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BACKGROUND: Chronic anal fissures are a painful condition characterized by a tear in the anal mucosa. Botulinum toxin injection is a minimally invasive treatment option, but long-term effectiveness in recurrent or persistent cases remains unclear. OBJECTIVE: This study evaluates the long-term outcomes of botulinum toxin injections for the treatment of chronic anal fissures. DESIGN: This study is a retrospective review. SETTINGS: The study was conducted at a tertiary academic center. PATIENTS: Adults with chronic anal fissures treated with botulinum toxin between 2018 and 2023 were included. MAIN OUTCOME MEASURES: Short- and long-term healing, recurrence, or persistence after botulinum toxin injection. Persistent or recurrent fissure(s) were followed for outcomes after subsequent repeat injections or surgery (lateral internal sphincterotomy or fissurectomy). RESULTS: Among 161 patients, 45.3% (n = 73) experienced short-term healing after botulinum toxin as first-line therapy, but only 26% (n = 42) had sustained healing. Subsequent treatment patterns were similar for recurrent (n = 31) and persistent (n = 88) fissures: 35% versus 31% no further intervention, 55% versus 42% multiple subsequent injections, 10% versus 23% surgery, respectively. Sustained healing was achieved in 63% (n = 10/16) of patients who underwent surgery compared with 37% (n = 14/38) who had repeat botulinum toxin injections ( p = 0.06). Only 49% achieved sustained healing after a single injection, multiple injections, or injection(s) with surgery. Complications included 5 episodes of mild fecal incontinence in the botulinum toxin group and 2 instances of surgical site infection in the surgery group. LIMITATIONS: Limitations include a single-institution, retrospective study design and loss to follow-up. CONCLUSION: Botulinum toxin remains a valuable therapy for chronic anal fissures. Many patients have persistent or recurrent fissures after botulinum toxin injection and undergo additional interventions. Despite multiple interventions, only half of the patients achieved sustained healing, regardless of the treatment pattern. These data do not support the use of botulinum toxin over surgery for the treatment of chronic fissures, are helpful for counseling patients on the safety profile of each, and set expectations regarding the need for multiple interventions. See Video Abstract . RESULTADOS A LARGO PLAZO DEL USO DE TOXINA BOTULÍNICA EN EL TRATAMIENTO DE FISURAS ANALES CRÓNICAS: UN ENFOQUE GRADUAL PARA EL MANEJO DE CASOS RECURRENTES Y PERSISTENTES ANTECEDENTES: Las fisuras anales crónicas son una afección dolorosa caracterizada por un desgarro en la mucosa anal. La inyección de toxina botulínica es una opción de tratamiento mínimamente invasiva, pero su eficacia a largo plazo en casos recurrentes o persistentes sigue sin estar clara. OBJETIVO: Evaluar los resultados a largo plazo de las inyecciones de toxina botulínica para el tratamiento de las fisuras. DISEÑO: Revisión retrospectiva. ENTORNO: Centro académico terciario. PACIENTES: Adultos con fisuras crónicas tratados con toxina botulínica entre 2018 y 2023. PRINCIPALES MEDIDAS DE RESULTADO: Curación a corto y largo plazo, recurrencia o persistencia después de la inyección de toxina botulínica. Se realizó un seguimiento de las fisuras persistentes o recurrentes para evaluar los resultados después de repetidas inyecciones o cirugía (esfinterotomía interna lateral o fisurectomía). RESULTADOS: Entre los 161 pacientes, el 45,3 % (n = 73) experimentó una curación a corto plazo tras la toxina botulínica como terapia de primera línea, pero solo el 26 % (n = 42) tuvo una curación sostenida. Los patrones de tratamiento posteriores fueron similares para las fisuras recurrentes (n = 31) o persistentes (n = 88): 35 % frente a 31 % sin intervención adicional, 55 % frente a 42 % con múltiples inyecciones posteriores, 10 % frente a 23 % con cirugía, respectivamente. Se logró una curación sostenida en el 63 % (n = 10/16) de los pacientes que se sometieron a cirugía, en comparación con el 37 % (n = 14/38) que recibió inyecciones repetidas de toxina botulínica ( p = 0,06). Solo el 49 % logró una curación sostenida después de una sola inyección, múltiples inyecciones o inyecciones con cirugía. Las complicaciones incluyeron 5 episodios de incontinencia fecal leve en el grupo de la toxina botulínica y dos casos de infección en el sitio quirúrgico en el grupo de la cirugía. LIMITACIONES: Estudio retrospectivo de una sola institución y pérdida de seguimiento. CONCLUSIÓN: La toxina botulínica sigue siendo una terapia valiosa para las fisuras anales crónicas. Muchos pacientes presentan fisuras persistentes o recurrentes tras la inyección de toxina botulínica y se someten a intervenciones adicionales. A pesar de las múltiples intervenciones, solo la mitad de los pacientes lograron una curación sostenida, independientemente del patrón de tratamiento. Estos datos no respaldan el uso de la toxina botulínica frente a la cirugía para el tratamiento de las fisuras crónicas, pero son útiles para asesorar a los pacientes sobre el perfil de seguridad de cada una y establecer expectativas con respecto a la necesidad de múltiples intervenciones. ( AI-generated translation )

Abstract Background The associations between bilateral oophorectomy or hysterectomy with ovarian conservation and the risk of Parkinson's disease (PD) remain inconclusive. Objectives To evaluate the evidence on these two associations. Methods We conducted a systematic search across Embase, PubMed, Scopus, MEDLINE, and Web of Science through May 15, 2024. Data were extracted independently by two reviewers, and random‐effects meta‐analyses were performed. Results Eight studies with a total of 242,275 women were included. For bilateral oophorectomy, the effect size (ES) was greater than 1.0 in 5 of 8 studies. The pooled analysis showed a significant association between premenopausal bilateral oophorectomy and an increased risk of PD in cohort studies (hazard ratio [HR] 1.32; 95% CI 1.12–1.56) but not in case–control studies or combining both cohort and case–control studies. There was a suggestive trend of increasing risk with younger age at bilateral oophorectomy. For hysterectomy with ovarian conservation, the ES was greater than 1.0 in all six studies. The pooled analysis showed a non‐significant association in cohort studies and in case–control studies; however, the association was significant when combining both cohort studies and case–control studies (ES 1.19; 95% CI 1.01–1.41). Conclusions Current studies provided low to moderate evidence for the associations between bilateral oophorectomy and hysterectomy with ovarian conservation and increased risk of PD. However, the evidence was only observational and there was important heterogeneity across the case–control studies. Future studies should focus on surgeries performed at younger ages and on the possible effects of estrogen replacement therapy.

Abstract Background Population aging is expected to increase the burden of Alzheimer's disease (AD) and related dementias (ADRD), yet up to 45% of ADRD risk may be modified. Disparities in ADRD burden among Hispanic/Latino and Black/African Americans suggests that socioeconomic deprivation and medical comorbidities may influence AD risk. The relationship between these factors, symptomatic age of onset, and neuropathologic findings in AD remains unclear. This study aims to investigate these associations in an ethnoracially diverse, neuropathologically diagnosed AD case series. Understanding these risk factors may help develop more effective AD risk reduction strategies. Method We queried the Florida Autopsied Multi‐Ethnic (FLAME) cohort database for neuropathologically‐diagnosed AD cases with available age onset of cognitive symptoms, who self‐identified as Hispanic/Latino ( n = 75) or Black/African American ( n = 22). Cases were matched to non‐Hispanic White decedents ( n = 101) by sex and year of birth. Medical records at the time of brain donation were retrospectively reviewed, assessing completeness for demographics, clinical characteristics, and medical comorbidities (Table 1). Result The table shows a comparative analysis stratified by young‐onset AD (YOAD, onset <65 years) and late‐onset AD (LOAD, onset ≥65 years). YOAD cases had a significantly higher level of education compared to LOAD ( p = 0.003). No differences were observed in sex , APOE ε4 carriership, or Area Deprivation Index between YOAD and LOAD. However, YOAD cases had a longer disease duration and were more likely to present with atypical clinical features compared to LOAD (both p <0.001). YOAD cases also showed a faster rate of decline on MMSE compared to LOAD ( p = 0.002), higher frequency of depression ( p = 0.018), and lower frequency of stroke/TIA ( p = 0.025). YOAD cases also had lower brain weight ( p = 0.041), less cerebrovascular disease burden ( p = 0.003) and higher neurofibrillary tangle density in association cortices ( p <0.001) compared to LOAD cases. Conclusion Socioeconomic deprivation and most medical comorbidities were not associated with AD symptomatic onset. Despite having higher education levels and lower cerebrovascular burden, YOAD decedents experienced faster cognitive decline but a longer disease course, with more frequent atypical clinical presentations and depression compared to LOAD. Further discussion will address the topographic distribution of tangle and plaque pathology.

Abstract Background The locus coeruleus (LC) degenerates early in Alzheimer's disease (AD), with profound volume and neuronal loss. The loss of noradrenergic LC projection neurons results in alterations in attention, memory, and arousal, and constitutes the first site of neurofibrillary tangle accumulation preceding the onset of cognitive symptoms. We sought to investigate the relationship between LC neuronal density and clinical heterogeneity in a neuropathologically‐diagnosed series of AD cases. Methods The FLorida Autopsied Multi‐Ethnic (FLAME) cohort database was queried for neuropathologically‐diagnosed AD cases with a clinical diagnosis of AD dementia or an atypical, non‐amnestic clinical syndrome (e.g., corticobasal syndrome, posterior cortical atrophy). AD cases were selected based on high AD neuropathologic change (ADNC) and lack of frontotemporal lobar degeneration or hippocampal sclerosis, resulting in 591 AD cases and an additional 74 none‐low ADNC controls. Databased clinical diagnosis for AD cases was classified as amnestic or non‐amnestic. Hematoxylin & eosin‐stained slides were digitized and neuronal density was quantified using an in‐house developed macro on 900µmx900µm region of interest using Aperio technology (Leica Biosystems). LC level was classified using neuroanatomic landmarks as rostral, middle, or caudal. Results Control cases had greater neuronal density in the LC compared to AD cases at all three levels, p <0.05. In AD cases, we observed an association between age and neuronal density. Examining these differences along the rostrocaudal‐axis, we found that a younger age at symptomatic onset was associated with lower LC neuronal density in the rostral (correlation coefficient: 0.48; p <0.001) and middle LC (correlation coefficient: 0.28; p <0.001), no association between age at onset and neuronal density was observed at the caudal level. Stratifying our analysis by clinical syndrome, we found fewer neurons in the rostral and middle LC in non‐amnestic AD compared to amnestic AD ( p = 0.006 and 0.029 respectively, Table 1). No significant differences between amnestic and non‐amnestic cases were observed in the caudal LC. Conclusions The locus coeruleus, especially the rostral and middle levels, are especially vulnerable in young‐onset and atypical forms of AD. The loss of noradrenergic neuromodulation may contribute to the atypical symptomatology.

Abstract Background In aging and dementia research, the relationships between modifiable risk factors and biomarkers often vary across cohorts. We aim to evaluate the consistency and generalizability of the association between the area deprivation index (ADI) ‐ an indicator of socioeconomic/resource disadvantage within a specific area ‐ and cognition and Alzheimer's disease (AD) biomarkers across three distinct research cohorts, two from the U.S. (U.S. POINTER Imaging, ADNI) and one from Spain (UBRAIN). Method We included a total of 3091 participants without dementia, 1879 from U.S. POINTER Imaging, 282 from ADNI and 930 from UBRAIN (Table 1). The ADI was calculated using validated indices from the US and Spain, with neighborhood deprivation ranked as Low, Moderate, and High in the US, and Low and High in Spain. Outcomes of interest included (1) the preclinical Alzheimer's cognitive composite (PACC‐5), (2) MRI‐derived gray matter volumes in AD‐vulnerable regions and (3) PET or CSF‐derived amyloid status (+/‐). We ran logistic regression models with ADI level as predictor adjusted by sex, age, and APOE4 and considered education and race or ethnicity (only US cohorts) in our analyses. Result Participants in more deprived areas had lower education across cohorts and were more likely to be female (U.S. POINTER) and African American (U.S. POINTER and ADNI, Table 1). Independent of age, sex and APOE4 status, higher ADI was associated with lower PACC in U.S. POINTER (Moderate: β=‐0.165, p <0.001; High β=‐0.412, p <0.001) and UBRAIN (ADI: High β=‐0.096, p = 0.022) but not in ADNI (Figure 1). After controlling for education, this association remained significant in U.S. POINTER (Moderate: β=‐0.166, p = 0.002; High: β=‐0.248, p = 0.007) but not in UBRAIN (β=‐0.021, p = 0.66). In U.S. POINTER, there was a trend towards an association of higher ADI with lower GM volume in AD‐vulnerable regions (β=‐0.126, p = 0.089) that was not observed in ADNI or UBRAIN (Figure 2). No associations between ADI and amyloid status were found across cohorts. Conclusion We observed differing associations in neighborhood deprivation and cognition across US cohorts, as well as between the US and Spain cohorts. Country‐specific factors and sample representativeness must be considered when investigating the pathophysiologic mechanisms underlying social determinants and disparities in AD.

Introduction: Adult hepatitis B vaccination coverage in the United States remains low despite updated national recommendations supporting universal adult immunization. Many adults remain unaware of their susceptibility to hepatitis B virus (HBV) infection. This quality improvement (QI) study evaluated a stepwise “Offer–Offer–Test–Vaccinate” workflow designed to improve hepatitis B vaccine uptake among vaccine-hesitant adults in a primary care setting. Methods: This retrospective QI study was conducted at a single primary care clinic in Rochester, Minnesota. Adult patients (≥19 years) seen between October 1, 2022, and October 1, 2024, were routinely offered hepatitis B vaccination during rooming. Two participating physicians implemented an enhanced workflow in which patients who declined vaccination were counseled and then offered serologic screening using the 2023 CDC-recommended triple panel (HBsAg, anti-HBs, and total anti-HBc). Patients with negative serology were notified via the patient portal and reoffered vaccination along with a link to the CDC Vaccine Information Statement. The primary endpoint was initiation of the hepatitis B vaccine series following receipt of negative serology results. Preliminary series-completion data through October 1, 2025, were also assessed. Results: Among 501 eligible adults, 104 (20.8%) accepted vaccination at the initial offer. Of the 397 who declined, 106 (26.7%) agreed to serologic testing; 91 (85.8%) were seronegative. Among seronegative patients, 41 (45.1%) subsequently accepted vaccination. Integrating serologic testing increased overall vaccination uptake from 20.8% to 28.9%, an absolute increase of 8.2 percentage points and a relative increase of 39.4%. Approximately 2.6 serologic tests were required to generate 1 additional first-dose vaccination. Preliminary series-completion rates were 74.0% among those vaccinated at the initial offer and 87.8% among those vaccinated following serologic testing. Discussion: In this primary care setting, incorporating serologic testing into the workflow was associated with modestly improved hepatitis B vaccination uptake among vaccine-hesitant adults. Serologic results may help re-engage patients by providing personalized immunity information. Implementation considerations include staffing needs, laboratory access, patient portal engagement, and insurance coverage. Conclusion: The “Offer–Offer–Test–Vaccinate” strategy was associated with a modest increase in hepatitis B vaccine uptake among hesitant adults. This EMR-integrated, stepwise approach may offer a feasible and scalable strategy to reduce missed vaccination opportunities and support HBV prevention in adult primary care.

Abstract Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used for weight management and cardiometabolic health. Common peroneal neuropathy (CPN) associated with rapid weight loss is attributed to adipose tissue reduction and subsequent nerve compression at the fibular head. Cases of “Slimmer’s Palsy” have been described in conditions involving rapid weight loss, including anorexia, malignancy, and post-biliary surgery, yet it remains underrecognized as a potential complication of GLP-1RA therapy. This case report describes two nondiabetic patients who developed acute foot drop after losing 14% and 18% of their total body weight over 3–6 months of semaglutide and tirzepatide use, respectively. As use of GLP-1RAs continues to rise, peripheral nerve surgeons should be aware of Slimmer's Palsy as a predictable and treatable complication of rapid weight loss and be prepared to intervene before permanent denervation occurs.

Abstract Objective Evidence on the duration of post-operative adrenal insufficiency (AI) in patients with endogenous hypercortisolism is scarce. We sought to determine the duration of post-operative AI and to identify factors associated with the duration of AI in patients undergoing surgery for endogenous hypercortisolism. Methods We conducted a single-center prospective cohort study, 2019-2025, of patients with endogenous hypercortisolism [Cushing syndrome (CS) or mild autonomous cortisol secretion (MACS)] treated with surgery. Associations of demographics, body mass index (BMI), clinical, and biochemical hypercortisolism severity, subtype of hypercortisolism, pre-surgical hypercortisolism duration, glucocorticoid type, and nadir cortisol in relation to duration of AI were investigated. Results The 242 patients [41% MACS, 46% pituitary CS, 12% adrenal CS, 1% ectopic CS, median age 50 years (IQR: 40-60), 85% women] who developed postsurgical AI were followed for a median duration of 13.7 months (IQR 7.2-26.3). The median time to recovery of AI was shorter in MACS vs. overt CS (3.9 months (95% CI: 3.3-6.2) vs. 13.5 months (95% CI 11.3-18.3), P value &lt; .001). On multivariable analysis adjusting for age, sex, BMI, and glucocorticoid type, moderate to severe biochemical severity score (β = 11, P value &lt; .001) and moderate to severe clinical severity score (β=8.7, P &lt; .001), were associated with a longer duration of AI. Conclusions Baseline clinical and biochemical hypercortisolism severity scores may inform individualized counseling on post-operative AI duration in patients treated for CS and MACS.

Regenerative medicine is transforming how we restore tissue function, leveraging advances in cell and molecular biology, biomaterials, and engineered microenvironments. While there have been notable advances and rapid progress over the past few decades, ongoing challenges persist in the technical development and effective translation of these advancements to clinical care. This perspective highlights clinically promising examples and critically assesses present challenges in translating tissue regenerative medicine therapies from the bench to the clinic. We further examine the evolving landscape of regenerative medicine by describing strategies to optimize the cellular microenvironment, the impact of patient demographics, and the use of artificial intelligence to shape the future of this field.

Abstract The Mayo Clinic Center for Clinical and Translational Science Rural Health Research Core emphasizes community engagement to address healthcare access and delivery. In 2023, the Midwest Rural Health Research Community Advisory Board (CAB) was established to guide research. Eleven of 13 researchers presenting to the CAB in 2023 completed a survey assessing influence of CAB feedback across seven domains. All reported >1 domain influenced by CAB feedback, most commonly on study design, pre-research activities and implementation. CAB feedback shaped many aspects of the rural health research process. CAB members valued seeing how their input contributed to the research process.