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OBJECTIVE Myelopathy in the cervical spine can present with diverse symptoms, many of which can be debilitating for patients. Patients with radiculopathy symptoms demonstrate added complexity because of the overlapping symptoms and treatment considerations. The authors sought to assess outcomes in patients with myelopathy presenting with or without concurrent radiculopathy. METHODS The Quality Outcomes Database, a prospectively collected multi-institutional database, was used to analyze demographic, clinical, and surgical variables of patients presenting with myelopathy or myeloradiculopathy as a result of degenerative pathology. Outcome measures included arm (VAS-arm) and neck (VAS-neck) visual analog scale (VAS) scores, modified Japanese Orthopaedic Association (mJOA) scale score, EuroQol VAS (EQ-VAS) score, and Neck Disability Index (NDI) at 3, 12, and 24 months compared with baseline. RESULTS A total of 1015 patients were included in the study: 289 patients with myelopathy alone (M0), 239 with myeloradiculopathy but no arm pain (MRAP−), and 487 patients with myeloradiculopathy and arm pain (MRAP+). M0 patients were older than the myeloradiculopathy cohorts combined (M0 64.2 vs MRAP− + MRAP+ 59.5 years, p < 0.001), whereas MRAP+ patients had higher BMI and a greater incidence of current smoking compared with the other cohorts. There were more anterior approaches used in in MRAP+ patients and more posterior approaches used in M0 patients. In severely myelopathic patients (mJOA scale score ≤ 10), posterior approaches were used more often for M0 (p < 0.0001) and MRAP+ (p < 0.0001) patients. Patients with myelopathy and myeloradiculopathy both exhibited significant improvement at 1 and 2 years across all outcome domains. The amount of improvement did not vary based on surgical approach. In comparing cohort outcomes, postoperative outcome differences were associated with patient-reported scores at baseline. CONCLUSIONS Patients with myelopathy and those with myeloradiculopathy demonstrated significant and similar improvement in arm and neck pain scores, myelopathy, disability, and quality of life at 3 months that was sustained at 1- and 2-year follow-up intervals. More radicular symptoms and arm pain increased the likelihood of a surgeon choosing an anterior approach, whereas more severe myelopathy increased the likelihood of approaching posteriorly. Surgical approach itself was not an independent predictor of outcome.

The objective of this manuscript is to present the protocol of a study aiming to test the effects of Accelerated Resolution Therapy® (ART) on pre-loss grief and prolonged grief among older adult family caregivers. This study also aims to better understand predictors of response to ART®, and cognitive processes that occur among grieving individuals following ART®. Design: The study is a double-blinded, randomized clinical trial. Setting: This study takes place at both inpatient and outpatient palliative care and hospice programs at two Mayo Clinic sites. Participants: Participants include older adult ( ≥ 60 years) immediate family members who are primary caregivers of someone with an advanced illness and life expectancy of less than 12 months. Intervention: Participants are randomized to either the ART® intervention group or the attention control group. In the ART® intervention, caregivers engage in imaginal exposure, lateral eye movements, and imagery rescripting via 4 sessions lasting 1-1.5 hours each. The attention control group receives a standard social work intervention, including education, resources, and active listening, which is matched for time and attention. Both interventions will longitudinally follow caregivers from active caregiving into bereavement. Outcomes Measured: The primary outcomes of pre-loss grief and prolonged grief will be measured with the Pre-Loss Grief 12 item (PG-12-R) before the care recipient’s death, and with the Prolonged Grief-13 (PG-13-R) afterwards.

Background We wished to explore possible sexual dimorphism in mechanisms sensitizing or activating meningeal nociceptors that can promote the headache phase of migraine. Methods Male and female C57BL6J mice received either supradural orexin B and an inflammatory mediator cocktail (IM) with migraine-like pain behaviors and photophobia recorded. Expression of orexin 2 receptor (OX2R) in trigeminal ganglion (TG) and phosphorylated extracellular signal-regulated kinases (ERK) levels in trigeminal nucleus caudalis (TNC) were evaluated. Orexin B-induced excitability of TG cells was assessed with patch-clamp electrophysiology. Intranasal delivery of CRISPR/Cas9 plasmids was used to edit the expression of OX2R in the TG. Results Supradural orexin B induced migraine-like pain behaviors, photophobia and increased TNC ERK phosphorylation exclusively in males. Blockade of orexin signaling with supradural suvorexant, a dual orexin receptor antagonist, prevented, but did not reverse, migraine-like pain in males induced by supradural IM cocktail. OX2R expression was higher in male TG and orexin B increased TG neuron excitability in males. Intranasal OX2R CRISPR/Cas9 reduced TG receptor expression and orexin B-induced TNC ERK phosphorylation and prevented migraine-like pain induced by supradural orexin B in males. Conclusions Our studies reveal a male-specific mechanism of TG nociceptor sensitization and migraine-like pain behavior mediated by orexin B/OX2R signaling. Sexually dimorphic mechanisms of trigeminal nociceptor sensitization and activation offer opportunities to improve patient outcomes by considering patient sex and may influence clinical trial design and interpretation.

Abstract Clinical and preclinical research has demonstrated that iPSC-derived NK (iNK) cells have a high therapeutic potential, yet poor understanding of the detailed process of their differentiation in vitro and their counterpart cell development in vivo has hindered therapeutic iNK cell production and engineering. Here we dissect the crucial differentiation of both fetal liver NK cells and iNK cells to enable the rational design of advanced iNK production protocols. We use a comparative analysis of single-cell RNA-seq (scRNA-seq) to pinpoint key factors lacking in the induced setting which we hypothesized would hinder iNK differentiation and/ or functionality. By analyzing key transcription factor regulatory networks, we discovered the importance of TBX21, EOMES, and STAT5A in the differentiation timeline. This analysis provides a blueprint for further engineering new iPSC lines to obtain iNK cells with enhanced functions. We validated this approach by creating a new line of STAT5A-iPSCs which can be differentiated to STAT5A-expressing macrophages with both NK cell and macrophage features such as perforin production, phagocytosis, and anti-tumor functions.

Goal: This research aimed to evaluate variations in perceived organizational support among physicians during the first year of the COVID-19 pandemic and the associations between perceived organizational support, physician burnout, and professional fulfillment. Methods: Between November 20, 2020, and March 23, 2021, 1,162 of 3,671 physicians (31.7%) responded to the study survey by mail, and 6,348 of 90,000 (7.1%) responded to an online version. Burnout was assessed using the Maslach Burnout Inventory, and perceived organizational support was assessed by questions developed and previously tested by the Stanford Medicine WellMD Center. Professional fulfillment was measured using the Stanford Professional Fulfillment Index. Principal Findings: Responses to organizational support questions were received from 5,933 physicians. The mean organizational support score (OSS) for male physicians was higher than the mean OSS for female physicians (5.99 vs. 5.41, respectively, on a 0–10 scale, higher score favorable; p < .001). On multivariable analysis controlling for demographic and professional factors, female physicians (odds ratio [OR] 0.66; 95% CI: 0.55–0.78) and physicians with children under 18 years of age (OR 0.72; 95% CI: 0.56–0.91) had lower odds of an OSS in the top quartile (i.e., a high OSS score). Specialty was also associated with perceived OSS in mean-variance analysis, with some specialties (e.g., pathology and dermatology) more likely to perceive significant organizational support relative to the reference specialty (i.e., internal medicine subspecialty) and others (e.g., anesthesiology and emergency medicine) less likely to perceive support. Physicians who worked more hours per week (OR for each additional hour/week 0.99; 95% CI: 0.99–1.00) were less likely to have an OSS in the top quartile. On multivariable analysis, adjusting for personal and professional factors, each one-point increase in OSS was associated with 21% lower odds of burnout (OR 0.79; 95% CI: 0.77–0.81) and 32% higher odds of professional fulfillment (OR 1.32; 95% CI: 1.28–1.36). Practical Applications: Perceived organizational support of physicians during the COVID-19 pandemic was associated with a lower risk of burnout and a higher likelihood of professional fulfillment. Women physicians, physicians with children under 18 years of age, physicians in certain specialties, and physicians working more hours reported lower perceived organizational support. These gaps must be addressed in conjunction with broad efforts to improve organizational support.

Background: Within the spectrum of gastroesophageal reflux disease (GERD), pathologic reflux applies to the subset of patients with either erosive esophagitis or abnormal esophageal acid exposure on pH-metry, consequences of a dysfunctional antireflux barrier (ARB). Methods: The American Foregut Society (AFS) tasked a 13-member working group of expert foregut surgeons and esophagologists (The ARB Cooperative) to develop a white paper on ARB function, dysfunction, and mechanisms of action of antireflux surgery through discussion of relevant literature summarized herein. Results: The ARB Cooperative concluded that pathologic reflux is a consequence of the interplay between progressive anatomical distortion of the ARB and physiology. Factors contributing to ARB dysfunction include (1) separation of crural diaphragm from the lower esophageal sphincter with widening of the hiatus and diminished crural diaphragm sphincteric function; (2) loss of the intra-abdominal lower esophageal sphincter segment with complete disabling of the flap valve component of the ARB; (3) axial hiatal hernia leading to reflux during swallow-induced lower esophageal sphincter (LES) relaxation, LES hypotension, inspiration related reflux, a lowered threshold for eliciting transient LES relaxations, and increased compliance of the gastroesophageal junction leading to greater diameter of sphincter opening during transient LES relaxations. With regard to antireflux surgery, the objectives include: (1) reduction of hiatal hernia and restoration of the intra-abdominal esophageal segment; (2) repair of the dilated hiatus; (3) restoring flap valve function by modifying gastroesophageal anatomy; and (4) restricting gastroesophageal junction opening during periods of relaxation. Conclusions: This ARB Cooperative white paper supports the concept of there being 3 major inter-related mechanisms promoting ARB competence: the LES as an intrinsic sphincter, the crural diaphragm as an extrinsic sphincter, and the gastroesophageal valve, a mechanical 1-way valve. Pathological reflux occurs with progressive anatomical disruption of the ARB which in turn leads to physiological dysfunction, the severity of which parallels the extent of anatomical disruption. The corollary of this is that the primary mechanism of antireflux surgery is to restore the ARB by eliminating or compensating for its anatomical disruption. It is the hope of the cooperative that understanding the proposed framework will help clinicians and researchers in improving antireflux procedures.

The objective of this project was to develop a standardized list of renally eliminated and potentially nephrotoxic drugs that will help inform initiatives to improve medication safety. Several available lists of medications from the published literature including original research articles and reviews, and from regulatory agencies, tertiary references, and clinical decision support systems were compiled, consolidated, and compared. Only systemically administered medications were included. Medication combinations were included if at least 1 active ingredient was considered renally dosed or potentially nephrotoxic. The medication list was reviewed for completeness and clinical appropriateness by a multidisciplinary team of individuals with expertise in critical care, nephrology, and pharmacy. An initial list of renally dosed and nephrotoxic drugs was created. After reconciliation and consensus from clinical experts, a standardized list of 681 drugs is proposed. The proposed evidence-based standardized list of renally dosed and potentially nephrotoxic drugs will be useful to harmonize epidemiologic and medication quality improvement studies. In addition, the list can be used for clinical purposes with surveillance in nephrotoxin stewardship programs. We suggest an iterative re-evaluation of the list with emerging literature and new medications on an approximately annual basis.

Abstract Background In the TOPAZ-1, patients with biliary tract cancers (BTC) and recurrence within 6 months after surgery were excluded, even if this event is frequently observed in clinical practice. Our study aimed to assess if the efficacy of cisplatin-gemcitabine-durvalumab (CGD) in this population is comparable to that reported in the phase 3 trial. Methods The study cohort included patients with BTC who underwent surgery on the primary tumor, experienced disease recurrence occurring ≤6 months or &gt;6 months after surgery or after the end of adjuvant therapy and started CGD. The primary objectives were overall survival (OS) and progression free survival (PFS). Results A total of 178 patients were enrolled. No significant differences were observed between early and late relapse groups in OS (23.4 months vs not reached; HR 1.26; 95% CI, 0.67-2.37; P = .45) and PFS [7.0 months vs 9.8 months; HR 1.3(95% CI, 0.9-2.1) P = .13]. Overall response rate and disease control rate (P = .33 and P = .62) were comparable between the 2 groups, as the overall safety profile. In addition, we compared survival outcomes between the selected population and a historical cohort of patients with BTC treated with cisplatin-gemcitabine (CG) and found that despite the absence of statistical significance, CGD showed an outcome trend compared with CG regardless of the time of recurrence after surgery or adjuvant chemotherapy [(CG ≤ 6 vs CGD ≤ 6 months: HR 0.59, 95%CI, 0.35-1.01, P = .05; HR 0.70; 95%CI, 0.46-1.06, P = .09, OS and PFS, respectively) and (CG &gt; 6 vs. CGD &gt; 6 months: HR 0.50; 95%CI, 0.29-0.88, P = 0.0165; HR 0.54; 95%CI, 0.35-0.84, P = .0068, OS and PFS, respectively)]. Conclusion Our analysis suggests that CGD retains its efficacy independently of the timing of relapse after surgery or completion of adjuvant treatment in patients with advanced BTC.

Background: With neck, aging the cervicomental angle becomes obtuse and may be influenced by hyoid bone aging. An understanding of hyoid position changes with aging will further our understanding of its role in neck contour changes. Methods: A 3D volumetric reconstruction of 282 neck computed tomography scans was performed. The cohort was categorized into three groups based on age: 20 years or older and younger than 40 years, 40 years or older and younger than 60 years, and 60 years or older and younger than 80 years. The vertical and horizontal hyoid distances in relation to the mandible were calculated for each patient. Results: A total of 282 patients (153 women, 129 men) were included in the cohort. The age groups were evenly distributed in men and women. Mean hyoid vertical and horizontal distances differed between women and men in all age groups. There was a significant difference in the hyoid vertical distance between 20–39 years old to 40–59 years old in men (P < 0.01), and 20–39 years old to 60–79 years old in both genders (women P = 0.005, men P < 0.01). Hyoid horizontal distance was not affected by age and sex (age and sex: P > 0.05), but rather by body mass index (BMI). Every 5 BMI points corresponded to a forward movement of 2 mm. Conclusions: As individuals age, the hyoid bone descends in both sexes, and an increase in BMI is associated with forward movement. Additional studies are needed to assess the correlation of the hyoid position between upright and supine positions.

PURPOSE Imlunestrant is a next-generation oral selective estrogen receptor (ER) degrader designed to deliver continuous ER target inhibition, including in ESR1- mutant breast cancer. This phase Ia/b trial determined the recommended phase II dose (RP2D), safety, pharmacokinetics, and efficacy of imlunestrant, as monotherapy and in combination with targeted therapy, in ER-positive (ER+) advanced breast cancer (ABC) and endometrial endometrioid cancer. The ER+/human epidermal growth factor receptor 2–negative (HER2–) ABC experience is reported here. METHODS An i3+3 dose-escalation design was used, followed by dose expansions of imlunestrant as monotherapy or in combination with abemaciclib with or without aromatase inhibitor (AI), everolimus, or alpelisib. Imlunestrant was administered orally once daily and with the combination partner per label. RESULTS Overall, 262 patients with ER+/HER2– ABC were treated (phase Ia, n = 74; phase Ib, n = 188). Among patients who received imlunestrant monotherapy (n = 114), no dose-limiting toxicities or discontinuations occurred. At the RP2D (400 mg once daily), patients (n = 51) reported grade 1-2 nausea (39.2%), fatigue (39.2%), and diarrhea (29.4%). Patients at RP2D had received previous cyclin-dependent kinase 4/6 inhibitor (CDK4/6i; 92.2%), fulvestrant (41.2%), and chemotherapy (29.4%) for ABC and achieved a median progression-free survival (mPFS) of 7.2 months (95% CI, 3.7 to 8.3). Among patients who received imlunestrant + abemaciclib (n = 42) and imlunestrant + abemaciclib + AI (n = 43), most (69.4%) were treatment-naïve for ABC; all were CDK4/6i-naïve. Patients treated with imlunestrant + everolimus (n = 42)/alpelisib (n = 21) had received previous CDK4/6i (100%), fulvestrant (34.9%), and chemotherapy (17.5%) for ABC. No new safety signals or interactions with partnered drugs were observed. The mPFS was 19.2 months (95% CI, 13.8 to not available) for imlunestrant + abemaciclib and was not reached for imlunestrant + abemaciclib + AI. The mPFS with imlunestrant + everolimus/alpelisib was 15.9 months (95% CI, 11.3 to 19.1)/9.2 months (95% CI, 3.7 to 11.1). Antitumor activity was evident regardless of ESR1 mutation status. CONCLUSION Imlunestrant, as monotherapy or in combination with targeted therapy, had a manageable safety profile with evidence of preliminary antitumor activity in ER+/HER2– ABC.