Health Disparities in Appalachian and Other Rural Communities.

Rural areas are home to a larger proportion of older adults and populations who age within these locales and suffer disproportionately from health, mental health, and economic disparities compared to their urban counterparts. This article will explore the disparities faced by persons that reside in rural communities across the lifespan. It will briefly discuss what is meant by rural. As a rural region at specific risk, the issues confronting those aging in Appalachia will be examined. Finally, best practices and future directions to combat health disparities among rural residents and elders will be discussed. This includes the Appalachian Gerontology Experiences: Advancing Diversity in Aging Research training program which recruits and trains minority and first-generation undergraduate students in aging and health disparity research.

Outdoor walking exhibits peak ankle and knee flexion differences compared to fixed and adaptive-speed treadmills in older adults.

BACKGROUND: Walking mechanics recorded with a traditional treadmill may not be the same as the mechanics exhibited during activities of daily living due to constrained walking speeds. Adaptive-speed treadmills allow for unconstrained walking speeds similar to outdoor walking. The aim of this study was to determine differences in kinematic walking parameters of older adults between adaptive-speed treadmill (AST), fixed-speed treadmill (FST) and outdoor walking. We hypothesized that self-selected walking speed (SSWS) during AST walking and outdoor walking would increase compared to FST walking. Furthermore, we hypothesized that AST walking and outdoor walking would increase peak knee flexion, hip flexion, and ankle plantarflexion angles compared to FST walking independent of walking speed changes. METHODS: Fourteen older adult participants were asked to complete 3 min of FST and AST walking on a split-belt treadmill. Participants were also asked to complete 6 min of outdoor walking following a circular route in a neighboring park. A wireless inertial measurement unit-based motion capture system was used to record lower extremity kinematics during all walking conditions. RESULTS: The outdoor walking condition produces significantly higher SSWS compared to FST (p < 0.001) and AST (p = 0.02) conditions. A significantly faster SSWS was exhibited during the AST condition compared to the FST condition (p = 0.026). Significantly higher peak ankle plantarflexion angles are exhibited during the outdoor walking condition compared to the AST (p < 0.001, g = 1.14) and FST (p < 0.001, g = 1.13) conditions after accounting for walking speed. There was a significantly lowered difference between the outdoor walking condition and both AST (p = 0.029, g = 0.49) and FST (p = 0.013, g = 0.63) conditions in peak knee flexion angles after accounting for SSWS. There are no significant differences between outdoor, AST, and FST conditions on peak hip flexion angles. Older adults exhibit changes in peak ankle plantarflexion and peak knee flexion angles during outdoor walking compared to treadmill walking but not between treadmill controller types. We found no differences in the kinematics exhibited by older adults between both AST and FST walking. CONCLUSIONS: Incorporating unconstrained walking speed with the AST while maintaining similar FST sagittal plane kinematics may allow for more translatable conditional balance and walking rehabilitation.

Comparison of LI-RADS with other non-invasive liver MRI criteria and radiological opinion for diagnosing hepatocellular carcinoma in cirrhotic livers using gadoxetic acid with histopathological explant correlation.

AIM: To establish the diagnostic accuracy of the Liver Imaging Reporting and Data System (LI-RADS) for hepatocellular carcinoma (HCC) and compare its performance to that of international criteria from European Assofor the Study of the Liver (EASL), Japan Society of Hepatology (JSH), Asian Pacific Association for the Study of the Liver (APASL), and Organ Procurement and Transplantation Network (OPTN), and to the reporting radiologist's overall opinion regarding the probability of a nodule being a HCC by correlating with a histological diagnosis from whole liver explants. MATERIALS AND METHODS: The present single-centre, retrospective review selected participants based on the following criteria: adults (≥18 years) listed for liver transplantation in 2014/2015, with liver cirrhosis at the time of magnetic resonance imaging (MRI) with hepatocyte specific contrast agent, and at least one liver lesion ≥10 mm on MRI with histology from subsequent liver explant for comparison. Each lesion was assessed against international criteria and given a "radiologist opinion" score of 1-5 (1 = definitely benign, 5 = definitely HCC). RESULTS: Total 268 patient records were reviewed, with 105 eligible lesions identified from 47 patients. Median lesion size was 15.5 mm (range 10-68 mm). Sensitivity (%), specificity (%), and positive predictive value (PPV; %) for LI-RADS LR5 was 45, 89, and 89, for LI-RADS LR4+5 + TIV was 61, 80, and 86, for EASL was 44, 86 and 86, for JSH/APASL was 64, 81, and 87, for OPTN was 36, 90, and 88, and for "radiologist impression" of probably or definitely HCC was 79, 79, and 88 respectively. CONCLUSIONS: MRI has moderate sensitivity and good specificity for the diagnosis of HCC with considerable variation depending on criteria used. OPTN criteria have the best specificity, but low sensitivity. "Radiologist opinion" gives highest overall accuracy with increases in sensitivity and reduction in specificity when compared to the imaging criteria.

Rates, costs, return to work and reoperation following spinal surgery in a workers' compensation cohort in New South Wales, 2010-2018: a cohort study using administrative data.

BACKGROUND: Internationally, elective spinal surgery rates in workers' compensation populations are high, as are reoperation rates, while return-to-work rates following spinal surgery are low. Little information is available from Australia. The aim of this study was to describe the rates, costs, return to work and reoperation following elective spinal surgery in the workers' compensation population in New South Wales (NSW), Australia. METHODS: This retrospective cohort study used administrative data from the State Insurance Regulatory Authority, the government organisation responsible for regulating and administering workers' compensation insurance in NSW. These data cover all workers' compensation-insured workers in New South Wales (over 3 million workers/year). We identified a cohort of insured workers who underwent elective spinal surgery (fusion or decompression) between January 1, 2010 and December 31, 2018. People who underwent surgery for spinal fracture or dislocation, or who had sustained a traumatic brain injury were excluded. The main outcome measures were annual spinal surgery rates, cost of the surgical episode, cumulative costs (surgical, hospital, medical and physical therapy) to 2 years post-surgery, and reoperation and return-to-work rates 2 years post-surgery. RESULTS: There were 9343 eligible claims (39.1 % fusion; 59.9 % decompression); claimants were predominantly male (75 %) with a mean age of 43 (range 18 to 75) years. Spinal surgery rates ranged from 15 to 29 surgeries per 100,000 workers per year, fell from 2011-12 to 2014-15 and rose thereafter. The average cost in Australian dollars for a surgical episode was $46,000 for a spinal fusion and $20,000 for a decompression. Two years post-fusion, only 19 % of people had returned to work at full capacity; 39 % after decompression. Nineteen percent of patients underwent additional spinal surgery within 2 years of the index surgery, to a maximum of 5 additional surgeries. CONCLUSION: Rates of workers' compensation-funded spinal surgery did not rise significantly during the study period, but reoperation rates are high and return-to-work rates are low in this population at 2 years post- surgery. In the context of the poor evidence base supporting lumbar fusion surgery, the high cost, increasing rates, and the increased likelihood of poor outcomes in the workers' compensation population, we question the value of this procedure in this setting.

A new roadmap for social medicine curriculum design based on mixed methods student and faculty evaluations of the preclinical curriculum.

BACKGROUND: To support the development of social medicine curricula that empower medical school graduates to redress health inequities, we conducted a mixed methods student and faculty evaluation of an expanded and innovative preclinical social medicine curriculum. METHODS: We implemented a longitudinal, interactive preclinical social medicine curriculum that was closely integrated with foundational science teaching then conducted a survey-based mixed methods student and faculty curriculum evaluation. Based on these results, we propose a novel conceptual roadmap for social medicine curriculum design. RESULTS: Student and faculty evaluations of an expanded and innovative longitudinal preclinical social medicine curriculum were strongly favorable. Both student and faculty respondents indicated a particular desire for deeper coverage of race and poverty among other social medicine domains. Qualitative student evaluations highlighted the importance of faculty champions to social medicine teaching as well as the educational impact of stories that exemplify the practical impact of the social determinants of health on specific patient experiences. Qualitative faculty evaluations pointed to the challenges of curriculum integration and the need for faculty career development in social medicine teaching. CONCLUSIONS: Based on mixed methods student and faculty curriculum evaluation data, we propose a novel conceptual roadmap for the design of social medicine curricula at other institutions.

The design and implementation of a longitudinal social medicine curriculum at the University of Vermont's Larner College of Medicine.

BACKGROUND: Despite an abundant literature advocating that social determinants of health (SDH) be taught during undergraduate medical education, there are few detailed descriptions of how to design and implement longitudinal core curricula that is delivered to all students and accomplishes this goal. METHODS: In this paper, we describe the design and implementation of a social medicine curriculum at the University of Vermont's Larner College of Medicine (UVM Larner). Using Kern's principles, we designed a longitudinal curriculum that extends through both preclinical and clinical training for all students and focused on integrating SDH material directly into basic science and clinical training. RESULTS: We successfully developed and implemented two primary tools, a "Social Medicine Theme of the Week" (SMTW) in preclinical training, and SDH rounds in the clinical setting to deliver SDH content to all learners at UVM Larner. CONCLUSIONS: Extensive student-faculty partnerships, robust needs assessment, and focusing on longitudinal and integrated SDH content delivery to all students were key features that contributed to successful design and implementation.

Wearable Sensor-Based Prediction Model of Timed up and Go Test in Older Adults.

The Timed Up and Go (TUG) test has been frequently used to assess the risk of falls in older adults because it is an easy, fast, and simple method of examining functional mobility and balance without special equipment. The purpose of this study is to develop a model that predicts the TUG test using three-dimensional acceleration data collected from wearable sensors during normal walking. We recruited 37 older adults for an outdoor walking task, and seven inertial measurement unit (IMU)-based sensors were attached to each participant. The elastic net and ridge regression methods were used to reduce gait feature sets and build a predictive model. The proposed predictive model reliably estimated the participants' TUG scores with a small margin of prediction errors. Although the prediction accuracies with two foot-sensors were slightly better than those of other configurations (e.g., MAPE: foot (0.865 s) > foot and pelvis (0.918 s) > pelvis (0.921 s)), we recommend the use of a single IMU sensor at the pelvis since it would provide wearing comfort while avoiding the disturbance of daily activities. The proposed predictive model can enable clinicians to assess older adults' fall risks remotely through the evaluation of the TUG score during their daily walking.

Perspectives of Interstitial Lung Disease Patients and Carers During COVID-19.

Aim To gain an understanding of the impact of COVID-19 on the daily life, healthcare needs, mental wellbeing and outlook of patients with Interstitial Lung Disease (ILD) and their caregivers. Methods ILD patients and caregivers were invited to participate in a quantitative survey. Respondents could self-select to then participate in in-depth structured telephone interviews. Survey data was compared to Department of Health COVID-19 public opinion tracker findings for the comparable time period. Results There were 170 survey respones (111 patients and 59 caregivers) and 14 in-depth interview participants. 32% (n=36) of patients and 42% (n=25) of caregivers expressed extreme worry regarding COVID-19 on a 1-10 scale. 83% (n=92) of patients expressed concern about safe hospital access, 33% (n=37) had received a telephone consultation with their clinician, 43% (n=48) reported test delays, 47% (n=52) were exercising less, 23% (n=26) reported worse sleep and 15% (n=17) reported being financially worse off. Carers reported that sleep was worse for 58% (n=34), 42% (n=25) reported being worse off financially, and 40% (n=24) reported a worse diet. Worry (66%, n=39), stress (51%, n=30), anxiety (49%, n=29) were commonly reported by carers. Discussion ILD patients and caregivers reported higher levels of worry regarding COVID-19 compared to the general public. Alternative pathways for quality ILD patient care and interventions to reduce the burden of care on ILD caregivers are required.

Imaging post liver transplantation part II: biliary complications.

Biliary complications post liver transplantation are a significant source of morbidity and mortality and early recognition is paramount to the long-term success of the liver graft. Part II of this series will focus on liver transplant biliary anatomy, including the blood supply to the biliary system and potential problems if it is interrupted. The imaging rationale for investigating suspected biliary complications, potential pitfalls, and treatment options will be discussed. The various biliary complications will be illustrated using a collection of cases.

Imaging post liver transplantation part I: vascular complications.

Liver transplantation continues to rise in frequency, with over 1,000 procedures performed in the UK in 2018. Complications are increasingly uncommon but when they occur, early recognition and intervention is vital to save grafts. Imaging after the perioperative period is often performed at patients' local hospitals meaning that all radiologists and sonographers need to have an understanding of how to assess a transplant liver. Part I of this series will focus on vascular complications, including the normal postoperative vascular anatomy following liver transplantation, normal post-transplantation vascular imaging findings and abnormal findings that may prompt further investigation. Vascular complications following liver transplantation will be illustrated using a collection of cases.

Self-assembly of model short triblock amphiphiles in dilute solution.

In this work, a molecular theory is used to study the self-assembly of short diblock and triblock amphiphiles, with head-tail and head-linker-tail structures, respectively. The theory was used to systematically explore the effects of the molecular architecture and the affinity of the solvent for the linker and tail blocks on the relative stability of the different nanostructures formed by the amphiphiles in dilute solution, which include spherical micelles, cylindrical fibers and planar lamellas. Moreover, the theory predicts that each of these nanostructures can adopt two different types of internal organization: (i) normal nanostructures with a core composed of tail segments and a corona composed of head segments, and (ii) nanostructures with a core formed by linker segments and a corona formed by tail and head segments. The theory predicts the occurrence of a transition from micelle to fiber to lamella when increasing the length of the tail or the linker blocks, which is in qualitative agreement with the geometric packing theory and with experiments in the literature. The theory also predicts a transition from micelle to fiber to lamella as the affinity of the solvent for the tail or linker block is decreased. This result is also in qualitative agreement with experiments in the literature but cannot be explained in terms of the geometric packing theory. The molecular theory provides an explanation for this result in terms of the competition between solvophobic attractions among segments in the core and steric repulsions between segments in the corona for the different types of self-assembled nanostructures.

Disruptions of working memory and inhibition mediate the association between exposure to institutionalization and symptoms of attention deficit hyperactivity disorder.

BACKGROUND: Young children raised in institutions are exposed to extreme psychosocial deprivation that is associated with elevated risk for psychopathology and other adverse developmental outcomes. The prevalence of attention deficit hyperactivity disorder (ADHD) is particularly high in previously institutionalized children, yet the mechanisms underlying this association are poorly understood. We investigated whether deficits in executive functioning (EF) explain the link between institutionalization and ADHD. METHOD: A sample of 136 children (aged 6-30 months) was recruited from institutions in Bucharest, Romania, and 72 never institutionalized community children matched for age and gender were recruited through general practitioners' offices. At 8 years of age, children's performance on a number of EF components (working memory, response inhibition and planning) was evaluated. Teachers completed the Health and Behavior Questionnaire, which assesses two core features of ADHD, inattention and impulsivity. RESULTS: Children with history of institutionalization had higher inattention and impulsivity than community controls, and exhibited worse performance on working memory, response inhibition and planning tasks. Lower performances on working memory and response inhibition, but not planning, partially mediated the association between early institutionalization and inattention and impulsivity symptom scales at age 8 years. CONCLUSIONS: Institutionalization was associated with decreased EF performance and increased ADHD symptoms. Deficits in working memory and response inhibition were specific mechanisms leading to ADHD in previously institutionalized children. These findings suggest that interventions that foster the development of EF might reduce risk for psychiatric problems in children exposed to early deprivation.

An alternative approach for assessment of liquid chromatography-mass spectrometry matrix effects using auto-sampler programmed co-injection.

We report the use of auto-sampler programmable functions to co-inject analyte standard solution and matrix extract to assess ion enhancement and suppression (matrix effects) in LC-MS. This is effectively an automated post-extraction addition (APEA) procedure, emulating the manual post-extraction addition (PEA) approach widely adopted for assessment of matrix effects. To verify that APEA was comparable to the conventional PEA approach, matrix effects were determined using both methods for a selection of 31 illicit and pharmaceutical drugs in 10 different human urine extracts. Matrix effects measured using APEA were statistically indistinguishable from manual PEA methodology for 27 of the 31 drugs. Of the four drugs that showed significant differences using the two methods, three differed by less than 2 %, which is within the expected accuracy limits required for matrix effect determinations. The remaining analyte, trimeprazine, was found to degrade in the spiked PEA matrix extract, accounting for the difference between matrix effects measured by the PEA and APEA approaches. APEA enables a single matrix extract to be assessed at multiple analyte concentrations, resulting in a considerable reduction in sample preparation time. In addition, APEA can reduce the quantity of analyte-free sample matrix required for matrix effect assessment, which is an important consideration in certain analytical and bioanalytical fields. This work shows that APEA may be considered as an acceptable alternative to PEA for the assessment of matrix effects in LC-MS method validation and may be applicable to a variety of matrices such as environmental samples.

The impact of violence reduction initiatives on emergency department attendance.

BACKGROUND: Recent violence reduction initiatives in Glasgow have led to a reduction in recorded levels of violent crime.(1) This study evaluates the impact of these initiatives on assault-related emergency department attendances and admissions. METHODS: A retrospective observational study conducted in Glasgow Royal Infirmary's emergency department comparing assault-related emergency department attendances and hospital admissions over two 30-day study periods (April 2010 and April 2012). The primary outcome measure was the change in assault-related emergency department attendances. The secondary outcome measure was the impact on assault-related hospital and critical care admissions. RESULTS: In April 2010, there were 6098 emergency department attendances, 301 (4.9%) were due to assault. In April 2012, there were 7236 emergency department attendances, 263 (3.6%) were due to assault, representing a significant reduction in assault-related attendances (p < 0.01). There were significant reductions in level 1 admissions 2010 n = 56 (19.2%), 2012 n = 36 (14.0%) p = 0.04 and critical care admissions, 2010 n = 5 (1.7%), 2012 n = 1 (0.4%) p = 0.04. CONCLUSIONS: Violence reduction initiatives in Glasgow have contributed to a reduction in assault-related emergency department attendance at Glasgow Royal Infirmary. The reduction in hospital admissions, in particular critical care admissions, suggests a reduction in morbidity and cost to the National Health Service.

Bosutinib: Pediatric First Approval.

Bosutinib (BOSULIF®), an orally administered BCR-ABL tyrosine kinase inhibitor (TKI) developed by Pfizer Inc., is well established in the EU and the USA as a treatment for adults with newly diagnosed (ND) chronic phase (CP) Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML), and for CP, accelerated phase and blast phase Ph+ CML that is resistant or intolerant (R/I) to prior therapy. In September 2023, based on clinical data from patients aged ≥ 1 to < 18 years, bosutinib was approved in the USA for the treatment of pediatric patients aged ≥ 1 year with CP Ph+ CML that is ND or R/I to prior therapy. This article summarizes the milestones in the development of bosutinib leading to this first pediatric approval.

Exagamglogene Autotemcel: First Approval.

Exagamglogene autotemcel (Casgevy™) is a genetically modified autologous CD34+ cell enriched population. It contains human haematopoietic stem and progenitor cells edited ex vivo by CRISPR/Cas9 (a DNA double strand break-inducing nuclease system) to differentiate into erythroid cells that produce high levels of foetal hemoglobin. Developed by Vertex Pharmaceuticals and CRISPR Therapeutics, exagamglogene autotemcel received its first approval on 16 November 2023 in the UK for the treatment of transfusion-dependent ß-thalassemia (TDT) in patients aged ≥ 12 years for whom haematopoietic stem cell (HSC) transplantation is appropriate and a human leukocyte antigen matched related HSC donor is not available. On the same day, it was also approved in the UK for the treatment of sickle cell disease (SCD) in patients aged ≥ 12 years with recurrent vasoocclusive crises (VOCs) who have the ßS/ßS, ßS/ß+ or ßS/ß0 genotype for whom HSC transplantation is appropriate and a human leukocyte antigen matched related HSC donor is not available. Subsequently, exagamglogene autotemcel was approved in the USA on 8 December 2023 for the treatment of SCD in patients aged ≥ 12 years with recurrent VOCs and received a positive opinion in the EU on 14 December 2023 for the treatment of TDT and SCD. A regulatory assessment of exagamglogene autotemcel is currently underway for the treatment of TDT in the USA. This article summarizes the milestones in the development of exagamglogene autotemcel leading to these first approvals.

Mavorixafor: First Approval.

Mavorixafor (XOLREMDI™) is an oral, selective C-X-C chemokine receptor 4 (CXCR4) antagonist developed by X4 Pharmaceuticals that blocks the binding of C-X-C chemokine ligand 12 (also known as stromal derived factor-1) to CXCR4. In April 2024, it became the first therapy to be approved for WHIM syndrome (named by an acronym for its observed characteristics of Warts, Hypogammaglobulinaemia, Infections and Myelokathexis) in the USA, where it is indicated for use in patients aged ≥ 12 years with WHIM syndrome to increase the number of circulating mature neutrophils and lymphocytes. Clinical development of mavorixafor is ongoing for chronic neutropenic disorders. This article summarizes the milestones in the development of mavorixafor leading to this first approval for use in patients aged ≥ 12 years with WHIM syndrome to increase the number of circulating mature neutrophils and lymphocytes.

Futibatinib: A Review in Locally Advanced and Metastatic Cholangiocarcinoma.

Futibatinib (LYTGOBI®) is an oral small molecule compound that selectively, irreversibly and potently inhibits the tyrosine kinase activity of fibroblast growth factor receptor (FGFR)1-4. It is approved in the EU, Japan and the USA for the treatment of adults with locally advanced or metastatic cholangiocarcinoma (CCA) harbouring an FGFR2 fusion or rearrangement who have progressed following systemic therapy. In the phase II part (FOENIX-CCA2) of a multinational phase I/II study in this patient population, monotherapy with futibatinib 20 mg once daily was associated with clinically meaningful and durable responses, sustained health-related quality of life (HR-QOL), and a manageable safety profile with supportive care and as-needed dose modifications. Indeed, hyperphosphataemia (the most common all grade and grade 3 treatment-related adverse event) was manageable with phosphate-lowering therapy and dose reductions or interruptions. Although further efficacy and tolerability data are expected, current evidence indicates that futibatinib is a valuable targeted therapy option for adults with locally advanced or metastatic CCA harbouring an FGFR2 fusion or rearrangement who have progressed following systemic therapy, a patient population with limited treatment options and poor life expectancy.

Cholangiocarcinoma (CCA) is an invasive tumour arising from the biliary tract. In the early stages it presents silently; this, along with its highly aggressive nature, means it is often diagnosed in the later (advanced) stages when surgery is not a treatment option. Up to half of CCAs have genetic aberrations that can be targeted for treatment. One such abnormality (present in 9­15% of CCAs) is found in fibroblast growth factor receptor (FGFR)2. The presence of this aberration promotes tumour survival and development. Futibatinib (LYTGOBI^®) is an oral drug that strongly inhibits the activity of FGFR1­4. When given to adults with unresectable or metastatic CCA harbouring an FGFR2 aberration who had disease progression after systemic therapy, futibatinib 20 mg once daily produced clinically meaningful and prolonged responses and sustained health-related quality of life; moreover, with supportive care and as-needed dose modifications, futibatinib had a manageable safety profile. In a patient population that has limited treatment options and poor life expectancy, current evidence indicates that futibatinib is a valuable targeted therapy option.