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Contents Kisspeptin is a neuropeptide involved in the hypothalamic regulation of reproduction in many species. Recent studies have revealed kisspeptin within the ovaries of rats, Siberian hamsters and humans, indicating a local role in reproduction. However, the role of kisspeptin in the ovary is poorly understood in the bitch. This study investigated the presence and location of kisspeptin protein ( KISS1) and kisspeptin receptors ( KISS1R) in the canine ovary during different stages of the reproductive cycle (pre-pubertal, anoestrus and cycling) by means of immunohistochemical staining. Ovaries from 24 bitches presented at local veterinary clinics for routine ovariohysterectomy were collected and grouped based on reproductive stage (pre-pubertal, anoestrus and cycling (proestrus, oestrus and dioestrus)). The presence or absence of immunoreactive KISS1 and KISS1R was recorded without any quantification of the levels of expression within cells. Immunoreactive KISS1 was found in the oocytes during all stages of the oestrous cycle, in the granulosa cells during all stages except anoestrus and in the corpus luteum ( CL) during dioestrus. KISS1 was absent in the ovaries of pre-pubescent bitches. Immunoreactive KISS1R were consistently found in the oocytes, primordial follicles, the granulosa cells and CL in cycling bitches. The finding of KISS1R in the granulosa cells is suggestive that kisspeptin and progesterone may be linked as this pattern of staining is seen in animals that show preovulatory luteinisation of follicles during oestrus, KISS1R were also observed in the ovaries of pre-pubescent and anoestrous bitches, suggesting a possible role of kisspeptin in oocyte proliferation, development and maturation of granulosa cells, and progesterone production. This study provides a starting point for the establishment of a canine model for kisspeptin regulation within the ovary. [ABSTRACT FROM AUTHOR]

Post-Acute Sequelae of SARS-CoV-2 infection (PASC), also known as Long-COVID, encompasses a variety of complex and varied outcomes following COVID-19 infection that are still poorly understood. We clustered over 600 million condition diagnoses from 14 million patients available through the National COVID Cohort Collaborative (N3C), generating hundreds of highly detailed clinical phenotypes. Assessing patient clinical trajectories using these clusters allowed us to identify individual conditions and phenotypes strongly increased after acute infection. We found many conditions increased in COVID-19 patients compared to controls, and using a novel method to associate patients with clusters over time, we additionally found phenotypes specific to patient sex, age, wave of infection, and PASC diagnosis status. While many of these results reflect known PASC symptoms, the resolution provided by this unprecedented data scale suggests avenues for improved diagnostics and mechanistic understanding of this multifaceted disease., (© 2024. The Author(s).)

Background: Adverse social determinants of health contribute to health inequities. Practice guidelines now recommend incorporating patient unmet social needs into patient care, and payors increasingly reimburse for screening and providing related referrals to community organizations. Emergent electronic health record (EHR)-based tools can enable clinical-community linkages, but their adoption commonly faces workflow and infrastructure barriers. Targeted implementation support such as training, championship, practice facilitation, and audit and feedback, can enhance such tools' adoption, but no prior research has assessed such strategies' impact on the adoption of 'enabling technologies' supporting clinical-community linkages. This study will test whether providing targeted implementation support to safety-net primary care health center care management teams improves the sustained adoption of EHR-based enabling technologies used to 1) screen for social needs and 2) link patients to community organizations., Methods: Formative evaluation of barriers and facilitators to adopting EHR-enabled social needs referrals and ascertainment of services received will include semi-structured interviews and a 'guided tour' of enabling technology used by care managers serving patients with complex health and/or social needs. A modified Delphi process conducted with care management staff and subject matter experts will then inform the development of an intervention targeting adoption of social risk EHR-enabled tools. The intervention will be piloted in three health centers, refined, then tested in a pragmatic stepped-wedge cluster-randomized trial in 20 health centers (five wedges of four health centers) that provide care management to high-risk patients with social needs., Discussion: This study is among the first to evaluate an intervention designed to support care management teams' adoption of enabling technologies to increase clinical-community linkages. It was funded in September 2023 by the National Institute of Nursing Research. Formative activities will take place from January to June 2024, the intervention will be developed in July-December 2024, the pilot study will be conducted from January-March 2025, and the cluster-randomized trial will occur from July 2025 -September 2026. Study data will be analyzed and results disseminated in 2027-2028. Study results have the potential to improve clinical-community linkages and in so doing to advance health equity., Trial Registration: Clinicaltrials.gov registration # NCT06489002. Registered July 5, 2024, https//clinicaltrials.gov/study/NCT06489002?term=NCT06489002&rank=1., Competing Interests: Declarations Competing interests The authors declare that they have no competing interests

Introduction: Federally Qualified Community Health Centers (FQHCs) are on the frontline of efforts to improve healthcare equity and reduce disparities exacerbated by the COVID-19 pandemic. This study assesses the provision and equity of preventive care and chronic disease management by FQHCs before, during, and after the pandemic., Methods: Using electronic health record data from 210 FQHCs nationwide and employing segmented regression in an interrupted time series design, preventive screening and chronic disease management were assessed for 939,053 patients from 2019 to 2022. Care measures included cancer screenings, blood pressure control, diabetes control, and childhood immunizations; patient-level factors including race and ethnicity, language preference, and multimorbidity status were analyzed for equitable care provision. Analyses were conducted in 2023-2024., Results: Cancer screening rates and blood pressure control initially declined after the onset of the pandemic but later rebounded, while diabetes control showed a slight increase, later stabilizing. Racial and ethnic disparities persisted, with Asian individuals having a higher prevalence of screenings and blood pressure control, and Black/African American individuals facing a lower prevalence for most screenings but a higher prevalence for cervical cancer screening. Hispanic/Latino individuals had a higher prevalence of various screenings and diabetes control. Disparities persisted for Native Hawaiian/Other Pacific Islander and American Indian/Alaska Native individuals and were observed based on language and multimorbidity status., Conclusions: While preventive screening and chronic disease management in FQHCs have largely rebounded to pre-pandemic levels following an initial decline, persistent disparities highlight the need for targeted interventions to support FQHCs in addressing healthcare inequities., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To compare morbidity burden captured from multimorbidity indices and aggregated measures of clinically meaningful categories captured in primary care community-based health center (CBHC) patients., Data Sources and Study Setting: Electronic health records of patients seen in 2019 in OCHIN's national network of CBHCs serving patients in rural and underserved communities., Study Design: Age-stratified analyses comparing the most common conditions captured by the Charlson, Elixhauser, and Multimorbidity Weighted (MWI) indices, and Classification Software Refined (CCSR) and Chronic Condition Indicator (CCI) algorithms., Data Collection/extraction Methods: Active ICD-10 conditions on patients' problem list in 2019., Principal Findings: Approximately 35%-56% of patients with at least one condition are not captured by the Charlson, Elixhauser, and MWI indices. When stratified by age, this range broadens to 9%-90% with higher percentages in younger patients. The CCSR and CCI reflect a broader range of acute and chronic conditions prevalent among CBHC patients., Conclusion: Three commonly used indices to capture morbidity burden reflect conditions most prevalent among older adults, but do not capture those on problem lists for younger CBHC patients. An index with an expanded range of care conditions is needed to understand the complex care provided to primary care populations across the lifespan., (© 2024 Health Research and Educational Trust.)

Abstract: McGrath, R, McGrath, BM, Jurivich, D, Knutson, P, Mastrud, M, Singh, B, and Tomkinson, GR. Collective weakness is associated with time to mortality in Americans. J Strength Cond Res 38(7): e398-e404, 2024-Using new weakness cutpoints individually may help estimate time to mortality, but their collective use could improve value. We sought to determine the associations of (a) each absolute and body size normalized cut point and (b) collective weakness on time to mortality in Americans. The analytic sample included 14,178 subjects aged ≥50 years from the 2006-2018 waves of the Health and Retirement Study. Date of death was confirmed from the National Death Index. Handgrip dynamometry measured handgrip strength (HGS). Men were categorized as weak if their HGS was <35.5 kg (absolute), <0.45 kg·kg -1 (body mass normalized), or <1.05 kg·kg -1 ·m -2 (body mass index [BMI] normalized). Women were classified as weak if their HGS was <20.0 kg, <0.337 kg·kg -1 , or <0.79 kg·kg -1 ·m -2 . Collective weakness categorized persons as below 1, 2, or all 3 cutpoints. Cox proportional hazard regression models were used for analyses. Subject values below each absolute and normalized cutpoint for the 3 weakness parameters had a higher hazard ratio for early all-cause mortality: 1.45 (95% confidence interval [CI]: 1.36-1.55) for absolute weakness, 1.39 (CI: 1.30-1.49) for BMI normalized weakness, and 1.33 (CI: 1.24-1.43) for body mass normalized weakness. Those below 1, 2, or all 3 weakness cut points had a 1.37 (CI: 1.26-1.50), 1.47 (CI: 1.35-1.61), and 1.69 (CI: 1.55-1.84) higher hazard for mortality, respectively. Weakness determined by a composite measure of absolute and body size adjusted strength capacity provides robust prediction of time to mortality, thus potentially informing sports medicine and health practitioner discussions about the importance of muscle strength during aging., (Copyright © 2024 National Strength and Conditioning Association.)

Aims: To examine the associations of 1) absolute and normalized weakness cut-points, 2) collective weakness categories, and 3) changes in weakness status on future activities of daily living (ADL) limitations in older Americans., Methods: The analytic sample included 11,656 participants aged ≥65-years from the 2006-2018 waves of the Health and Retirement Study. ADL were self-reported. A handgrip dynamometer measured handgrip strength (HGS). Males were classified as weak if their HGS was <35.5-kg (absolute), <0.45-kg/kg (body mass normalized), or <1.05-kg/kg/m 2 (body mass index (BMI) normalized); females were considered weak if their HGS was <20.0-kg, <0.337-kg/kg, or <0.79-kg/kg/m 2 . Collective weakness categorized those below 1, 2, or all 3 absolute and normalized cut-points. These collective categories were also used to classify observed changes in weakness status over time (onset, persistent, progressive, recovery)., Results: Older Americans below absolute and normalized weakness cut-points had greater future ADL limitations odds: 1.34 (95% confidence interval (CI): 1.22-1.47) for absolute, 1.36 (CI: 1.24-1.50) for BMI normalized, and 1.56 (CI: 1.41-1.73) for body mass normalized. Persons below 1, 2, or 3 cut-points had 1.36 (CI: 1.19-1.55), 1.60 (CI: 1.41-1.80), and 1.70 (CI: 1.50-1.92) greater odds for future ADL limitations, respectively. Those in each changing weakness classification had greater future ADL limitation odds: 1.28 (CI: 1.01-1.62) for onset, 1.53 (CI: 1.22-1.92) for persistent, 1.72 (CI: 1.36-2.19) for progressive, and 1.34 (CI: 1.08-1.66) for recovery., Conclusions: The presence of weakness, regardless of cut-point and change in status over time, was associated with greater odds for future ADL limitations., Competing Interests: PMC is a consultant and owns stock in Myocorps for work unrelated to this research. In the past 5-years, BCC has received grant support from NMD Pharma, Myolex Inc., and Astella Pharma Global Development for contracted studies related to aging and muscle health. BCC is also co-founder with equity of OsteoDx Inc.

To understand better the role that kisspeptin plays in regulating seasonal and estrous cycle changes in the mare, this study investigated the number, location and interactions between GnRH, kisspeptin and RFRP-3 neurons in the equine hypothalamus. Hypothalami were collected from mares during the non-breeding season, vernal transition and various stages of the breeding season. Fluorescent immunohistochemistry was used to label the neuropeptides of interest. GnRH cells were observed primarily in the arcuate nucleus (ARC), while very few labeled cells were identified in the pre-optic area (POA). Kisspeptin cells were identified primarily in the ARC, with a small number of cells observed dorsal to the ARC, surrounding the third ventricle (3V). The mean number of kisspeptin cells varied between animals and typically showed no pattern associated with season or stage of estrous cycle, but a seasonal difference was identified in the ARC population. Small numbers of RFRP-3 cells were observed in the ARC, ventromedial hypothalamus (VMH) and dorsomedial hypothalamus (DMH). The mean number of RFRP-3 cells appeared higher in pre-ovulatory animals compared to all other stages. The percentage of GnRH cell bodies with kisspeptin appositions did not change with season or stage of estrous cycle. The percentage of kisspeptin cells receiving inputs from RFRP-3 fibers did not vary with season or stage of estrous cycle. These interactions suggest the possibility of the presence of an ultra-short loop feedback system between these three peptides. The changes in RFRP-3 neurons suggest the possibility of a role in the regulation of reproduction in the horse, but it is unlikely to be as a gonadotropin inhibitory factor., Competing Interests: Declaration of competing interest None., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

Background: Weakness can be operationalized with several thresholds, which in turn, could impact associations with cognitive impairment when considering obesity status., Objective: We examined the associations of absolute, normalized, and collective weakness thresholds on future cognitive impairment by obesity status in older adults., Methods: We performed a secondary data analysis on the 2006-2018 waves of the Health and Retirement Study. A spring-type dynamometer collected handgrip strength (HGS). Males were categorized weak if their HGS was <35.5-kg (absolute), <0.45-kg/kg (body mass normalized), or <1.05-kg/kg/m 2 (body mass index (BMI) normalized), while females were defined as weak if their HGS was <20.0-kg, <0.337-kg/kg, or <0.79-kg/kg/m 2 . The modified Telephone Interview of Cognitive Status examined cognitive function. Persons scoring ≤10 had a cognitive impairment. Obesity was categorized as BMI ≥30 kg/m 2 ., Results: We included 7,532 and 3,584 persons aged ≥65-years living without and with obesity, respectively. Those without obesity but beneath the absolute weakness threshold had 1.54 (95% confidence interval (CI): 1.24-1.91) greater odds for future cognitive impairment. Persons with obesity and beneath each threshold also had greater odds for future cognitive impairment: 1.89 (95% CI: 1.28-2.78) for absolute, 2.17 (95% CI: 1.02-4.62) for body mass normalized, and 1.75 (95% CI: 1.10-2.80) for BMI normalized. Older Americans without obesity but underneath all the weakness thresholds had 1.32 (95% CI: 1.00-1.74) greater odds for impairment in cognitive function, while persons with obesity had 2.76 (95% CI: 1.29-5.93) greater odds., Conclusions: There should be consideration for how body size and different weakness thresholds may influence future cognitive outcomes., Competing Interests: The authors have no conflict of interest to report., (© 2024 – The authors. Published by IOS Press.)

Background: Several registries for hidradenitis suppurativa (HS) already exist in Europe and the USA. There is currently no global consensus on a core dataset (CDS) for these registries. Creating a global HS registry is challenging, owing to logistical and regulatory constraints, which could limit opportunities for global collaboration as a result of differences in the dataset collected. The solution is to encourage all HS registries to collect the same CDS of information, allowing registries to collaborate., Objectives: To establish a core set of items to be collected by all HS registries globally. The core set will cover demographic details, comorbidities, clinical examination findings, patient-reported outcome measures and treatments., Methods: Beginning in September 2022, 20 participants - including both clinicians with expertise in HS and patient advocates - from eight countries across three continents participated in a Delphi process consisting of four rounds of voting, with all participants completing each round. A list of potential items for inclusion in the core set was generated from the relevant published literature, including systematic reviews of comorbidities in HS, clinical and examination findings, and epidemiology. For disease severity and progression items, the Hidradenitis SuppuraTiva Core outcome set International Collaboration (HiSTORIC) core set and other relevant instruments were considered for inclusion. This resulted in 47 initial items. Participants were invited to suggest additional items to include during the first round. Anonymous feedback was provided to inform each subsequent round of voting to encourage consensus., Results: The eDelphi process established a CDS of 48 items recommended for inclusion in all HS registries globally., Conclusions: The routine adoption of this CDS in current and future HS registries should allow registries in different parts of the world to collaborate, enabling research requiring large numbers of participants., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Understanding variation in multimorbidity across sociodemographics and social drivers of health is critical to reducing health inequities., Methods: From the multi-state OCHIN network of community-based health centers (CBHCs), we identified a cross-sectional cohort of adult (> 25 years old) patients who had a visit between 2019-2021. We used generalized linear models to examine the relationship between the Multimorbidity Weighted Index (MWI) and sociodemographics and social drivers of health (Area Deprivation Index [ADI] and social risks [e.g., food insecurity]). Each model included an interaction term between the primary predictor and age to examine if certain groups had a higher MWI at younger ages., Results: Among 642,730 patients, 28.2% were Hispanic/Latino, 42.8% were male, and the median age was 48. The median MWI was 2.05 (IQR: 0.34, 4.87) and was higher for adults over the age of 40 and American Indians and Alaska Natives. The regression model revealed a higher MWI at younger ages for patients living in areas of higher deprivation. Additionally, patients with social risks had a higher MWI (3.16; IQR: 1.33, 6.65) than those without (2.13; IQR: 0.34, 4.89) and the interaction between age and social risk suggested a higher MWI at younger ages., Conclusions: Greater multimorbidity at younger ages and among those with social risks and living in areas of deprivation shows possible mechanisms for the premature aging and disability often seen in community-based health centers and highlights the need for comprehensive approaches to improving the health of vulnerable populations., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Background: Virtual care increased dramatically during the COVID-19 pandemic. The specific modality of virtual care (video, audio, eVisits, eConsults, and remote patient monitoring) has important implications for the accessibility and quality of care, but rates of use are relatively unknown. Methods for identifying virtual care modalities, especially in electronic health records (EHR) are inconsistent. This study (a) developed a method to identify virtual care modalities using EHR data and (b) described the distribution of these modalities over a 3-year study period., Methods: EHR data from 316 primary care safety net clinics throughout the study period (4/1/2020-3/31/2023) were included. Visit type (in-person vs virtual) by adults >18 years old were classified. Expert consultation informed the development of two algorithms to classify virtual care visit modalities; these algorithms prioritized different EHR data elements. We conducted descriptive analyses comparing algorithms and the frequency of virtual care modalities., Results: Agreement between the algorithms was 96.5% for all visits and 89.3% for virtual care visits. The majority of disagreement between the algorithms was among encounters scheduled as audio-only but billed as a video visit. Restricting to visits where the algorithms agreed on visit modality, there were 2-fold more audio-only than video visits., Conclusion: Visit modality classification varies depending upon which data in the EHR are prioritized. Regardless of which algorithm is utilized, safety net clinics rely on audio-only and video visits to provide care in virtual visits. Elimination of reimbursement for audio visits may exacerbate existing inequities in care for low-income patients., Competing Interests: The authors declare no other conflicts of interest., (© 2024 The Authors. Learning Health Systems published by Wiley Periodicals LLC on behalf of University of Michigan.)

Introduction: Health centers provide primary and behavioral health care to the nation's safety net population. Many health centers served on the frontlines of the COVID-19 pandemic, which brought major changes to health center care delivery., Objective: To elucidate primary care and behavioral health service delivery patterns in health centers before and during the COVID-19 public health emergency (PHE)., Methods: We compared annual and monthly patients from 2019 to 2022 for new and established patients by visit type (primary care, behavioral health) and encounter visits by modality (in-person, telehealth) across 218 health centers in 13 states., Results: There were 1581,744 unique patients in the sample, most from health disparate populations. Review of primary care data over 4 years show that health centers served fewer pediatric patients over time, while retaining the capacity to provide to patients 65+. Monthly data on encounters highlights that the initial shift in March/April 2020 to telehealth was not sustained and that in-person visits rose steadily after November/December 2020 to return as the predominant care delivery mode. With regards to behavioral health, health centers continued to provide care to established patients throughout the PHE, while serving fewer new patients over time. In contrast to primary care, after initial uptake of telehealth in March/April 2020, telehealth encounters remained the predominant care delivery mode through 2022., Conclusion: Four years of data demonstrate how COVID-19 impacted delivery of primary care and behavioral health care for patients, highlighting gaps in pediatric care delivery and trends in telehealth over time., Competing Interests: Conflict of interest:: The authors have no conflicts of interest to declare., (© Copyright by the American Board of Family Medicine.)

Background: The prevalence of Post Traumatic Stress Disorder (PTSD) has been rising since the start of the COVID-19 pandemic, and affects females, sexual and gender minorities, and individuals with social risks at higher rates., Objective: This study examines if the prevalence of PTSD increased from 2019 to 2022 among patients who received care in a national network of safety-net, community-based health centers with integrated behavioral health programs that serve patients at high risk for PTSD., Methods: We analyzed electronic health record data from patients with 1 or more behavioral health visits during 2019 to 2022 using repeated cross-sectional data to visualize trends. Change in PTSD prevalence based on the diagnoses associated with each visit from 2019 to 2022 was assessed using a general linear mixed model adjusted for patient-level factors., Results: Over 4 years, 182 419 distinct patients received care for PTSD, with prevalence increasing from 2019 to 2022 (OR = 1.09, 95% CI = 1.08, 1.10). Females (OR = 1.81, 95% CI = 1.78, 1.84), LGBTQIA individuals (OR = 1.29, 95% CI = 1.26, 1.33), gender diverse individuals (OR = 1.36, 95% CI = 1.29, 1.42), and patients who reported 1 or more social determinants of health needs (OR = 1.52, 95% CI = 1.46, 1.57) were more likely to have a diagnosis of PTSD., Conclusions: In a worrying trend, PTSD prevalence has increased among people receiving integrated behavioral health care at community-based health centers, with disparities observed in subpopulations. Continued effort and investment are needed to meet this increasing need in safety-net settings, particularly for those subpopulations observed to have higher prevalence., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The purpose of this study was to evaluate the associations of (1) individual absolute and body size normalized weakness cut-points, and (2) the collective weakness classifications on time to diabetes in Americans., Methods: We analyzed data from 9577 adults aged at least 50-years from the Health and Retirement Study. Diabetes diagnosis was self-reported. A handgrip dynamometer measured handgrip strength (HGS). Males with HGS <35.5 kg (absolute), <0.45 kg/kg (normalized to body weight), or <1.05 kg/kg/m 2 (normalized to BMI) were categorized as weak. Females were classified as weak if their HGS was <20.0 kg, <0.337 kg/kg, or <0.79 kg/kg/m 2 . Compounding weakness included falling below 1, 2, or all 3 cut-points., Results: Persons below the body weight normalized weakness cut-points had a 1.29 (95% confidence interval (CI): 1.15-1.47) higher hazard for incident diabetes, while those below the BMI normalized cut-points had a 1.30 (CI: 1.13-1.51) higher hazard. The association between absolute weakness and incident diabetes was insignificant (hazard ratio: 1.06; CI: 0.91-1.24). Americans below 1, 2, or all 3 collective weakness categories had a 1.28 (CI: 1.10-1.50), 1.29 (CI: 1.08-1.52), and 1.33 (CI: 1.09-1.63) higher hazard for the incidence of diabetes, respectively., Conclusions: Our findings indicate that while absolute weakness, which is confounded by body size, was not associated with time to diabetes, adjusting for the influence of body size by normalizing HGS to body weight and BMI was significantly associated with time to diabetes. This suggests that muscle strength, not body size, may be driving such associations with time to diabetes., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no conflicts of interest.

Rationale: Shorter time-to-antibiotics is lifesaving in sepsis, but programs to hasten antibiotic delivery may increase unnecessary antibiotic use and adverse events. Objectives: We sought to estimate both the benefits and harms of shortening time-to-antibiotics for sepsis. Methods: We conducted a simulation study using a cohort of 1,559,523 hospitalized patients admitted through the emergency department with meeting two or more systemic inflammatory response syndrome criteria (2013-2018). Reasons for hospitalization were classified as septic shock, sepsis, infection, antibiotics stopped early, and never treated (no antibiotics within 48 h). We simulated the impact of a 50% reduction in time-to-antibiotics for sepsis across 12 hospital scenarios defined by sepsis prevalence (low, medium, or high) and magnitude of "spillover" antibiotic prescribing to patients without infection (low, medium, high, or very high). Outcomes included mortality and adverse events potentially attributable to antibiotics (e.g., allergy, organ dysfunction, Clostridiodes difficile infection, and culture with multidrug-resistant organism). Results: A total of 933,458 (59.9%) hospitalized patients received antimicrobial therapy within 48 hours of presentation, including 38,572 (2.5%) with septic shock, 276,082 (17.7%) with sepsis, 370,705 (23.8%) with infection, and 248,099 (15.9%) with antibiotics stopped early. A total of 199,937 (12.8%) hospitalized patients experienced an adverse event; most commonly, acute liver injury (5.6%), new MDRO (3.5%), and Clostridiodes difficile infection (1.7%). Across the scenarios, a 50% reduction in time-to-antibiotics for sepsis was associated with a median of 1 to 180 additional antibiotic-treated patients and zero to seven additional adverse events per death averted from sepsis. Conclusions: The impacts of faster time-to-antibiotics for sepsis vary markedly across simulated hospital types. However, even in the worst-case scenario, new antibiotic-associated adverse events were rare.

Objectives: Limited research has assessed how virtual care (VC) affects cardiovascular disease (CVD) risk management, especially in community clinic settings. This study assessed change in community clinic patients' CVD risk management during the COVID-19 pandemic and CVD risk factor control among patients who had primarily in-person or primarily VC visits., Study Design: Retrospective interrupted time-series analysis., Methods: Data came from an electronic health record shared by 52 community clinics for index (March 1, 2019, to February 29, 2020) and follow-up (July 1, 2020, to February 28, 2022) periods. Analyses compared follow-up period changes in slope and level of population monthly means of 10-year reversible CVD risk score, blood pressure (BP), and hemoglobin A1c (HbA1c) among patients whose completed follow-up period visits were primarily in person vs primarily VC. Propensity score weighting minimized confounding., Results: There were 10,028 in-person and 6593 VC patients in CVD risk analyses, 9874 in-person and 5390 VC patients in BP analyses, and 8221 in-person and 4937 VC patients in HbA1c analyses. The VC group was more commonly younger, female, White, and urban. Mean reversible CVD risk, mean systolic BP, and percentage of BP measurements that were 140/90 mm Hg or higher increased significantly from index to follow-up periods in both groups. Rate of change between these periods was the same for all outcomes in both groups, regardless of care modality., Conclusions: Among community clinic patients with CVD risk, receiving a majority of care in person vs a majority of care via VC was not significantly associated with longitudinal trends in reversible CVD risk score or key CVD risk factors.

Objectives: Understanding how the COVID-19 pandemic affected cardiovascular disease (CVD) risk monitoring in primary care may inform new approaches for addressing modifiable CVD risks. This study examined how pandemic-driven changes in primary care delivery affected CVD risk management processes., Study Design: This retrospective study used electronic health record data from patients at 70 primary care community clinics with scheduled appointments from September 1, 2018, to September 30, 2021., Methods: Analyses examined associations between appointment type and select care process measures: appointment completion rates, time to appointment, and up-to-date documentation for blood pressure (BP) and hemoglobin A1c (HbA1c)., Results: Of 1,179,542 eligible scheduled primary care appointments, completion rates were higher for virtual care (VC) vs in-person appointments (10.7 percentage points [PP]; 95% CI, 10.5-11.0; P < .001). Time to appointment was shorter for VC vs in-person appointments (-3.9 days; 95% CI, -4.1 to -3.7; P < .001). BP documentation was higher for appointments completed pre- vs post pandemic onset (16.2 PP; 95% CI, 16.0-16.5; P < .001) and for appointments completed in person vs VC (54.9 PP; 95% CI, 54.6-55.2; P < .001). HbA1c documentation was higher for completed appointments after pandemic onset vs before (5.9 PP; 95% CI, 5.1-6.7; P < .001) and for completed VC appointments vs in-person appointments (3.9 PP; 95% CI, 3.0-4.7; P < .001)., Conclusions: After pandemic onset, appointment completion rates were higher, time to appointment was shorter, HbA1c documentation increased, and BP documentation decreased. Future research should explore the advantages of using VC for CVD risk management while continuing to monitor for unintended consequences.

Introduction: Area-level social determinants of health (SDoH) and individual-level social risks are different, yet area-level measures are frequently used as proxies for individual-level social risks. This study assessed whether demographic factors were associated with patients being screened for individual-level social risks, the percentage who screened positive for social risks, and the association between SDoH and patient-reported social risks in a nationwide network of community-based health centers., Methods: Electronic health record data from 1,330,201 patients with health center visits in 2021 were analyzed using multilevel logistic regression. Associations between patient characteristics, screening receipt, and screening positive for social risks (e.g., food insecurity, housing instability, transportation insecurity) were assessed. The predictive ability of three commonly used SDoH measures (Area Deprivation Index, Social Deprivation Index, Material Community Deprivation Index) in identifying individual-level social risks was also evaluated., Results: Of 244,155 (18%) patients screened for social risks, 61,414 (25.2%) screened positive. Sex, race/ethnicity, language preference, and payer were associated with both social risk screening and positivity. Significant health system-level variation in both screening and positivity was observed, with an intraclass correlation coefficient of 0.55 for social risk screening and 0.38 for positivity. The three area-level SDoH measures had low accuracy, sensitivity, and area under the curve when used to predict individual social needs., Conclusion: Area-level SDoH measures may provide valuable information about the communities where patients live. However, policymakers, healthcare administrators, and researchers should exercise caution when using area-level adverse SDoH measures to identify individual-level social risks., Competing Interests: The authors report no relevant conflicts., (© The Author(s) 2023.)

Drainage from chronic wounds can significantly negatively impact a patient's quality of life. Change in severity of wound drainage is an important measure of treatment efficacy for wounds. This study reviews existing tools used to assess wound drainage. Qualitative drainage tools are overall less burdensome, and however, differences in user interpretation may reduce inter-rater reliability. Quantitative drainage tools enable more reliable comparisons of drainage severity and treatment response between patients but sometimes require equipment to administer, increasing responder burden. Gaps in the current wound drainage measurement landscape are highlighted. Many of the existing scales have not been validated in robust studies. There is also a lack of validated global drainage measurement tools for patients with chronic inflammatory skin disorders with drainage, such as hidradenitis suppurativa or pyoderma gangrenosum. Development of a succinct drainage measurement tool for inflammatory skin diseases where drainage is a prominent symptom will improve monitoring of meaningful treatment response., (© 2023. The Author(s).)

Competing Interests: Conflicts of interest see Appendix S1 in the Supporting Information.

Background: Spontaneous coronary artery dissection (SCAD) is an important cause of myocardial infarction (MI) in young to middle-aged women., Objectives: We aim to define the long-term natural history of SCAD., Methods: We performed a multicenter, prospective, observational study of patients with nonatherosclerotic SCAD presenting acutely from 22 North American centers. We recorded baseline demographics, in-hospital characteristics, precipitating and predisposing conditions, angiographic features (adjudicated), in-hospital and 3-year major adverse cardiovascular events (MACE). Cox regression multivariable analysis was performed., Results: We prospectively enrolled 750 consecutive patients with SCAD from June 2014 to June 2018. Mean age was 51.7 ± 10.5 years, 88.5% were women (55.0% postmenopausal); 31.3% presented with ST-segment elevation myocardial infarction, and 68.3% with non-ST-segment elevation myocardial infarction. Precipitating emotional stressor was reported in 50.3%, and physical stressor in 28.9%. Predisposing conditions included fibromuscular dysplasia in 42.9% (56.4% in those with complete screening), peripartum state 4.5%, and genetic disorders 1.6%. Most patients were treated conservatively (84.3%); 14.1% underwent percutaneous coronary intervention (PCI), 0.7% coronary artery bypass graft. At 3.0-year median follow-up, mortality was 0.8%, recurrent MI 9.9% (extension of previous SCAD 3.5%, de novo recurrent SCAD 2.4%, iatrogenic dissection 1.9%), with overall MACE 14.0%. Presence of genetic disorders, peripartum SCAD, and extracoronary fibromuscular dysplasia were independent predictors of 3-year MACE. Patients who underwent PCI at index hospitalization had similar postdischarge MACE compared with no PCI. At 3 years, 80.0% remained on aspirin and 73.5% on beta-blockade., Conclusions: Long-term mortality and de novo recurrent SCAD was low in our contemporary large SCAD cohort that included low revascularization rate and high use of beta-blockade and aspirin. Genetic disorders, extracoronary fibromuscular dysplasia, and peripartum SCAD were independent predictors of long-term MACE., Competing Interests: Funding Support and Author Disclosures This study was funded by the Canadian Institutes of Health Research, Abbott Vascular, AstraZeneca, St Jude Medical, and Servier. Dr Saw has received unrestricted research grant support from the Canadian Institutes of Health Research, Heart & Stroke Foundation of Canada, National Institutes of Health, University of British Columbia Division of Cardiology, AstraZeneca, Abbott, St Jude Medical, Boston Scientific, and Servier; has received salary support from Michael Smith Foundation of Health Research; has received speaker honoraria from AstraZeneca, Abbott, Boston Scientific, and Sunovion; has received consultancy and advisory board honoraria from AstraZeneca, St Jude Medical, Abbott, Boston Scientific, Baylis, Gore, and FEops; and has received proctorship honoraria from Abbott, St Jude Medical, and Boston Scientific. Dr So has received unrestricted research grant supports from the Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, National Institutes of Health, Eli Lilly, Spartan Biosciences, Roche Diagnostics, and Aggredyne; and has received speaker honoraria and advisory board honoraria from AstraZeneca and Bayer. Dr Gornik has received research support from CVR Global; has received equity and intellectual property from Flexlife Health; and is on the advisory board of FMD Society of America. Dr Lavoie has received speaking honoraria from Boehringer Ingelheim, Pfizer, BMS Sanofi, Novartis, Servier, and Bayer. Dr Ganesh has received research grants from the National Heart, Lung, and Blood Institute (HL139672), NIH, Doris Duke Charitable Foundation, and the Frankel Cardiovascular Center at the University of Michigan; and is on advisory boards of FMD Society of America and SCAD Alliance. Dr Ko is supported by the Jack Tu Chair in Cardiovascular Outcomes, Sunnybrook Hospital, and University of Toronto. Dr Madan is supported by the Heart & Stroke Foundation Polo Chair in Cardiology at the University of Toronto; and has received advisory board honoraria from Medtronic Canada, HLS therapeutics, JAMP Pharma, Novartis Canada, and Pendopharm Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022. Published by Elsevier Inc.)

This investigation examined the association between slow gait speed, as defined with newly established cut-points, and all-cause mortality in older Americans with a matched cohort analysis. The analytic sample included 10,259 Americans aged ≥65 years from the 2006-2014 waves of the Health and Retirement Study. Walking speed was measured in participant residences. Slow gait speed cut-points of <0.60 and <0.75 m/s were used separately for classifying participants as having slow walking speed. Nearest-neighbor propensity score matching was used to match the slow to the not-slow cohorts separately using both cut-points using relevant covariates. Persons with gait speed <0.60 m/s had a 1.42 higher hazard for mortality (95% CI: 1.28-1.57). Older Americans with gait speed <0.75 m/s had a 1.36 higher hazard for mortality (95% CI: 1.23-1.50). Slow gait speed may represent failing health and addressing how slow gait speed could be improved may help with referrals to appropriate interventions.

Background: Most antibiotics are prescribed in the ambulatory setting with estimates that up to 50% of use is inappropriate. Understanding factors associated with antibiotic misuse is essential to advancing better stewardship in this setting. We sought to assess the frequency of unnecessary antibiotic use for upper respiratory infections (URIs) among primary care providers and identify patient and provider characteristics associated with misuse., Methods: Unnecessary antibiotic prescribing was assessed in a descriptive study by using adults ≥18 years seen for common URIs in a large, Upper Midwest, integrated health system, electronic medical records from June 2017 through May 2018. Individual provider rates of unnecessary prescribing were compared for primary care providers practicing in the departments of internal medicine, family medicine, or urgent care. Patient and provider characteristics associated with unnecessary prescribing were identified with a logistic regression model., Results: A total of 49 463 patient encounters were included. Overall, antibiotics were prescribed unnecessarily for 42.2% (95% confidence interval [CI], 41.7-42.6) of the encounters. Patients with acute bronchitis received unnecessary antibiotics most frequently (74.2%; 95% CI, 73.4-75.0). Males and older patients were more likely to have an unnecessary antibiotic prescription. Provider characteristics associated with higher rates of unnecessary prescribing included being in a rural practice, having more years in practice, and being in higher volume practices such as an urgent care setting. Fifteen percent of providers accounted for half of all unnecessary antibiotic prescriptions., Conclusions: Although higher-volume practices, a rural setting, or longer time in practice were predictors, unnecessary prescribing was common among all providers., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Hospital-specific template matching (HS-TM) is a newer method of hospital performance assessment., Objective: To assess the interpretability, credibility, and usability of HS-TM-based vs. regression-based performance assessments., Research Design: We surveyed hospital leaders (January-May 2021) and completed follow-up semi-structured interviews. Surveys included four hypothetical performance assessment vignettes, with method (HS-TM, regression) and hospital mortality randomized., Subjects: Nationwide Veterans Affairs Chiefs of Staff, Medicine, and Hospital Medicine., Measures: Correct interpretation; self-rated confidence in interpretation; and self-rated trust in assessment (via survey). Concerns about credibility and main uses (via thematic analysis of interview transcripts)., Results: In total, 84 participants completed 295 survey vignettes. Respondents correctly interpreted 81.8% HS-TM vs. 56.5% regression assessments, p < 0.001. Respondents "trusted the results" for 70.9% HS-TM vs. 58.2% regression assessments, p = 0.03. Nine concerns about credibility were identified: inadequate capture of case-mix and/or illness severity; inability to account for specialized programs (e.g., transplant center); comparison to geographically disparate hospitals; equating mortality with quality; lack of criterion standards; low power; comparison to dissimilar hospitals; generation of rankings; and lack of transparency. Five concerns were equally relevant to both methods, one more pertinent to HS-TM, and three more pertinent to regression. Assessments were mainly used to trigger further quality evaluation (a "check oil light") and motivate behavior change., Conclusions: HS-TM-based performance assessments were more interpretable and more credible to VA hospital leaders than regression-based assessments. However, leaders had a similar set of concerns related to credibility for both methods and felt both were best used as a screen for further evaluation., (© 2022. The Author(s).)

Background: Recurring nodules, abscesses, and lesions characterise hidradenitis suppurativa (HS): a chronic, inflammatory skin disorder. Globally the prevalence of HS is estimated to be around 1% of the population. Leakage, pain, and odour from HS wounds require substantial management. Little is known of the personal burdens that routine wound management imposes on the patient., Objectives: To evaluate how routine HS wound management impacts patients in terms of the time spent changing dressings, the number of dressings required per day, pain experienced during dressing changes, and negative impact on various domains of their personal lives., Methods: An anonymous online questionnaire was posted on closed social media patient support groups between April and May 2019. Pearson χ2 test was used to evaluate if Hurley stages influenced the personal impact of wound care routines on patients. Statistical significance was determined as p value <0.05., Results: In total, 908 people from 28 countries responded. Of these, 81% (n = 734) reported that regular dressing changes negatively impacted on their quality of life. Most patients, 82% (n = 744), experience pain during dressing changes. 16% (n = 142) of patients required five or more dressings daily, and 12% (n = 108) spend over 30 min daily tending to wounds. Patients indicated high levels of dissatisfaction with currently available wound dressings., Conclusion: HS wound management imposes a substantial personal burden on patients. There is a clear unmet need for HS-specific wound dressings and wound care provisions, and a greater awareness of the condition and its impact is needed among clinicians., (© 2021 S. Karger AG, Basel.)

Background: The morning period which is recognized as the highest risk for cardiovascular events is associated with a surge in blood pressure (BP). However, it is unclear what aspect of this rise is important., Aim: To determine whether the rate of rise (RoR), the magnitude (day night difference) or the product [BP power (BPPower)] is associated with increased cardiovascular risk., Methods: We developed a logistic equation method to fit individual 24-h patterns of BP to determine RoR, amplitude and BPPower using the ambulatory recordings from the Ohasama study including 564 men and 971 women (16.6 years follow-up)., Results: Men had a higher risk of cardiovascular events than women (24, 16%, P < 0.001). Age and night BP were strong linear risk predictors. In men sorting risk by quintiles of BPPower (adjusted for age, night BP, smoking status) revealed no clear linear or nonlinear pattern. However, in women BPPower had a U-shaped relationship with the lowest risk being the 2-3rd quintile for all cardiovascular events (Pquadratic = 0.01) including cardiovascular death (Pquadratic = 0.03) and nonfatal stroke (Pquadratic = 0.02). A similar but less clear trend was observed with the RoR but only stroke (infarct) reached significance (Pquadratic = 0.03) while sorting by range showed a U shaped pattern for combined cardiovascular events (Pquadratic = 0.04)., Conclusion: These findings suggest that the morning BPPower is an important independent risk factor for predicting cardiovascular events and stroke but only in women with median levels having the lowest risk.

The control of reproductive processes involves the integration of a number of factors from the internal and external environment, with the final output signal of these processes being the pulsatile secretion of gonadotrophin releasing hormone (GnRH) from the hypothalamus. These factors include the feedback actions of sex steroids, feed intake and nutritional status, season/photoperiod, pheromones, age and stress. Understanding these factors and how they influence GnRH secretion and hence reproduction is important for the management of farm animals. There is evidence that the RF-amide neuropeptide, kisspeptin, may be involved in relaying the effects of these factors to the GnRH neurons. This paper will review the evidence from the common domestic animals (sheep, goats, cattle, horses and pigs), that kisspeptin neurons are i) regulated by the factors listed above, ii) contact GnRH neurons, and iii) involved in the regulation of GnRH/gonadotrophin secretion.

Aims: The aim of this study is to investigate the long-term relationship between revascularization technique and health status in diabetics with multivessel disease., Methods and Results: Using the Alberta Provincial Project for Outcomes Assessment in Coronary Heart Disease (APPROACH) registry, we captured 1319 diabetics with multivessel disease requiring revascularization for an acute coronary syndrome (January 2009-December 2012) and reported health status using the Seattle Angina Questionnaire (SAQ) at baseline, 1, 3 and 5-years [599 underwent coronary artery bypass grafting (CABG); 720 underwent percutaneous coronary intervention (PCI)]. Adjusted analyses were performed using a propensity score-matching technique. After adjustment (including baseline SAQ domain scores), 1-year mean (95% CI) SAQ scores (range 0-100 with higher scores reflecting improved health status) were significantly greater in selected domains for CABG compared to PCI (exertional capacity: 81.7 [79.5-84.0] vs. 78.8 [76.5-81.0], P = 0.07; angina stability: 83.1 [80.4-85.9] vs. 75.0 [72.3-77.8], P < 0.001]; angina frequency 93.2 [91.6-95.0] vs. 90.0 [87.8-91.3], P = 0.003; treatment satisfaction: 93.6 [92.2-94.9] vs. 90.8 [89.2-92.0], P = 0.003; quality of life [QOL]: 83.8 [81.7-85.8] vs. 77.2 [75.2-79.2] P < 0.001). At 3-years, these benefits were attenuated (exertional capacity: 79.3 [76.9-81.7] vs. 78.7 [76.3-81.1], P = 0.734; angina stability 79.3 [76.3-82.3] vs. 75.5 [72.5-78.5], P = 0.080; angina frequency: 93.2 [91.3-95.1] vs. 90.9 [89.0-92.8], P = 0.095; treatment satisfaction: 92.5 [91.0-94.0] vs. 91.5 [90.0-93.0] P = 0.382; QOL: 83.2 [81.1-85.2] vs. 80.3 [78.2-82.4], P = 0.057). At 5-years, majority of domains were similar (exertional capacity: 77.8 [75.0-80.6] vs. 76.3 [73.2-79.3], P = 0.482; angina stability: 78.0 [74.8-81.2] vs. 74.8 [71.4-78.2], P = 0.175; angina frequency: 94.2 [92.3-96.0] vs. 90.9 [89.0-92.9], P = 0.018; treatment satisfaction: 93.7 [92.2-95.1] vs. 92.2 [90.6-93.7], P = 0.167; QOL: 84.1 [82.0-86.3] vs. 81.1 [78.8-83.4], P = 0.058). Majority in both groups remained angina-free at 5-years (75.0% vs. 70.3%, P = 0.15)., Conclusion: Improvements in health status with CABG compared with PCI were not sustained long-term. This temporal sequence should be considered when contemplating a revascularization strategy in diabetics with multivessel disease., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For Permissions, please email: journals.permissions@oup.com.)

Managing the return to regular cyclicity after the winter anestrous period in the mare has been a challenge for the equine breeding industry. Specifically, efforts have been made to shift or shorten the vernal transition period and to have it followed by a predictable first ovulation at the commencement of the breeding season. Intravenous administration of kisspeptin is known to stimulate an LH response in both reproductively active and inactive mares. This study examined the effects of a constant rate infusion (CRI) of kisspeptin on mares during vernal transition. Mares were given a 30 hours infusion of kisspeptin at a low and high rate (66 nmol [88 μg] and 100 nmol [130 μg] per hour, respectively) or saline, and the LH and follicular response tracked. Plasma samples were collected every 15 minutes for the first 6 hours to determine if there is an acute effect of kisspeptin infusion on LH secretion. Plasma samples were then collected every 3 hours for a total of 72 hours to examine the ability of kisspeptin to stimulate an LH surge. A CRI of kisspeptin increased LH secretion in these mares but was not able to stimulate an LH surge. To examine the effect of kisspeptin on ovarian activity, follicular measurements were collected ultrasonographically until ovulation occurred or the follicles regressed. CRI of kisspeptin at these rates was unable to induce ovulation earlier than controls., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: Hyperkalemia is rare in individuals with normal renal function, regardless of dietary intake. This is due to the ability of the kidneys to adapt to increasing serum potassium concentrations. In patients with renal compromise, potassium homeostasis can become impaired. Palmaria palmata (dulse) is an edible seaweed known to be very rich in potassium. We report a case of hyperkalemia precipitated by the consumption of dulse by a patient with known renal disease., Case Presentation: A 66-year-old Caucasian woman with diabetes and chronic renal disease presented to our emergency department with nausea, vomiting, and worsening malaise, which had been present for less than a day. She had undergone electrocardiogram monitoring, which showed bradycardia, and periods of asystole. Our patient denied any other symptoms. Laboratory analysis revealed a serum potassium level of 8.6 mmol/L (normal range 3.5 to 4.9 mmol/L). Although our patient was taking some medications known to influence renal function, the only recent change that she could recount was that she had consumed approximately 200 g of dulse within the preceding 24 hours. A diagnosis of hyperkalemia was made, and the patient was treated successfully, and discharged home in her pre-morbid state., Conclusion: To the best of our knowledge, this is the first published report of hyperkalemia due to dulse consumption. Dulse is high in potassium, with concentrations upwards of 34 times greater than that found in bananas. Caution should be taken in prescribing medications with potential adverse renal effects for patients with known renal impairment. In such instances, renal function should be monitored closely. Patients should be counseled to avoid dietary sources high in potassium, with particular attention paid to unusual geographical dietary variations.

Detailed knowledge of the vascular anatomy of the anterior skull base is critical to successful surgery in this area. Whereas conventional neuronavigational approaches combine MRI (+/- contrast) for tumor visualization and CT (+/- C) for bony and vascular anatomy, we describe the Canadian and Austrian experiences using a novel protocol integrating MR angiography (MRA) into surgical neuronavigation to provide superior visualization of the carotid arteries. The pre-operative imaging protocol employs a T1-weighted, 3D fast spoiled gradient echo MRI (+/- C) for soft tissue anatomy, a plain CT for bony anatomy, and a 3D time-of-flight MR angiography for carotid anatomy. The series are imported into the Medtronic StealthStation((R)) TREON((R)) Treatment Guidance System; during intra-operative neuronavigation, each series (MRI, CT, MRA) can be viewed individually, or layered and viewed as a composite image. Our protocol has important advantages. First, it provides detailed tissue, tumor, vascular and bony anatomy. Second, a contrast CT is not necessary; this is important, as numerous reports have highlighted the nephrotoxic nature of radiographic contrast material. Third, visualization of the carotid system is superior than can be obtained from CT angiography. We use this unique imaging protocol routinely for our endoscopic transsphenoidal surgeries to provide superior visualization of the carotid arteries during anterior skull base surgery.

Over 25 years ago it was suggested that the mechanism by which lithium was clinically effective may be due to a stabilizing effect on the phosphoinositol second messenger system (PI-cycle), which has multiple effects within cells. It was proposed that lithium, which is an inhibitor of one of the key enzymes in the PI-cycle, acted to lower myo-inositol concentrations; termed the 'inositol-depletion hypothesis'. Initial animal evidence supported this hypothesis, and also suggested that it was possible that sodium valproate could affect the PI-cycle. Since the first magnetic resonance studies in this area in the early 1990s many studies have examined various aspects of this hypothesis in both healthy volunteers and patients utilizing magnetic resonance spectroscopy (MRS). The present review considers research in this area and concludes that, despite initial promise, current evidence suggests that it is unlikely that either lithium or valproate produce clinically relevant changes in myo-inositol concentrations or the PI-cycle. These findings do not suggest that lithium-induced changes in the PI-cycle are the primary mechanism by which lithium or valproate exert their beneficial clinical effects in bipolar disorder. Nonetheless, given the current technical and clinical limitations of the literature to date, this conclusion cannot be considered completely definitive.

The pathophysiological underpinnings of bipolar disorder are not fully understood. However, they may be due in part to changes in the phosphatidylinositol second messenger system (PI-cycle) generally, or changes in myo-inositol concentrations more specifically. Dextro-amphetamine has been used as a model for mania in several human studies as it causes similar subjective and physiological symptoms. We wanted to determine if dextro-amphetamine altered myo-inositol concentrations in vivo as it would clearly define a mechanism linking putative changes in the PI-cycle to the subjective psychological changes seen with dextro-amphetamine administration. Fifteen healthy human volunteers received a baseline scan, followed by second scan 75 min after receiving a 25 mg oral dose of dextro-amphetamine. Stimulated echo proton magnetic resonance spectroscopy (MRS) scans were preformed at 3.0 Tesla (T) in the dorsal medial prefrontal cortex (DMPFC). Metabolite data were adjusted for tissue composition and analyzed using LCModel. Twelve adult male rats were treated acutely with a 5-mg/kg intraperitoneal dose of dextro-amphetamine. After 1 h rats were decapitated and the brains were rapidly removed and frozen until dissection. Rat brains were dissected into frontal, temporal, and occipital cortical areas, as well as hippocampus. Tissue was analyzed using a Varian 18.8 T spectrometer. Metabolites were identified and quantified using Chenomx Profiler software. The main finding in the present study was that myo-inositol concentrations in the DMPFC of human volunteers and in the four rat brain regions were not altered by acute dextro-amphetamine. While it remains possible that the PI-cycle may be involved in the pathophysiology of bipolar disorder, it is not likely that the subjective and physiological of dextro-amphetamine are mediated, directly or indirectly, via alternations in myo-inositol concentrations.