Citations

Background: There is a paucity of evidence to inform the value of pharmacogenomic (PGx) results in patients after kidney transplant and how these results differ between Indigenous Americans and Whites. This study aims to identify the frequency of recommended medication changes based on PGx results and compare the pharmacogenomic (PGx) results and patients’ perceptions of the findings between a cohort of Indigenous American and White kidney transplant recipients. Methods: Thirty-one Indigenous Americans and fifty White kidney transplant recipients were studied prospectively. Genetic variants were identified using the OneOme RightMed PGx test of 27 genes. PGx pharmacist generated a report of the genetic variation and recommended changes. Pre- and post-qualitative patient surveys were obtained. Results: White and Indigenous American subjects had a similar mean number of medications at the time of PGx testing (mean 13 (SD 4.5)). In the entire cohort, 53% received beta blockers, 30% received antidepressants, 16% anticoagulation, 47% pain medication, and 25% statin therapy. Drug–gene interactions that warranted a clinical action were present in 21.5% of patients. In 12.7%, monitoring was recommended. Compared to the Whites, the Indigenous American patients had more normal CYP2C19 (p = 0.012) and CYP2D6 (p = 0.012) activities. The Indigenous American patients had more normal CYP4F2 (p = 0.004) and lower VKORC (p = 0.041) activities, phenotypes for warfarin drug dosing, and efficacy compared to the Whites. SLC6A4, which affects antidepressant metabolism, showed statistical differences between the two cohorts (p = 0.017); specifically, SLC6A4 had reduced expression in 45% of the Indigenous American patients compared to 20% of the White patients. There was no significant difference in patient perception before and after PGx. Conclusions: Kidney transplant recipients had several drug–gene interactions that were clinically actionable; over one-third of patients were likely to benefit from changes in medications or drug doses based on the PGx results. The Indigenous American patients differed in the expression of drug-metabolizing enzymes and drug transporters from the White patients.

The enteric nervous system (ENS), a collection of neural cells contained in the wall of the gut, is of fundamental importance to gastrointestinal and systemic health. According to the prevailing paradigm, the ENS arises from progenitor cells migrating from the neural crest and remains largely unchanged thereafter. Here, we show that the lineage composition of maturing ENS changes with time, with a decline in the canonical lineage of neural-crest derived neurons and their replacement by a newly identified lineage of mesoderm-derived neurons. Single cell transcriptomics and immunochemical approaches establish a distinct expression profile of mesoderm-derived neurons. The dynamic balance between the proportions of neurons from these two different lineages in the post-natal gut is dependent on the availability of their respective trophic signals, GDNF-RET and HGF-MET. With increasing age, the mesoderm-derived neurons become the dominant form of neurons in the ENS, a change associated with significant functional effects on intestinal motility which can be reversed by GDNF supplementation. Transcriptomic analyses of human gut tissues show reduced GDNF-RET signaling in patients with intestinal dysmotility which is associated with reduction in neural crest-derived neuronal markers and concomitant increase in transcriptional patterns specific to mesoderm-derived neurons. Normal intestinal function in the adult gastrointestinal tract therefore appears to require an optimal balance between these two distinct lineages within the ENS.

Abstract The enteric nervous system (ENS), a collection of neural cells contained in the wall of the gut, is of fundamental importance to gastrointestinal and systemic health. According to the prevailing paradigm, the ENS arises from progenitor cells migrating from the neural crest and remains largely unchanged thereafter. Here, we show that the lineage composition of maturing ENS changes with time, with a decline in the canonical lineage of neural-crest derived neurons and their replacement by a newly identified lineage of mesoderm-derived neurons. Single cell transcriptomics and immunochemical approaches establish a distinct expression profile of mesoderm-derived neurons. The dynamic balance between the proportions of neurons from these two different lineages in the post-natal gut is dependent on the availability of their respective trophic signals, GDNF-RET and HGF-MET. With increasing age, the mesoderm-derived neurons become the dominant form of neurons in the ENS, a change associated with significant functional effects on intestinal motility which can be reversed by GDNF supplementation. Transcriptomic analyses of human gut tissues show reduced GDNF-RET signaling in patients with intestinal dysmotility which is associated with reduction in neural crest-derived neuronal markers and concomitant increase in transcriptional patterns specific to mesoderm-derived neurons. Normal intestinal function in the adult gastrointestinal tract therefore appears to require an optimal balance between these two distinct lineages within the ENS.

AimsGiant cell arteritis (GCA) is a systemic vasculitis affecting medium and large arteries in patients aged over 50 years. Involvement of temporal arteries (TA) can lead to complications such as blindness and stroke. While the diagnostic gold standard is temporal artery biopsy (TAB), comorbidities and age‐related changes can make interpretation of such specimens difficult. This study aims to establish a baseline of TA changes in subjects without GCA to facilitate the interpretation of TAB.Methods and resultsBilateral TA specimens were collected from 100 consecutive eligible postmortem examinations. Subjects were divided into four age groups and specimens semiquantitatively evaluated for eccentric intimal fibroplasia, disruption and calcification of the internal elastic lamina (IEL), medial attenuation and degree of lymphocytic inflammation of the peri‐adventitia, adventitia, media and intima. The individual scores of intimal fibroplasia, IEL disruption and medial attenuation were added to yield a ‘combined score (CS)’. Seventy‐eight 78 decedents were included in the final analysis following exclusion of 22 individuals for either lack of clinical information or inability to collect TA tissue. A total of 128 temporal artery specimens (50 bilateral from individual decedents, 28 unilateral) were available for examination. Intimal proliferation, IEL loss, IEL calcification and CS increased with age in a statistically significant fashion. Comparison of the oldest age group with the others showed statistically significant differences, although this was not uniformly preserved in comparison between the three youngest groups.ConclusionSenescent arterial changes and healed GCA exhibit histological similarity and such changes increase proportionally with age. The CS demonstrates significant association with age overall and represents a potential avenue for development to ‘normalise’ TA biopsies from older individuals.

ABSTRACT Most women worldwide experience menopausal symptoms during the menopause transition or postmenopause. Vasomotor symptoms are most pronounced during the first four to seven years but can persist for more than a decade, and genitourinary symptoms tend to be progressive. Although the hallmark symptoms are hot flashes, night sweats, disrupted sleep, and genitourinary discomfort, other common symptoms and conditions are mood fluctuations, cognitive changes, low sexual desire, bone loss, increase in abdominal fat, and adverse changes in metabolic health. These symptoms and signs can occur in any combination or sequence, and the link to menopause may even be elusive. Estrogen based hormonal therapies are the most effective treatments for many of the symptoms and, in the absence of contraindications to treatment, have a generally favorable benefit:risk ratio for women below age 60 and within 10 years of the onset of menopause. Non-hormonal treatment options are also available. Although a symptom driven treatment approach with individualized decision making can improve health and quality of life for midlife women, menopausal symptoms remain substantially undertreated by healthcare providers.

Background: Femoroacetabular impingement (FAI) is a common cause of hip pain, especially in young patients. When left untreated, it has been demonstrated to be a risk factor for the onset or progression of osteoarthritis (OA) and has been identified as one of the main contributors leading to the need for total hip arthroplasty (THA) at a young age. While the short-term therapeutic potential of hip arthroscopy is widely recognized, little is known regarding its potential mid- to long-term preventive effect on the progression of hip OA. Purpose: To (1) report clinical outcomes of arthroscopically treated FAI syndrome with a minimum 5-year follow-up and compare the results to a cohort with FAI treated nonsurgically and (2) determine the influence of hip arthroscopy on the onset and progression of hip OA in patients diagnosed with FAI. Study Design: Cohort study; Level of evidence, 3. Methods: Patients who had hip pain and were diagnosed with FAI were included. Exclusion criteria were (1) previous or concomitant hip surgery, (2) <5 years of follow-up, and (3) insufficient radiographs. Patients treated with hip arthroscopy were compared with a cohort of patients with FAI who were treated nonsurgically. Kaplan-Meier estimates of failure (defined as conversion to THA) were performed. Bivariate analysis and Cox regression were used to identify factors associated with inferior clinical and radiographic outcomes. Results: A total of 957 patients (650 female, 307 male; 1114 hips) (mean age, 28.03 ± 8.9 years [range, 6.5-41.0 years]) with FAI were included. A total of 132 hips underwent hip arthroscopy and 982 hips were nonoperatively treated. The mean follow-up was 12.5 ± 4.7 years (range, 5.0-23.4 years). At the final follow-up, the rate of OA progression was 26.5% in the operative group and 35.2% in the nonoperative cohort ( P < .01). Conversion to THA was performed in 6.8% of the surgical patients and 10.5% of the initially nonsurgical patients ( P = .19). Additionally, there was no significant difference in the risk of failure between the operatively and nonoperatively treated patients. Male sex, increased age at initial diagnosis, presence of cam morphology, and increased initial Tönnis grade were risk factors for failure (male sex: hazard ratio [HR], 2.3; P < .01; per year of increased age: HR, 1.1; P < .01; presence of cam: HR, 3.5; P < .01; per Tönnis grade: HR, 4.0; P < .01). Conclusion: At a mean follow-up of nearly 13 years, 7% of patients of the surgical group experienced progression to THA, compared with 11% of the nonoperative control group. While most of the operative group showed little to no OA at final follow-up, moderate OA (Tönnis grade 2) was present in 12% of the cohort compared with 22% of nonsurgical patients. Increased age at diagnosis, male sex, presence of a cam morphology, and presence of initial arthritic joint changes were found to be risk factors for failure. The results of this study demonstrated evidence for a preventive effect of hip arthroscopy on the development and progression of OA in young patients with FAI at mid- to long-term follow-up.

To understand why US patients refused participation in hospital-at-home (H@H) during the coronavirus disease 2019 Public Health Emergency, eligible adult patients seen at 2 Mayo Clinic sites, Mayo Clinic Health System—Northwest Wisconsin region (NWWI) and Mayo Clinic Florida (MCF), from August 2021 through March 2022, were invited to participate in a convergent-parallel study. Quantitative associations between H@H participation status and patient baseline data at hospital admission were investigated. H@H patients were more likely to have a Mayo Clinic patient portal at baseline ( P-value: .014), indicating a familiarity with telehealth. Patients who refused were more likely to be from NWWI ( P-value < .001) and have a higher Epic Deterioration Index score ( P-value: .004). The groups also had different quarters (in terms of fiscal calendar) of admission ( P-value: .040). Analyzing qualitative interviews (n = 13) about refusal reasons, 2 themes portraying the quantitative associations emerged: lack of clarity about H@H and perceived domestic challenges. To improve access to H@H and increase patient recruitment, improved education about the dynamics of H@H, for both hospital staff and patients, and inclusive strategies for navigating domestic barriers and diagnostic challenges are needed.

Background Procedural success following mechanical thrombectomy for acute ischemic stroke is assessed using the thrombolysis in cerebral infarction scale. We conducted a systematic review and meta-analysis to determine whether outcomes differed between first pass thrombolysis in cerebral infarction 2b and multiple pass thrombolysis in cerebral infarction 2c-3. Methods We conducted a systematic review of the literature using PubMed, Embase, Scopus, and Web of Science. We included original studies in which outcomes were stratified based on first pass thrombolysis in cerebral infarction 2b and multiple pass thrombolysis in cerebral infarction 2c-3. The primary outcome of interest was the rate of modified Rankin Scale 0-2. Secondary outcomes of interest were rates of modified Rankin Scale 0-1, symptomatic intracranial hemorrhage, and mortality. We calculated odds ratios and corresponding 95% confidence intervals. Results Four studies with 1554 patients were included in the quantitative analysis. Rate of modified Rankin Scale 0–2 (odds ratio = 0.91, 95% confidence interval = 0.70–1.18; P -value = 0.49), modified Rankin Scale 0–1 (odds ratio = 1.21, 95% confidence interval = 0.86–1.71; P -value = 0.27), symptomatic intracranial hemorrhage (odds ratio = 1.36, 95% confidence interval = 0.47–3.98; P -value = 0.57), and mortality (odds ratio = 0.91, 95% confidence interval = 0.67–1.25; P -value = 0.56) did not differ between first pass thrombolysis in cerebral infarction 2b and multiple pass thrombolysis in cerebral infarction 2c-3. There was no heterogeneity among included studies for modified Rankin Scale 0–2, modified Rankin Scale 0–1, or mortality; however, there was moderate heterogeneity among studies for symptomatic intracranial hemorrhage ( I 2 = 53%, P -value = 0.12). Conclusions Clinical and safety outcomes did not differ between first pass thrombolysis in cerebral infarction 2b and multiple pass thrombolysis in cerebral infarction 2c-3. Future prospective studies and clinical trials should determine whether first pass thrombolysis in cerebral infarction 2b is a viable endpoint to thrombolysis in cerebral infarction 2c-3.

Background: National data about the outcomes of children undergoing mechanical mitral valve replacement (m-MVR) are scarce. Methods: A retrospective review of hospitalizations from the Kids’ Inpatient Database was performed for patients ≤18 years of age in the United States. A total of 500 patients underwent m-MVR in 2009, 2012, 2016, and 2019. Patients with single ventricle physiology were excluded (n = 13). These patients were categorized into three groups according to age: neonates (<1 month, n = 20), infants (1-12 months, n = 76 patients), and children (1-18 years, n = 404). Outcomes were compared between the three groups. Results: The proportion of m-MVR involving children undergoing MV procedures (repair and replacement) has increased from 17.3% in 2009 to 30.8% in 2019 (Ptrend < .01). History of cardiac surgery was present in 256 patients (51.2%). Concomitant procedures were performed in 119 patients (23.8%). Intra- or postoperative extracorporeal membrane oxygenation was required in 19 patients (3.8%). The overall in-hospital mortality was 4.8% and was significantly higher in neonates and infants compared with older children (10% vs 11.8% vs 3.2%, P = .003). The length of hospital stay was longer in the neonatal group (median, 57 days, interquartile range, [24.8-90] vs 29.5 days [15.5-61] vs 10 days [7-18], P < .01). Nonhome discharges were more common in neonates and infants (40% vs 36.8% vs 13.1%, P < .01). Conclusion: Mechanical mitral valve replacement is increasingly performed over time with acceptable in-hospital morbidity and mortality, especially in older children and adolescents. Neonates and infants are associated with worse hospital survival, prolonged hospitalization, and significant rates of nonhome discharges.