Phylogenomic analysis of the Lake Kronotskoe species flock of Dolly Varden charr reveals genetic and developmental signatures of sympatric radiation.

Recent adaptive radiations provide evolutionary case studies, which provide the context to parse the relationship between genomic variation and the origins of distinct phenotypes. Sympatric radiations of the charr complex (genus Salvelinus) present a trove for phylogenetics as charrs have repeatedly diversified into multiple morphs with distinct feeding specializations. However, species flocks normally comprise only two to three lineages. Dolly Varden charr inhabiting Lake Kronotske represent the most extensive radiation described for the charr genus, containing at least seven lineages, each with defining morphological and ecological traits. Here, we perform the first genome-wide analysis of this species flock to parse the foundations of adaptive change. Our data support distinct, reproductively isolated lineages with little evidence of hybridization. We also find that specific selection on thyroid signaling and craniofacial genes forms a genomic basis for the radiation. Thyroid hormone is further implicated in subsequent lineage partitioning events. These results delineate a clear genetic basis for the diversification of specialized lineages, and highlight the role of developmental mechanisms in shaping the forms generated during adaptive radiation.

Femoral rotational osteotomy for femoroacetabular impingement: A systematic review.

Purpose: To synthesize existing literature regarding the indications and outcomes of femoral rotational osteotomies (FDO) for femoroacetabular impingement (FAI) due to. Methods: Medline, Cochrane, and Embase were searched using keywords "femoroacetabular impingement", "rotational osteotomy" and others to identify FAI patients undergoing FDO. Double-screened studies were reviewed by blinded authors according to inclusion criteria. Data from full texts was extracted including study type, number of patients, sex, mean age, surgical indication, type of dysplasia, associated pathology, surgical technique, follow-up, and pre-op/post-op evaluations of the following: impingement test, femoral version (FV), 'other angles measured', outcome scores, range of motion (ROM). Results: 7 studies including 91 patients (97 FDO surgeries), 73 females (80 %) with mean age of 28.3 years, and follow-up mean of 2.44 ± 2.83 years. Pain or impingement was the most common clinical indication, while others included aberrant FV and ROM measurements for both anteverted and retroverted femurs. There were reports of FDO being performed with concomitant procedures addressing other pathology. Various outcome scores and ROM measurements showed postoperative improvement after FDO. Complication data was sparse, preventing aggregation. The rate of unplanned reoperation was 40 % (where reported), with 'hardware removal' being the most common. Conclusions: FDO is effective in treating FAI due to increased FV, improving clinical symptoms, and potentially delaying articular degeneration. Hardware removal surgery remains an inherent risk in undergoing FDO. Further work is needed to discover indications warranting FDO as a primary treatment versus hip arthroscopy. Level of evidence: This review contains 4 studies with Level IV evidence and 3 studies with Level III evidence.

Cardiac magnetic resonance predictors for successful primary biventricular repair of unbalanced complete common atrioventricular canal.

BACKGROUND: Patients with unbalanced common atrioventricular canal can be difficult to manage. Surgical planning often depends on pre-operative echocardiographic measurements. We aimed to determine the added utility of cardiac MRI in predicting successful biventricular repair in common atrioventricular canal. METHODS: We conducted a retrospective cohort study of children with common atrioventricular canal who underwent MRI prior to repair. Associations between MRI and echocardiographic measures and surgical outcome were tested using logistic regression, and models were compared using area under the receiver operator characteristic curve. RESULTS: We included 28 patients (median age at MRI: 5.2 months). The optimal MRI model included the novel end-diastolic volume index (using the ratio of left ventricular end-diastolic volume to total end-diastolic volume) and the left ventricle-right ventricle angle in diastole (area under the curve 0.83, p = 0.041). End-diastolic volume index ≤ 0.18 and left ventricle-right ventricle angle in diastole ≤ 72° yield a sensitivity of 83% and specificity of 81% for successful biventricular repair. The optimal multimodality model included the end-diastolic volume index and the echocardiographic atrioventricular valve index with an area under the curve of 0.87 (p = 0.026). CONCLUSIONS: Cardiac MRI can successfully predict successful biventricular repair in patients with unbalanced common atrioventricular canal utilising the end-diastolic volume index alone or in combination with the MRI left ventricle-right ventricle angle in diastole or the echocardiographic atrioventricular valve index. A prospective cardiac MRI study is warranted to better define the multimodality characteristic predictive of successful biventricular surgery.

Learning from the universal, proactive outreach of the Brazilian Community Health Worker model: impact of a Community Health and Wellbeing Worker initiative on vaccination, cancer screening and NHS health check uptake in a deprived community in the UK.

BACKGROUND: Delays in preventative service uptake are increasing in the UK. Universal, comprehensive monthly outreach by Community Health and Wellbeing Workers (CHW), who are integrated at the GP practice and local authority, offer a promising alternative to general public health campaigns as it personalises health promotion and prevention of disease holistically at the household level. We sought to test the ability of this model, which is based on the Brazilian Family Health Strategy, to increase prevention uptake in the UK. METHODS: Analysis of primary care patient records for 662 households that were allocated to five CHWWs from July 2021. Primary outcome was the Composite Referral Completion Indicator (CRCI), a measure of how many health promotion activities were received by members of a household relative to the ones that they were eligible for during the period July 2021-April 2022. The CRCI was compared between the intervention group (those who had received at least one visit) and the control group (allocated households that were yet to receive a visit). A secondary outcome was the number of GP visits in the intervention and control groups during the study period and compared to a year prior. RESULTS: Intervention and control groups were largely comparable in terms of household occupancy and service eligibilities. A total of 2251 patients in 662 corresponding households were allocated to 5 CHWs and 160 households had received at least one visit during the intervention period. The remaining households were included in the control group. Overall service uptake was 40% higher in the intervention group compared to control group (CRCI: 0.21 ± 0.15 and 0.15 ± 0.19 respectively). Likelihood of immunisation uptake specifically was 47% higher and cancer screening and NHS Health Checks was 82% higher. The average number of GP consultations per household decreased by 7.4% in the intervention group over the first 10 months of the pilot compared to the 10 months preceding its start, compared with a 0.6% decrease in the control group. CONCLUSIONS: Despite the short study period these are promising findings in this deprived, traditionally hard to reach community and demonstrates potential for the Brazilian community health worker model to be impactful in the UK. Further analysis is needed to examine if this approach can reduce health inequalities and increase cost effectiveness of health promotion approaches.

Enhancing biofeedback-driven self-guided virtual reality exposure therapy through arousal detection from multimodal data using machine learning.

Virtual reality exposure therapy (VRET) is a novel intervention technique that allows individuals to experience anxiety-evoking stimuli in a safe environment, recognise specific triggers and gradually increase their exposure to perceived threats. Public-speaking anxiety (PSA) is a prevalent form of social anxiety, characterised by stressful arousal and anxiety generated when presenting to an audience. In self-guided VRET, participants can gradually increase their tolerance to exposure and reduce anxiety-induced arousal and PSA over time. However, creating such a VR environment and determining physiological indices of anxiety-induced arousal or distress is an open challenge. Environment modelling, character creation and animation, psychological state determination and the use of machine learning (ML) models for anxiety or stress detection are equally important, and multi-disciplinary expertise is required. In this work, we have explored a series of ML models with publicly available data sets (using electroencephalogram and heart rate variability) to predict arousal states. If we can detect anxiety-induced arousal, we can trigger calming activities to allow individuals to cope with and overcome distress. Here, we discuss the means of effective selection of ML models and parameters in arousal detection. We propose a pipeline to overcome the model selection problem with different parameter settings in the context of virtual reality exposure therapy. This pipeline can be extended to other domains of interest where arousal detection is crucial. Finally, we have implemented a biofeedback framework for VRET where we successfully provided feedback as a form of heart rate and brain laterality index from our acquired multimodal data for psychological intervention to overcome anxiety.

Rural versus Urban Residence in Adulthood and Incident Cognitive Impairment.

INTRODUCTION: Rural versus urban living is a social determinant of cognitive health. We estimated the association of rural versus urban residence in the USA with incident cognitive impairment (ICI) and assessed effect heterogeneity by sociodemographic, behavioral, and clinical factors. METHODS: The Reasons for Geographic and Racial Differences in Stroke Study (REGARDS) is a population-based prospective observational cohort of 30,239 adults, 57% female, 36% Black, aged 45+ years, sampled from 48 contiguous states in the USA in 2003-2007. We analyzed 20,878 participants who at baseline were cognitively intact with no history of stroke and had ICI assessed on average 9.4 years later. We classified participants' home addresses at baseline as urban (population ≥50,000), large rural (10,000-49,999), or small rural (≤9,999) by Rural-Urban Commuting Area codes. We defined ICI as ≥1.5 SD below the mean on at least 2 of the following tests: word list learning, word list delayed recall, and animal naming. RESULTS: Participants' home addresses were 79.8% urban, 11.7% large rural, and 8.5% small rural. ICI occurred in 1,658 participants (7.9%). Small rural residents had higher odds of ICI than urban residents, adjusted for age, sex, race, region, and education (OR = 1.34 [95% CI: 1.10, 1.64]), and after further adjustment for income, health behaviors, and clinical characteristics (OR = 1.24 [95% CI: 1.02, 1.53]). Former smoking versus never, nondrinking versus light alcohol drinking, no exercise versus ≥4 times/week, CES-D depressive symptom score of 2 versus 0, and fair versus excellent self-rated health had stronger associations with ICI in small rural areas than in urban areas. For example, in urban areas, lack of exercise was not associated with ICI (OR = 0.90 [95% CI: 0.77, 1.06]); however, lack of exercise combined with small rural residence was associated with 1.45 times the odds of ICI compared with ≥4 bouts of exercise/week in urban areas (95% CI: 1.03, 2.03). Overall, large rural residence was not associated with ICI; however, black race, hypertension, and depressive symptoms had somewhat weaker associations with ICI, and heavy alcohol drinking a stronger association with ICI, in large rural areas than in urban areas. CONCLUSION: Small rural residence was associated with ICI among USA adults. Further research to better understand why rural residents are at higher risk for developing ICI and mechanisms to ameliorate that risk will support efforts to advance rural public health.

Myokine Musclin Is Critical for Exercise-Induced Cardiac Conditioning.

This study investigates the role and mechanisms by which the myokine musclin promotes exercise-induced cardiac conditioning. Exercise is one of the most powerful triggers of cardiac conditioning with proven benefits for healthy and diseased hearts. There is an emerging understanding that muscles produce and secrete myokines, which mediate local and systemic "crosstalk" to promote exercise tolerance and overall health, including cardiac conditioning. The myokine musclin, highly conserved across animal species, has been shown to be upregulated in response to physical activity. However, musclin effects on exercise-induced cardiac conditioning are not established. Following completion of a treadmill exercise protocol, wild type (WT) mice and mice with disruption of the musclin-encoding gene, Ostn, had their hearts extracted and exposed to an ex vivo ischemia-reperfusion protocol or biochemical studies. Disruption of musclin signaling abolished the ability of exercise to mitigate cardiac ischemic injury. This impaired cardioprotection was associated with reduced mitochondrial content and function linked to blunted cyclic guanosine monophosphate (cGMP) signaling. Genetic deletion of musclin reduced the nuclear abundance of protein kinase G (PKGI) and cyclic adenosine monophosphate (cAMP) response element binding (CREB), resulting in suppression of the master regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), and its downstream targets in response to physical activity. Synthetic musclin peptide pharmacokinetic parameters were defined and used to calculate the infusion rate necessary to maintain its plasma level comparable to that observed after exercise. This infusion was found to reproduce the cardioprotective benefits of exercise in sedentary WT and Ostn-KO mice. Musclin is essential for exercise-induced cardiac protection. Boosting musclin signaling might serve as a novel therapeutic strategy for cardioprotection.

Pediatric Forearm Fracture Characteristics as Prognostic Indicators of Healing.

Background This study was conducted to investigate the characteristics, complications, radiologic features, and clinical course of patients undergoing reduction of forearm fractures to better inform patient prognosis and postoperative management. Methodology We conducted a retrospective chart review of 75 pediatric patients treated for forearm fractures between January 2014 and September 2021 in a 327-bed regional medical center. A preoperative radiological assessment and chart review was performed. Percent fracture displacement, location, orientation, comminution, fracture line visibility, and angle of angulation were determined by anteroposterior (AP) and lateral radiographs. Percent fracture displacement was calculated as 𝐵𝑜𝑛𝑒 𝑆ℎ𝑎𝑓𝑡 𝐷𝑖𝑠𝑝𝑙𝑎𝑐𝑒𝑚𝑒𝑛𝑡 / 𝐷𝑖𝑎𝑚𝑒𝑡𝑒𝑟 × 100% = % 𝐷𝑖𝑠𝑝𝑙𝑎𝑐𝑒𝑚𝑒𝑛𝑡. The angle of angulation and percent fracture displacement were calculated by averaging AP and lateral radiograph measurements. Results A total of 75 cases, averaging 11.6 ± 4.1 years, were identified as having a complete fracture of the radius and/or ulna, with 66 receiving closed reduction and nine receiving fixation via an intramedullary device or percutaneous pinning. Eight (10.7%) patients experienced complications, with four resulting in a refracture and four resulting in significant loss of reduction without refracture. Fractures in the proximal two-thirds of the radius were associated with a significant increase in complications compared to fractures in the distal one-third of the radius (33.3% vs 3.6%) (p = 0.0005). Likewise, a greater fracture displacement percentage was associated with a lower risk of refracture post-reduction as those experiencing complications had over 30% greater total displacement pre-reduction compared to patients who did not experience complications such as refracture or loss of reduction (p < 0.0001). No elevated risk of complications was found based on fracture orientation, angulation, fracture line visibility, forearm bone(s) fractured, sex, age, or arm affected. Conclusions Our results highlight radius fracture location and percent fracture displacement as markers with prognostic value following forearm fracture. These measurements are simply calculated via pre-reduction radiographs, providing an efficient method of informing the risk of complications following forearm fracture reduction.

Economic evaluations of interventional opportunities for the management of mental-physical multimorbidity: a systematic review.

OBJECTIVES: Economic evaluations of interventions for people with mental-physical multimorbidity, including a depressive disorder, are sparse. This study examines whether such interventions in adults are cost-effective. DESIGN: A systematic review. DATA SOURCES: MEDLINE, CINAHL Plus, PsycINFO, Cochrane CENTRAL, Scopus, Web of Science and NHS EED databases were searched until 5 March 2022. ELIGIBILITY CRITERIA: We included studies involving people aged ≥18 with two or more chronic conditions (one being a depressive disorder). Economic evaluation studies that compared costs and outcomes of interventions were included, and those that assessed only costs or effects were excluded. DATA EXTRACTION AND SYNTHESIS: Two authors independently assessed risk of bias in included studies using recommended checklists. A narrative analysis of the characteristics and results by type of intervention and levels of healthcare provision was conducted. RESULTS: A total of 19 studies, all undertaken in high-income countries, met inclusion criteria. Four intervention types were reported: collaborative care, self-management, telephone-based and antidepressant treatment. Most (14 of 19) interventions were implemented at the organisational level and were potentially cost-effective, particularly, the collaborative care for people with depressive disorder and diabetes, comorbid major depression and cancer and depression and multiple long-term conditions. Cost-effectiveness ranged from £206 per quality-adjusted life year (QALY) for collaborative care programmes for older adults with diabetes and depression at primary care clinics (USA) to £79 723 per QALY for combining collaborative care with improved opportunistic screening for adults with depressive disorder and diabetes (England). Conclusions on cost-effectiveness were constrained by methodological aspects of the included studies: choice of perspectives, time horizon and costing methods. CONCLUSIONS: Economic evaluations of interventions to manage multimorbidity with a depressive disorder are non-existent in low-income and middle-income countries. The design and reporting of future economic evaluations must improve to provide robust conclusions. PROSPERO REGISTRATION NUMBER: CRD42022302036.

Localized heterochrony integrates overgrowth potential of oncogenic clones.

Somatic mutations occur frequently and can arise during embryogenesis, resulting in the formation of a patchwork of mutant clones. Such mosaicism has been implicated in a broad range of developmental anomalies; however, their etiology is poorly understood. Patients carrying a common somatic oncogenic mutation in either PIK3CA or AKT1 can present with disproportionally large digits or limbs. How mutant clones, carrying an oncogenic mutation that often drives unchecked proliferation, can lead to controlled and coordinated overgrowth is unknown. We use zebrafish to explore the growth dynamics of oncogenic clones during development. Here, in a subset of clones, we observed a local increase in proportion of the fin skeleton closely resembling overgrowth phenotypes in patients. We unravel the cellular and developmental mechanisms of these overgrowths, and pinpoint the cell type and timing of clonal expansion. Coordinated overgrowth is associated with rapid clone expansion during early pre-chondrogenic phase of bone development, inducing a heterochronic shift that drives the change in bone size. Our study details how development integrates and translates growth potential of oncogenic clones, thereby shaping the phenotypic consequences of somatic mutations.

64Cu Treatment Planning and 67Cu Therapy with Radiolabeled [64Cu/67Cu]MeCOSar-Octreotate in Subjects with Unresectable Multifocal Meningioma: Initial Results for Human Imaging, Safety, Biodistribution, and Radiation Dosimetry.

Our aim was to report the use of 64Cu and 67Cu as a theranostic pair of radionuclides in human subjects. An additional aim was to measure whole-organ dosimetry of 64Cu and 67Cu attached to the somatostatin analog octreotate using the sarcophagine MeCOSar chelator (SARTATE) in subjects with somatostatin receptor-expressing lesions confined to the cranium, thereby permitting normal-organ dosimetry for the remainder of the body. Methods: Pretreatment PET imaging studies were performed up to 24 h after injection of [64Cu]Cu-SARTATE, and normal-organ dosimetry was estimated using OLINDA/EXM. Subsequently, the trial subjects with multifocal meningiomas were given therapeutic doses of [67Cu]Cu-SARTATE and imaged over several days using SPECT/CT. Results: Five subjects were initially recruited and imaged using PET/CT before treatment. Three of the subjects were subsequently administered 4 cycles each of [67Cu]Cu-SARTATE followed by multiple SPECT/CT imaging time points. No serious adverse events were observed, and no adverse events led to withdrawal from the study or discontinuation from treatment. The estimated mean effective dose was 3.95 × 10-2 mSv/MBq for [64Cu]Cu-SARTATE and 7.62 × 10-2 mSv/MBq for [67Cu]Cu-SARTATE. The highest estimated organ dose was in spleen, followed by kidneys, liver, adrenals, and small intestine. The matched pairing was shown by PET and SPECT intrasubject imaging to have nearly identical targeting to tumors for guiding therapy, demonstrating a potentially accurate and precise theranostic product. Conclusion: 64Cu and 67Cu show great promise as a theranostic pair of radionuclides. Further clinical studies will be required to examine the therapeutic dose required for [67Cu]Cu-SARTATE for various indications. In addition, the ability to use predictive 64Cu-based dosimetry for treatment planning with 67Cu should be further explored.

Longitudinal Trends of Vascular Flow and Growth in Patients Undergoing Fontan Operation.

BACKGROUND: Single ventricle (SV) patients undergo multiple surgeries with subsequent changes in anatomy and hemodynamics. There are little cardiac magnetic resonance (CMR) data on serial changes in these patients. This study aimed to assess longitudinal changes of SV anatomy and hemodynamics in a large cohort. METHODS: Anatomy and flow in SV patients with serial CMRs performed between 2008 and 2019 at a single institution were retrospectively reviewed. Mixed-effects linear regression was used to estimate changes over time at 3 to 9 months, 1 to 5 years, and >5 years after Fontan. RESULTS: A total of 119 patients were included (51% with hypoplastic left heart syndrome; 77% underwent extracardiac Fontan). A total of 88 patients had 3 serial CMRs. Indexed right superior vena cava, inferior vena cava, neoaortic valve, and descending aorta area decreased over time (beta = -0.19, -0.44, and -0.23, respectively; P < .01), as did indexed right superior vena cava, neoaorta and native aorta, and descending aorta flow (beta = -0.49, -0.53, and -0.59, respectively; P < .0001). Inferior vena cava flow and its contribution to total caval flow increased (beta = 0.33; P < .0001). Indexed right and left pulmonary artery flow did not change; however, indexed left pulmonary artery area decreased (beta = -0.16; P = .0014) with time. Systemic-to-pulmonary collateral flow remained unchanged before and early after Fontan (beta = -0.54; P = .42) but decreased with time from Fontan (beta = -0.22; P < .0001). CONCLUSIONS: In this cohort of longitudinally followed SV patients, there are significant trends in vascular size and flow over time from Fontan. These findings can be used as a framework to interpret serial CMR data in the SV and noninvasively identify deviations from expected patterns before the development of clinical symptoms.

Osteoclast activity sculpts craniofacial form to permit sensorineural patterning in the zebrafish skull.

Efforts to understand the morphogenesis of complex craniofacial structures have largely focused on the role of chondrocytes and osteoblasts. Along with these bone-creating cells, bone-resorbing osteoclasts are critical in homeostasis of adult skeletal structures, but there is currently limited information on their role in the complex morphogenetic events of craniofacial development. Fundamental aspects of skull formation and general skeletal development are conserved from zebrafish to mammals. Using a cathepsinK reporter, we documented osteoclast location in the developing zebrafish skull over several weeks, from 5.18 mm to 9.6 mm standard length (approximately 15 to 34 days post fertilization). While broad distribution of osteoclasts is consistent across individuals, they are sparse and the exact locations vary among fish and across developmental time points. Interestingly, we observed osteoclasts concentrating at areas associated with neuromasts and their associated nerves, in particular the hyomandibular foramina and around the supraorbital lateral line. These are areas of active remodeling. In contrast, other areas of rapid bone growth, such as the osteogenic fronts of the frontal and parietal bones, show no particular concentration of osteoclasts, suggesting that they play a special role in shaping bone near neuromasts and nerves. In csf1ra mutants lacking functional osteoclasts, the morphology of the cranial bone was disrupted in both areas. The hyomandibular foramen is present in the initial cartilage template, but after the initiation of ossification, the diameter of the canal is significantly smaller in the absence of osteoclasts. The diameter of the supraorbital lateral line canals was also reduced in the mutants, as was the number of pores associated with neuromasts, which allow for the passage of associated nerves through the bone. Our findings define important and previously unappreciated roles for osteoclast activity in shaping craniofacial skeletal structures with a particular role in bone modeling around peripheral cranial nerves, providing a scaffold for wiring the sensioneural system during craniofacial development. This has important implications for the formation of the evolutionarily diverse lateral line system, as well understanding the mechanism of neurologic sequelae of congenital osteoclast dysfunction in human craniofacial development.

Cardiac surgery receipt and outcomes for people using secondary mental healthcare services: Retrospective cohort study using a large mental healthcare database in South London.

BACKGROUND: Patients diagnosed with mental health problems are more predisposed to cardiovascular disease, including cardiac surgery. Nevertheless, health outcomes after cardiac surgery for patients with mental health problems as a discrete group are unknown. This study examined the association between secondary care mental health service use and postoperative health outcomes following cardiac surgery. METHODS: We conducted a retrospective observational research, utilizing data from a large South London mental healthcare supplier linked to national hospitalization data. OPCS-4 codes were applied to classify cardiac surgery. Health results were compared between those individuals with a mental health disorder diagnosis from secondary care and other local residents, including the length of hospital stay (LOS), inpatient mortality, and 30-day emergency hospital readmission. RESULTS: Twelve thousand three hundred and eighty-four patients received cardiac surgery, including 1,481 with a mental disorder diagnosis. Patients with mental health diagnosis were at greater risk of emergency admissions for cardiac surgery (odds ratio [OR] 1.60; 1.43, 1.79), longer index LOS (incidence rate ratio 1.28; 1.26, 1.30), and at higher risk of 30-day emergency readmission (OR 1.53; 1.31, 1.78). Those who underwent pacemaker insertion and major open surgery had worse postoperative outcomes during index surgery hospital admission while those who had major endovascular surgery had worse health outcomes subsequent 30-day emergency hospital readmission. CONCLUSION: People with a mental health disorder diagnosis undertaking cardiac surgery have significantly worse health outcomes. Personalized guidelines and policies to manage preoperative risk factors require consideration and evaluation.

Copper-67-Labeled Bombesin Peptide for Targeted Radionuclide Therapy of Prostate Cancer.

The gastrin-releasing peptide receptor (GRPR) is a promising molecular target for imaging and therapy of prostate cancer using bombesin peptides that bind to the receptor with high affinity. Targeted copper theranostics (TCTs) using copper radionuclides, 64Cu for imaging and 67Cu for therapy, offer significant advantages in the development of next-generation theranostics. [64Cu]Cu-SAR-BBN is in clinical development for PET imaging of GRPR-expressing cancers. This study explores the therapeutic efficacy of [67Cu]Cu-SAR-BBN in a pre-clinical mouse model. The peptide was radiolabeled with 67Cu, and specific binding of the radiolabeled peptide towards GRPR-positive PC-3 prostate cancer cells was confirmed with 52.2 ± 1.4% total bound compared to 5.8 ± 0.1% with blocking. A therapy study with [67Cu]Cu-SAR-BBN was conducted in mice bearing PC-3 tumors by injecting 24 MBq doses a total of six times. Tumor growth was inhibited by 93.3% compared to the control group on day 19, and median survival increased from 34.5 days for the control group to greater than 54 days for the treatment group. The ease and stability of the radiochemistry, favorable biodistribution, and the positive tumor inhibition demonstrate the suitability of this copper-based theranostic agent for clinical assessment in the treatment of cancers expressing GRPR.

Perinatal versus adult loss of ULK1 and ULK2 distinctly influences cardiac autophagy and function.

Impairments in macroautophagy/autophagy, which degrades dysfunctional organelles as well as long-lived and aggregate proteins, are associated with several cardiomyopathies; however, the regulation of cardiac autophagy remains insufficiently understood. In this regard, ULK1 and ULK2 are thought to play primarily redundant roles in autophagy initiation, but whether their function is developmentally determined, potentially having an impact on cardiac integrity and function remains unknown. Here, we demonstrate that perinatal loss of ULK1 or ULK2 in cardiomyocytes (cU1-KO and cU2-KO mice, respectively) enhances basal autophagy without altering autophagy machinery content while preserving cardiac function. This increased basal autophagy is dependent on the remaining ULK protein given that perinatal loss of both ULK1 and ULK2 in cU1/2-DKO mice impaired autophagy causing age-related cardiomyopathy and reduced survival. Conversely, adult loss of cardiac ULK1, but not of ULK2 (i.e., icU1-KO and icU2-KO mice, respectively), led to a rapidly developing cardiomyopathy, heart failure and early death. icU1-KO mice had impaired autophagy with robust deficits in mitochondrial respiration and ATP synthesis. Trehalose ameliorated autophagy impairments in icU1-KO hearts but did not delay cardiac dysfunction suggesting that ULK1 plays other critical, autophagy-independent, functions in the adult heart. Collectively, these results indicate that cardiac ULK1 and ULK2 are functionally redundant in the developing heart, while ULK1 assumes a more unique, prominent role in the adult heart.Abbreviations: ATG4: autophagy related 4, cysteine peptidase; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG9: autophagy related 9; ATG13: autophagy related 13; CYCS: Cytochrome C; DNM1L, dynamin 1-like; MAP1LC3A: microtubule-associated protein 1 light chain 3 alpha; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MFN1: mitofusin 1; MFN2: mitofusin 2; MT-CO1: mitochondrially encoded cytochrome c oxidase I; MYH: myosin, heavy polypeptide; NBR1: NBR1 autophagy cargo receptor; NDUFA9: NADH:ubiquinone oxidoreductase subunit A9; OPA1: OPA1, mitochondrial dynamin like GTPase; PPARGC1A, peroxisome proliferator activated receptor, gamma, coactivator 1 alpha; SDHA: succinate dehydrogenase complex, subunit A, flavoprotein (Fp); SQSTM1: sequestosome 1; ULK1: unc-51 like kinase 1; ULK2: unc-51 like kinase 2; UQCRC1: ubiquinol-cytochrome c reductase core protein 1.

Is a Low-Cost Drill Cover System Noninferior to Conventional Surgical Drills for Skeletal Traction Pin Placement?

SUMMARY: The Drill Cover system was developed as a low-cost alternative to conventional surgical drills with specific applicability to low- and middle-income countries. However, the system may also be useful for the sterile placement of traction pins in the emergency department of high-income country hospitals. In September 2019, a US-based Level-1 trauma center began using the Drill Cover system to apply skeletal traction pins in patients with femoral shaft fractures. With these data, we performed a retrospective interrupted time series study to determine if the Drill Cover system was noninferior to conventional surgical drills in terms of infections at the traction pin site. The study included 205 adult patients with femoral shaft fractures initially placed in skeletal traction using a conventional surgical drill (n = 150, preintervention group) or the Drill Cover system (n = 55, postintervention group). The primary outcome was an infection at the site of skeletal traction pin placement that required surgery or antibiotics, which was compared between groups using a noninferiority test with a 1-sided alpha of 0.05 and a noninferiority margin of 3%. No infections at the site of skeletal traction pin placement were found in either the preintervention or the postintervention group (difference, 0%; 95% confidence interval: 0.0%-1.4%; noninferiority P value < 0.01). The results suggest that the Drill Cover system was noninferior to conventional surgical drills regarding infections at the site of skeletal traction pins. The Drill Cover system may be a safe alternative to the more expensive surgical drills for skeletal traction pin placement in the emergency room environment.

Emerging roles of adhesion G protein-coupled receptors.

Adhesion G protein-coupled receptors (aGPCRs) form a sub-group within the GPCR superfamily. Their distinctive structure contains an abnormally large N-terminal, extracellular region with a GPCR autoproteolysis-inducing (GAIN) domain. In most aGPCRs, the GAIN domain constitutively cleaves the receptor into two fragments. This process is often required for aGPCR signalling. Over the last two decades, much research has focussed on aGPCR-ligand interactions, in an attempt to deorphanize the family. Most ligands have been found to bind to regions N-terminal to the GAIN domain. These receptors may bind a variety of ligands, ranging across membrane-bound proteins and extracellular matrix components. Recent advancements have revealed a conserved method of aGPCR activation involving a tethered ligand within the GAIN domain. Evidence for this comes from increased activity in receptor mutants exposing the tethered ligand. As a result, G protein-coupling partners of aGPCRs have been more extensively characterised, making use of their tethered ligand to create constitutively active mutants. This has led to demonstrations of aGPCR function in, for example, neurodevelopment and tumour growth. However, questions remain around the ligands that may bind many aGPCRs, how this binding is translated into changes in the GAIN domain, and the exact mechanism of aGPCR activation following GAIN domain conformational changes. This review aims to examine the current knowledge around aGPCR activation, including ligand binding sites, the mechanism of GAIN domain-mediated receptor activation and how aGPCR transmembrane domains may relate to activation. Other aspects of aGPCR signalling will be touched upon, such as downstream effectors and physiological roles.

CGRP, adrenomedullin and adrenomedullin 2 display endogenous GPCR agonist bias in primary human cardiovascular cells.

Agonist bias occurs when different ligands produce distinct signalling outputs when acting at the same receptor. However, its physiological relevance is not always clear. Using primary human cells and gene editing techniques, we demonstrate endogenous agonist bias with physiological consequences for the calcitonin receptor-like receptor, CLR. By switching the receptor-activity modifying protein (RAMP) associated with CLR we can "re-route" the physiological pathways activated by endogenous agonists calcitonin gene-related peptide (CGRP), adrenomedullin (AM) and adrenomedullin 2 (AM2). AM2 promotes calcium-mediated nitric oxide signalling whereas CGRP and AM show pro-proliferative effects in cardiovascular cells, thus providing a rationale for the expression of the three peptides. CLR-based agonist bias occurs naturally in human cells and has a fundamental purpose for its existence. We anticipate this will be a starting point for more studies into RAMP function in native environments and their importance in endogenous GPCR signalling.

Vascular surgery receipt and outcomes for people with serious mental illnesses: Retrospective cohort study using a large mental healthcare database in South London.

OBJECTIVE: Vascular surgery can be common among people with serious mental illness (SMI) given the high prevalence of cardiovascular disease. However, post-operative outcomes following vascular surgery have received little investigation, particularly in a subpopulation of SMI. METHODS: We conducted a retrospective observational study using data from the South London and Maudsley NHS Foundation Trust (SLaM) via its Clinical Record Interactive Search (CRIS) platform and linkage with Hospital Episode Statistic (HES). Vascular surgery recipients were identified using OPCS version 4 codes. Length of stay (LOS) was modelled using Incidence Rate Ratios (IRRs), and 30-day emergency hospital readmissions using Odds Ratios (ORs) for people with SMI compared with the general population. RESULTS: Vascular surgery was received by 152 patients with SMI diagnoses (schizophrenia, schizoaffective disorder, bipolar disorder) and 8821 catchment residents without any mental health conditions. People with active SMI symptoms more likely to be admitted to hospital via emergency route OR: 1.80 (95% CI: 1.06, 3.07) and more likely to stay longer in the hospital for vascular surgery IRR: 1.35 (1.01, 1.80) and more likely to be readmitted to hospital via emergency route within 30 days OR: 1.53 (1.02, 2.67). People with SMI who had major open vascular surgery and peripheral endovascular surgery more likely to have worse post-operative outcomes. CONCLUSION: Our study highlights the risks faced by people with SMI following vascular surgery. These suggest tailored guidelines and policies are needed, based on the identification of pre-operative risk factors, allowing for focused post-vascular surgery care to minimise adverse outcomes.