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Background: To compare degrees of cSVA correction and to theorize possible minimum and maximum thresholds of cSVA correction for patients to benefit clinically., Methods: 657 operative ACD patients in a retrospective cohort study of a prospectively enrolled database with complete baseline and two year radiographic and HRQL data were examined. Patients were grouped into an optimally corrected cohort (OC; postop cSVA ≤ 4 cm) and an undercorrected cohort (UC; postop cSVA > 4 cm) based on postoperative radiographs., Results: 265 patients met inclusion criteria (mean age 58.2 ± 11.4 years, BMI 28.9 ± 7.5, CCI 0.9 ± 1.3). 11.2 % of patients were UC, while 88.8 % of patients were OC. UC cohort experienced a significantly greater occurrence of radiographic complications (47.8 % v. 27.6 %, p = 0.046). UC also demonstrated a significantly greater rate of severe 6 M DJK (p < 0.001) and 1Y DJK (26.1 % v. 2.7 %, p < 0.001). In terms of HRQLs, the OC cohort demonstrated significantly greater 2Y EQ5D-Health values (76.9 v. 46.7, p = 0.012). Being UC was a significant predictor of moderate-high 1Y mJOA score (OR 3.0, CI 95 % 1.2-7.3, p = 0.015) Still, in terms of CIT, the threshold for DJF risk increased significantly (p = 0.026) when the cSVA were surgically corrected greater than 5 cm., Conclusion: Undercorrection of cSVA yielded worse clinical outcomes and posed a significant risk for radiographic complications. Although undercorrection does not seem to be efficacious, surgical correction beyond certain thresholds should still be respected as there is a risk for DJK on either end of the spectrum., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Competing Interests: Competing interests: The authors declare no competing interests.

Background: Vertebral fractures are associated with enduring back pain, diminished quality of life, as well as increased morbidity and mortality. Existing epidemiological data for cervical and thoracic vertebral fractures are limited by insufficiently powered studies and a failure to evaluate the mechanism of injury., Question/purpose: What are the temporal trends in incidence, patient characteristics, and injury mechanisms of cervical and thoracic vertebral fractures in the United States from 2003 to 2021?, Methods: The United States National Electronic Injury Surveillance System-All Injury Program (NEISS-AIP) database collects data on all nonfatal injuries treated in US hospital emergency departments and is well suited to capture epidemiological trends in vertebral fractures. As such, the NEISS-AIP was queried from 2003 to 2021 for cervical and thoracic fractures. The initial search by upper trunk fractures yielded 156,669 injuries; 6% (9900) of injuries, with a weighted frequency of 638,999 patients, met the inclusion criteria. The mean age was 62 ± 25 years and 52% (334,746 of 638,999) of patients were females. Descriptive statistics were obtained. Segmented regression analysis, accounting for the year before or after 2019 when the NEISS sampling methodology was changed, was performed to assess yearly injury trends. Multivariable logistic regression models with age and sex as covariates were performed to predict injury location, mechanism, and disposition., Results: The incidence of cervical and thoracic fractures increased from 2.0 (95% CI 1.4 to 2.7) and 3.6 (95% CI 2.4 to 4.7) per 10,000 person-years in 2003 to 14.5 (95% CI 10.9 to 18.2) and 19.9 (95% CI 14.5 to 25.3) in 2021, respectively. Incidence rates of cervical and thoracic fractures increased for all age groups from 2003 to 2021, with peak incidence and the highest rate of change in individuals 80 years or older. Most injuries occurred at home (median 69%), which were more likely to impact older individuals (median [range] age 75 [2 to 106] years) and females (median 61% of home injuries); injuries at recreation/sports facilities impacted younger individuals (median 32 [3 to 96] years) and male patients (median 76% of sports facility injuries). Falls were the most common injury mechanism across all years, with females more likely to be impacted than males. The proportion of admissions increased from 33% in 2003 to 50% in 2021, while the proportion of treated and released patients decreased from 53% to 35% in the same period., Conclusion: This epidemiological study identified a disproportionate increase in cervical and thoracic fracture incidence rates in patients older than 50 years from 2003 to 2021. Furthermore, high hospital admission rates were also noted resulting from these fractures. These findings indicate that current osteoporosis screening guidelines may be insufficient to capture the true population at risk of osteoporotic fractures, and they highlight the need to initiate screening at an earlier age., Level of Evidence: Level III, prognostic study., Competing Interests: All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request., (Copyright © 2024 by the Association of Bone and Joint Surgeons.)

Objective: We sought to determine whether aggressive local treatment provides a benefit in patients with stage IV esophageal adenocarcinoma and to determine factors associated with survival., Methods: Patients with clinical stage IV esophageal adenocarcinoma at diagnosis who underwent esophagectomy from 2010 to 2023 were identified from our prospectively maintained database. Clinicopathologic and demographic characteristics were compared among patients by stage. Overall survival was estimated using the Kaplan-Meier approach., Results: In total, 66 patients met the inclusion criteria. Of these, 30 (45%) had stage IVA disease, and 36 (55%) had stage IVB disease. Of the 36 patients with stage IVB disease, 26 had oligometastatic disease, and 10 had disseminated disease. All patients with stage IVA disease received standard neoadjuvant therapy followed by curative-intent surgery; 26 of these patients (87%) received chemoradiation. Patients with oligometastatic stage IVB disease underwent systemic therapy with the goal of surgical resection. Patients with disseminated stage IVB disease underwent palliative chemotherapy, which led to improvement in disease burden and performance of esophagectomy. Median time from the start of therapy to surgery was shorter for patients with stage IVA disease than patients with stage IVB disease (p<0.001). Three-year progression-free survival was lower for patients with stage IVA disease (40% vs. 56%), as was 3-year overall survival (57% vs. 85%). Adjusted OS, from the start of therapy to most recent follow-up, was higher for patients with stage IVB disease., Conclusions: Aggressive local treatment may provide a benefit for highly selected patients with advanced or metastatic esophageal adenocarcinoma., (Copyright © 2024. Published by Elsevier Inc.)

Buprenorphine has demonstrated benefit for acute and chronic pain and various psychiatric disorders. However, many studies evaluating buprenorphine's effect on psychiatric conditions are not specific to the chronic pain population. This retrospective study was conducted to assess the impact of buprenorphine on depressive symptoms in patients with chronic pain at a Veterans Affairs healthcare facility. Adults with chronic pain started on any formulation of buprenorphine or traditional opioid (non-buprenorphine opioid) with at least two depression screenings between May 1, 2016 and November 1, 2021 were included. The primary outcome was change in depressive symptoms, measured by Patient Health Questionnaire-9 (PHQ-9), from baseline to 6-18 months after starting therapy. Secondary outcomes included changes in Columbia-Suicide Severity Rating Scale and mental health services utilization. Twenty-one patients were included. Median baseline PHQ-9 in the buprenorphine and traditional opioid groups were 14 and 13, respectively. Median change in PHQ-9 was -5 in the buprenorphine group and -1.5 in the traditional opioid group. Compared to traditional opioids, buprenorphine was associated with a greater reduction in depressive symptoms among Veterans with chronic pain. Although this reduction met the threshold for clinically significant improvement, further investigation is needed to evaluate the clinical relevance of these findings.

Background: Adult cervical deformity (ACD) surgery is more frequently being performed in frail patients. Although surgical outcomes are largely successful, there remains significant risk of poor outcomes. The ideal length of fusion constructs in these patients remains debatable., Methods: Patients undergoing cervical fusion for ACD with lower instrumented vertebra (LIV) at T4-or-above, with clinical and radiographic data from baseline (BL) to 2 years (2Y) were stratified by CD-modified frailty index into not frail (NF), frail (F) and severely frail (SF) categories. Deformity was classified by Kim et al. criteria. Means comparisons tests were used to assess differences between both groups. Logistic regression analyses were used to analyze associations between frailty categories, lower instrumented vertebra (LIV) and outcomes., Results: 286 patients (Age: 57.3 ± 10.9 years, BMI: 28.9 ± 6.4 kg/m2, CCI: 0.84 ± 1.26). 47% of patients were female. 32.2% of patients were NF, 50.3% F and 17.5% SF. By deformity, 66% were focal kyphosis (FK), 12% were flatneck, and 22% were cervicothoracic. Only FK type differed between NF and F/SF patients (39.2 vs 73.6%, p = 0.005). At baseline (BL), differences in age, BMI, CCI and deformity were not significant. F/SF patients had longer LOS (p = 0.018) and higher rates of distal junctional kyphosis/failure (DJK/F) at 2 years. Controlling for baseline disability, F and SF patients were more likely to experience poor outcomes at 2 years with C7 compared with more distal LIVs. The risk for poorer outcomes was not significant when comparing LIVs within the upper thoracic spine. Similar trends were seen performing sub-analyses specifically comparing F vs SF patients., Conclusions: Frail patients are at risk for poor outcomes following ACD surgery due to their comorbidities. These patients appear to be at even greater risk for poor outcomes with a lower instrumented vertebra proximal to T1., Competing Interests: Declarations. Ethical approval: This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of NYU School of Medicine. Informed consent: Informed consent was obtained from each patient prior to enrollment. Ethical review committee: Institutional Review Board approval was obtained before enrolling patients in the prospective database. Informed consent was obtained from each patient prior to enrollment. Competing interests: Bassel G. Diebo Clariance: Consulting SpineVision: Consulting Spineart: Consulting Alan H. Daniels Alphatec Spine: Research support Medtronic Sofamor Danek: IP royalties; Paid consultant; Research support Orthofix, Inc.: Research support Spineart: IP royalties; Paid consultant Springer: Publishing royalties, financial or material support Stryker: IP royalties Carl B. Paulino DePuy, A Johnson & Johnson CompanyEthicon: Paid presenter or speaker Peter G. Passias MD Cerapedics: Other financial or material support Cervical Scoliosis Research Society: Research support Globus Medical: Paid presenter or speaker Medtronic: Paid consultant Royal Biologics: Paid consultant Spine: Editorial or governing board Spinevision: Other financial or material support SpineWave: Paid consultant JNS Spine: Editorial Board JCM: Editorial Board., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background: Lumbar spine fractures are common injuries associated with substantial morbidity for patients and socioeconomic burden. This study sought to epidemiologically analyze lumbar spine fractures by mechanism of injury and identify temporal trends in patient demographics and disposition, which few studies have previously evaluated., Materials and Methods: A retrospective analysis was done of the US National Electronic Injury Surveillance System (NEISS) database between 2003 and 2022. The sample contained all patients 2 to 101 years old with product-related lumbar fractures presenting to participating institutions' emergency departments. A total of 15,196 unweighted injuries (642,979 weighted injuries) were recorded., Results: Overall, there was a 20-year incidence rate of 10.14 cases per 100,000 person-years with a 2-fold increase in fracture incidence. Females were more prone to lumbar fracture than males ( P =.032). Injuries primarily stemmed from a fall (76.6%). The incidence of lumbar fracture increased most significantly in older patients, with patients 80 years and older showing the greatest annual increase (β=8.771, R 2 =0.7439, P <.001) and patients 60 to 69 years showing the greatest percent increase with a 3.24-fold increase in incidence. Most (58.9%) of the fractures occurred at home. Females were more often injured at home compared with males ( P <.001), who more often sustained lumbar fractures during recreational or athletic activity ( P <.001). All patients older than 40 years showed at least a doubling in incidence rate of lumbar fracture between 2003 and 2022., Conclusion: These data demonstrate the pressing need to address poor bone health in the aging population, shown here to have an increasing fracture burden. [ Orthopedics . 2024;47(6):e297-e302.].

Objective: To compare the clinical outcomes of early pars plana vitrectomy (PPV) versus delayed PPV in patients with first episode of vitreous hemorrhage (VH) secondary to proliferative diabetic retinopathy (PDR)., Design: Retrospective, comparative, interventional study., Subjects, Participants, And/or Controls: Consecutive patients with type 1 or II diabetes diagnosed with new onset VH secondary to PDR who underwent PPV at Moorfields Eye Hospital between December 2014 and December 2016. Exclusions were prior vitrectomy, iris neovascularization, neovascular glaucoma, macular edema, or presence of tractional/rhegmatogenous retinal detachment., Methods, Intervention, or Testing: Patients were divided into two groups based on the timing of their surgery: early PPV (≤6 weeks) and delayed PPV (>6 weeks). Demographic and clinical features, including best-corrected visual acuity (BCVA), expressed in logMAR at baseline and 12 months were collected. Statistical analyses, including propensity score matching, were performed using Python 3.10, Scikit-learn, Pandas, and GraphPad Prism 10., Main Outcome Measures: BCVA at 12 months postoperatively, reoperation rates, and severity of complications., Results: A total of 178 eyes were analyzed (48 early PPV, 130 delayed PPV). The mean (SD) number of weeks before surgery was 3.36 (SD 1.6) for the early PPV group and 22.56 (SD 17.23) for the delayed PPV group (P < .0001). Baseline BCVA prior to PPV was similar between groups (P = .08). At 12 months, the early PPV group had significantly better BCVA (0.40 logMAR vs 0.67 logMAR; P = .02). Patients without evidence of posterior vitreous detachment on ultrasound or OCT showed more pronounced differences (0.3 logMAR vs 0.7 logMAR; P = .001). The early PPV group had fewer sight-threatening complications (P = .005). Multivariable logistic regression identified initial BCVA, early PPV, and absence of preoperative panretinal photocoagulation as significant predictors of better visual outcomes., Conclusions: Early PPV significantly improves visual outcomes and reduces severe complications in patients with VH secondary to PDR. These findings support the benefits of early surgical intervention to enhance long-term visual prognosis in these patients. However, a randomized clinical trial is warranted., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Family physicians are well-positioned to provide injections for patients who have wrist pain, especially when initial treatments such as nonsteroidal anti-inflammatory drugs and rest fail. Although corticosteroid injections can offer pain relief, possible risks (e.g., infection, cartilage damage, skin depigmentation) should be discussed. Techniques and procedures for injections vary. Studies have shown significant improvement in carpal tunnel syndrome severity over 12 weeks using ultrasound-guided injections compared with landmark-guided injections. Ganglion cyst aspiration can be helpful for patients with significant symptoms, although more than 50% of ganglion cysts may recur within a year. Corticosteroid injections of ganglion cysts do not appear to produce additional benefits to aspiration. Intersection syndrome is an overuse injury; management involves rest, adjustment of activities, use of braces, nonsteroidal anti-inflammatory drugs, and physical or occupational therapy. For symptoms not improved by these methods, an ultrasound-guided glucocorticoid injection may be administered. Treatment options for a triangular fibrocartilage complex injury include immobilization, kinesio taping, relative rest, and analgesics; corticosteroid injection may relieve acute inflammatory pain. De Quervain tenosynovitis is treated conservatively with palpation- or ultrasound-guided corticosteroid injection, splinting, occupational therapy, and activity modification.

Family physicians are well-positioned to provide injections for patients who have pain due to hand and finger conditions, especially when initial treatments such as splinting and nonsteroidal anti-inflammatory drugs are ineffective. Corticosteroid injections can offer pain relief; however, potential risks such as infection, cartilage damage, and skin depigmentation should be discussed. Techniques and procedures for injections vary. Corticosteroid injections for ste-nosing flexor tenosynovitis (trigger finger) can be performed with or without ultrasound guidance. To maximize benefits of corticosteroid injection for carpometacarpal joint osteoarthritis, topical nonsteroidal anti-inflammatory drugs and other conservative treatment modalities should be used concurrently. Because of the risks of disease recurrence and adverse effects, corticosteroid injections for palmar fibromatosis should be approached with caution in the context of shared decision-making.

Immunotherapy-related colitis (irC) frequently emerges as an immune-related adverse event during immune checkpoint inhibitor therapy and is presumably influenced by the gut microbiota. We longitudinally studied microbiomes from 38 ICI-treated cancer patients. We compared 13 ICI-treated subjects who developed irC against 25 ICI-treated subjects who remained irC-free, along with a validation cohort. Leveraging a preclinical mouse model, predisease stools from irC subjects induced greater colitigenicity upon transfer to mice. The microbiota during the first 10 days of irC closely resembled inflammatory bowel disease microbiomes, with reduced diversity, increased Proteobacteria and Veillonella, and decreased Faecalibacterium, which normalized before irC remission. These findings highlight the irC gut microbiota as functionally distinct but phylogenetically similar to non-irC and healthy microbiomes, with the exception of an acute, transient disruption early in irC. We underscore the significance of longitudinal microbiome profiling in developing clinical avenues to detect, monitor, and mitigate irC in ICI therapy cancer patients., (© 2024 Shang et al.)

Study Design: Retrospective cohort study., Purpose: The impact of neuromuscular disorders such as multiple sclerosis (MS) on outcomes following long segment fusion is underreported. This study evaluates the impact of MS on two-year (2Y) postoperative complications and revisions following ≥ 4-level fusion for adult spinal deformity (ASD)., Methods: Patients undergoing ≥ 4-level fusion for ASD were identified from a statewide database. Patients with a baseline diagnosis of MS were also identified. Patients with infectious/traumatic/neoplastic indications were excluded. Subjects were 1:1 propensity score-matched (MS to no-MS) based on age, sex and race and compared for rates of 2Y postoperative complications and reoperations. Logistic regression models were utilized to determine risk factors for adverse outcomes at 2Y., Results: 86 patients were included overall (n = 43 per group). Age, sex, and race were comparable between groups (p > 0.05). MS patients incurred higher charges for their surgical visit ($125,906 vs. $84,006, p = 0.007) with similar LOS (8.1 vs. 5.3 days, p > 0.05). MS patients experienced comparable rates of overall medical complications (30.1% vs. 25.6%) and surgical complications (34.9% vs. 30.2%); p > 0.05. MS patients had similar rates of 2Y revisions (16.3% vs. 9.3%, p = 0.333). MS was not associated with medical, surgical, or overall complications or revisions at minimum 2Y follow-up., Conclusion: Patients with MS experienced similar postoperative course compared to those without MS following ≥ 4-level fusion for ASD. This data supports the findings of multiple previously published case series' that long segment fusions for ASD can be performed relatively safely in patients with MS., (© 2024. The Author(s), under exclusive licence to Scoliosis Research Society.)

Abstract: Secondary kinase domain mutations in BCR::ABL1 represent the most common cause of resistance to tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia. The first 5 approved BCR::ABL1 TKIs target the adenosine triphosphate (ATP)-binding pocket. Mutations confer resistance to these ATP-competitive TKIs and those approved for other malignancies by decreasing TKI affinity and/or increasing ATP affinity. Asciminib, the first highly active allosteric TKI approved for any malignancy, targets an allosteric regulatory pocket in the BCR::ABL1 kinase C-lobe. As a non-ATP-competitive inhibitor, the activity of asciminib is predicted to be impervious to increases in ATP affinity. Here, we report several known mutations that confer resistance to ATP-competitive TKIs in the BCR::ABL1 kinase N-lobe that are distant from the asciminib binding pocket yet unexpectedly confer in vitro resistance to asciminib. Among these is BCR::ABL1 M244V, which confers clinical resistance even to escalated asciminib doses. We demonstrate that BCR::ABL1 M244V does not impair asciminib binding, thereby invoking a novel mechanism of resistance. Molecular dynamic simulations of the M244V substitution implicate stabilization of an active kinase conformation through impact on the α-C helix as a mechanism of resistance. These N-lobe mutations may compromise the clinical activity of ongoing combination studies of asciminib with ATP-competitive TKIs., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Cardiac magnetic resonance is a useful clinical tool to identify late gadolinium enhancement in heart failure patients with implantable electronic devices. Identification of LGE in patients with CIED is limited by artifact, which can be improved with a wide band radiofrequency pulse sequence., Objective: The authors hypothesize that image quality of LGE images produced using wide-band pulse sequence in patients with devices is comparable to image quality produced using standard LGE sequences in patients without devices., Methods: Two independent readers reviewed LGE images of 16 patients with CIED and 7 patients without intracardiac devices to assess for image quality, device-related artifact, and presence of LGE using the American Society of Echocardiography/American Heart Association 17 segment model of the heart on a 4-point Likert scale. The mean and standard deviation for image quality and artifact rating were determined. Inter-observer reliability was determined by calculating Cohen's kappa coefficient. Statistical significance was determined by T -test as a p {less than or equal to} 0.05 with a 95% confidence interval., Results: All patients underwent CMR without any adverse events. Overall IQ of WB LGE images was significantly better in patients with devices compared to standard LGE in patients without devices ( p  = 0.001) with reduction in overall artifact rating ( p  = 0.05)., Conclusion: Our study suggests wide-band pulse sequence for LGE can be applied safely to heart failure patients with devices in detection of LV myocardial scar while maintaining image quality, reducing artifact, and following routine imaging protocol after intravenous gadolinium contrast administration., Competing Interests: Authors XM, MJ and AB were employed by company GE Healthcare. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Shah, Krishnam, Ambale Venkatesh, Khan, Smith, Jones, Koon, Mao, Janich, Brau, Salerno, Dash, Chan and Yang.)

Treatment options are limited for patients with non-clear cell renal cell carcinoma (nccRCC). Patients with nccRCC experienced a favorable objective response rate (ORR) in a phase 2 trial of cabozantinib plus nivolumab. We now report updated efficacy and safety results at median follow-up of 34 mo for patients with papillary, unclassified, or translocation-associated RCC. Cabozantinib and nivolumab were administered at standard doses to patients with metastatic nccRCC that had progressed on zero or one line of systemic therapy. The primary endpoint was the ORR according to Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and adverse events. Forty patients were treated. At median follow-up of 34 mo for survivors, the ORR was 48% (95% confidence interval [CI] 31.5-63.9%). Median PFS was 13 mo (95% CI 7-16); the 12-mo and 24-mo PFS rates were 51% (95% CI 34-65%) and 23% (95% CI 11-37%), respectively. Median OS was 28 mo (95% CI 23-43); the 18-mo and 36-mo OS rates were 70% (95% CI 53-82%) and 44% (95% CI 28-60%), respectively. No new safety signals were seen with cabozantinib and nivolumab. This extended follow-up analysis demonstrates promising efficacy, and highlights the potential for sustained responses with cabozantinib plus nivolumab in patients with metastatic nccRCC., (Copyright © 2024. Published by Elsevier B.V.)

Background: Although different kidney cancers represent a heterogeneous group of malignancies, multiple subtypes including Von Hippel-Lindau (VHL)-altered clear cell renal cell carcinoma (ccRCC), fumarate hydratase (FH)- and succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC), and renal medullary carcinoma (RMC) are affected by genomic instability. Synthetic lethality with poly ADP-ribose polymerase inhibitors (PARPis) has been suggested in preclinical models of these subtypes, and paired PARPis with immune checkpoint blockade (ICB) may achieve additive and/or synergistic effects in patients with previously treated advanced kidney cancers., Objective: To evaluate combined PARPi + ICB in treatment-refractory metastatic kidney cancer., Design, Setting, and Participants: We conducted a single-center, investigator-initiated phase 2 trial in two genomically selected advanced kidney cancer cohorts: (1) VHL-altered RCC with at least one prior ICB agent and one vascular endothelial growth factor (VEGF) inhibitor, and (2) FH- or SDH-deficient RCC with at least one prior ICB agent or VEGF inhibitor and RMC with at least one prior line of chemotherapy., Intervention: Patients received talazoparib 1 mg daily plus avelumab 800 mg intravenously every 14 d in 28-d cycles., Outcome Measurements and Statistical Analysis: The primary endpoint was objective response rate (ORR) by Immune Response Evaluation Criteria in Solid Tumors at 4 mo, and the secondary endpoints included progression-free survival (PFS), overall survival, and safety., Results and Limitations: Cohort 1 consisted of ten patients with VHL-altered ccRCC. All patients had previously received ICB. The ORR was 0/9 patients; one patient was not evaluable due to missed doses. In this cohort, seven patients achieved stable disease (SD) as the best response. The median PFS was 3.5 mo (95% confidence interval [CI] 1.0, 3.9 mo). Cohort 2 consisted of eight patients; four had FH-deficient RCC, one had SDH-deficient RCC, and three had RMC. In this cohort, six patients had previously received ICB. The ORR was 0/8 patients; two patients achieved SD as the best response and the median PFS was 1.2 mo (95% CI 0.4, 2.9 mo). The most common treatment-related adverse events of all grades were fatigue (61%), anemia (28%), nausea (22%), and headache (22%). There were seven grade 3-4 and no grade 5 events., Conclusions: The first clinical study of combination PARPi and ICB therapy in advanced kidney cancer did not show clinical benefit in multiple genomically defined metastatic RCC cohorts or RMC., Patient Summary: We conducted a study to look at the effect of two medications, talazoparib and avelumab, in patients with metastatic kidney cancer who had disease progression on standard treatment. Talazoparib blocks the normal activity of molecules called poly ADP-ribose polymerase, which then prevents tumor cells from repairing themselves and growing, while avelumab helps the immune system recognize and kill cancer cells. We found that the combination of these agents was safe but not effective in specific types of kidney cancer., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Importance: Immuno-oncology agents have changed the treatment paradigm for metastatic renal cell carcinoma (mRCC). Such therapies improve survival but can impose considerable health care resource use (HCRU) and associated costs, necessitating their examination., Objective: To compare HCRU, costs, and clinical outcomes among patients receiving first-line pembrolizumab plus axitinib (P+A) or ipilimumab plus nivolumab (I+N)., Design, Setting, and Participants: This retrospective cohort study used data from an administrative claims database on patients with mRCC receiving first-line P+A or I+N that was initiated between January 2018 and May 2020. Data were analyzed from February 2021 to July 2022., Exposure: First-line P+A or I+N., Main Outcome and Measures: HCRU and costs during the first 90 days, full first-line treatment, and full follow-up periods were assessed. Using Kaplan-Meier analysis, time on treatment, overall survival, time to first emergency department (ED) visit, and time to first inpatient stay were compared., Results: Among 507 patients, there were 126 patients receiving P+A (91 male [72.2%]; mean [SD] age, 67.93 [9.66] y) and 381 patients receiving I+N (271 male [71.1%]; mean [SD] age, 66.52 [9.94] years). The median time on treatment was longer for the P+A compared with I+N group (12.4 months [95% CI, 8.40 months to not estimable] vs 4.1 months [95% CI, 3.07 to 5.30 months]; P < .001). The median time to first ED visit was longer for the P+A than I+N group (7.2 months [95% CI 3.9 to 11.1 months ] vs 3.3 months [95% CI, 2.6 to 3.9 months]; P = .005), as was time to first inpatient stay (9.0 months [95% CI 6.5 months to not estimable] vs 5.6 months [95% CI, 3.9 to 7.9 months]; P = .02). During the first 90 days, a lower proportion of the P+A than N+I group had ED visits (43 patients [34.1%] vs 182 patients [47.8%] and inpatient stays (24 patients [19.1%) vs144 patients [37.8%]; P < .001). During full follow-up, mean total adjusted costs were similar for P+A and I+N groups, but adjusted 12-month estimated total costs were higher for P+A than I+N groups ($325 574 vs $ 263 803; P = .03)., Conclusions and Relevance: In this study, treatment with P+A was associated with longer time on treatment, time to first ED visit, and inpatient stay, while 12-month estimated costs were higher for the P+A group. This is among the first clinical studies to evaluate economic burden associated with modern treatments for mRCC.

Objective: To compare the comparative effects of treatment with contemporary mechanical thrombectomy (MT) or anticoagulation (AC) on Villalta scores and post-thrombotic syndrome (PTS) incidence through 12 months in iliofemoral deep vein thrombosis (DVT)., Methods: Patients with DVT in the Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis (ATTRACT) randomized trial and the ClotTriever Outcomes (CLOUT) registry were included in this analysis. Both studies evaluated the effects of thrombus removal on the incidence of PTS. Patients with bilateral DVT, isolated femoral-popliteal DVT, symptom duration of >4 weeks, or incomplete case data for matching covariates were excluded. Propensity scores were used to match patients 1:1 who received AC (from ATTRACT) with those treated with mechanical thrombectomy (from CLOUT) using nearest neighbor matching on nine baseline covariates, including age, body mass index, leg treated, provoked DVT, prior venous thromboembolism, race, sex, Villalta score, and symptom duration. Clinical outcomes, including Villalta score and PTS, were assessed. Logistic regression was used to estimate the likelihood of developing PTS at 12 months., Results: A total of 164 pairs were matched, with no significant differences in baseline characteristics after matching. There were fewer patients with any PTS at 6 months (19% vs 46%; P < .001) and 12 months (17% vs 38%; P < .001) in the MT treatment group. Modeling revealed that, after adjusting for baseline Villalta scores, patients treated with AC had significantly higher odds of developing any PTS (odds ratio, 3.1; 95% confidence interval, 1.5-6.2; P = .002) or moderate to severe PTS (odds ratio, 3.1; 95% confidence interval, 1.1-8.4; P = .027) at 12 months compared with those treated with MT. Mean Villalta scores were lower through 12 months among those receiving MT vs AC (3.3 vs 6.3 at 30 days, 2.5 vs 5.5 at 6 months, and 2.6 vs 4.9 at 12 months; P < .001 for all)., Conclusions: MT treatment of iliofemoral DVT was associated with significantly lower Villalta scores and a lower incidence of PTS through 12 months compared with treatment using AC. Results from currently enrolling clinical trials will further clarify the role of these therapies in the prevention of PTS after an acute DVT event., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: Immune-related cutaneous adverse events (ircAE) occur in ≥50% of patients treated with checkpoint inhibitors, but the underlying mechanisms for ircAEs are poorly understood., Experimental Design: Phenotyping/biomarker analyses were conducted in 200 patients on checkpoint inhibitors [139 with ircAEs and 61 without (control group)] to characterize their clinical presentation and immunologic endotypes. Cytokines were evaluated in skin biopsies, skin tape strip extracts, and plasma using real-time PCR and Meso Scale Discovery multiplex cytokine assays., Results: Eight ircAE phenotypes were identified: pruritus (26%), maculopapular rash (MPR; 21%), eczema (19%), lichenoid (11%), urticaria (8%), psoriasiform (6%), vitiligo (5%), and bullous dermatitis (4%). All phenotypes showed skin lymphocyte and eosinophil infiltrates. Skin biopsy PCR revealed the highest increase in IFNγ mRNA in patients with lichenoid (P < 0.0001) and psoriasiform dermatitis (P < 0.01) as compared with patients without ircAEs, whereas the highest IL13 mRNA levels were detected in patients with eczema (P < 0.0001, compared with control). IL17A mRNA was selectively increased in psoriasiform (P < 0.001), lichenoid (P < 0.0001), bullous dermatitis (P < 0.05), and MPR (P < 0.001) compared with control. Distinct cytokine profiles were confirmed in skin tape strip and plasma. Analysis determined increased skin/plasma IL4 cytokine in pruritus, skin IL13 in eczema, plasma IL5 and IL31 in eczema and urticaria, and mixed-cytokine pathways in MPR. Broad inhibition via corticosteroids or type 2 cytokine-targeted inhibition resulted in clinical benefit in these ircAEs. In contrast, significant skin upregulation of type 1/type 17 pathways was found in psoriasiform, lichenoid, bullous dermatitis, and type 1 activation in vitiligo., Conclusions: Distinct immunologic ircAE endotypes suggest actionable targets for precision medicine-based interventions., (©2024 The Authors; Published by the American Association for Cancer Research.)

Type II kinase inhibitors bind in the "DFG-out" kinase conformation and are generally considered to be more potent and selective than type I inhibitors, which target a DFG-in conformation. Nine type II inhibitors are currently clinically approved, with more undergoing clinical development. Resistance-conferring secondary mutations emerged with the first series of type II inhibitors, most commonly at residues within the kinase activation loop and at the "gatekeeper" position. Recently, new inhibitors have been developed to overcome such mutations; however, mutations activating other pathways (and/or other targets) have subsequently emerged on occasion. Here, we systematically summarize the secondary mutations that confer resistance to type II inhibitors, the structural basis for resistance, newer inhibitors designed to overcome resistance, as well as the challenges and opportunities for the development of new inhibitors to overcome secondary kinase domain mutations.

Regulatory approval of immune checkpoint inhibitors (ICIs) was based on results of large, randomized clinical trials, resulting in limited outcomes data in patient cohorts typically underrepresented in such trials. The objective of this study was to evaluate the efficacy and safety of ICIs in these unique patient cohorts. This is a multicenter, retrospective analysis of real-world data at six academic and community clinics in the United States from 1 January 2011 to 1 April 2018. Patients were included if they had received at least one cycle of ICI treatment. Unique patient cohorts included age > 75 years, non-White race, positive smoking history, ECOG performance status (PS) ≥ 2, BMI ≥ 30 kg/m 2 , autoimmune diseases (AIDs), chronic viral infections (CVI), extensive prior lines of therapy (LOTs), or >three metastatic sites. Immune-related adverse events (irAEs), overall survival (OS), and time to treatment failure were evaluated in the entire cohort and in NSCLC patients treated with PD-(L)1 monotherapy. Outcomes and their association with unique patient cohorts were compared on univariate analysis and multivariate analysis to those without a particular characteristic in the entire NSCLC PD-(L)1 monotherapy cohorts. In total, 1453 patients were included: 56.5%-smokers, 30.4%-non-White, 22.8%-elderly, 20.8%-ECOG PS ≥ 2, 15.7%-history of AIDs, and 4.7%-history of CVI. The common ICIs were nivolumab (37.1%) and pembrolizumab (22.2%). Black patients, compared to White patients, experienced fewer irAEs (OR 0.54, p < 0.001). An ECOG PS of ≥2 (HR = 2.01, p < 0.001) and an increased number of previous LOTs were associated with poor OS (the median OS of 26.2 vs. 16.2 vs. 9.6 months for one vs. two vs. three prior LOTs, p < 0.001). The above results were confirmed in anti-PD-(L)1 monotherapy non-small cell lung cancer patients (n = 384). Overall, ICIs were safe and efficacious in these typically underrepresented patient cohorts. We noted ECOG PS ≥ 2 and an increased prior LOTs were associated with poor ICI efficacy, and Black patients, compared to White patients, experienced fewer irAEs.

The maternal/newborn dyad presents special challenges to infection management. Early in the COVID-19 pandemic, lack of information regarding SARS-CoV-2 transmission and virulence made it difficult to develop appropriate care guidance when pregnant persons had COVID-19 at the time of presentation for childbirth. We will review the considerations for the parturient, newborn, and care team, and describe the evolution of perinatal COVID management guidance., Competing Interests: Declaration of competing interest The authors report no conflicts of interest, including no competing financial interests, in relation to the work described. All information and materials in the manuscript are original. No honorarium or grant was given to anyone to produce the manuscript. This manuscript will not be submitted to any other journal while under consideration by Seminars of Perinatology. All authors have reviewed the manuscript and agreed to submission., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Many guidelines have been published to help diagnose food allergies, which have included feeding difficulties as a presenting symptom (particularly for non-IgE-mediated gastrointestinal allergies). This study aimed to investigate the prevalence of feeding difficulties in children with non-IgE-mediated gastrointestinal allergies and the association of such difficulties with symptoms and food elimination. An observational study was performed at Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK. Children aged 4 weeks to 16 years without non-allergic co-morbidities who improved on an elimination diet using a previously published Likert scale symptom score were included. This study recruited 131 children, and 114 (87%) parents completed the questionnaire on feeding difficulties. Feeding difficulties were present in 61 (53.5%) of the 114 children. The most common feeding difficulties were regular meal refusals (26.9%), extended mealtimes (26.7%), and problems with gagging on textured foods (26.5%). Most children (40/61) had ≥2 reported feeding difficulties, and eight had ≥4. Children with feeding difficulties had higher rates of constipation and vomiting: 60.7% (37/61) vs. 35.8% (19/53), p = 0.008 and 63.9% (39/61) vs. 41.5% (22/53), p = 0.017, respectively. Logistic regression analysis demonstrated an association between having feeding difficulties, the age of the child, and the initial symptom score. Gender and the number of foods excluded in the elimination diet were not significantly associated with feeding difficulties. This study found that feeding difficulties are common in children with non-IgE-mediated gastrointestinal allergies, but there is a paucity of food allergy specific tools for establishing feeding difficulties, which requires further research in the long-term and consensus in the short term amongst healthcare professions as to which tool is the best for food allergic children.

Abiotic stress results in various physiological and biochemical changes in plants. Osmolytes play a pivotal role in improving the tolerance to abiotic stress in plants. This study evaluated the effectiveness of a commercial formulation, Carrabiitol ® , an oligosaccharide polyol composition, in alleviating adverse impacts of abiotic stress in tomato ( Solanum lycopersicum L. var. Arka Rakshak ) plants. Plants were raised from seed and treated with 1 mL/L, 2 mL/L, and 3 mL/L of Carrabiitol ® . The foliage of developing plants was treated at the 2-3 leaf stage (T2, T3, and T4) and at pre-flowering stage (T5, T6, and T7). Growth conditions were compared with those of plants developed from untreated seed (T1). Developing tomato plants were then exposed to flooding, salinity (50 mM NaCl), high temperature (41.1 °C), or drought at the flowering stage. Plants were evaluated for their dry weight, leaf water potential, stomatal conductance, transpiration rate, antioxidant potential, chlorophyll, carotenoid, glucose, sucrose, malondialdehyde, and proline contents. Pre-treated seed, which received a booster treatment at the 2-3 leaf stage (T4 = seed treatment and booster at the 2-3 leaf stage with 3 mL/L Carrabiitol ® ) and pre-flowering stages (T5, T6, and T7 = seed treatment and booster doses at the pre-flowering stage with 1, 2, and 3 mL/L Carrabiitol ® , respectively), was effective in mitigating negative impacts on various growth parameters of stressed tomato plants ( p < 0.05). Carrabiitol ® may be an effective, sustainable, and bio-rational organic osmolyte formulation for reducing the effects of abiotic stress on plant growth and productivity.

Purpose: The number of patients with asymptomatic human immunodeficiency virus (AHIV) is increasing as the efficacy of antiretroviral therapy improves. While there is research on operative risks associated with having HIV, there is a lack of literature describing the impact of well-controlled HIV on postoperative complications. This study seeks to elucidate the impact of AHIV on postoperative outcomes after total hip (THA) and knee (TKA) arthroplasty., Methods: The Nationwide Inpatient Sample was retrospectively reviewed for patients undergoing TKA and THA from 2005 to 2013. Subjects were subdivided into those with AHIV and those without HIV (non-HIV). Patient demographics, hospital-related parameters, and postoperative complications were all collected. One-to-one propensity score-matching, Chi-square analysis, and multivariate logistical regressions were performed to compare both cohorts., Results: There were no significant differences between AHIV and non-HIV patients undergoing TKA or THA in terms of sex, age, insurance status, or total costs (all, p ≥ 0.081). AHIV patients had longer lengths of stay (4.0 days) than non-HIV patients after both TKA (3.3 days) and THA (3.1 days) (p ≤ 0.011). Both TKA groups had similar postoperative complication rates (p > 0.081). AHIV patients undergoing THA exhibited an increased rate of overall surgical complications compared non-HIV patients (0 vs. 4.5%, p = 0.043). AHIV was not associated with increased complications following both procedures., Conclusion: Despite lengthier hospital stays among AHIV patients, baseline AHIV was not associated with adverse outcomes following TKA and THA. This adds to the literature and warrants further research into the impact of asymptomatic, well-controlled HIV infection on postoperative outcomes following total joint arthroplasty., (© 2024. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Competing Interests: Robert J. Fontana conducts research funded by Kezar Pharmaceuticals and Takeda. The remaining authors have no conflicts to report.

Cancer research is dependent on accurate and relevant information of patient's medical journey. Data in radiology reports are of extreme value but lack consistent structure for direct use in analytics. At Memorial Sloan Kettering Cancer Center (MSKCC), the radiology reports are curated using gold-standard approach of using human annotators. However, the manual process of curating large volume of retrospective data slows the pace of cancer research. Manual curation process is sensitive to volume of reports, number of data elements and nature of reports and demand appropriate skillset. In this work, we explore state of the art methods in artificial intelligence (AI) and implement end-to-end pipeline for fast and accurate annotation of radiology reports. Language models (LM) are trained using curated data by approaching curation as multiclass or multilabel classification problem. The classification tasks are to predict multiple imaging scan sites, presence of cancer and cancer status from the reports. The trained natural language processing (NLP) model classifiers achieve high weighted F1 score and accuracy. We propose and demonstrate the use of these models to assist in the manual curation process which results in higher accuracy and F1 score with lesser time and cost, thus improving efforts of cancer research., Significance: Extraction of structured data in radiology for cancer research with manual process is laborious. Using AI for extraction of data elements is achieved using NLP models' assistance is faster and more accurate., (© 2024 The Authors; Published by the American Association for Cancer Research.)

The exception point system for liver allocation in the United States allows for additional waitlist priority for candidates where the Model for End-Stage Liver Disease or Pediatric End-stage Liver Disease does not effectively represent their urgency or need for a transplant. In May 2019, the review process for liver exception cases transitioned from 11 Regional Review Boards (RRBs) to 1 National Liver Review Board (NLRB), intended to increase consistency nationwide, improve efficiency, and balance transplant access for candidates with and without exception scores. This report provides a review of liver exception request and review practices, waitlist outcomes, and transplant activity in the first 2 years after implementation of the NLRB and acuity circle-based distribution in the United States. We compared initial and extension exception request forms submitted from May 13, 2017 to May 13, 2019 (prepolicy or RRB era) to the period from February 4, 2020 to February 3, 2022 (postpolicy or NLRB era). During this time, the NLRB reviewed 10,083 initial exception requests and 12,686 extension requests. Notable postpolicy highlights include (1) an increase in the proportion of initial and extension requests that were automatically approved instead of manually reviewed; (2) a decrease in the overall approval rates of initial exception requests (87.8% for adult HCC, 64.3% for adult other diagnoses, and 71.5% for pediatric); and (3) reduction in the time from exception request submission to adjudication to a median of 3.73 days. The proportions of waitlist registration and deceased donor liver transplants for patients with exception scores decreased, and waitlist outcomes between patients with and without exception scores are now comparable. Implementation of the NLRB improved efficiency, reduced case workloads, and standardized criteria for exception cases, with similar waitlist outcomes between patients with and without exception scores and improved equity in terms of access to liver transplants., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Introduction: Genetic ancestry (GA) refers to population hereditary patterns that contribute to phenotypic differences seen among race/ethnicity groups, and differences among GA groups may highlight unique biological determinants that add to our understanding of health care disparities., Methods: A retrospective review of patients with renal cell carcinoma (RCC) was performed and correlated GA with clinicopathologic, somatic, and germline molecular data. All patients underwent next-generation sequencing of normal and tumor DNA using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets, and contribution of African (AFR), East Asian (EAS), European (EUR), Native American, and South Asian (SAS) ancestry was inferred through supervised ADMIXTURE. Molecular data was compared across GA groups by Fisher exact test and Kruskal-Wallis test., Results: In 953 patients with RCC, the GA distribution was: EUR (78%), AFR (4.9%), EAS (2.5%), SAS (2%), Native American (0.2%), and Admixed (12.2%). GA distribution varied by tumor histology and international metastatic RCC database consortium disease risk status (intermediate-poor: EUR 58%, AFR 88%, EAS 74%, and SAS 73%). Pathogenic/likely pathogenic germline variants in cancer-predisposition genes varied (16% EUR, 23% AFR, 8% EAS, and 0% SAS), and most occurred in CHEK2 in EUR (3.1%) and FH in AFR (15.4%). In patients with clear cell RCC, somatic alteration incidence varied with significant enrichment in BAP1 alterations (EUR 17%, AFR 50%, SAS 29%; p = .01). Comparing AFR and EUR groups within The Cancer Genome Atlas, significant differences were identified in angiogenesis and inflammatory pathways., Conclusion: Differences in clinical and molecular data by GA highlight population-specific variations in patients with RCC. Exploration of both genetic and nongenetic variables remains critical to optimize efforts to overcome health-related disparities., (© 2023 American Cancer Society.)

Ponatinib, the only approved all known-BCR::ABL1 inhibitor, is a third-generation tyrosine-kinase inhibitor (TKI) designed to inhibit BCR::ABL1 with or without any single resistance mutation, including T315I, and induced robust and durable responses at 45 mg/day in patients with CP-CML resistant to second-generation TKIs in the PACE trial. However, cardiovascular toxicities, including arterial occlusive events (AOEs), have emerged as treatment-related AEs within this class of TKIs. The OPTIC trial evaluated the efficacy and safety of ponatinib using a novel, response-based, dose-reduction strategy in patients with CP-CML whose disease is resistant to ≥2 TKIs or who harbor T315I. To assess the dose-response relationship and the effect on the safety of ponatinib, we examined the outcomes of patients with CP-CML enrolled in PACE and OPTIC who received 45 mg/day of ponatinib. A propensity score analysis was used to evaluate AOEs across both trials. Survival rates and median time to achieve ≤1% BCR::ABL1 IS in OPTIC were similar or better than in PACE. The outcomes of patients with T315I mutations were robust in both trials. Patients in OPTIC had a lower exposure-adjusted incidence of AOEs compared with those in PACE. This analysis demonstrates that response-based dosing for ponatinib improves treatment tolerance and mitigates cardiovascular risk., (© 2024. The Author(s).)

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome resulting from a reciprocal translocation between chromosomes 9 and 22 [t9;22] that gives rise to a BCR::ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase in developed countries. Tyrosine kinase inhibitor (TKI) therapy is a highly effective treatment option for patients with chronic phase-CML. The primary goal of TKI therapy in patients with chronic phase-CML is to prevent disease progression to accelerated phase-CML or blast phase-CML. Discontinuation of TKI therapy with careful monitoring is feasible in selected patients. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase-CML.

Activating mutations within FLT3 make up 30 % of all newly diagnosed acute myeloid leukemia (AML) cases, with the most common mutation being an internal tandem duplication (FLT3-ITD) in the juxtamembrane region (25 %). Currently, two generations of FLT3 kinase inhibitors have been developed, with three inhibitors clinically approved. However, treatment of FLT3-ITD mutated AML is limited due to the emergence of secondary clinical resistance, caused by multiple mechanism including on-target FLT3 secondary mutations - FLT3-ITD/D835Y and FLT3-ITD/F691L being the most common, as well as the off-target activation of alternative pathways including the BCR-ABL pathway. Through the screening of imidazo[1,2-a]pyridine derivatives, N-(3-methoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine (compound 1) was identified as an inhibitor of both the FLT3-ITD and BCR-ABL pathways. Compound 1 potently inhibits clinically related leukemia cell lines driven by FLT3-ITD, FLT3-ITD/D835Y, FLT3-ITD/F691L, or BCR-ABL. Studies indicate that it mediates proapoptotic effects on cells by inhibiting FLT3 and BCR-ABL pathways, and other possible targets. Compound 1 is more potent against FLT3-ITD than BCR-ABL, and it may have other possible targets; however, compound 1 is first step for further optimization for the development of a balanced FLT3-ITD/BCR-ABL dual inhibitor for the treatment of relapsed FLT3-ITD mutated AML with multiple secondary clinical resistant subtypes such as FLT3-ITD/D835Y, FLT3-ITD/F691L, and cells co-expressing FLT3-ITD and BCR-ABL., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Glycerol monolaurate (GML), a monoglyceride found in human milk (HM), has antimicrobial properties against a broad spectrum of bacteria, viruses, and fungi. In this study, an LC-MS/MS method was developed and validated for quantifying GML in HM based on quantification of two distinct isomers, 1-monolaurin and 2-monolaurin. The method validation included assessments of selectivity (no interferences), linearity (r 2 range of 0.9954- 0.9985 and 96 of 98 individual points having residual <15%), accuracy (average recovery of 96.4% across both isomers and a range of spiked levels), and precision (total GML repeatability 6.6% RSD and intermediate precision 9.7% RSD). This validated method was used to measure the concentration of GML in unpasteurized HM from 60 mothers and compared geographical locations (Cincinnati and Shanghai), lactation time (weeks 2 and 26), and self-reported maternal allergy status (yes or no). Our findings suggest GML concentration in unpasteurized HM is considerably lower than previously reported in a study characterizing pasteurized HM. The data reported here highlights a novel, validated method used to quantify GML in HM and identified no differences in total GML concentrations when comparing HM from different geographical locations, lactation times, and mother's allergy status., Competing Interests: Declaration of Competing Interest TV, NAM, SDM, LB, RS, MAG, and SCP are all employees of Reckitt/Mead Johnson Nutrition, NS was previously employed by Reckitt/Mead John Nutrition and ALM received funding from Reckitt/Mead Johnson Nutrition for the GEHM study., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

FLT3 activating mutations are detected in approximately 30 % of newly diagnosed acute myeloid leukemia (AML) cases, most commonly consisting of internal tandem duplication (ITD) mutations in the juxtamembrane region. Recently, several FLT3 inhibitors have demonstrated clinical activity and three are currently approved - midostaurin, quizartinib, and gilteritinib. Midostaurin is a first-generation FLT3 inhibitor with minimal activity as monotherapy. Midostaurin lacks selectivity and is only approved by the USFDA for use in combination with other chemotherapy agents. The second-generation inhibitors quizartinib and gilteritinib display improved specificity and selectivity, and have been approved for use as monotherapy. However, their clinical efficacies are limited in part due to the emergence of drug-resistant FLT3 secondary mutations in the tyrosine kinase domain at positions D835 and F691. Therefore, in order to overcome drug resistance and further improve outcomes, new compounds targeting FLT3-ITD with secondary mutants are urgently needed. In this study, through the structural modification of a reported compound Ling-5e, we identified compound 24 as a FLT3 inhibitor that is equally potent against FLT3-ITD and the clinically relevant mutants FLT3-ITD/D835Y, and FLT3-ITD/F691L. Its inhibitory effects were demonstrated in both cell viability assays and western blots analyses. When tested against cell lines lacking activating mutations in FLT3, no non-specific cytotoxicity effect was observed. Interestingly, molecular docking results showed that compound 24 may adopt different binding conformations with FLT3-F691L compared to FLT3, which may explain its retained activity against FLT3-ITD/F691L. In summary, compound 24 has inhibition potency on FLT3 comparable to gilteritinib, but a more balanced inhibition on FLT3 secondary mutations, especially FLT3-ITD/F691L which is gilteritinib resistant. Compound 24 may serve as a promising lead for the drug development of either primary or relapsed AML with FLT3 secondary mutations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Masson SAS.)

Acupuncture is gaining popularity and wider acceptance as a treatment modality within the field of sports medicine. Our objective was to provide a comprehensive review of the existing literature pertaining to acupuncture in sports medicine to shed light on approaches utilized in acupuncture while revealing its personalized nature and its impact on athletes' preparation, performance, and recovery. We evaluated acupuncture research in the context of medicine and sports-related injury treatment, assessing its impact on athletic performance across demographics of athletes. Athletes participating in most sports have shown positive outcomes from acupuncture interventions. Acupuncture improves peak oxygen levels, maximum heart rate, delayed-onset muscle soreness, pain, swelling, explosive force production, and joint mobility. Furthermore, the efficacy of acupuncture appears to be similar regardless of age and sex. Lastly, the acceptance of acupuncture is influenced by cultural factors, with Western and traditional East Asian cultures exhibiting distinct perspectives on its rationale and mechanisms of action. Traditional East Asian acupuncturists typically employ qi and meridian theories in their acupuncture practices, with the recent incorporation of Western concepts. Acupuncture shows promise as an effective treatment for musculoskeletal pain and neuropathies in athletes across different age groups and for addressing injuries in various sports. Our comprehensive review will enhance our understanding of acupuncture's potential as a complementary or distinct therapeutic approach compared to conventional therapies. Additionally, our review explores its specific applications within different sports and delves into the cultural dimensions involved in integrating this practice into modern sports medicine.

Background: Cannabis is the most commonly used recreational drug in the USA. Studies evaluating cannabis use and its impact on outcomes following cervical spinal fusion (CF) are limited. This study sought to assess the impact of isolated (exclusive) cannabis use on postoperative outcomes following CF by analyzing outcomes like complications, readmissions, and revisions., Methods: The New York Statewide Planning and Research Cooperative System (SPARCS) was queried for patients who underwent CF between January 2009 and September 2013. Inclusion criteria were age ≥18 years and either a minimum 90-day (for complications and readmissions) or 2-year (for revisions) follow-up surveillance. Patients with systemic disease, osteomyelitis, cancer, trauma, and concomitant substance or polysubstance abuse/dependence were excluded. Patients with a preoperative International Classification of Diseases, 9th Edition, Clinical Modification (ICD-9-CM) diagnosis of isolated cannabis abuse (Cannabis) or dependence were identified. The primary outcome measures were 90-day complications, 90-day readmissions, and two-year revisions following CF. Cannabis patients were 1:1 propensity score-matched by age, gender, race, Deyo score, surgical approach, and tobacco use to non-cannabis users and compared for outcomes. Multivariate binary stepwise logistic regression models identified independent predictors of outcomes., Results: 432 patients (n=216 each) with comparable age, sex, Deyo scores, tobacco use, and distribution of anterior or posterior surgical approaches were identified (all p>0.05). Cannabis patients were predominantly Black (27.8% vs. 12.0%), primarily utilized Medicaid (29.6% vs. 12.5%), and had longer LOS (3.0 vs. 1.9 days), all p≤0.001. Both cohorts experienced comparable rates of 90-day medical and surgical, as well as overall complications (5.6% vs. 3.7%) and two-year revisions (4.2% vs. 2.8%, p=0.430), but isolated cannabis patients had higher 90-day readmission rates (11.6% vs. 6.0%, p=0.042). Isolated cannabis use independently predicted 90-day readmission (Odds Ratio=2.0), but did not predict any 90-day complications or two year revisions (all p>0.05)., Conclusion: Isolated baseline cannabis dependence/abuse was associated with increased risk of 90-day readmission following CF. Further investigation of the physiologic impact of cannabis on musculoskeletal patients may elucidate significant contributory factors. Level of Evidence: III ., Competing Interests: Disclosures: No conflicts of interest impacted this study in any aspect or manner. The following authors have no conflicts of interest to report: NVS, CRM, JDL, BK, GAB, CBP, BGD. PGP has received grant funding from CSRS, speaker and consultant honoraria from Globus Medical, Medicrea, SpineWave, and Zimmer, and other financial support from Allosource. RL has stock in Nemaris. HJK has received grant funding from ISSGF, speaker and consultant honoraria from Alphatec, royalties from K2M and Zimmer, and serves on boards or committees for AAOS, AO SPINE, CSRS, HSS, Asian Spine, and SRS. FJS has received grant funding from DePuy, NuVasive, Allosource, K2M, Medtronic, and Si Bone, speaker and consultant honoraria from Globus Medical, Mainstay Medical, Medtronic, and ZimmerBiomet, royalties from Medicrea, Medtronic, and Zimmer and serves on boards or committees for SRS, Spine Deformity, and ISSG. VL has received grant funding from DePuy, NuVasive, Allosource, K2M, Medtronic, and Si-Bone, speaker and consultant honoraria from Globus Medical, DePuy, and Stryker, stock in VFT Solutions, and serves on boards or committees for ISSG and SRS., (Copyright © The Iowa Orthopaedic Journal 2023.)

Importance: Patients with chronic myeloid leukemia (CML) who have a sustained deep molecular response using tyrosine kinase inhibitors (TKIs) can safely attempt to stop their use. As these medications are very costly, this change in treatment protocols may result in large savings., Objective: To estimate future savings from attempting to stop TKI use among patients with CML who have deep molecular response., Design, Setting, and Participants: A microsimulation model was developed for this decision analytical modeling study to estimate costs for US adults moving from using a TKI, to attempting discontinuation and then reinitiating TKI therapy, if clinically appropriate. Estimates were calculated for US patients who currently have CML and simulated newly diagnosed cohorts of patients over the next 30 years., Exposure: Attempting to stop using a TKI., Main Outcomes and Measures: Estimated savings after attempted discontinuation of TKI use., Results: A simulated population of individuals with CML in 2018 and future populations were created using estimates from the SEER*Explorer website. The median age at diagnosis was 66 years for men and 65 years for women. Between 2022 and 2052, the savings associated with eligible patients attempting discontinuation of TKI therapy was estimated at more than $30 billion among those currently diagnosed and over $15 billion among those who will develop CML in the future, for a total savings of over $54 billion by 2052 for drug treatment and polymerase chain reaction testing. The estimate is conservative as it does not account for complications and other health care-associated costs for patients continuing TKI therapy., Conclusions and Relevance: The findings of this decision analytical modeling study of patients with CML suggest that attempting discontinuation of TKI therapy could save over $54 billion during the next 30 years. Further education for patients and physicians is needed to safely increase the number of patients who can successfully attain treatment-free remission.

Background: Patient-reported outcomes (PRO) measures relevant to domains most important to patients with HCC who received locoregional therapies are needed to advance patient-centered research. Furthermore, electronic PRO monitoring in clinical care has been shown to reduce hospitalizations and deaths in patients with other cancers. We conducted a qualitative study among patients with HCC who recently received locoregional therapies to (1) identify common and distressing posttreatment symptoms to prioritize PRO domain selection and (2) gauge interest in an electronic PRO symptom monitoring system., Methods: We performed semi-structured telephone interviews among adult patients who received locoregional therapies (median of 26 days after treatment) for treatment-naïve HCC at a single tertiary care center. Interviews were conducted until thematic saturation was reached. Qualitative content analysis was conducted to identify emerging themes and sub-themes., Results: Ten of 26 patients (38%) reported at least 1 symptom before treatment. In contrast, all participants (n = 26) with recently treated HCC reported at least 1 posttreatment physical symptom, with the most common being appetite loss (73%), fatigue (58%), abdominal pain (46%), and nausea (35%). Most participants (77%) stated they saw potential benefits in posttreatment ePRO symptom monitoring., Conclusions: Posttreatment symptoms after HCC locoregional therapies are common and often severe. These data can inform and prioritize PRO domain selection. Patients are interested in ePRO monitoring to monitor and proactively address posttreatment symptoms. Given the clinical benefits in patients with metastatic cancers, ePRO monitoring warrants investigation in patients with HCC., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background : Immune-related cutaneous adverse events (ircAEs) are frequent and may reduce quality of life and consistent dosing. IL12/23 has been implicated in psoriasis, which is reminiscent of the psoriasiform/lichenoid ircAE phenotype. We report the use of ustekinumab as a therapeutic option. Methods : Patients at Memorial Sloan Kettering Cancer Center, New York, who received immune checkpoint inhibitors and were treated with ustekinumab or had the keywords "ustekinumab" or "Stelara" in their clinical notes between 1 March 2017 and 1 December 2022 were retrospectively identified via a database query. Documentation from initial and follow-up visits was manually reviewed, and response to ustekinumab was categorized into complete cutaneous response (CcR, decrease to CTCAE grade 0), partial cutaneous response (PcR, any decrease in CTCAE grade exclusive of decrease to grade 0), and no cutaneous response (NcR, no change in CTCAE grade or worsening). Labs including complete blood count (CBC), cytokine panels, and IgE were obtained in a subset of patients as standard of care. Skin biopsies were reviewed by a dermatopathologist. Results : Fourteen patients with psoriasiform (85.7%), maculopapular (7.1%), and pyoderma gangrenosum (7.1%) ircAEs were identified. Ten (71.4%) receiving ustekinumab had a positive response to treatment. Among these 10 responders, 4 (40%) demonstrated partial cutaneous response and 6 (60%) demonstrated complete cutaneous resolution. Six patients (42.9%) experienced interruptions to their checkpoint inhibitor treatment as a result of intolerable ircAEs, and following ircAE management with ustekinumab, two (33.3%) were successfully rechallenged with their checkpoint inhibitors. On histopathology, patients primarily had findings of interface or psoriasiform dermatitis. No patients reported an adverse event related to ustekinumab. Conclusions : Ustekinumab showed a benefit in a subset of patients with psoriasiform/lichenoid ircAEs. No safety signals were identified. However, further prospective randomized controlled trials are needed to confirm our findings.

Background: Immune-Oncology (IO) therapies have changed first-line (1L) treatment paradigm for metastatic renal cell carcinoma (mRCC) in last few years with robust clinical trial data. We examined clinical outcomes among clear cell mRCC (mccRCC) patients who received pembrolizumab + axitinib (pembro-axi) or ipilimumab + nivolumab (ipi-nivo) in the US community oncology setting., Methods: This retrospective cohort study utilized data from electronic health records and chart review within The US Oncology Network to identify adult patients with mccRCC initiating 1L pembro-axi or ipi-nivo from January 01, 2019 to December 31, 2020 and followed through March 31, 2021. Physician-recorded response (real-world overall response rate [rwORR] and real-world disease control rate [rwDCR]) was assessed descriptively. Real-world progression-free survival (rwPFS), real-world time to next treatment (rwTTNT) and time on treatment (rwToT) were estimated using Kaplan-Meier analysis. Association of 1L systemic treatment with time-to-event outcomes was examined using multivariable cox proportional hazards models., Results: Study included 331 mccRCC patients (pembro-axi:44%, ipi-nivo:56%). Median age was 65 years, 75.5% were male, and 82.5% had intermediate/poor (I/P) IMDC risk score. RwORR and rwDCR were 71.0% and 80.0% for pembro-axi and 45.2% and 58.6% for ipi-nivo. In multivariable analysis, pembro-axi was associated with longer rwToT (aHR, 0.53 [95% CI, 0.40, 0.71]), rwTTNT (aHR, 0.60 [95% CI, 0.42, 0.87]), and rwPFS (aHR, 0.70 [95% CI, 0.49, 0.99]) compared to ipi-nivo (P < 0.01)., Conclusions: Our study provides insight into newer mccRCC treatment tolerability and effectiveness in the real-world US community setting. Our real-world results were comparable to data from clinical trials, which is encouraging for mccRCC patients., Competing Interests: Declaration of Competing Interest Neil J. Shah has a consulting/advisory role from Merck & Co., Inc., Rahway, NJ, USA and research funding from Aravive. Sneha Sura and Junxin She are employee of Ontada. Reshma Shinde, Puneet Singhal and Rodolfo Perini are employees of Merck & Co., Inc., Rahway, NJ, USA and own stock in Merck & Co., Inc., Rahway, NJ, USA. Robert J. Motzer has a consulting/advisory role from Novartis, Eisai, Exelixis, Merck, Genentech/Roche, Incyte, Lilly, Pfizer, AstraZeneca, EMD Serono, and Calithera Biosciences and travel, accommodations, and expenses from Bristol-Myers Squibb, and research funding from Pfizer, Bristol-Myers Squibb, Eisai, Novartis, Genentech/Roche, Exelixis and Merck., (Copyright © 2023 Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Mechanical thrombectomy for the treatment of deep vein thrombosis (DVT) is being increasingly utilized to reduce symptoms and prevent postthrombotic syndrome (PTS), but more data on clinical outcomes are needed. Mechanical thrombectomy was studied in the ClotTriever Outcomes (CLOUT) registry with 6-month full analysis outcomes reported herein., Materials and Methods: The CLOUT registry is a prospective, all-comer study that enrolled 500 lower extremity DVT patients across 43 US sites treated with mechanical thrombectomy using the ClotTriever System. Core-lab assessed Marder scores and physician-assessed venous patency by duplex ultrasound, PTS assessment using Villalta score, venous symptom severity, pain, and quality of life scores through 6 months were analyzed. Adverse events were identified and independently adjudicated., Results: All-cause mortality at 30 days was 0.9%, and 8.6% of subjects experienced a serious adverse event (SAE) within the first 30 days, 1 of which (0.2%) was device related. SAE rethrombosis/residual thrombus incidence was 4.8% at 30 days and 8.0% at 6 months. Between baseline and 6 months, venous flow increased from 27.2% to 92.5% of limbs (P < 0.0001), and venous compressibility improved from 28.0% to 91.8% (P < 0.0001), while median Villalta scores improved from 9.0 at baseline to 1.0 at 6 months (P < 0.0001). Significant improvements in venous symptom severity, pain, and quality of life were also demonstrated. Outcomes from iliofemoral and isolated femoral-popliteal segments showed similar improvements., Conclusion: Outcomes from the CLOUT study, a large prospective registry for DVT, indicate that mechanical thrombectomy is safe and demonstrates significant improvement in symptoms and health status through 6 months. Level of Evidence 3: Non-randomized controlled cohort/follow-up study., (© 2023. The Author(s).)

Purpose: While bone health is instrumental in orthopedic surgery, few studies have described the long-term outcomes of osteoporosis (OP) in patients undergoing total hip (THA) or knee (TKA) arthroplasties., Methods: Using the New York State statewide planning and research cooperative system database, all patients who underwent primary TKA or THA for osteoarthritis from 2009 to 2011 with minimum 2-year follow-up were identified. They were divided based on their OP status (OP and non-OP) and 1:1 propensity score matched for age, sex, race, and Charlson/Deyo index. Cohorts were compared for demographics, hospital-related parameters, and 2-year postoperative complications and reoperations. Multivariate binary logistic regression was utilized to identify significant independent associations with 2-year medical and surgical complications and revisions., Results: A total of 11,288 TKA and 8248 THA patients were identified. OP and non-OP TKA patients incurred comparable overall hospital charges for their surgical visit and hospital length of stay (LOS) (both, p ≥ 0.125). Though OP and non-OP THA patients incurred similar mean hospital charges for their surgical visit, they experienced longer hospital LOS (4.3 vs. 4.1 days, p = 0.035). For both TKA and THA, OP patients had higher rates of overall and individual medical and surgical complications (all, p < 0.05). OP was independently associated with the 2-year occurrence of any overall, surgical, and medical complications, and any revision in TKA and THA patients (all, OR ≥ 1.42, p < 0.001)., Conclusion: Our study found OP was associated with a greater risk of 2-year adverse outcomes following TKA or THA, including medical, surgical, and overall complications as well as revision operations compared to non-OP patients., (© 2023. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Competing Interests: The authors have no conflicts to report.