An Update on Emerging Regenerative Medicine Applications: The Use of Extracellular Vesicles and Exosomes for the Management of Chronic Pain.

PURPOSE OF REVIEW: Chronic pain affects nearly two billion people worldwide, surpassing heart disease, diabetes, and cancer in terms of economic costs. Lower back pain alone is the leading cause of years lived with disability worldwide. Despite limited treatment options, regenerative medicine, particularly extracellular vesicles (EVs) and exosomes, holds early promise for patients who have exhausted other treatment options. EVs, including exosomes, are nano-sized structures released by cells, facilitating cellular communication through bioactive molecule transfer, and offering potential regenerative properties to damaged tissues. Here, we review the potential of EVs and exosomes for the management of chronic pain. RECENT FINDINGS: In osteoarthritis, various exosomes, such as those derived from synovial mesenchymal stem cells, human placental cells, dental pulp stem cells, and bone marrow-derived mesenchymal stem cells (MSCs), demonstrate the ability to reduce inflammation, promote tissue repair, and alleviate pain in animal models. In intervertebral disc disease, Wharton's jelly MSC-derived EVs enhance cell viability and reduce inflammation. In addition, various forms of exosomes have been shown to reduce signs of inflammation in neurons and alleviate pain in neuropathic conditions in animal models. Although clinical applications of EVs and exosomes are still in the early clinical stages, they offer immense potential in the future management of chronic pain conditions. Clinical trials are ongoing to explore their therapeutic potential further, and with more research the potential applicability of EVs and exosomes will be fully understood.

National recommendations for the management of children and young people with IgA vasculitis: a best available evidence, group agreement-based approach.

OBJECTIVE: IgA vasculitis (IgAV) is the most frequently experienced subtype of vasculitis seen in children. Most children fully recover, however, complications including chronic kidney disease are recognised. The aim of this project was to use a best available evidence, group agreement, based approach to develop national recommendations for the initial management of IgAV and its associated complications. METHODS: A fully representative multiprofessional guideline development group (GDG), consisting of 28 members, was formed and met monthly. Graded recommendations were generated using nationally accredited methods, which included a predefined scope, open consultation, systematic literature review, evidence appraisal, review of national or international guidelines and a period of open consultation. Audit measures and research priorities were incorporated. RESULTS: The IgAV GDG met over a 14-month period. A total of 82 papers were relevant for evidence synthesis. For the initial management, four topic areas were identified with five key questions generating six graded recommendations related to classification, specialist referral and musculoskeletal involvement. For the associated complications, five topic areas with 12 key questions generated 15 graded recommendations covering nephritis, gastrointestinal and testicular involvement, atypical disease and follow-up. Open consultation feedback was incorporated. The guidelines were endorsed by the UK Kidney Association and Royal College of Paediatrics and Child Health and are available online. CONCLUSION: Despite IgAV being a rare disease with limited evidence, a national standardised approach to the clinical management for children and young people has been achieved. This should unite approaches to care and act as a foundation for improvement.

Detection of Residual iPSCs Following Differentiation of iPSC-Derived Retinal Pigment Epithelial Cells.

Purpose: The goal of this study was to develop a lot release assay for iPSC residuals following directed differentiation of iPSCs to retinal pigment epithelial (RPE) cells. Methods: RNA Sequencing (RNA Seq) of iPSCs and RPE derived from them was used to identify pluripotency markers downregulated in RPE cells. Quantitative real time PCR (qPCR) was then applied to assess iPSC residuals in iPSC-derived RPE. The limit of detection (LOD) of the assay was determined by performing spike-in assays with known quantities of iPSCs serially diluted into an RPE suspension. Results: ZSCAN10 and LIN28A were among 8 pluripotency markers identified by RNA Seq as downregulated in RPE. Based on copy number and expression of pseudogenes and lncRNAs ZSCAN10 and LIN28A were chosen for use in qPCR assays for residual iPSCs. Reverse transcription PCR indicated generally uniform expression of ZSCAN10 and LIN28A in 21 clones derived from 8 iPSC donors with no expression of either in RPE cells derived from 5 donor lines. Based on qPCR, ZSCAN10, and LIN28A expression in iPSCs was generally uniform. The LOD for ZSCAN10 and LIN28A in qPCR assays was determined using spike in assays of RPE derived from 2 iPSC lines. Analysis of ΔΔCt found the limit of detection to be <0.01% of cells, equivalent to <1 iPSC/10,000 RPE cells in both iPSC lines. Conclusions: qPCR for ZSCAN10 and LIN28A detects <1 in 10,000 residual iPSCs in a population of iPSC-derived RPE providing an adequate LOD of iPSC residuals for lot release testing.

It's complicated: relationships between integrative and conjugative elements and their bacterial hosts.

Integrative and conjugative elements (ICEs) are typically found integrated in a bacterial host chromosome. They can excise, replicate, and transfer from cell to cell. Many contain genes that confer phenotypes to host cells, including antibiotic resistances, specialized metabolisms, phage defense, and symbiosis or pathogenesis determinants. Recent studies revealed that at least three ICEs (ICEclc, Tn916, and TnSmu1) cause growth arrest or death of host cells upon element activation. This review highlights the complex interactions between ICEs and their hosts, including the recent examples of the significant costs to host cells. We contrast two examples of killing, ICEclc and Tn916, in which killing, respectively, benefits or impairs conjugation and emphasize the importance of understanding the impacts of ICE-host relationships on conjugation. ICEs are typically only active in a small fraction of cells in a population, and we discuss how phenotypes normally occurring in a small subset of host cells can be uncovered.

Sub-THz and THz Cherenkov radiation source with two-dimensional periodic surface lattice and multistage depressed collector.

We present the theory, concept and design of an efficient, megawatt coherent Cherenkov radiation source based on a two-dimensional periodic surface lattice (2D-PSL) cavity combined with a novel energy recovery system for the generation of highly efficient (> 50%) single-frequency radiation. We demonstrate the scalability of the transverse dimension of the 2D-PSL cavity of the Cherenkov source and thus the potential for efficient, continuous-wave, high-power (> 1 MW) operation; fundamental to the eventual realization of clean, fusion energy. These new sources, with the capacity to operate in the 0.1-10THz range, hold strong promise to address the long-standing "Terahertz gap". By combining a Cherenkov oscillator driven by a non-gyrating beam with an innovative four-stage depressed collector energy recovery system, the overall device efficiency can be increased to be competitive with gyrotrons in the requirements for heating and current drive in fusion plasma. In these Cherenkov devices, the frequency independence of the magnetic guide field enables advantageous frequency scaling without deployment constraints, making them especially attractive for high-impact applications in fusion science, turbulence diagnostics, non-destructive testing and biochemical spectroscopy. The novel energy recovery techniques presented in this paper have broad applicability to many electron-beam driven devices, bringing revolutionary potential to future THz source technologies.

Availability and Pricing of Drugs Prescribed by Otolaryngologists Through a Direct-to-Consumer Pharmacy: Medicare Savings Implications.

High prescription drug prices can financially strain patients and insurers, with substantial clinical repercussions. In recent years, direct-to-consumer (DTC) pharmacies have emerged as potentially lower-cost alternatives for patients to fill prescriptions. We evaluated whether drugs commonly prescribed by otolaryngologists were available at a national DTC pharmacy (Mark Cuban Cost Plus Drug Company [MCCPDC]) and estimated potential Medicare savings from DTC pricing. We identified drugs and prices paid by Medicare Part D plans using the 2021 Drug Spending Dashboard. Our analysis included 16 generic drugs within the MCCPDC formulary, which offered lower prices for 14 (87.5%) drugs. If plans had secured MCCPDC pricing for all 16 drugs, Medicare patients and plans would have saved $2.9 billion (relative reduction: 62.3%) in 2021. Estimated total savings were greatest for budesonide-formoterol ($1.9 billion), dexlansoprazole ($464.6 million), and levothyroxine ($327.4 million). Otolaryngologists and insurers may consider utilizing DTC pharmacies with lower drug prices, though patients may face challenges projecting out-of-pocket costs across pharmacies, medications, benefit phases, and formulary tiers.

Regulation of the SOS response and homologous recombination by an integrative and conjugative element.

Integrative and conjugative elements (ICEs) are mobile genetic elements that transfer between bacteria and influence host physiology and promote evolution. ICEBs1 of Bacillus subtilis modulates the host DNA damage response by reducing RecA filament formation. We found that the two ICEBs1-encoded proteins, RamT and RamA that modulate the SOS response in donors also function in recipient cells to inhibit both the SOS response and homologous recombination following transfer of the element. Expression of RamT and RamA caused a decrease in binding of the host single strand binding protein SsbA to ssDNA. We found that RamA interacted with PcrA, the host DNA translocase that functions to remove RecA from DNA, likely functioning to modulate the SOS response and recombination by stimulating PcrA activity. These findings reveal how ICEBs1 can modulate key host processes, including the SOS response and homologous recombination, highlighting the complex interplay between mobile genetic elements and their bacterial hosts in adaptation and evolution.

Activation and modulation of the host response to DNA damage by an integrative and conjugative element.

Mobile genetic elements help drive horizontal gene transfer and bacterial evolution. Conjugative elements and temperate bacteriophages can be stably maintained in host cells. They can alter host physiology and regulatory responses and typically carry genes that are beneficial to their hosts. We found that ICEBs1, an integrative and conjugative element of Bacillus subtilis, inhibits the host response to DNA damage (the SOS response). Activation of ICEBs1 before DNA damage reduced host cell lysis that was caused by SOS-mediated activation of two resident prophages. Further, activation of ICEBs1 itself activated the SOS response in a subpopulation of cells, and this activation was attenuated by the functions of the ICEBs1 genes ydcT and yddA (now ramT and ramA, for RecA modulator). Double mutant analyses indicated that RamA functions to inhibit and RamT functions to both inhibit and activate the SOS response. Both RamT and RamA caused a reduction in RecA filaments, one of the early steps in activation of the SOS response. We suspect that there are several different mechanisms by which mobile genetic elements that generate ssDNA during their lifecycle inhibit the host SOS response and RecA function, as RamT and RamA differ from the known SOS inhibitors encoded by conjugative elements.

Simultaneous electrochemical removal of three microcystin congeners and sulfamethoxazole in natural water.

Microcystins (MCs), frequently detected in freshwater ecosystems, have raised significant human health and ecological concerns. New approaches are being developed to control and remove MCs. In this study, we examined factors influencing the efficacy of electrochemical oxidation as a means of control. Anode material (Pt/Ti, Ta2O5-IrO2/Ti, SnO2-SbO2/Ti, boron-doped diamond (BDD/Si), anode surface area ratios and solution volumes, initial pollutant concentrations, and the co-existing antibiotic sulfamethoxazole (SMX) were investigated. MCs and SMX were dissolved in filtered Taihu Lake water to simulate the natural aquatic environment. The results showed that non-active anodes, lower initial concentration of MC, larger surface area ratio of cathode to anode, and smaller ratio of reaction solution volume to anode surface area could promote the degradation target pollutants. Under optimal conditions in this study, the degradation rates of MC-LR, MC-YR, MC-RR, and SMX each reached more than 90% within 6 h, and the removal efficiency of MC-YR was the highest among three congeners. The effect of SMX on the degradation of MC congeners depended mainly on their concentration differences, such that when the initial concentration of SMX was one to two orders of magnitude lower than microcystin, the presence of SMX would promote the degradation of MCs. In contrast, when the initial concentration of SMX was higher than that of microcystin by approximately an order of magnitude, sulfamethoxazole would inhibit the degradation of MCs by between 4.6% and 24.5%. Ultra-high-performance liquid chromatography tandem mass spectrometry analysis revealed that the three MC congeners were electrochemically degraded through aromatic ring oxidation, alkene oxidation, and bond cleavage on the ADDA (3-amino-9-methoxy-2,6,8-trimethyl-10-phenyldeca-4,6-dienoic acid) side chain. Notably, the removal of MCs was accompanied by a decline in the hardness of the reaction water. This study provided insights into electrochemical degradation of microcystins and antibiotics in natural water, offering suggestions for its practical application.

Lead Toxicity From Imported Jewelry.

We summarize here the presentation and course of lead poisoning in a 1-year-old who ingested a lead-containing metallic medallion from India. We analyzed the medallion to determine its composition, using x-ray fluorescence spectroscopy and field emission scanning electron microscopy. A simple extraction test was used to estimate oral bioavailability. We used the US Environmental Protection Agency Integrated Exposure Uptake Biokinetic model to compare actual versus predicted blood lead levels. X-ray fluorescence analysis revealed the composition of the medallion to be: Lead 155 000 ppm (15%), copper 530 000 ppm (53%), nickel 49 000 ppm (4.9%), arsenic 22 000 ppm (2.2%), antimony 12 000 ppm (1.2%), tin 3000 ppm (0.3%), and silver 1300 ppm (0.13%). With a fixed ingestion of 7786 µg/d (estimated by simulated gastric extraction analysis) and assuming 50% bioavailability, Integrated Exposure Uptake Biokinetic modeling predicted the geometric mean blood lead level would increase from 2.05 µg/dL to 173.9 µg/dL. This patient had potentially life-threatening lead poisoning from an ingested piece of jewelry. The medallion contained 550 times the allowable content of lead in children's metallic jewelry sold in the United States. This case highlights the ubiquitous nature of lead in our global environment and the risk of exposure to novel sources, especially for children.

The four Cs of physician leadership: A key to academic physician success.

Leadership is increasingly recognized as important in medicine. Physician leadership impacts healthcare delivery and quality. Little work has been done to determine how physician leadership in practice aligns with established models in leadership theory. We conducted 40 semi-structured, 50-minute interviews of physicians who had achieved the rank of professor in our school of medicine and were serving, or had served, in leadership positions. We used an inductive content analysis approach to identify content categories, with leadership emerging as one such category. Subsequently, for the present study, we performed a secondary analysis of the data. To do this, we reviewed all transcripts, seeking to identify if and how participants discussed leadership in relation to success in academic medicine. Following identification of sub-categories related to leadership, we performed qualitative content analysis. We then used a deductive content analysis approach to determine how participants' discussions of leadership aligned with major leadership theories. Then, the principal investigator conducted a secondary inductive content analysis revealing leadership themes that were synthesized into a new model of physician leadership. Twenty-nine participants spontaneously discussed leadership and leadership-related topics as important to their own academic success and comprised the present study cohort. Participants identified contributors to leadership success that aligned with multiple major leadership theories, including leadership traits, skills, behaviors styles, and situational leadership. None of the leadership theories aligned completely with our physician leaders' discussions, suggesting an alternate leadership framework was operating. Further analysis revealed a new model of leadership comprised of the "Four Cs of Physician Leadership": character, competence, caring, and communication. Our participant group of academic physicians identified leadership capabilities as being important in their academic success. While they discussed leadership in ways that fit to varying degrees with the major leadership theories, their discussions revealed a novel, more holistic leadership framework. Further work will be beneficial to determine if this model of leadership is specific to physicians or is more generalizable.

Iliotibial-Band and Gluteus Medius Percutaneous Ultrasound Tenotomy for Refractory Trochanteric Pain Syndrome: A Longitudinal Observational Study with One-Year Durability Results.

BACKGROUND: Greater trochanteric pain syndrome (GTPS) is a common cause of lateral hip pain that affects patients' quality of life and functioning. The condition is often associated with tightness of the iliotibial band (ITB) and tendinopathy of the gluteus medius (GMed) tendon, which are subjected to excessive stress and inflammation. A traditional treatment for GTPS is conservative medical management (CMM), which includes but is not limited to physiotherapy, oral anti-inflammatory medication, and/or local steroid injections. Surgery is performed when these treatments fail. The failure of these techniques indicates that some treatments classified as CMM may not be feasible for some patients. OBJECTIVES: This study aimed to evaluate the efficacy and safety of combined GMed and ITB injections for a cohort of CMM-refractory GTPS patients. STUDY DESIGN: A retrospective chart review. SETTING: Single-center, academic hospital. METHODS: Between 01/01/2022 and 12/31/2022, a retrospective analysis of 68 hips that underwent combination GMed-ITB percutaneous ultrasound tenotomy (PUT) was performed. The primary outcome measure was a numeric rating scale (NRS) for hip pain, and the secondary outcome measures were VISA-G (Victorian Institute of Sports Assessment-Gluteal Tendinopathy) scores, sitting-to-standing and walking tolerance, and side-lying tolerance. RESULTS: The patients' NRS scores decreased, and the VISA-G scores and all functional measures increased one year after the procedure, indicating significant improvement in pain and functioning (P < 0.001). Treatment success, defined as 50% reduction in pain and side-lying tolerance, was achieved by 83% of the patients. No major complications were reported. LIMITATIONS: The lack of a comparable cohort reduces the data's interpretative significance. Having a control arm would have enabled a statistical comparison between treated and untreated patients to provide a valid assessment of the procedure's benefit. CONCLUSIONS: This study demonstrated the feasibility and efficacy of combined GMed-ITB PUT as a novel treatment for GTPS in patients who failed CMM. The results showed significant and durable improvement in pain, function, and quality of life at the one-year follow-up. Our study suggests that both ITB and GMed tendons are involved in the pathogenesis of GTPS. The present study compared favorably with previous studies that reported outcomes of either ITB PUT or GMed PUT alone, implying that combining the approaches may offer superior benefits. Furthermore, the study had several strengths, such as the use of a validated outcome measure (VISA-G), the elimination of bias by independent practitioners, and the inclusion of a difficult population with severe pain.

Single Institutional Cross-Sectional Phone Survey Study: Evaluation of Causes for Loss to Follow-up After Spinal Cord Stimulator Implantation.

BACKGROUND: Spinal cord stimulation (SCS) is often an option of last resort for patients with post-laminectomy syndrome or an alternative option for patients with complex regional pain syndrome, chronic nonsurgical low back pain, or painful diabetic peripheral neuropathy when conservative management has failed. Although SCS is a helpful option, it is not without complications that can frequently lead to explantation of the SCS device and dissatisfaction with the treatment. Furthermore, as with any technology, SCS has potential issues that may lead to patient frustration and ultimately result in patient noncompliance and lack of follow-up visits. OBJECTIVES: The goals of this study are to explore the magnitude of and reasons for patient loss to follow-up after SCS device implantation. STUDY DESIGN: A cross-sectional phone survey. SETTING: A tertiary-care academic hospital. METHODS: A cross-sectional phone survey was performed on 49 patients who were deemed lost to follow-up when they did not return to the clinic one month after being implanted with permanent SCS devices at Beth Israel Deaconess Medical Center. Patients were administered an institutional review board-approved questionnaire exploring their reasons for not returning to the clinic. RESULTS: Over a 5-year period, 257 patients underwent full implantation of an SCS device. Of the 49 patients lost to follow-up, 24 were able to be contacted, and they completed the questionnaire. Twenty of the patients continued to use the SCS device but were lost to follow-up for the following reasons: 58% (14/24) due to improvement of pain, 13% (3/24) due to minimal improvement in pain control, 4% (1/24) due to other urgent health conditions, and 8% (2/24) due to patient noncompliance and missing follow-up appointments (4/24). Four patients discontinued using the SCS device after an average of 1.5 years +/- one year, 12% (3/24) due to inadequate pain control and 4% (1/24) due to inability to recharge the device (1/24). Of these patients, 2 of the 4 contacted their SCS representatives for help with troubleshooting prior to discontinuation. None of the patients was explanted. LIMITATIONS: The main limitation of this study was the incompletion rate, which was 51.0% (25 out of 49 patients). CONCLUSIONS: This paper, the first cross-sectional study of loss to follow-up among patients who are implanted with SCS devices, identifies that up to 19% of patients are quickly lost to follow-up after implantation. Only half of the patients in this study could be reached, with most successfully using their device for meaningful pain control, but a substantial number of patients likely required additional device optimization for pain relief.

Ruin-of-the-rivers? A global review of run-of-the-river dams.

The classification of a hydropower scheme as run-of-the-river (or run-of-river; ROR) evokes an image of a low-impact installation; however, examination of eight case studies worldwide shows that substantial negative societal and ecological impacts are tied to them, albeit in somewhat different ways. We conclude that ROR dams not only potentially displace communities, disrupt livelihoods, and degrade environments in surrounding areas, but they also divert water from areas of need, impact aquatic ecology through habitat destruction and disruption of fish migrations, emit non-trivial amounts of greenhouse gases over the lifespan of the project, and disrupt streamflow in downstream river sections. While these negative impacts vary on a case-by-case basis, medium and large ROR dams consistently have multiple and cumulative impacts, even when not having appreciable reservoirs. We contend that many impactful dams do not qualify as low-impact ROR projects, despite being defined as such. Such mislabeling is facilitated in part by the ambiguous definition of the term, which risks the ROR concept being used by proponents of impactful structures to downplay their negative effects and thus mislead the public or gain status, including within the Clean Development Mechanism in relation to mitigating climate change.

Virtual Reality for Postoperative Pain Management: A Review of Current Evidence.

PURPOSE OF REVIEW: With the ongoing opioid crisis, there is a continued need to develop multimodal pain management strategies inclusive of non-pharmacological treatments. Virtual reality (VR) offers a non-invasive treatment approach for the management of acute and chronic pain including postoperative pain. The aim of this review is to describe the use of VR and its effect on pain-related outcome measures compared to routine care in various types of surgical procedures. RECENT FINDINGS: Severe postoperative pain is associated with an increased risk of medical complications and may lead to the development of chronic pain. VR-based interventions are a form of distraction therapy that attenuates pain perception and have been shown to reduce activity in central pain-processing regions. In patients undergoing cardiac surgery, VR may reduce postoperative pain and improve physiological parameters such as heart rate and blood pressure. VR technology was found to have a high satisfaction rate in patients undergoing laparoscopic abdominal surgeries. Three-dimensional (3D) VR interventions may be useful for postoperative pain control in patients undergoing head and neck surgery. VR technology has revealed mixed results for postoperative pain control following orthopedic procedures although it has beneficial effects on functional outcomes during postoperative rehabilitation. In the pediatric population, VR is notable for its applicability in postoperative pain control and anxiety. VR technology is a novel, non-pharmacologic adjunct in the management of postoperative pain. Current studies are limited regarding therapy adaptations for the elderly population. High-quality randomized controlled trials are needed to establish the clinical effectiveness of VR-based therapies in the postoperative setting.

Investigating the cause of cardiovascular dysfunction in chronic kidney disease: capillary rarefaction and inflammation may contribute to detrimental cardiovascular outcomes.

Myocardial ischemia-reperfusion (IR) injury is a major cause of morbidity and mortality in patients with chronic kidney disease (CKD). The most frequently used and representative experimental model is the rat dietary adenine-induced CKD, which leads to CKD-associated CVD. However, the continued intake of adenine is a potential confounding factor. This study investigated cardiovascular dysfunction following brief adenine exposure, CKD development and return to a normal diet. Male Wistar rats received a 0.3% adenine diet for 10 weeks and normal chow for an additional 8 weeks. Kidney function was assessed by urinalysis and histology. Heart function was assessed by echocardiography. Sensitivity to myocardial IR injury was assessed using the isolated perfused rat heart (Langendorff) model. The inflammation profile of rats with CKD was assessed via cytokine ELISA, tissue histology and RNA sequencing. Induction of CKD was confirmed by a significant increase in plasma creatinine and albuminuria. Histology revealed extensive glomerular and tubular damage. Diastolic dysfunction, measured by the reduction of the E/A ratio, was apparent in rats with CKD even following a normal diet. Hearts from rats with CKD had significantly larger infarcts after IR injury. The CKD rats also had statistically higher levels of markers of inflammation including myeloperoxidase, KIM-1 and interleukin-33. RNA sequencing revealed several changes including an increase in inflammatory signaling pathways. In addition, we noted that CKD induced significant cardiac capillary rarefaction. We have established a modified model of adenine-induced CKD, which leads to cardiovascular dysfunction in the absence of adenine. Our observations of capillary rarefaction and inflammation suggest that these may contribute to detrimental cardiovascular outcomes.

Managing Menopause: The Evolving Role of Estrogens, Selective Serotonin Reuptake Inhibitors, and Phytoestrogens in Balancing Hormonal Fluctuations.

Menopause is characterized by the cessation of menstruation for 12 consecutive months. In this narrative review, we describe the transitional stages of menopause, clinical presentation, pharmacological management of symptoms, and effects on fluctuating hormone levels. To standardize the stages of menopause, the Stages of Reproductive Aging Workshop + 10 (STRAW+10) system was designed with five distinct categories corresponding to symptom presentation and numerical years. Common clinical presentations consist of vasomotor hot flashes, mood changes, decreased libido, osteoporosis, and genitourinary changes, all of which are associated with changes in hormone levels. Because hormones play a major role in the mechanism of menopause, hormone replacement therapy with estrogen, progesterone, or a combination is explored and shown to demonstrate symptom reduction in a large percentage of women. Nonhormonal treatment and alternative therapies are used to treat vasomotor symptoms if contraindications present to hormone therapy or for those who prefer fewer side effects. Thus, many women experience uncomfortable symptoms during menopause, some of which cause significant changes in quality of life. In this regard, understanding the pathophysiology, symptomatology, and current treatment options with side effect profiles allows for continued research and discovery of advanced therapy for treating symptoms to ameliorate discomfort and pain in menopausal women.

Mind-wandering when studying valuable information: The roles of age, dispositional traits, and contextual factors.

The factors that trigger lapses of attention (e.g., mind-wandering) during new learning remain unclear. The present study investigated whether the likelihood of experiencing an attentional lapse depends on (a) the importance of the material being studied and (b) the learner's age. In two experiments, younger and older adults completed a delayed free recall task in which to-be-remembered words were paired with point values. Thought probes were embedded into the encoding phase of each list to provide an index of one's ability to maintain attention on task and prevent recurrent lapses of attention (i.e., the consistency of attention). Experiment 1 revealed all individuals better remembered high-value information at the expense of low-value information, and older adults were more frequently focused on the task than younger adults. Participants were also less likely to remember an item at test if they experienced an attentional lapse while learning said item, and they were more consistently focused on the task when studying high-value information than when studying low-value information. Age did not moderate either of these effects. Experiment 2 replicated the findings from Experiment 1 and further revealed that the positive association between age and attentional consistency was explained by age-related differences in affect, motivation, personality, and attention-deficit hyperactivity disorder symptomology. Once these factors were accounted for, older age was associated with increased attentional inconsistency (less on-task focus). While future replication of this finding is needed, implications for education and theories of both mind-wandering and aging are discussed. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Transcripts with high distal heritability mediate genetic effects on complex metabolic traits.

Although many genes are subject to local regulation, recent evidence suggests that complex distal regulation may be more important in mediating phenotypic variability. To assess the role of distal gene regulation in complex traits, we combined multi-tissue transcriptomes with physiological outcomes to model diet-induced obesity and metabolic disease in a population of Diversity Outbred mice. Using a novel high-dimensional mediation analysis, we identified a composite transcriptome signature that summarized genetic effects on gene expression and explained 30% of the variation across all metabolic traits. The signature was heritable, interpretable in biological terms, and predicted obesity status from gene expression in an independently derived mouse cohort and multiple human studies. Transcripts contributing most strongly to this composite mediator frequently had complex, distal regulation distributed throughout the genome. These results suggest that trait-relevant variation in transcription is largely distally regulated, but is nonetheless identifiable, interpretable, and translatable across species.