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Most disorders of steroidogenesis, such as forms of congenital adrenal hyperplasia (CAH) are caused by mutations in genes encoding the steroidogenic enzymes and are often recognized clinically by cortisol deficiency, hyper- or hypo-androgenism, and/or altered mineralocorticoid function. Most steroidogenic enzymes are forms of cytochrome P450. Most P450s, including several steroidogenic enzymes, are microsomal, requiring electron donation by P450 oxidoreductase (POR); however, several steroidogenic enzymes are mitochondrial P450s, requiring electron donation via ferredoxin reductase (FDXR) and ferredoxin (FDX). POR deficiency is a rare but well-described form of CAH characterized by impaired activity of 21-hydroxylase (P450c21, CYP21A2) and 17-hydroxylase/17,20-lyase (P450c17, CYP17A1); more severely affected individuals also have the Antley-Bixler skeletal malformation syndrome and disordered genital development in both sexes, and hence is easily recognized. The 17,20-lyase activity of P450c17 requires both POR and cytochrome b5 (b5), which promote electron transfer. Mutations of POR, b5, or P450c17 can cause selective 17,20-lyase deficiency. In addition to providing electrons to mitochondrial P450s, FDX, and FDXR are required for the synthesis of iron-sulfur clusters, which are used by many enzymes. Recent work has identified FDXR mutations in patients with visual impairment, optic atrophy, neuropathic hearing loss, and developmental delay, resembling the global neurologic disorders seen with mitochondrial diseases. Many of these patients have had life-threatening events or deadly infections, often without an apparent triggering event. Adrenal insufficiency has been predicted in such individuals but has only been documented recently. Neurologists, neonatologists, and geneticists should seek endocrine assistance in evaluating and treating patients with mutations in FDXR., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

The current understanding of the biology, biochemistry and genetics of the steroidogenic acute regulatory protein (StAR) and its deficiency state (lipoid congenital adrenal hyperplasia, lipoid CAH) involves the complex interplay of four areas of study: the acute regulation of steroidogenesis, clinical phenomena in lipoid CAH, the enzymatic conversion of cholesterol to pregnenolone in steroidogenic mitochondria, and the cell biology of StAR. This review traces the origins of these areas of study, describes how they have been woven into an increasingly coherent fabric and tries to explore some remaining loose ends in this ongoing field of endocrine research. Extensive research from multiple laboratories has established that StAR is required for the rapid, abundant steroidal responses of the adrenals and gonads, but all steroidogenic cells, especially the placenta, also have StAR-independent steroidogenesis, whose basis remains under investigation. Lipoid CAH is the StAR knockout of nature whose complex (and unexpected) clinical features are explained by the 'two-hit model', in which StAR-dependent steroidogenesis and StAR-independent steroidogenesis are lost sequentially. StAR is targeted to mitochondria and acts on the outer mitochondrial membrane before being imported via the 'translocase of outer membrane' system and is then inactivated by mitochondrial proteases. A role for the 'translocator protein' (TSPO) has long been proposed, but an essential role for TSPO is excluded by recent transgenic mouse experiments. Crystal structures show that a StAR molecule can bind one cholesterol but does not explain how each StAR molecule triggers the import of hundreds of cholesterol molecules; this is the most pressing area for future research.

Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: Quantitative methods have shown clinically significant heterogeneity in blood volume (BV) profiles in patients with chronic heart failure (HF). How patients' sex might impact this volume heterogeneity and its relationship to cardiac hemodynamics remains to be defined., Methods: Retrospective analysis of clinical and quantitative BV, plasma volume (PV) and red blood cell (RBC) mass data was undertaken across 3 medical centers. BV was quantitated using nuclear medicine I-131-labeled plasma albumin indicator-dilution methodology with cardiac hemodynamics obtained within 24 hours., Results: In an analysis of 149 males and 106 females, absolute BV was greater, on average, in males (6.9 ± 1.7 vs 5.0 ± 1.2 liters; P < 0.001); however, a wide range in BVs was demonstrated in both sexes (2.9-14.5 liters). Male sex was associated with higher prevalence of large (+ 25% of normal) BV and PV expansions (36% vs 15% and 51% vs 21%, respectively; both P < 0.001). In contrast, female sex was associated with higher prevalence of normal total BV (44% vs 27%; P = 0.005), PV (54% vs 27%; P < 0.001), hypovolemia (23% vs 11%; P = 0.005), and true anemia (42% vs 26%; P < 0.001). Cardiac hemodynamics differed by sex, but only modest associations were demonstrated between volume profiles and cardiac filling pressures., Conclusions: Findings support unique intravascular volume profiles reflecting sex-specific differences in the prevalence and distributions of total BV, PV and RBC mass profiles in patients with chronic HF. This underscores the importance of recognizing patients' sex as a significant factor influencing volume homeostasis, which needs to be taken into account to individualize volume-management strategies effectively., Competing Interests: Disclosures MF, DMY and WLM receive consulting fees from Daxor. All other authors have no relevant disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aims: Quantitative methods have shown clinically significant heterogeneity in blood volume (BV) profiles across heart failure (HF) phenotypes. These profiles extend from hypovolaemia to normal BV and to variable degrees of BV hypervolaemia, frequently with similar clinical presentations. However, a comprehensive survey of BV profiles providing practical clinical guidance for the interpretation and management of quantitative plasma volume (PV) and red blood cell (RBC) mass findings has not been reported. The intent of this study is to advance this concept through a multicentre analysis., Methods and Results: A retrospective analysis of clinical and BV data was undertaken in stable NYHA class II-III HF patients (N = 546). BV was quantitated using established nuclear medicine indicator-dilution methodology. Differing combinations of PV and RBC mass were identified contributing to marked heterogeneity in overall BV profiles. A quantitatively normal BV was identified in 32% of the cohort but of these only ~1/3 demonstrated a true normal BV (i.e., normal PV + normal RBC mass). The remaining portion of normal BV profiles reflected balanced combinations of compensatory PV expansion with RBC mass deficit (anaemia) (14% of cohort) and PV contraction with RBC mass excess (erythrocythemia) (6% of cohort). Main contributors to BV hypervolaemia were PV excess with a normal RBC mass (21% of cohort; 23% female) and PV excess with erythrocythemia (24% of cohort; 26% female). Hypovolaemia was predominately defined by RBC mass deficit with a normal PV (6% of cohort; 57% female) or RBC mass deficit with PV contraction (5% of cohort; 48% female)., Conclusions: Findings support the clinical relevance of identifying and accurately interpreting the varying combinations of PV and RBC mass in patients with chronic HF. This in turn helps guide appropriate individualized patient management strategies. A practical volume-based guideline is provided in an effort to aid clinician interpretation., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Clinical congestion remains a major cause of hospitalization and re-hospitalizations in patients with chronic heart failure (HF). Despite the high prevalence of this issue and clinical concern in HF practice, there is limited understanding of the complex pathophysiology relating to the "congestion" of congestive HF. There is no unifying definition or clear consensus on what is meant or implied by the term "congestion." Further, the discordance in study findings relating congestion to physical signs and symptoms of HF, cardiac hemodynamics, or metrics of weight change or fluid loss with diuretic therapy has not added clarity. In this review, these factors will be discussed to add perspective to this issue and consider the factors driving "congestion." There remains a need to better understand the roles of fluid retention promoting intravascular and interstitial compartment expansions, blood volume redistribution from venous reservoirs, altered venous structure and capacity, elevated cardiac filling pressure hemodynamics, and heterogeneous intravascular volume profiles (plasma volume and red blood cell mass) with a goal to help demystify "congestion" in HF. Further, this includes highlighting the importance of recognizing that congestion is not the result of a single pathway but a complex of responses some of which produce symptoms while others do not; yet, we confine these varied responses to the single and somewhat vague term "congestion.", (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Objectives: Physicians have long been considered valued members of a solid US health care system. Significant changes in medical education, health care, and society at-large suggest that current medical students may face a different future. To help guide educators and policy makers, we set out to understand medical students' perceptions of the future of health care and their place in it., Methods: In year one of a longitudinal study, we conducted in-depth interviews of Case Western Reserve University medical students. A multidisciplinary team performed iterative thematic analyses and sampling until reaching saturation on major themes., Results: Eleven medical student participants described social and health care issues as major influences on their professional futures. Concerns included health care system failings, unsustainable costs, climate change, demographic shifts, disinformation, and public distrust in health care. Students looked forward to team practice and using technology, data, and artificial intelligence in care delivery. They hoped for greater access and equity in health care, with a focus on prevention and social, behavioral, and environmental drivers of health. Most students expected to be employed rather than in private practice and sought time/flexibility for professional and personal interests. Paying off medical school debt and advocating for patients and change were priorities. Many saw primary care as important, but fewer envisioned it as their career path of choice., Conclusions: Medical students envision a future shaped by health care systems and social issues. These findings can inform those helping students prepare for uncertainty and rapid change in their careers, their lives, and the lives of their patients.

focused Rapid Assessment Process (fRAP) 2.0 is a community engagement approach combining geospatial mapping with rapid qualitative assessment in cyclical fashion within communities to capture multifactorial and multilevel features impacting primary care problems. fRAP 2.0 offers primary care researchers a methodology framework for exploring complex community features that impact primary healthcare delivery and outcomes. The fRAP 2.0 study design expands the fRAP from a sequential design to a cyclical process of geospatial mapping and rapid qualitative assessment in search of modifiable contextual factors. Research participants are stakeholders from various socioecological levels whose perspectives inform study outcomes that they may use to then become the agents of change for the very problems they helped explore. Here, we present a proof-of-concept study for fRAP 2.0 examining disparities in cervical cancer mortality rates among Hispanic women in Texas. The primary outcomes of interest are features at the community level, medical health system level and regional government policy levels that offer opportunities for collaborative interventions to improve cervical cancer outcomes. In this study, geospatial mapping of county and ZIP code-level variables impacting postdiagnosis cervical cancer care at community, medical and policy levels were created using publicly available data and then overlaid with maps created with Texas Cancer Registry data for cervical cancer cases in three of the largest population counties. Geographically disparate areas were then qualitatively explored using participant observation and ethnographic field work, alongside 39 key informant interviews. Roundtable discussion groups and stakeholder engagement existed at every phase of the study. Applying the fRAP 2.0 method, we created an action-oriented roadmap of next steps to improve cervical cancer care disparities in the three Texas counties with emphasis on the high disparity county. We identified local change targets for advocacy and the results helped convene a stakeholder group that continues to actively create on-the-ground change in the high-disparity county to improve cervical cancer outcomes for Hispanic women., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Distinguishing between septic arthritis and crystal arthropathy flares can be challenging. The purpose of this study was to determine how the presence of synovial crystals affects the diagnostic criteria of septic arthritis., Methods: A retrospective review identified patients undergoing joint aspirations to rule out native septic arthritis. Differences between septic arthritis presenting with and without synovial crystals were analyzed. A receiver-operating characteristic curve was plotted for laboratory markers to determine the area under the curve, or diagnostic accuracy, for septic arthritis and to evaluate thresholds that maximized sensitivity and specificity., Results: There were 302 joint aspirations in 267 patients. Septic arthritis was diagnosed in 17.9% (54/302). Patients with synovial crystals were less likely to have septic arthritis (4.2% [5/119] vs. 26.8% [49/183], P < 0.0001). Septic arthritis in patients with no synovial crystals was associated with fever and a higher synovial white blood cell (WBC) count, synovial polymorphonuclear cell percentage (PMN%), serum WBC, and C-reactive protein (CRP) ( P < 0.05). Septic arthritis in patients with synovial crystals was only associated with inability to bear weight and a higher synovial WBC and CRP ( P < 0.05). Synovial PMN% was considered nondiagnostic of septic arthritis (area under the curve 0.56) in patients with crystals while synovial WBC and CRP had acceptable (0.76) and excellent (0.83) diagnostic utility, respectively. The WBC and CRP value thresholds that maximized sensitivity and specificity for septic arthritis were greater in patients with crystals (21,600 vs. 17,954 cells/μL and 125 vs. 69 mg/L, respectively)., Discussion: The presence of synovial crystals reduced the likelihood of septic arthritis and altered the laboratory diagnostic criteria. PMN% was nondiagnostic in the setting of synovial crystals., (Copyright © 2024 by the American Academy of Orthopaedic Surgeons.)

Background: Blood volume (BV) profiles vary markedly in patients with heart failure (HF), but how HF phenotypes and patient sex impact volume profiles remain to be explored. The aim of the study was to differentiate BV, plasma volume, and red blood cell mass profiles by phenotypes of preserved and reduced left ventricular ejection fractions and assess the impact of patient sex on profile heterogeneity., Methods: Retrospective analysis of clinical and BV data was undertaken in patients with chronic New York Heart Association II-III heart failure. BV was quantitated using the nuclear medicine indicator-dilution methodology., Results: A total of 530 BV analyses (360 HF with reduced ejection fraction and 170 HF with preserved ejection fraction) were identified in 395 unique patients. Absolute BV was greater in HF with reduced ejection fraction (6.7±1.8 versus 5.9±1.6 liters: P <0.001); however, large variability in frequency distribution of volume profiles was observed in both phenotypes (-22% deficit to +109% excess relative to normal volumes). HF with reduced ejection fraction was characterized by a higher prevalence of BV expansion ≥+25% of normal (39% versus 26%; P =0.003), and HF with preserved ejection fraction was characterized a by more frequent normal BV (42% versus 24%; P <0.001). Male sex in both phenotypes was associated with a larger absolute BV (7.0±1.6 versus 5.1±1.3 liters; P <0.001) and higher frequency of large BV and plasma volume expansions above normal (both P <0.001), while females in both phenotypes demonstrated a higher prevalence of normal BV and plasma volume (both P <0.001)., Conclusions: Findings support significant differences in BV, plasma volume, and red blood cell mass profile distributions between heart failure phenotypes, driven in large part by sex-specific factors. This underscores the importance of identifying and distinguishing individual patient volume profiles to help guide volume management strategies., Competing Interests: Disclosures None.

Purpose: To identify associations with unplanned repeat irrigation and debridement (I&D) after arthrotomy for native septic arthritis., Methods: A retrospective review identified patients with native septic arthritis treated with open arthrotomies. The primary outcome was unplanned repeat I&D within 90 days. Associations evaluated for included comorbidities, ability to bear weight, fever, immunosuppressed status, purulence, C-reactive protein, erythrocyte sedimentation rate, white blood cell count (synovial fluid and serum levels), and synovial fluid polymorphonuclear cell percentage (PMN%)., Results: There were 59 arthrotomies in 53 patients involving the knee (n = 32), shoulder (n = 10), elbow (n = 8), ankle (n = 6), and hip (n = 3). The median patient age was 52, and a 71.2% were male. An unplanned repeat I&D was required in 40.7% (n = 24). The median time to the second I&D was 4 days (interquartile range 3 to 9). On univariate analysis, unplanned repeat I&Ds were associated with fever (p = 0.03), purulence (p = 0.01), bacteria growth on cultures (p = 0.02), and the use of deep drains (p = 0.05). On multivariate analysis, the only variables that remained associated with unplanned repeat I&Ds were fever (odds ratio (OR) 5.5, 95% confidence interval (CI) 1.3, 23.6, p = 0.02) and purulence (OR 5.3, CI 1.1, 24.4, p = 0.03)., Conclusions: An unplanned repeat I&D was required in 40.7% of patients and was associated with fever and purulence. These findings highlight the difficulty of controlling these infections and support the need for future research into better methods of management., Level of Evidence: Diagnostic, Level III., (© 2024. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

The relationship of blood volume (BV) to systemic blood pressure (BP) is not well defined in resistant hypertension (RH). The goal of this study was to examine the extent to which systemic BP stratified by patient sex would impact BV phenotypes. A retrospective analysis of clinical and quantitative BV data was undertaken in a cohort of ambulatory patients with a history of controlled and uncontrolled RH. We analyzed 253 unique BVs with 54% of patients above goal BP of <150 mmHg. BV phenotypes were highly variable but no correlation of systolic BP to absolute BV or percentage deviation from normal volume was identified in either sex. Males demonstrated overall larger absolute BVs with higher prevalence of large plasma volume (PV) expansion; females were overall more hypovolemic by total BV but with a higher frequency of normal PV than males. Females trended towards more RBC mass deficit (true anemia) (49% vs. 38%. P  = 0.084) while more males demonstrated RBC mass excess (erythrocythemia) (21% vs. 11%, P  = 0.029). Importantly, a significant portion (52%) of patients with true anemia identified by BVA would go undetected by hemoglobin measurement alone. BV phenotypes are highly diverse in patients with RH. However, absolute BV or variability in BV phenotypes even when stratified by patient sex did not demonstrate an association with systemic BP. BV phenotyping provides a key to optimizing clinical management by identifying RBC mass profiles particularly distinguishing true anemia, dilutional anemia, and erythrocythemia and the contribution of PV expansion. Findings support the clinical utility of BV phenotyping in RH., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Storylines of Family Medicine is a 12-part series of thematically linked mini-essays with accompanying illustrations that explore the many dimensions of family medicine, as interpreted by individual family physicians and medical educators in the USA and elsewhere around the world. In 'XII: Family medicine and the future of the healthcare system', authors address the following themes: 'Leadership in family medicine', 'Becoming an academic family physician', ' Advocare- our call to act', 'The paradox of primary care and three simple rules', 'The quadruple aim-melding the patient and the health system', 'Fit-for-purpose medical workforce', 'Universal healthcare-coverage for all', 'The futures of family medicine' and 'The 100 th essay.' May readers of these essays feel empowered to be part of family medicine's exciting future., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Storylines of Family Medicine is a 12-part series of thematically linked mini-essays with accompanying illustrations that explore the many dimensions of family medicine, as interpreted by individual family physicians and medical educators in the USA and elsewhere around the world. In 'VI: ways of being-in the office with patients', authors address the following themes: 'Patient-centred care-cultivating deep listening skills', 'Doctor as witness', 'Words matter', 'Understanding others-metaphor and its use in medicine', 'Communicating with patients-making good use of time', 'The patient-centred medical home-aspirations for the future', 'Routine, ceremony or drama?' and 'The life course'. May readers better appreciate the nuances of patient care through these essays., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Population health in the United States continues to lag behind other wealthy nations. Primary care has the promise of enhancing population health; however, the implementation of a population health approach within primary care deserves further consideration. Clinicians and staff from a national sample of 10 innovative primary care practices participated in a working conference to reflect upon population health approaches in primary care. A series of small- and large-group discussions were recorded, transcribed, and coded through an immersion/crystallization approach. Two prominent themes emerged: (1) Transitioning to a population health focus generally develops through stages, with early implementation focusing on risk stratification and later, more advanced stages focusing on community health; and (2) Several inherent barriers confront implementation of a population health approach, including tensions with patient-centered care, and limitations of health information technology. A broader conceptualization of population health in terms of community health could more effectively allow partnerships among primary care, large health care systems, public health organizations, patients, and other partners in the community., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Haggstrom, Gabbay, Miller, Howard and Crabtree.)

Background: The COVID-19 pandemic challenged health care delivery globally, providing unique challenges to primary care. Australia's primary healthcare system (primarily general practices) was integral to the response. COVID-19 tested the ability of primary health care to respond to the greater urgency and magnitude than previous pandemics. Early reflections highlighted the critical role of leaders in helping organisations negotiate the pandemic's consequences. This study explores how general practice leadership was enacted during 2020, highlighting how leadership attributes were implemented to support practice teams., Methodology: We performed secondary analysis on data from a participatory prospective qualitative case study involving six general practices in Melbourne, Victoria, between April 2020 and February 2021. The initial coding template based on Miller et al.'s relationship-centred model informed a reflexive thematic approach to data re-analysis, focused on leadership. Our interpretation was informed by Crabtree et al.'s leadership model., Results: All practices realigned clinical and organisational routines in the early months of the pandemic - hierarchical leadership styles often allowing rapid early responses. Yet power imbalances and exclusive communication channels at times left practice members feeling isolated. Positive team morale and interdisciplinary teamwork influenced practices' ability to foster emergent leaders. However, emergence of leaders generally represented an inherent 'need' for authoritative figures in the crisis, rather than deliberate fostering of leadership., Conclusion: This study demonstrates the importance of collaborative leadership during crises while highlighting areas for better preparedness. Promoting interdisciplinary communication and implementing formal leadership training in crisis management in the general practice setting is crucial for future pandemics.

Hypertension and metabolic syndrome frequently coexist to increase the risk for adverse cardiometabolic outcomes. To date, no drug has been proven to be effective in treating hypertension with metabolic syndrome. M-atrial natriuretic peptide is a novel atrial natriuretic peptide analog that activates the particulate guanylyl cyclase A receptor. This study conducted a double-blind, placebo-controlled trial in 22 patients and demonstrated that a single subcutaneous injection of M-atrial natriuretic peptide was safe, well-tolerated, and exerted pleiotropic properties including blood pressure-lowering, lipolytic, and insulin resistance-improving effects. (MANP in Hypertension and Metabolic Syndrome [MANP-HTN-MS]; NCT03781739)., Competing Interests: This work was supported by the Marie Ingalls Cardiovascular Research Career Development Award in honor of Dr Alexander Schirger, Mayo Clinic CV Circulatory Program Award, and Scientist Development Award of the American Heart Association 16SDG29930003 (to Dr Cannone); Postdoctoral Fellowship 903661 (to Dr Ma) from the American Heart Association; and grants R01HL134668 and R01HL136340 (to Dr Burnett) from the National Heart, Lung and Blood Institute. Dr Burnett is the inventor of MANP, which the Mayo Clinic has licensed to E-STAR BIO TECH. All other authors have reported that they have no relationships relevant to the contents in this paper to disclose., (© 2024 The Authors.)

Background: Innovative Models Promoting Access to Care Transformation (IMPACT) was a five-year (2013-2018), Canadian-Australian research program that aimed to use a community-based partnership approach to transform primary health care (PHC) organizational structures to improve access to appropriate care for vulnerable populations. Local Innovation Partnerships (LIPs) were developed to support the IMPACT research program, and to be ongoing structures that would continue to drive local improvements to PHC., Methods: A longitudinal development-focused evaluation explored the overall approach to governance, relationships and processes of the LIPs in the IMPACT program. Semi-structured interviews were conducted with purposively selected participants including researchers with implementation roles and non-researchers who were members of LIPs at four time points: early in the development of the LIPs in 2014; during intervention development in 2015/2016; at the intervention implementation phase in 2017; and nearing completion of the research program in 2018.  A hybrid deductive-inductive thematic analysis approach was used. A Guide developed to support the program was used as the framework for designing questions and analysing data using a qualitative descriptive method initially. A visual representation was developed and refined after each round of data collection to illustrate emerging themes around governance, processes and relationship building that were demonstrated by IMPACT LIPs. After all rounds of data collection, an overarching cross-case analysis of narrative summaries of each site was conducted., Results: Common components of the LIPs identified across all rounds of data collection related to governance structures, stakeholder relationships, collaborative processes, and contextual barriers.  LIPs were seen primarily as a structure to support implementation of a research project rather than an ongoing multisectoral community-based partnership.  LIPs had relationships with many and varied stakeholders although not necessarily in ways that reflected the intended purpose. Collaboration was valued, but multiple barriers impeded the ability of LIPs to enact real collaboration in daily operations over time. We learned that experience, history, and time matter, especially with respect to community-oriented collaborative skills, structures, and relationships., Conclusions: This longitudinal multiple case study offers lessons and implications for researchers, funders, and potential stakeholders in community-based participatory research., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Among patients with chronic heart failure (HF) intravascular volume profiles vary significantly despite similar clinical compensation. However, little is known regarding changes in blood volume (BV) profiles over time. The objective of this analysis was to identify the extent and character of changes in volume profiles over time. A prospective analysis was undertaken in patients who were hospitalized and treated for fluid overload. Quantitative BV analyses were obtained in a compensated state at hospital discharge (baseline) and follow-up at 1, 3, and 6 mo. Data were available on 10 patients who remained stable without rehospitalization or medication change over a 6-mo period. Baseline BV profiles were highly variable at hospital discharge with an average deviation of +28% above normal in 6 patients and normal BV in 4 patients. Over the follow-up period, the median change in BV was -201 mL [-3% (-6, +3%)] from baseline with profiles remaining in the same volume category in 9 out of 10 patients. Crossover from normal BV to mild contraction (-13% of normal) occurred in one patient. Red blood cell mass demonstrated the largest change over 6 mo [median -275 (-410, +175) mL] with a deviation from normal of -14 (-20, +8) % (reflecting mild anemia). These findings suggest that BV profiles in clinically compensated patients with HF do not change substantially over a 6-mo period regardless of baseline expanded or normal BV. This lack of change in volume profiles particularly from an expanded BV has implications for long-term volume management, clinical outcomes, and also our understanding of volume homeostasis in HF. NEW & NOTEWORTHY The novel findings of this study demonstrate that blood volume profiles while highly variable in clinically compensated patients with HF on stable medical therapy do not change substantially over a 6-mo period regardless of baseline expanded or normal blood volumes. This lack of change in volume profiles particularly from an expanded blood volume has implications for long-term volume management and also for how we understand the pathophysiology of volume homeostasis in chronic HF.

The development of clinical congestion resulting from volume overload, either by renal fluid retention or redistribution of blood volume from venous reservoirs, is a recurrent scenario in patients with chronic heart failure (HF). As a result, the treatment of congestion, most commonly by initiating aggressive diuretic therapy, is a front-line issue in the management of patients with HF. However, the association of clinical congestion and volume overload with physical signs and symptoms, as well as other surrogates of volume assessment, has limitations in accuracy and, therefore, reliability to direct appropriate interventions. The ability to quantitate intravascular volume and identify the variability in volume profiles among patients with HF can uniquely inform individualized volume management and aid in risk stratification. This tool is provided by contemporary nuclear medicine-based BVA-100 methodology, which uses the well-established indicator-dilution principle and is a requested topic for discussion in this review., Competing Interests: Disclosures: Wayne L Miller receives unrestricted research grant support from Daxor and Feldschuh Foundation for Clinical Research., (© Touch Medical Media 2023.)

Aims: To identify different red blood cell mass (RBCM) profiles, separate from haemoglobin concentrations, and their impact on blood volume expansion and clinical outcomes in chronic heart failure., Methods and Results: RBCM was measured at hospital discharge using standardized nuclear medicine indicator-dilution methodology in patients following diuretic treatment for clinical congestion. Individual RBCM phenotypes were prospectively identified and analysed for heart failure-related mortality or first rehospitalization over 1 year. Of 132 patients, 42 (32%) demonstrated normal RBCM, 36 (27%) RBCM deficit (true anaemia), and 54 (41%) RBCM excess (erythrocythemia). Dilutional 'anaemia' defined by haemoglobin <12 g/dL with normal or an excess in RBCM with plasma volume expansion was identified in 37 (28%) patients. There were 61 composite outcome events, which included 38 deaths (29% of cohort) occurring over the 1 year follow-up period [14/36 (39%) in RBCM deficit, 12/42 (29%) in normal RBCM, and 12/54 (22%) in RBCM excess subgroups]. By Kaplan-Meier and multivariate analyses, RBCM excess was independently associated with the best event-free survival while RBCM deficit (true anaemia) the poorest outcomes; both compared with normal RBCM (P < 0.001). Dilutional 'anaemia' demonstrated a lower risk compared with true anaemia (P = 0.03)., Conclusions: Markedly different RBCM profiles are identifiable among comparably compensated heart failure patients, and this variability carries significant implications for post-hospital outcomes. Novel to this analysis and in contrast to RBCM deficit is the independent association of RBCM excess with better event-free survival compared with normal RBCM. The distinction of RBCM profiles to guide risk stratification and individualized patient management strategies warrants further study., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Policy Points Systems based on primary care have better population health, health equity, and health care quality, and lower health care expenditure. Primary care can be a boundary-spanning force to integrate and personalize the many factors from which population health emerges. Equitably advancing population health requires understanding and supporting the complexly interacting mechanisms by which primary care influences health, equity, and health costs., (© 2023 The Authors. The Milbank Quarterly published by Wiley Periodicals LLC on behalf of The Milbank Memorial Fund.)

Objectives: The rapid onset and progressive course of the COVID-19 pandemic challenged primary care practices to generate rapid solutions to unique circumstances, creating a natural experiment of effectiveness, resilience, financial stability and governance across primary care models. We aimed to characterise how practices in Melbourne, Australia modified clinical and organisational routines in response to the pandemic in 2020-2021 and identify factors that influenced these changes., Design: Prospective, qualitative, participatory case study design using constant comparative data analysis, conducted between April 2020 and February 2021. Participant general practitioner (GP) investigators were involved in study design, recruitment of other participants, data collection and analysis. Data analysis included investigator diaries, structured practice observation, documents and interviews., Setting: The cases were six Melbourne practices of varying size and organisational model., Participants: GP investigators approached potential participants. Practice healthcare workers were interviewed by social scientists on three occasions, and provided feedback on presentations of preliminary findings., Results: We conducted 58 interviews with 26 practice healthcare workers including practice owners, practice managers, GPs, receptionists and nurses; and six interviews with GP investigators. Data saturation was achieved within each practice and across the sample. The pandemic generated changes to triage, clinical care, infection control and organisational routines, particularly around telehealth. While collaboration and trust increased within several practices, others fragmented, leaving staff isolated and demoralised. Financial and organisational stability, collaborative problem solving, creative leadership and communication (internally and within the broader healthcare sector) were major influences on practice ability to negotiate the pandemic., Conclusions: This study demonstrates the complex influences on primary care practices, and reinforces the strengths of clinician participation in research design, conduct and analysis. Two implications are: telehealth, triage and infection management innovations are likely to continue; the existing payment system provides inadequate support to primary care in a global pandemic., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The adrenal is a small, anatomically unimposing structure that escaped scientific notice until 1564 and whose existence was doubted by many until the 18th century. Adrenal functions were inferred from the adrenal insufficiency syndrome described by Addison and from the obesity and virilization that accompanied many adrenal malignancies, but early physiologists sometimes confused the roles of the cortex and medulla. Medullary epinephrine was the first hormone to be isolated (in 1901), and numerous cortical steroids were isolated between 1930 and 1949. The treatment of arthritis, Addison's disease, and congenital adrenal hyperplasia (CAH) with cortisone in the 1950s revolutionized clinical endocrinology and steroid research. Cases of CAH had been reported in the 19th century, but a defect in 21-hydroxylation in CAH was not identified until 1957. Other forms of CAH, including deficiencies of 3β-hydroxysteroid dehydrogenase, 11β-hydroxylase, and 17α-hydroxylase were defined hormonally in the 1960s. Cytochrome P450 enzymes were described in 1962-1964, and steroid 21-hydroxylation was the first biosynthetic activity associated with a P450. Understanding of the genetic and biochemical bases of these disorders advanced rapidly from 1984 to 2004. The cloning of genes for steroidogenic enzymes and related factors revealed many mutations causing known diseases and facilitated the discovery of new disorders. Genetics and cell biology have replaced steroid chemistry as the key disciplines for understanding and teaching steroidogenesis and its disorders., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: To examine the association of prior investment on the effectiveness of organizations delivering large-scale external support to improve primary care., Methods: Mixed-methods study of 7 EvidenceNOW grantees (henceforth, Cooperatives) and their recruited practices (n = 1720). Independent Variable : Cooperatives's experience level prior to EvidenceNOW, defined as a sustained track record in delivering large-scale quality improvement (QI) to primary care practices (high, medium, or low). Dependent Variables: Implementation of external support, measured as facilitation dose; effectiveness at improving (1) clinical quality, measured as practices' performance on Aspirin, Blood Pressure, Cholesterol, and Smoking (ABCS); and (2) practice capacity, measured using the Adaptive Reserve (AR) score and Change Process Capacity Questionnaire (CPCQ). Data were analyzed using multivariable linear regressions and a qualitative inductive approach., Results: Cooperatives with High (vs low) levels of prior experience with and investment in large-scale QI before EvidenceNOW recruited more geographically dispersed and diverse practices, with lower baseline ABCS performance (differences ranging from 2.8% for blood pressure to 41.5% for smoking), delivered more facilitation (mean=+20.3 hours, P = .04 ), and made greater improvements in practices' QI capacity (CPCQ: +2.04, P < .001 ) and smoking performance (+6.43%, P = .003 ). These Cooperatives had established networks of facilitators at the start of EvidenceNOW and leadership experienced in supporting this workforce, which explained their better recruitment, delivery of facilitation, and improvement in outcomes., Discussion: Long-term investment that establishes regionwide organizations with infrastructure and experience to support primary care practices in QI is associated with more consistent delivery of facilitation support, and greater improvement in practice capacity and some clinical outcomes., Competing Interests: Conflict of interest: The authors of this manuscript have no conflicts of interest to report., (© Copyright by the American Board of Family Medicine.)

For 2 years, the Larry A. Green Center conducted weekly to monthly surveys among a national sample of primary medical care practices on how they were faring during the on-going COVID-19 pandemic in the United States. As both a family physician and as one of the analysts of these surveys and the thousands of detailed comments accompanying them, I witnessed a courageous, professional, and deeply distressing saga. The most recent surveys hint at an impending collapse of primary medical care as we have known it. This Commentary reflects what I heard, from remarkable efforts to rapidly implement virtual care platforms and reach out to vulnerable patients in the face of workforce losses and inadequate assistance including lack of personal protective equipment to a sense of betrayal when vaccines finally arrived but primary medical care was, too often, left out of the distribution efforts. The last surveys highlighted a loss of primary care workforce and the potential collapse of relationship-centered primary medical care. One of the respondents asks, "When is someone going to notice?"Three areas for change are recommended. Build a larger, more diverse primary medical care workforce. Emphasize capitation as a foundation for payment reform in primary medical care. Establish primary health care extension services that focus on supporting practices and in helping them integrate with public health and their communities. Listening to each other, let us rise together with our patients and be noticed., Competing Interests: Conflict of interest: None., (© Copyright by the American Board of Family Medicine.)

Rationale, Aims and Objectives: Generalists manage a broad range of biomedical and biographical knowledge as part of each clinical encounter, often in multiple encounters over time. The sophistication of this broad integrative work is often misunderstood by those schooled in reductionist or constructivist approaches to evidence. There is a need to describe the practical and philosophically robust ways that understanding about the whole person is formed. In this paper we describe first principles of generalist approaches to knowledge formation in clinical practice. We name the Craft of Generalism., Methods: The newly described methodology of Transdisciplinary Generalism is examined by skilled generalist clinicians and translated into skills and attitudes useful for everyday generalist person-centred practice and research., Results: The Craft of Generalism defines the required scope, process, priorities, and knowledge management skills of all generalists seeking to care for the whole person. These principles are Whole Person Scope, Relational Process, Healing Orientation, and Integrative Wisdom. These skills and attitudes are required for whole person care. If any element of these first principles is left out, the resultant knowledge is incomplete and philosophically incoherent., Conclusions: Naming the Craft of Generalism defines the generalist gaze and protects generalism from the colonization of a narrowed medical gaze that excludes all but reductionist evidence or constructivist experience. Defining the Craft of Generalism enables clear teaching of the sophisticated skills and attitudes of the generalist clinician. These philosophically robust principles encourage and defend the use of generalist approaches to knowledge in settings across the community - including health policy, education, and research., (© 2021 John Wiley & Sons Ltd.)

Intravascular volume is largely regulated by the kidneys but how differences in intravascular volume profiles interact with chronic kidney disease (CKD) to influence outcomes in chronic heart failure (HF) has not been explored. Our hypothesis was that a greater degree of volume expansion (VE) would moderate the impact of CKD on HF-related clinical outcomes. Quantitative blood volume (BV) data were available in 137 patients at the time of hospital discharge using a nuclear medicine radiolabeled albumin indicator-dilution technique. The study patients were stratified by the cohort median glomerular filtration rate (GFR, 44 ml/min/1.73 m 2 ). An a priori cut-point of ≥+25% above normal BV was then used to further stratify the two GFR subgroups and prospectively analyzed for 1-year HF-related mortality or 1st re-hospitalization. Persistent BV expansions ≥+25% were present in 51% of the cohort. In the subgroup with GFR above the median (N = 68) greater or lesser BV expansion from +25% did not differentiate outcomes. However, in the subgroup with GFR below the median (N = 69), BV expansion-stratified risk (log-rank p = 0.022) with <+25% VE associated with poorer outcomes, while VE ≥ + 25% was associated with lower risk and comparable to GFR above the median. In patients with chronic HF, significant intravascular VE and CKD are common co-existing conditions. The presence of larger VE, however, appears to be a factor mitigating the impact of declining renal function on clinical outcomes, and as an element of volume pathophysiology warrants further study., (© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Fluid volume homeostasis in health and heart failure (HF) requires a complex interaction of 2 systems, the intravascular and interstitial-lymphatic circulations. With the development of HF both the intravascular and interstitial compartments undergo variable degrees of volume remodeling which can include significant expansion. This reflects the impact of multiple pathophysiologic mechanisms on both fluid compartments which initially play a compensatory role to stabilize intravascular circulatory integrity but with progression in HF can evolve to produce the various manifestations of volume overload and clinical HF congestion. The intent of this review is to help enhance recognition of the pathophysiologic and clinical importance of the interlinked roles of these 2 circulatory systems in volume regulation and chronic HF. It would also be hoped that a better understanding of the interacting functions of the intravascular and interstitial-lymphatic fluid compartments can potentially aid development of novel management strategies particularly addressing the generally undertargeted interstitial-lymphatic system and help bring such approaches forward through a more integrated view of these 2 circulatory systems.