinical guidelines. All 4 topics received higher confidence ratings demonstrated by descriptive statistics, highlighting the webinar's effective role in surgeon education and in identifying ongoing trends in spine surgery. The logarithmic transformation of these data during Rasch analysis showed noticeable shifts in surgeon confidence levels postwebinar, with increased endorsement for transforaminal full-endoscopic thoracolumbar interbody fusion for hard disc herniation and standalone endoscopic lumbar interbody fusion. The Wright plot and person-item map analyses demonstrated that the webinar effectively targeted areas of initial low confidence, significantly impacting surgeons' perceptions. Disordered endorsement thresholds remained in the topics of uniportal transforaminal discectomy/foraminotomy and patient feedback during endoscopic spine surgery, indicating issues in response category discrimination or confounding factors not captured by the survey. Ongoing controversies were highlighted by the influence of confounding factors, stemming from preconceived notions and limited familiarity with high-grade evidence. The first in the 4-part webinar series effectively shifted professional confidence and acceptance of innovative surgical approaches among spine surgeons. Observations indicated a high level of interest in applying the endoscopic surgery platform with other advanced technologies. The polytomous Rasch analysis provided nuanced insights into ongoing trends and areas in need of further clarification. Assessing surgeon confidence and acceptance of endoscopic spinal surgeries using polytomous Rasch analysis. Level 2 (inferential) and 3 (observational) evidence because Rasch analysis provides statistical validation of instruments rather than direct clinical outcomes.

Entering the Temple of Mars: Why There Is Not Substitute for the Spiritual in War

Recent scholarship validates the importance of spirituality and spiritual fitness. This article operationalizes the 2023 article “Holistic Health as a Twenty-First-Century Military Strategy: Stoic Philosophy and Spiritual Fitness for Optimizing Warfighter Readiness,” which argues that the U.S. Department of Navy should actively advocate spiritual fitness at the unit level as a means of improving military personnel’s overall health and readiness. Accordingly, this article aims to provide a scholarly response to the concept of spiritual fitness that has been discussed in various official U.S. Marine Corps documents, including Spiritual Fitness, All Marine Corps Activities (ALMAR) 033/16 (2016); Resiliency and Spiritual Fitness, ALMAR 027/20 (2020); Spiritual Fitness, ALMAR 020/24 (2024); Spiritual Fitness Leader’s Guide, Marine Corps Reference Publication 6-10.1 (2023); and Religious Ministry in the United States Marine Corps, Marine Corps Tactical Publication 3-30D (2023). This article offers a comprehensive understanding of the subject and its relevance to the Marine Corps. It does so by tracing the significance of spirituality in these documents back through Marine Corps history to Lieutenant General John A. Lejeune’s famous statement, “There is no substitute for the spiritual in war.” As such, the article systematically reviews the importance of spirituality through the statements of famed Marine Corps commandants, other revered Marine Corps leaders, as well as celebrated military leaders, noted military strategists, and philosophers. In so doing, it emphasizes the necessity of operationalizing spiritual fitness at the unit level to improve military personnel’s overall health and readiness. To this end, recent scholarship validates the importance of spirituality and spiritual fitness, supporting what many military commanders have always believed about the need for spiritual fitness. As such, the article highlights how command leadership can effectively build character and achieve this result by operationalizing spiritual fitness at the unit level in order to “enter the temple of Mars,” if called on to do so. The article concludes by acknowledging that clinical evidence and practical military wisdom validate the crucial importance of spiritual fitness in character development, military readiness, and battlefield victory.