Exploring the link between comorbidities and Alzheimer's dementia in the Australian Imaging, Biomarker & Lifestyle (AIBL) study.

INTRODUCTION: Mounting evidence suggests that certain comorbidities may influence the clinical evolution of Alzheimer's dementia (AD). METHODS: We conducted logistic regression analyses on the medical history and cognitive health diagnoses of participants in the Australian Imaging, Biomarker & Lifestyle study (n = 2443) to investigate cross-sectional associations between various comorbidities and mild cognitive impairment (MCI)/AD. RESULTS: A mixture of associations were observed. Higher comorbidity of anxiety and other neurological disorders was associated with higher odds of AD, while arthritis, cancer, gastric complaints, high cholesterol, joint replacement, visual defect, kidney and liver disease were associated with lower odds of AD. DISCUSSION: This study underscores the links between specific comorbidities and MCI/AD. Further research is needed to elucidate the longitudinal comorbidity-MCI/AD associations and underlying mechanisms of these associations. Highlights: Comorbidities that significantly increased AD odds included anxiety and other neurological disorders.Arthritis, cancer, gastric complaints, high cholesterol, joint replacement, visual defect, kidney and liver disease were associated with lower odds of AD.Alcohol consumption had the most significant confounding effect in the study.Visual-AD association was modified by age, sex, and APOE ε4 allele status.Anxiety-AD and depression-AD associations were modified by sex.

Impact of age at ivacaftor initiation on pulmonary outcomes among people with cystic fibrosis.

BACKGROUND: Ivacaftor (IVA) improves lung function and other extrapulmonary outcomes in people with cystic fibrosis (CF). However, the effect of initiating IVA at earlier versus later ages has not been studied. METHODS: We conducted an observational cohort study of people in the US CF Foundation Patient Registry aged ≥6 years with ≥1 CF transmembrane conductance regulator-gating mutation to compare the effects of initiating IVA at earlier ages on per cent predicted forced expiratory volume in 1 s (ppFEV1) and pulmonary exacerbation (PEx) outcomes. People with CF were grouped by age at IVA initiation (ages 6-10, 11-15, 16-20 and 21-25 years) to perform three analyses of younger versus older IVA initiation (6-10 vs 11-15, 11-15 vs 16-20 and 16-20 vs 21-25 years). For each analysis, baseline characteristics assessed over 1-year periods at the same age prior to IVA initiation were balanced by standardised mortality/morbidity ratio (SMR) weighting. For each analysis, outcomes were compared over a 5-year outcome assessment period when both groups were in the same age range and receiving IVA. FINDINGS: Baseline characteristics were well balanced between younger and older IVA initiator groups after SMR weighting. In the outcome assessment period, younger IVA initiators had significantly higher mean ppFEV1 than older initiators across all comparisons, and those initiating IVA between ages 6-10 and 11-15 years had significantly lower PEx rates. INTERPRETATION: Study findings showed the importance of early IVA initiation in people with CF.

Emerging Medications and Strategies in Acute Pain Management: Evolving Role of Novel Sodium and Calcium Channel Blockers, Peptide-Based Pharmacologic Drugs, and Non-Medicinal Methods.

PURPOSE OF REVIEW: The present investigation evaluated integration of novel medication technology to enhance treatment options, while improving patient outcomes in acute pain management. In this regard, we focused on determining the role of development and utilization of cutting-edge pharmaceutical advancements, such as targeted drug delivery systems, as well as non-pharmacologic interventions in addressing acute pain states. Further research in this area is warranted related to the need for increased patient comfort and reduced adverse effects. RECENT FINDINGS: Recent innovations and techniques are discussed including pharmacologic drugs targeting sodium and calcium channels, peptide-based pharmacologic drugs, and non-medicinal methods of alleviating pain such as soothing music or virtual reality. The present investigation included review of current literature on the application of these innovative technologies, analyzing mechanisms of action, pharmacokinetics, and clinical effectiveness. Our study also investigated the potential benefits in terms of pain relief, reduced side effects, and improved patient adherence. The research critically examines the challenges and considerations associated with implementing these technologies in acute pain management, considering factors like cost, accessibility, and regulatory aspects. Additionally, case studies and clinical trials are highlighted which demonstrate practical implications of these novel medication technologies in real-world scenarios. The findings aim to provide healthcare professionals with a comprehensive understanding of the evolving landscape in acute pain management while guiding future research and clinical practices toward optimizing their use in enhancing patient care.

Peripheral Nerve Stimulation in Postoperative Analgesia: A Narrative Review.

PURPOSE OF REVIEW: Recent research has shown the effectiveness of peripheral nerve stimulators (PNS) in managing chronic pain conditions. Ongoing studies aim to explore its potential application in treating acute postoperative pain states. The purpose of this systematic review is to assess the role of PNS in providing relief for postoperative pain. RECENT FINDINGS: Clinical studies investigating the use of peripheral nerve stimulators (PNS) for analgesia following various surgeries, such as total knee arthroplasty, anterior cruciate ligament repair, ankle arthroplasty, rotator cuff repair, hallux valgus correction, and extremity amputation, have shown promising results. Lead placement locations include the brachial plexus, sciatic, femoral, tibial, genicular, perineal, sural, radial, median, and ulnar nerves. These studies consistently report clinically significant reductions in pain scores, and some even indicate a decrease in opioid consumption following PNS for postoperative pain. PNS involves the subcutaneous placement of electrode leads to target peripheral nerve(s) followed by delivery of an electric current via an external pulse generator. While the precise mechanism is not fully understood, the theory posits that PNS modulates electrical stimulation, hindering the signaling of nociceptive pain. PNS presents itself as an alternative to opioid therapy, holding promise to address the opioid epidemic by offering a nonpharmacologic approach for both acute and chronic pain states.

Early outcomes associated with de novo once-daily extended-release versus twice-daily immediate-release tacrolimus in a predominantly African American kidney transplant population: A single-center observational study.

INTRODUCTION: The purpose of this study was to compare early outcomes of de novo LCPT (once-daily extended-release tacrolimus) to IR TAC (twice-daily immediate-release tacrolimus) in a predominantly African American (AA) adult kidney transplant population. METHODS: This is a single center, retrospective cohort study. Patients were divided into two cohorts: IR TAC (administered between January 1, 2017, and January 31, 2019) and LCPT (administered between February 1, 2019, and May 31, 2020). Primary endpoints were changes in tacrolimus trough levels (ng/mL) and estimated glomerular filtration rate up to 12 months post-transplantation. Clinical endpoints included graft survival, delayed graft function, biopsy-proven rejection, CMV viremia, and BK. A propensity score weighted generalized linear mixed effects model was used for analysis. RESULTS: The rate of change in tacrolimus levels was significantly higher in the LCPT cohort compared to the IR TAC cohort at 14 days post-discharge (.2455 ng/mL per day vs. .1073 ng/mL, respectively; p < .001). Subsequently, the LCPT cohort had a slightly higher rate of decline (-.015 ng/mL per day vs. -.010 ng/mL with IR TAC; p = .0894) up to 12 months post-discharge. Although eGFR was similar between the two cohorts at 12 months post-transplant, the rate of increase was slower in the LCPT cohort (.1371 mL/min per day vs. .1852 mL/min per day, p = .0314). No significant differences were found in graft survival, DGF, BPAR, CMV, or BK infection. CONCLUSION: This study demonstrates that despite higher early trough levels with immediate post-transplant LCPT use, clinical outcomes are comparable to IR TAC at one-year post-transplant. Notably, LCPT use does not increase the incidence of DGF and that this formulation of CNI can be used as first line therapy post-transplant.

Differential transcript usage across mammalian oocytes at the germinal vesicle and metaphase II stages.

Ongoing progress in mRNA-Sequencing technologies has significantly contributed to the refinement of assisted reproductive technologies. However, the prior investigations have predominantly concentrated on alterations in overall gene expression levels, thereby leaving a considerable gap in our understanding of the influence of transcript isoform expression on fundamental cellular mechanisms of oocytes. Given the efficacy of differential transcript usage (DTU) analysis to address such knowledge, we conducted comprehensive DTU analysis utilizing mRNA-Seq datasets of germinal vesicle (GV) and metaphase II (MII) oocytes across six mammalian species from the SRA database, including cow, donkey, horse, human, mouse, and pig. To further illuminate the roles of these genes, we also conducted a rigorous Gene Ontology (GO) term enrichment analysis. While the DTU analysis of each species exhibited several genes with alterations in their transcript isoform usage, referred to as DTU genes, this study focused on only ten cross-species DTU genes sharing among a minimum of five distinct species (FDR≤0.05). These cross-species DTU genes were as follows: ABCF1, CDC6, CFAP36, CNOT10, DNM3, IWS1, NBN, NDEL1, RAD50 and ZCCHC17. GO term enrichment analysis unveiled the alignment of these cross-species DTU gene functions with RNA and cell-cycle control mechanisms across diverse mammalian species, thereby suggesting their vital roles during oocyte maturation. Further exploration of the transcript isoforms of these genes hence bore the potential to uncover novel transcript isoform markers for future reproductive technologies in both human and animal contexts.

LUMBAR Syndrome and Bladder Exstrophy: A Case Report.

LUMBAR syndrome is rare with a multitude of features that requires a high index of suspicion for timely diagnosis and appropriate management. We present on a newborn female whose untreated segmental infantile hemangioma lead to poor healing of her bladder exstrophy closure. The objective of this report is to describe bladder exstrophy as a urogenital anomaly in patients with LUMBAR syndrome and the importance of balancing management of infantile hemangioma and time to surgery.

Mid-infrared supermirrors with finesse exceeding 400 000.

For trace gas sensing and precision spectroscopy, optical cavities incorporating low-loss mirrors are indispensable for path length and optical intensity enhancement. Optical interference coatings in the visible and near-infrared (NIR) spectral regions have achieved total optical losses below 2 parts per million (ppm), enabling a cavity finesse in excess of 1 million. However, such advancements have been lacking in the mid-infrared (MIR), despite substantial scientific interest. Here, we demonstrate a significant breakthrough in high-performance MIR mirrors, reporting substrate-transferred single-crystal interference coatings capable of cavity finesse values from 200 000 to 400 000 near 4.5 µm, with excess optical losses (scatter and absorption) below 5 ppm. In a first proof-of-concept demonstration, we achieve the lowest noise-equivalent absorption in a linear cavity ring-down spectrometer normalized by cavity length. This substantial improvement in performance will unlock a rich variety of MIR applications for atmospheric transport and environmental sciences, detection of fugitive emissions, process gas monitoring, breath-gas analysis, and verification of biogenic fuels and plastics.

Utilizing a quality of life tool to examine the presence of fatigue in subjects with diabetes mellitus.

Introduction: The prevalence of fatigue in patients with diabetes mellitus (DM) can be as high as 50 %. Physical, mental, and psychosocial components of fatigue negatively impact quality of life (QOL), morbidity and mortality. Several tools have been developed to address fatigue, but none specifically for measuring fatigue in DM. The aim of this study was to assess the impact of diabetes and neuropathy on fatigue using the Norfolk QOL-Fatigue (QOL-F) survey. Methods: 605 adult participants from [Anonymous] were recruited (400 subjects with type 1 or type 2 DM and 205 subjects without diabetes (controls)). All subjects completed the Norfolk QOL-F. Demographics, weight, BMI, and duration of diabetes were obtained. The Norfolk QOL-F, a 35-item validated questionnaire, assesses five domains: subjective fatigue, physical and cognitive fatigue, reduced activities, impaired activities of daily living, and depression. Results: Subjects with DM reported significantly higher fatigue total scores (52.63vs33.89, p < 0.0001) and in all five domains when compared to controls. Patients with DM with neuropathy were significantly more fatigued than those without (59.72vs27.83, p < 0.0001). Fatigue scores in patients with DM without neuropathy were similar to controls (27.83vs33.89, p = NS). In multivariate analysis, age, gender, and presence of neuropathy significantly impacted fatigue scores. Conclusions: The Norfolk QOL-F questionnaire can potentially identify the impact of chronic diseases such as diabetes on fatigue. Assessing the different components of fatigue is important for clinicians in improving disease management and outcomes. Further investigations are needed to confirm these observations in specific cohorts with other comorbidities.

Cross-species analysis of differential transcript usage in humans and chickens with fatty liver disease.

Background and Aim: Fatty liver disease is a common condition, characterized by excess fat accumulation in the liver. It can contribute to more severe liver-related health issues, making it a critical concern in avian and human medicine. Apart from modifying the gene expression of liver cells, the disease also alters the expression of specific transcript isoforms, which might serve as new biological markers for both species. This study aimed to identify cross-species genes displaying differential expressions in their transcript isoforms in humans and chickens with fatty liver disease. Materials and Methods: We performed differential gene expression and differential transcript usage (DTU) analyses on messenger RNA datasets from the livers of both chickens and humans with fatty liver disease. Using appropriate cross-species gene identification methods, we reviewed the acquired candidate genes and their transcript isoforms to determine their potential role in fatty liver disease's pathogenesis. Results: We identified seven genes - ALG5, BRD7, DIABLO, RSU1, SFXN5, STIMATE, TJP3, and VDAC2 - and their corresponding transcript isoforms as potential candidates (false discovery rate ≤0.05). Our findings showed that these genes most likely contribute to fatty disease development and progression. Conclusion: This study successfully identified novel human-chicken DTU genes in fatty liver disease. Further research is encouraged to verify the functions and regulations of these transcript isoforms as potential diagnostic markers for fatty liver disease in humans and chickens.

Hydrogen-Bonded Complexes in Binary Mixture of Imidazolium-Based Ionic Liquids with Organic Solvents.

Though local structures in ionic liquids are dominated by strong Coulomb forces, directional hydrogen bonds can also influence the physicochemical properties of imidazolium-based ionic liquids. In particular, the C-2 position of the imidazolium cation is acidic and can bind with suitable hydrogen bond acceptor sites of molecular solvents dissolved in imidazolium-based ionic liquids. In this report, we identify hydrogen-bonded microenvironments of the model ionic liquid, 1-ethyl-3-methylimidazolium tris(pentafluoroethyl) trifluorophosphate, and the changes that occur when molecular solvents are dissolved in it by using a C-D infrared reporter at the C-2 position of the cation. Our linear and nonlinear infrared experiments, along with computational studies, indicate that the molecular solvent dimethyl sulfoxide can form strong hydrogen-bonded dimers with the cation of the ionic liquid at the C-2 position. In contrast, acetone, which is also a hydrogen bond acceptor similar to dimethyl sulfoxide, does not show evidence of cation-solvent hydrogen-bonded conformers at the C-2 position. The outcome of our study on a broad scale strengthens the importance of cation-solute interactions in ionic liquids.

Pharmacology and Therapeutic Potential of Benzothiazole Analogues for Cocaine Use Disorder.

Pharmacological targeting of the dopamine D4 receptor (D4R)─expressed in brain regions that control cognition, attention, and decision-making─could be useful for several neuropsychiatric disorders including substance use disorders (SUDs). This study focused on the synthesis and evaluation of a novel series of benzothiazole analogues designed to target D4R. We identified several compounds with high D4R binding affinity (Ki ≤ 6.9 nM) and >91-fold selectivity over other D2-like receptors (D2R, D3R) with diverse partial agonist and antagonist profiles. Novel analogue 16f is a potent low-efficacy D4R partial agonist, metabolically stable in rat and human liver microsomes, and has excellent brain penetration in rats (AUCbrain/plasma > 3). 16f (5-30 mg/kg, i.p.) dose-dependently decreased iv cocaine self-administration in rats, consistent with previous results produced by D4R-selective antagonists. Off-target antagonism of 5-HT2A or 5-HT2B may also contribute to these effects. Results with 16f support further efforts to target D4R in SUD treatment.

Brainstem Modulation of Nociception by Periaqueductal Gray Neurons Expressing the µ-Opioid Receptor in Mice.

BACKGROUND: Pharmacologic manipulations directed at the periaqueductal gray have demonstrated the importance of the µ-opioid receptor in modulating reflexive responses to nociception. The authors hypothesized that a supraspinal pathway centered on neurons in the periaqueductal gray containing the µ-opioid receptor could modulate nociceptive and itch behaviors. METHODS: The study used anatomical, optogenetic, and chemogenetic approaches in male and female mice to manipulate µ-opioid receptor neurons in the periaqueductal gray. Behavioral assays including von Frey, Hargreaves, cold plantar, chloroquine-induced itch, hotplate, formalin-induced injury, capsaicin-induced injury, and open field tests were used. In separate experiments, naloxone was administered in a postsurgical model of latent sensitization. RESULTS: Activation of µ-opioid receptor neurons in the periaqueductal gray increased jumping (least-squares mean difference of -3.30 s; 95% CI, -6.17 to -0.44; P = 0.023; n = 7 or 8 mice per group), reduced itch responses (least-squares mean difference of 70 scratching bouts; 95% CI, 35 to 105; P < 0.001; n = 8 mice), and elicited modestly antinociceptive effects (least-squares mean difference of -0.7 g on mechanical and -10.24 s on thermal testing; 95% CI, -1.3 to -0.2 and 95% CI, -13.77 to -6.70, and P = 0.005 and P < 0.001, respectively; n = 8 mice). Last, the study uncovered the role of the periaqueductal gray in suppressing hyperalgesia after a postsurgical state of latent sensitization (least-squares mean difference comparing saline and naloxone of -12 jumps; 95% CI, -17 to -7; P < 0.001 for controls; and -2 jumps; 95% CI, -7 to 4; P = 0.706 after optogenetic stimulation; n = 7 to 9 mice per group). CONCLUSIONS: µ-Opioid receptor neurons in the periaqueductal gray modulate distinct nocifensive behaviors: their activation reduced responses to mechanical and thermal testing, and attenuated scratching behaviors, but facilitated escape responses. The findings emphasize the role of the periaqueductal gray in the behavioral expression of nociception using reflexive and noxious paradigms.

Neurological applications of belzutifan in von Hippel-Lindau disease.

Von Hippel-Lindau (VHL) disease is a tumor predisposition syndrome caused by mutations in the VHL gene that presents with visceral neoplasms and growths, including clear cell renal cell carcinoma, and central nervous system manifestations, such as hemangioblastomas of the brain and spine. The pathophysiology involves dysregulation of oxygen sensing caused by the inability to degrade HIFα, leading to the overactivation of hypoxic pathways. Hemangioblastomas are the most common tumors in patients with VHL and cause significant morbidity. Until recently, there were no systemic therapies available for patients that could effectively reduce the size of these lesions. Belzutifan, the first approved HIF-2α inhibitor, has demonstrated benefit in VHL-associated tumors, with a 30% response rate in hemangioblastomas and ~30%-50% reduction in their sizes over the course of treatment. Anemia is the most prominent adverse effect, affecting 76%-90% of participants and sometimes requiring dose reduction or transfusion. Other significant adverse events include hypoxia and fatigue. Overall, belzutifan is well tolerated; however, long-term data on dosing regimens, safety, and fertility are not yet available. Belzutifan holds promise for the treatment of neurological manifestations of VHL and its utility may influence the clinical management paradigms for this patient population.

Readability of online patient education materials for Merkel cell carcinoma.

The Internet is a significant source of information for patients. According to the National Institutes of Health, patient education materials (PEMs) should be at or below an eighth-grade reading level. Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer that affects patients over 50 with rising incidence. Unfortunately, US adults aged 65 + have the least proficiency in health literacy. This study assessed the readability of online PEMs and factors that contribute to readability. We retrieved 50 PEM websites and extracted primary content. A readability software package calculated six readability statistics and generated a consensus standard readability. Overall, only eight articles had a standard reading level of eighth-grade level or below (16%). The median standard reading level was at the 11th-grade level. We also examined MCC PEMs from cancer treatment institution websites (N = 20). We determined whether they contained institution-specific information, meaning they contained text information about the institution-specific expertise and specialist team. Websites containing this information (N = 13) had a significantly higher reading level than websites that did not (N = 7) in five of six readability metrics (p < 0.05). We concluded that MCC PEMs with institution-specific information led to significantly higher reading level scores. We propose that such information may increase cognitive load, as patients are learning about their disease and treatment and contending with the institution-specific information. The Cognitive Load Theory principles of intrinsic load (learning the material relevant to the disease and treatment) and extraneous load (institution-specific information and increased reading level) are constrained by limited working memory. Working memory decreases with age; hence, the patient demographic most sensitive to increased extraneous load tends to overlap with that of MCC. As patients typically read pages linked from their search engine, we suggest moving institution-specific information to another page, separate from the PEMs.

Hybrid membrane-external-cavity surface-emitting laser.

We develop, analyze, and demonstrate an optically-pumped semiconductor disk laser using an active mirror architecture formed by sandwiching the semiconductor gain membrane between two heatspreaders, one of which is coated with a high-reflectivity multilayer. Thermal modeling indicates that this structure outperforms traditional VECSELs. Employing an InGaAs/GaAs MQW gain structure, we demonstrate output powers of approximately 30 W at a center wavelength of λ ≈ 1178 nm in a TEM00 mode using an in-well pumped geometry.