Citations

Abstract The kinesin-5 motor protein KIF11 is crucial for mitotic spindle assembly, driving the separation of spindle poles through microtubule sliding. Src-family kinases phosphorylate KIF11 at multiple tyrosine residues within its motor domain, but the mechanistic consequences of these modifications remain unclear. Here, we dissect the role of phosphorylation at Y211 using phospho-mimetic (Y211E) and non-phosphorylatable mutants (Y211F) in biochemical, biophysical, and cellular assays. Optical trapping and Förster resonance energy transfer (FRET) analyses reveal that Y211 phosphorylation slows neck-linker docking, reducing motor velocity and force generation under load. In human cells, Y211E expression impairs bipolar spindle formation and decreases spindle pole separation velocity, while Y211F shortens steady-state spindle length. Fluorescence recovery after photobleaching (FRAP) analyses show that Y211E accelerates motor turnover on spindle microtubules, consistent with the mutant motor’s heightened load sensitivity. Together, these findings support a model in which Src-mediated phosphorylation at Y211 acts as a rheostat to tune KIF11 mechanochemistry and spindle assembly dynamics, linking cancer-relevant kinase signaling to mitotic force generation.

Abstract Cellular senescence is a key mechanism of skeletal aging in both physiological and accelerated conditions, such as radiotherapy. This study aimed to identify common differentially regulated microRNAs (miRs) across these contexts. We performed miR sequencing on three models: femurs from young (5-month-old) versus old (24-month-old) mice; focally radiated versus non-radiated femurs; and osteocytes from young versus old mice. Osteocytes were included in the comparison, as they have the longest lifespan in the mineralized bone matrix and they form 90-95% of all mesenchymal bone cell types. Among the three groups, miR-135a-5p and miR-671-5p were the common (i.e., shared) miRs that were downregulated, and miR-183-5p, a miR that regulates the WNT pathway, was the only shared upregulated miR, while miR-155-5p, a miR that regulates the Senescence-Associated Secretory Phenotype (SASP), was elevated in two conditions. The WNT-pathway has been positively associated with bone health and Sclerostin, a WNT-pathway inhibitor produced and secreted by osteocytes, has been implicated in accelerated skeletal deterioration following radiation. Thus, we used a neutralizing antibody to Sclerostin (Scl-Ab), to assess genes related to the WNT pathway and senescence, which are regulated by miR-183-5p and miR-155-5p, respectively. We further performed miR sequencing in radiated bones from mice treated with Scl-Ab and identified miR-133a-3p, a key miR that inhibits bone metabolism and function, which is upregulated in accelerated skeletal aging (i.e., focal radiation) downregulated by Scl-Ab. Overall, our study identifies potential regulatory gene pathways that modulate skeletal aging in the presence and absence of a WNT activator, Scl-Ab.

Abstract Coaching is considered the next generation of professional development in academic medicine, building on the historically important roles of advisor, mentor, and sponsor. A growing number of organizations are exploring or currently using coaching to support their employees and/or learners. Positive impressions of coaching have contributed to its ubiquitous use. However, to avoid confusion about the aim, approach, and outcomes of coaching, a thorough stakeholder analysis, an intentional organizational design, and a sustainable execution plan are necessary. Faculty and workforce coaching programs are distinct from learner coaching. Workplace coaching has pivoted from a disciplinary, problem-based reaction to a proactive investment in top performers. Coaching has also broadened beyond the C-suite, as a meaningful investment across all workforce layers. A coaching relationship helps high-achieving faculty elevate or sustain performance by having a thinking partner to reflect on situations, values, or vision; analyze and build awareness of needs or gaps; investigate impact factors of actions or inactions; strategize goals, priorities, and timelines; and evaluate decisions and options. Offering coaching as part of contemporary benefits packages signals career-long organizational interest in supporting talent. Coaching for faculty is a versatile and personalized approach to professional development and can be achieved through individualized, group, online, and in-person interactions. Key considerations for planning, launching, redesigning or evaluating a faculty coaching program are outlined, including expected faculty consumers, stakeholder concerns, access, benefits, goals, and outcomes of coaching within an academic medicine environment.

Background: In patients with irritable bowel syndrome with constipation (IBS-C), rapid, sustained relief from constipation and abdominal symptoms, such as pain, discomfort, and bloating, can improve quality of life. Objective: This post hoc analysis evaluates the time to constipation and abdominal symptom relief achieved with tenapanor. Design: Post hoc analysis of data pooled from three randomized placebo-controlled studies (phase IIb, T3MPO-1, and T3MPO-2) of tenapanor 50 mg twice daily in patients with IBS-C. Methods: The time to first response for complete spontaneous bowel movement (CSBM) frequency, abdominal pain, discomfort, bloating, and 3-item abdominal score (AS3) were assessed. The AS3 was derived as the average of the weekly scores for abdominal pain, discomfort, and bloating. Cumulative incidences of response over time were estimated using the Kaplan–Meier method. A Cox proportional hazards model was used to assess the effect of baseline and demographic characteristics on the time to first response. Results: Among 1372 patients with IBS-C (684 tenapanor; 688 placebo), median time to first CSBM response was 2 weeks, and median time to abdominal pain, discomfort, bloating, or AS3 response was 4–5 weeks in those treated with tenapanor, with 67.8%–76.7% achieving first response in CSBM frequency and abdominal symptoms by week 12. These time frames were shorter than those observed with the placebo (4 weeks for CSBM and 6–8 weeks for pain, discomfort, bloating, and AS3), of whom 59.1%–69.4% achieved the first response in CSBM and abdominal symptoms by week 12. Higher weekly response rates were observed with tenapanor than with placebo for all endpoints in each week of the 12-week treatment period. Conclusion: This novel post hoc analysis demonstrates that, compared with placebo, tenapanor reduces the time to first response in CSBM frequency and abdominal symptoms and consistently increases the weekly response rate during 12 weeks of treatment. Trial registration: NCT01923428; NCT02621892; NCT02686138.

Babesiosis and Lyme disease are tick-borne infections endemic to the northeastern and upper Midwestern United States. Although both diseases can involve multiple organ systems, acute liver failure (ALF) is exceedingly uncommon. Co-infection with Babesia microti and Borrelia burgdorferi may exacerbate disease severity, create diagnostic uncertainty, and delay appropriate therapy. We describe a 77-year-old man with type II diabetes mellitus, stage IV chronic kidney disease, and heart failure with preserved ejection fraction who presented with dyspnea, cough, and peripheral edema. Initial evaluation suggested decompensated heart failure and acute kidney injury consistent with cardiorenal syndrome. Within 24 h, however, he developed ALF (total bilirubin 6.8 mg/dL; aspartate aminotransferase 2656 U/L; alanine aminotransferase 1421 U/L; INR 3.5), thrombocytopenia (95 × 10 9 /L), acute anemia (hemoglobin 7.7 g/dL), and encephalopathy. Initial infectious, autoimmune, and ischemic evaluations were unrevealing. Despite empiric antimicrobial therapy with intravenous ceftriaxone, vancomycin, and doxycycline, his condition rapidly deteriorated, and he died. Postmortem testing identified B. microti parasitemia of 2.4% and B. burgdorferi co-infection. This case highlights the importance of considering tick-borne coinfections in patients presenting with ALF and shock, even in the absence of classic features such as fever, rash, or overt hemolysis. Increased clinician awareness of atypical presentations of endemic tick-borne diseases may help reduce diagnostic delays and improve outcomes in severe or unusual clinical scenarios.

Abstract Introduction The Hunger Vital Sign (HVS) is a two‐item, validated food insecurity screener recommended by the American Academy of Pediatrics. Given its brevity, HVS could be useful in assessing food insecurity in pregnant populations, for whom high‐quality nutrition and food access is essential. However, the HVS has not been evaluated in obstetric settings. Thus, we aimed to evaluate the performance of the HVS compared to the gold standard, the 18‐item US Household Food Security Survey Module (HFSSM) among low‐income, urban pregnant people. Methods We conducted a prospective study at a multi‐hospital tertiary health system (September 2023 to April 2024) in the United States. English‐ or Spanish‐speaking individuals from zip codes in which ≥10% of households were under the federal poverty line or who had publicly funded antenatal care completed a 20‐min self‐administered survey, which included the HFSSM and HVS. Food insecurity was defined as marginal, low, or very low food insecurity on the HFSSM; the prevalence of food insecurity was assessed and evaluated by participant characteristics. A positive screen on the HVS was defined as a “often true” or “sometimes true” to either item. Descriptive statistics were performed to characterize the performance of the HVS compared to the HFSSM. Results Of 713 potentially eligible participants based on medical record review, 192 (27%) completed an eligibility screener and were found to be eligible. Of these, 171 (89%) completed the survey. Nearly half (41%) of participants ( n = 70; of whom 74% received publicly funded care) screened positive for food insecurity on the HFSSM. HVS sensitivity was 83%, while specificity was 96%. The positive predictive value of the HVS was 94% and negative predictive value was 89%. Conclusion The two‐item HVS had relatively high accuracy for detecting food insecurity in this low‐income, urban obstetric population. Incorporating this brief screener into prenatal care may enable efficient, clinically useful food insecurity detection and intervention to address this need.

Abstract Objective Despite being safe and effective, surgery for pediatric epilepsy is underutilized. Social determinants of health (SDoH) are important to consider when examining this treatment gap. This study examined the potential systemic inequities at three different stages in the journey toward epilepsy surgery across the Pediatric Epilepsy Research Consortium (PERC). Methods Any youth in the PERC prospective surgery database (≤18 years) was eligible and included if sociodemographic factors were also available. We examined if there were differences in disparity factors in: (1) referral to Phase I evaluation, (2) offering of surgery, and (3) completion of surgery. Results Of 1309 patients, the majority were male (53%, p = .04), White (82.2%, p < .001), not Hispanic or Latino (84.3%, p < .001), and privately insured (56.3%, p < .001). Of the youth who were offered surgical treatment ( n = 1103, 84.3%), there were no significant differences in race/ethnicity or sex. Those with a structural lesion were more likely to be offered surgery, and historically marginalized youth were more likely to have a lesion. Of patients who completed surgery ( n = 927, 84.0%), White patients were 1.88 times (95% confidence interval [CI]: 1.14–3.04) more likely than Black patients to complete surgery ( p = .01). Significance Youth who began surgery evaluation are not representative of the demographics of those with epilepsy in the United States, with greater representation of White, non‐Hispanic male individuals. In addition, youth who began surgery evaluation disproportionally have private insurance. At the next stage of offering surgery, there were no differences based on SDoH. However, there is evidence that underrepresented youth that were magnetic resonance negative were less likely to be referred for surgical workup and that Black youth were less likely to undergo surgery. Therefore, efforts to provide equitable opportunity for all youth with refractory epilepsy should be concentrated at the referral for surgery evaluation point of care; however, additional efforts are also needed at later stages.

ABSTRACT Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disorder leading to kidney failure. Recent advancements in artificial intelligence (AI) are transforming the diagnosis, risk stratification, management and prognostication in ADPKD by enabling more accurate assessments and individualized care. AI-powered imaging tools enhance the measurement of total kidney volume (TKV), improving the precision and efficiency of monitoring disease progression and more reliable assessment of therapeutic response. Machine learning algorithms can integrate genetic, imaging and clinical data to predict kidney function decline, facilitating personalized treatment strategies. In addition, AI is being used to identify genetic variants and to refine genotype–phenotype relationships, offering deeper insights into disease variability. AI-enabled monitoring technologies can support longitudinal tracking of TKV measurements obtained through magnetic resonance imaging or computed tomography, thereby improving clinical decision-making and management. Furthermore, AI can optimize clinical trial design by improving patient selection, prediction of treatment responses and safety monitoring. Despite these promising developments, integrating AI into the clinical practice remains controversial and may pose several challenges. This review highlights the emerging clinical applications of AI in ADPKD, emphasizing its potential to advance precision medicine and improve patient outcomes.

Abstract Cancer occurs in ∼1 per 1000 pregnancies; thousands of patients may require radiation procedures for diagnosis and treatment each year in the United States alone. This rare but high-risk scenario, coupled with fear of radiation, has created ambiguity in the ideal management of pregnant patients. Without a comprehensive guide for the use of radiation in imaging and treatment for pregnant cancer patients, it is difficult for providers to offer optimal patient-centered care without introducing disparities. The goal of this paper is to provide guidance on the use of radiation for screening, diagnosis, staging, and treatment of cancer, while highlighting gaps in existing knowledge and guidelines. The intention is that physicians, medical physicists, and patients could use this document as a resource for shared decision-making, ensuring safe and effective practice. A team of physicians and medical physicists with expertise in imaging, radiotherapy, and maternal fetal medicine was assembled, along with a patient advocate and lawyer. Existing guidelines and recent literature were reviewed. Authors also drew from their experience where published guidance was lacking. The resulting document discusses best practice to guide use of radiation for cancer, as well as patient-centered care management and legal considerations. Overall, it is possible to safely and effectively deliver radiation to pregnant patients in numerous circumstances. Use of radiation or other modalities should be discussed through shared decision-making with the physician and patient, contextualizing the maternal and fetal risk from treatments. Healthcare providers should support wide access to reproductive healthcare to allow equitable, evidence-based, patient-centered healthcare.

Abstract Background Polycystic ovary syndrome (PCOS) affects 10% to 13% of individuals assigned female at birth (AFAB), although a greater prevalence is reported in transgender/gender diverse individuals (TGD) (23.8-38.8%). Testosterone therapy (TT) in TGD individuals is linked to worsening cardiovascular risk factors (CVRFs). Whether TT induces more adverse cardiometabolic changes in TGD with PCOS than TGD without PCOS remains uncertain. Objective To compare the effects of TT on CVRF in TGD with and without PCOS. Methods We retrospectively reviewed 373 records to identify 62 TGD with PCOS (withestablished guideline criteria) and 132 age-matched TGD without PCOS. Data included longitudinal anthropometric measurements, hormone and metabolic parameters, and CVRF before and after TT. Group comparison of PCOS vs without PCOS before and after TT was conducted via independent t-tests, Mann–Whitney-U, and Chi-square. Results At baseline, TGD with PCOS had significantly greater body mass index (BMI), obesity prevalence, and, after controlling for BMI, baseline metformin use. There were no significant differences between TGD with and without PCOS when comparing intra-participant changes after TT. Controlling for BMI, TGD with PCOS on TT exhibited significantly greater hyperlipidemia prevalence, alanine transaminase (ALT) levels, and bioavailable testosterone concentrations than TGD without PCOS on TT. Conclusion Greater baseline cardiometabolic risk was largely BMI-related in TGD with PCOS compared to TGD without PCOS. Only hyperlipidemia and elevated ALT were more prevalent during TT after adjusting for BMI. These findings support cardiometabolic monitoring during TT in all TGD individuals without significant increased risk with PCOS history.