Efficacy and Safety of Acoramidis in Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Transthyretin amyloid cardiomyopathy is characterized by the deposition of misfolded monomeric transthyretin (TTR) in the heart. Acoramidis is a high-affinity TTR stabilizer that acts to inhibit dissociation of tetrameric TTR and leads to more than 90% stabilization across the dosing interval as measured ex vivo. METHODS: In this phase 3, double-blind trial, we randomly assigned patients with transthyretin amyloid cardiomyopathy in a 2:1 ratio to receive acoramidis hydrochloride at a dose of 800 mg twice daily or matching placebo for 30 months. Efficacy was assessed in the patients who had an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m2 of body-surface area. The four-step primary hierarchical analysis included death from any cause, cardiovascular-related hospitalization, the change from baseline in the N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, and the change from baseline in the 6-minute walk distance. We used the Finkelstein-Schoenfeld method to compare all potential pairs of patients within strata to generate a P value. Key secondary outcomes were death from any cause, the 6-minute walk distance, the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary, and the serum TTR level. RESULTS: A total of 632 patients underwent randomization. The primary analysis favored acoramidis over placebo (P<0.001); the corresponding win ratio was 1.8 (95% confidence interval [CI], 1.4 to 2.2), with 63.7% of pairwise comparisons favoring acoramidis and 35.9% favoring placebo. Together, death from any cause and cardiovascular-related hospitalization contributed more than half the wins and losses to the win ratio (58% of all pairwise comparisons); NT-proBNP pairwise comparisons yielded the highest ratio of wins to losses (23.3% vs. 7.0%). The overall incidence of adverse events was similar in the acoramidis group and the placebo group (98.1% and 97.6%, respectively); serious adverse events were reported in 54.6% and 64.9% of the patients. CONCLUSIONS: In patients with transthyretin amyloid cardiomyopathy, the receipt of acoramidis resulted in a significantly better four-step primary hierarchical outcome containing components of mortality, morbidity, and function than placebo. Adverse events were similar in the two groups. (Funded by BridgeBio Pharma; ATTRibute-CM ClinicalTrials.gov number, NCT03860935.).

Highly multiplexed immune profiling throughout adulthood reveals kinetics of lymphocyte infiltration in the aging mouse prostate.

Aging is a significant risk factor for disease in several tissues, including the prostate. Defining the kinetics of age-related changes in these tissues is critical for identifying regulators of aging and evaluating interventions to slow the aging process and reduce disease risk. An altered immune microenvironment is characteristic of prostatic aging in mice, but whether features of aging in the prostate emerge predominantly in old age or earlier in adulthood has not previously been established. Using highly multiplexed immune profiling and time-course analysis, we tracked the abundance of 29 immune cell clusters in the aging mouse prostate. Early in adulthood, myeloid cells comprise the vast majority of immune cells in the 3-month-old mouse prostate. Between 6 and 12 months of age, there is a profound shift towards a T and B lymphocyte-dominant mouse prostate immune microenvironment. Comparing the prostate to other urogenital tissues, we found similar features of age-related inflammation in the mouse bladder but not the kidney. In summary, our study offers new insight into the kinetics of prostatic inflammaging and the window when interventions to slow down age-related changes may be most effective.

Rural health in the Progressive Era: revisiting the hookworm intervention in the American South.

Objective: In this study, we investigated Progressive Era public health interventions and connected two subsequent efforts to improve outcomes in the American South: the Rockefeller Sanitary Commission's hookworm eradication efforts in the early 1910s and investments in local health infrastructure between the 1910s and the 1930s. We tested whether hookworm eradication had the largest effects in areas that invested in public health and whether county health organizations-cooperative public-private institutional arrangements-impacted the Rockefeller Sanitary Commission program's success. Materials and Methods: The methods used to measure the effects involved estimation of difference-in-difference and triple-difference models across the geographic samples of the Rockefeller Sanitary Commission's surveyed area, the American South, and the United States. Material on hookworm infection rates and activities by the Rockefeller Sanitary Commission is obtained from the Rockefeller Foundation Annual Reports. Material on the activities, spending, and duration of the different county health organizations is obtained from the Public Health Service Bulletin 222 titled, "A history of county health organizations in the United States: 1908-1933". Results: By comparing similar cooperative and independent county health organizations in the American South with the rest of the United States, we find that cooperative efforts are generally important and strengthen the Rockefeller Sanitary Commission's impact on human capital outcomes in the American South. Simultaneously, independent county health organizations produced negative or non-significant effects. Conclusion: The Rockefeller Sanitary Commission is important in guiding local health efforts. Our results are robust in both the short and long runs. This study sheds light on the effectiveness of public-private partnerships in rural public health during the Progressive Era.

Autosomal Dominant Hypocalcemia Type 1: A Systematic Review.

Autosomal dominant hypocalcemia type 1 (ADH1) is a rare form of hypoparathyroidism due to activating variants of the calcium-sensing receptor gene (CASR). Inherited or de novo activating variants of the CASR alter the set point for extracellular calcium, resulting in inadequate parathyroid hormone (PTH) secretion and inappropriate renal calcium excretion leading to hypocalcemia and hypercalciuria. Conventional therapy includes calcium and activated vitamin D, which can worsen hypercalciuria, resulting in renal complications. A systematic literature review, using published reports from 1994 to 2021, was conducted to catalog CASR variants, to define the ADH1 clinical spectrum, and to determine the effect of treatment on patients with ADH1. There were 113 unique CASR variants reported, with a general lack of genotype/phenotype correlation. Clinical data were available in 191 patients; 27% lacked symptoms, 32% had mild/moderate symptoms, and 41% had severe symptoms. Seizures, the most frequent clinical presentation, occurred in 39% of patients. In patients with blood and urine chemistries available at the time of diagnosis (n = 91), hypocalcemia (99%), hyperphosphatemia (59%), low PTH levels (57%), and hypercalciuria (34%) were observed. Blood calcium levels were significantly lower in patients with severe symptoms compared with asymptomatic patients (6.8 ± 0.7 versus 7.6 ± 0.7 mg/dL [mean ± SD]; p < 0.0001), and the age of presentation was significantly lower in severely symptomatic patients (9.1 ± 15.0 versus 19.3 ± 19.4 years; p < 0.01). Assessments for complications including nephrocalcinosis, nephrolithiasis, renal impairment, and brain calcifications in 57 patients on conventional therapy showed that 75% had at least one complication. Hypercalciuria was associated with nephrocalcinosis, nephrolithiasis, renal impairment, or brain calcifications (odds ratio [OR] = 9.3; 95% confidence interval [CI] 2.4-37.2; p < 0.01). In 27 patients with urine calcium measures before and after starting conventional therapy, the incidence of hypercalciuria increased by 91% (p < 0.05) after therapy initiation. ADH1 is a condition often associated with severe symptomatology at presentation with an increase in the risk of renal complications after initiation of conventional therapy. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Cellular Localization of Kynurenine 3-Monooxygenase in the Brain: Challenging the Dogma.

Kynurenine 3-monooxygenase (KMO), a key player in the kynurenine pathway (KP) of tryptophan degradation, regulates the synthesis of the neuroactive metabolites 3-hydroxykynurenine (3-HK) and kynurenic acid (KYNA). KMO activity has been implicated in several major brain diseases including Huntington's disease (HD) and schizophrenia. In the brain, KMO is widely believed to be predominantly localized in microglial cells, but verification in vivo has not been provided so far. Here, we examined KP metabolism in the brain after depleting microglial cells pharmacologically with the colony stimulating factor 1 receptor inhibitor PLX5622. Young adult mice were fed PLX5622 for 21 days and were euthanized either on the next day or after receiving normal chow for an additional 21 days. Expression of microglial marker genes was dramatically reduced on day 22 but had fully recovered by day 43. In both groups, PLX5622 treatment failed to affect Kmo expression, KMO activity or tissue levels of 3-HK and KYNA in the brain. In a parallel experiment, PLX5622 treatment also did not reduce KMO activity, 3-HK and KYNA in the brain of R6/2 mice (a model of HD with activated microglia). Finally, using freshly isolated mouse cells ex vivo, we found KMO only in microglia and neurons but not in astrocytes. Taken together, these data unexpectedly revealed that neurons contain a large proportion of functional KMO in the adult mouse brain under both physiological and pathological conditions.

Identification and characterization of Eimeria spp. in western north American Bison (Bison bison) herds and potential risk of cross-species transmission.

The American bison (Bison bison) is an iconic native wildlife species of the Great Plains of North America. Recently, farmed bison have also gained importance to the livestock industry across the United States and Canada. One of the common diseases in young bison is coccidiosis, a diarrheal disease caused by protozoa that can result in significant morbidity. The goal of the present study was to investigate occurrence and identity of bison coccidia of the genus Eimeria in both farmed and free-ranging bison with focus on potential Eimeria species transmissibility between bison and cattle. Individual bison (up to one year of age) were sampled across Wyoming, Colorado, Nebraska, and South Dakota on six bison ranches (n = 137) and in two free-range herds (n = 70). Eimeria populations were assessed by fecal analyses. Morphological identification revealed presence of oocysts consistent with Eimeria (E.) bovis, E. zuernii, E. ellipsoidalis, E. cylindrica, E. alabamensis, E. auburnensis, E. canadensis, E. pellita, E. subspherica, and E. bukidnonensis, all of which are described in cattle. Additional Eimeria species specific ITS1 sequencing data along with generated phylogenetic maximum likelihood trees suggest that Eimeria species from cattle, namely E. bovis, E. zuernii, E. alabamensis, E. cylindrica, E. brasiliensis, E. ellipsoidalis, and E. wyomingensis, are genetically consistent with the detected bison coccidia. In conclusion, the study results indicate that bison harbor a variety of Eimeria species and bison Eimeria species appear to be transmissible between different bovine species such as bison and cattle.

Use of Actigraphy (Wearable Digital Sensors to Monitor Activity) in Heart Failure Randomized Clinical Trials: A Scoping Review.

BACKGROUND: Actigraphy-based measurements of physiologic parameters may enable design of patient-centric heart failure (HF) clinical trials. Recently, the Heart Failure Collaboratory focused on recommendations for meaningful change and use of actigraphy as an end point in HF clinical trials. We aimed to evaluate randomized controlled trials (RCTs) that have quantified the impact of HF interventions using actigraphy. METHODS: Using a scoping review strategy, we evaluated the use of actigraphy in HF RCTs. Studies were identified through electronic searches of Embase, OVID Medline, PubMed, and Cochrane Review. Data on trial characteristics and results were collected. RESULTS: We identified 11 RCTs with a total of 1,455 participants. The risk of bias across the included trials was high overall. All trials had the primary outcomes reflecting measures of either physical activity (n = 8), sleep (n = 2), or both (n = 1). Five trials evaluated response to pharmacologic therapies compared with placebo, 3 evaluated physical activity interventions, 2 evaluated group or cognitive therapy, and 1 evaluated sleep-ventilation strategy. Sample sizes ranged from 30 to 619 participants. There was significant heterogeneity relating to device type, body placement site, and handling of missing actigraphy data. Duration of monitoring ranged from 48 hours to 12 weeks. None of the studies evaluating pharmacologic therapies (n = 5) demonstrated a significant improvement of actigraphy-based primary end point measurements. CONCLUSIONS: There is significant heterogeneity in the use, methodology, and results of actigraphy-based HF RCTs. Our results highlight the need to develop, standardize, and validate actigraphy-specific outcomes for use in HF clinical trials.

An online discussion between students and teachers: a way forward for meaningful teacher feedback?

BACKGROUND: Student evaluation is an essential component in feedback processes in faculty and learner development. Ease of use and low cost have made paper evaluation forms a popular method within teaching programmes, but they are often seen as a formality, offering variable value towards the improvement of teaching. Students report poor motivation to engage with existing feedback tools whilst teachers describe receiving vague, contradicting, or irrelevant information. We believe that feedback for teachers needs to be a two-way process, similar to feedback for students, for it to be effective. An online feedback tool has been implemented for third-year medical students from Imperial College London to promote open discussion between teachers and students. The feedback tool is accessible throughout students' clinical attachment with the option of maintaining anonymity. We aim to explore the benefits and challenges of this online feedback tool and assess its value as a method for teacher feedback. METHODS: Qualitative data was obtained from both volunteer third-year medical students of Imperial College London and Clinical Teaching Fellows using three focus groups and a questionnaire. Data was analysed through iterative coding and thematic analysis to provide over-arching analytical themes. RESULTS: Twenty-nine students trialled this feedback tool with 17 responding to the evaluative questionnaire. Four over-arching themes were identified: reasons for poor participation with traditional feedback tools; student motivators to engage with 'open feedback'; evaluative benefits from open feedback; concerns and barriers with open feedback. CONCLUSION: This feedback tool provides a platform for two-way feedback by encouraging open, transparent discussion between teachers and learners. It gives a unique insight into both teachers and peers' perspectives. Students engage better when their responses are acknowledged by the teachers. We elaborate on the benefits and challenges of public open feedback and approaches to consider in addressing the self-censorship of critical comments.

Iron activates microglia and directly stimulates indoleamine-2,3-dioxygenase activity in the N171-82Q mouse model of Huntington's disease.

Huntington's disease (HD) is a neurodegenerative disorder caused by a dominant CAG-repeat expansion in the huntingtin gene. Microglial activation is a key feature of HD pathology, and is present before clinical disease onset. The kynurenine pathway (KP) of tryptophan degradation is activated in HD, and is thought to contribute to disease progression. Indoleamine-2,3-dioxygenase (IDO) catalyzes the first step in this pathway; this and other pathway enzymes reside with microglia. While HD brain microglia accumulate iron, the role of iron in promoting microglial activation and KP activity is unclear. Here we utilized the neonatal iron supplementation model to investigate the relationship between iron, microglial activation and neurodegeneration in adult HD mice. We show in the N171-82Q mouse model of HD microglial morphologic changes consistent with immune activation. Neonatal iron supplementation in these mice promoted neurodegeneration and resulted in additional microglial activation in adults as determined by increased soma volume and decreased process length. We further demonstrate that iron activates IDO, both in brain lysates and purified recombinant protein (EC50 = 1.24 nM). Brain IDO activity is increased by HD. Neonatal iron supplementation further promoted IDO activity in cerebral cortex, altered KP metabolite profiles, and promoted HD neurodegeneration as measured by brain weights and striatal volumes. Our results demonstrate that dietary iron is an important activator of microglia and the KP pathway in this HD model, and that this occurs in part through a direct effect on IDO. The findings are relevant to understanding how iron promotes neurodegeneration in HD.

Patient and family experience with transthyretin amyloid cardiomyopathy (ATTR-CM) and polyneuropathy (ATTR-PN) amyloidosis: results of two focus groups.

BACKGROUND: Transthyretin amyloidosis, or ATTR, is a progressive and debilitating rare proteopathy generally manifested as either transthyretin amyloid polyneuropathy (ATTR-PN) or transthyretin amyloid cardiomyopathy (ATTR-CM). Irrespective of the clinical presentation, affected patients manage a chronic and life-threatening condition that severely impacts their quality of life. Although the primary symptoms and diagnostic criteria for ATTR are increasingly being discussed in the medical literature, due in large part by continual advances in uncovering disease pathophysiology, there exists a surprising paucity of published data on the patient journey and family experience. In order to address this disparity, two focus groups, one for ATTR-CM and one for ATTR-PN, were convened and asked to describe the diagnostic process, symptoms, and impact on their own quality of life that was experienced from these rare and typically misdiagnosed illnesses. RESULTS: Patients in both ATTR groups often underwent a long and difficult diagnostic odyssey characterized by seemingly nonspecific physical manifestations resulting in mismanagement and suboptimal care, inadequate interventions, and delays in establishing the correct diagnosis, which was integral to determining the specialized treatment they needed. Collectively, patients with ATTR-CM and patients with ATTR-PN reported a similar number of symptoms, but the type of symptoms varied. The ATTR-CM group identified intolerance to activity, inability to exercise, insomnia and fatigue as the most challenging symptoms. The ATTR-PN group identified fatigue, diarrhea/constipation and sensory deficits as the most difficult symptoms. In general, ATTR was reported to be highly stressful for both patients and their families. Spouses of patients with ATTR-CM were often in a caregiver role and reported experiencing considerable anxiety. Patients with ATTR-PN were stressed not only by the physical consequences of their illness, but also by its effects on their parents and other relatives, as well as concerns about children and grandchildren inheriting the disease-causing mutations associated with ATTR. Despite such challenges, family members are identified as an important resource of coping, motivation, inspiration and support. CONCLUSIONS: Several steps can be taken to reduce the challenges and burdens of living with ATTR, including increased education for primary care physicians and specialists who unknowingly encounter ATTR, increased access to and ready availability of mental health services and support, and increased engagement with support groups and advocacy organizations. Input from patients and their representatives should guide clinical trials, increase the availability of genetic testing, and generate natural history and qualitative studies detailing patients' experience. Although each recommendation is impactful in itself, taken together they would jointly facilitate a shortened and ameliorated patient journey through more timely diagnosis and greater access to personalized medical care.

Fatal Chlamydia psittaci infection in a domestic kitten.

Chlamydia psittaci has not been reported to cause disease in domestic cats, to our knowledge. In contrast, C. felis infection is common in domestic cats and typically results in conjunctivitis, upper respiratory tract infection, and less frequently pneumonia. Herein, we report the pathologic findings and diagnostic features of a fatal case of psittacosis in a 7-wk-old domestic kitten. The animal was 1 of a litter of 5 that, together with the queen, were yielded to a pet rescue center in Wyoming. Over a period of ~3 wk, the kittens and queen became sick, thin, and icteric prior to death, despite antimicrobial treatments. Postmortem evaluation of a kitten revealed necrosuppurative hepatitis with Gimenez stain-positive intracellular bacteria, nonsuppurative pneumonia, and mild leptomeningitis. The diagnosis of psittacosis was made by 16S rRNA PCR using multiple primer sets and sequencing from liver. Psittacosis should be considered a differential diagnosis in domestic cats with intracellular bacterial hepatitis and interstitial pneumonia.

Holistic approach to assess co-benefits of local climate mitigation in a hot humid region of Australia.

Overheated outdoor environments adversely impact urban sustainability and livability. Urban areas are particularly affected by heat waves and global climate change, which is a serious threat due to increasing heat stress and thermal risk for residents. The tropical city of Darwin, Australia, for example, is especially susceptible to urban overheating that can kill inhabitants. Here, using a modeling platform supported by detailed measurements of meteorological data, we report the first quantified analysis of the urban microclimate and evaluate the impacts of heat mitigation technologies to decrease the ambient temperature in the city of Darwin. We present a holistic study that quantifies the benefits of city-scale heat mitigation to human health, energy consumption, and peak electricity demand. The best-performing mitigation scenario, which combines cool materials, shading, and greenery, reduces the peak ambient temperature by 2.7 °C and consequently decreases the peak electricity demand and the total annual cooling load by 2% and 7.2%, respectively. Further, the proposed heat mitigation approach can save 9.66 excess deaths per year per 100,000 people within the Darwin urban health district. Our results confirm the technological possibilities for urban heat mitigation, which serves as a strategy for mitigating the severity of cumulative threats to urban sustainability.

Hematuria Is Associated with More Severe Acute Tubulointerstitial Nephritis.

Acute tubulointerstitial nephritis (ATIN) is a common cause of acute kidney injury. Although haematuria is a risk factor for the development of renal disease, no previous study has analyzed the significance of haematuria in ATIN. Retrospective, observational analysis of 110 patients with biopsy-proven ATIN was conducted. Results: Haematuria was present in 66 (60%) ATIN patients. A higher percentage of ATIN patients with haematuria had proteinuria than patients without haematuria (89.4% vs. 59.1%, p = 0.001) with significantly higher levels of proteinuria (median (interquartile range) protein:creatinine ratio 902.70 (513-1492) vs. 341.00 (177-734) mg/g, p <0.001). Moreover, those patients with more haematuria intensity had a higher urinary protein:creatinine ratio (1352.65 (665-2292) vs. 849.60 (562-1155) mg/g, p = 0.02). Those patients with higher proteinuria were more likely to need renal replacement therapy (22.7 vs. 0%, p = 0.03) and to suffer relapse (4 vs. 0%, p = 0.03). At the end of follow up, haematuric ATIN patients had higher serum creatinine levels (3.19 ± 2.91 vs. 1.91 ± 1.17 mg/dL, p = 0.007), and a trend towards a higher need for acute dialysis (7 vs. 1%, p = 0.09) and renal replacement therapy (12.1 vs. 2.3%, p = 0.12). Haematuria is common in ATIN and it is associated with worse renal function outcomes.

Outpatient learning perspectives at a UK hospital.

BACKGROUND: Undergraduate students spend much of their training in the clinical workplace, increasingly in hospital outpatient settings; however, they report that this does not always yield the educational value that they expect. This study investigates ways in which outpatient learning can be enhanced from the perspectives of students and teachers, exploring which approaches may be most appropriate in different circumstances. METHODS: We conducted 14 semi-structured interviews with medical students from one UK medical school and consultants (specialists) at a single teaching hospital. We explored their experiences and perceptions of clinical teaching and learning in this outpatient setting. Transcripts were analysed through a consensual qualitative research approach. An evaluation of established frameworks for outpatient teaching was conducted and strategies were matched to stakeholder needs. FINDINGS: A total of 24 core ideas were identified, which were categorised into: individual factors (student, doctor and patient), interpersonal factors, team factors and organisational factors. Teaching strategies that address stakeholder needs included: student-led clinics, case-based discussions, one-minute preceptor, the SNAPPS tool (summarize, narrow differential, analyse, probe preceptor, plan and select issues for self-learning), advanced organisers and supplementing. DISCUSSION: There is a complex interplay between personal, interpersonal, team and organisational factors that contribute to the effectiveness of the outpatient setting as a learning environment. Strategies at the personal and interpersonal levels are unlikely to be successful or sustained without organisational resourcing and support. Further research is needed to implement and evaluate these suggested strategies.