Citations

Introduction: Telemedicine has been widely utilized in the healthcare marketplace since the beginning of the COVID-19 pandemic. Over the last 3 years, virtual care has been widely employed in the care of patients with polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF) at Mayo Clinic. These rare disorders have few experts; therefore, telemedicine becomes an optimal approach for patients receive expert care even when they are not close to the medical center. 1 Additionally, telemedicine reduces financial burden for the patients. We aim to estimate potential cost savings to patients utilizing telemedicine. Methods: We identified patients with MPN seen at Mayo Clinic, Arizona who have had at least 2 visits (1 or more virtual visits) between March 2020 and June 2022. We extracted retrospective data from electronic medical records (EMR) including sociodemographic data, disease related data and number of visits - both virtual and in person - of the patients identified. The address recorded from the EMR was assumed to be the patient's location at the time of virtual visit. Driving distances were determined using zip codes in Google Maps and the patients were stratified into quartiles based on round trip travel distances. Patients in quartiles 1 through 3 were assumed to have driven while patients in quartile 4 were assumed to have traveled by plane. Patients in quartile 1 were assumed to have 1 travel day including the follow-up visit and no accommodation, patients in quartile 2 were assumed to have 2 travel days including the follow up visit and 1 night of accommodation whereas patients in quartiles 3 and 4 were assumed to have 2 travel days, 1 day for the follow up visit and 2 nights of accommodation. Mileage rate costs were based on US Internal Revenue Service (IRS) standard mileage rates for medical or moving purposes for 2021. 2 Owing to extreme variability in flight costs, flying costs were assumed to be equal to the driving costs. Per diem costs for accommodation and meals and incidentals were based on the US General Services Administration (GSA) 2021 rates for Phoenix 3 with the cost being 75% of the full per diem rate on traveling days via GSA formulaic approach. Results: One hundred and eight patients having 282 virtual visits were identified. Patients ranged from 30 - 87 years with the mean and median age of 65 years and 67 years respectively. Majority of the patients were female (62%) and white (98%) with gender distribution varying by distance. Descriptive statistics of the estimated out-of-pocket costs for patients by distance quartiles are summarized in Table 1a. Mean estimated cost savings ranged from $46.8 to $877.3 with the savings of $43.8 - $1372.2 at extremes. The total cost savings by all patients was $90,306.7. The breakdown of costs by category for each quartile is shown in Table 1b which shows that the majority of costs saved by patients in quartile 1 were due to avoiding costs spent on meals and incidentals (~90% of mean costs) whereas costs saved due to meals and incidentals for patients in quartile 4 were only ~16% of the mean costs. Conclusions: Our research highlighted telemedicine as a cost-effective approach for patients with MPN who received virtual care from March 2020 - June 2022. Study limitations included not weighing costs for childcare or accompanying individuals and using driving costs instead of flying costs, however, these considerations potentially underestimate the actual cost savings to the patient. Additionally, since the median age of this population was 65, we didn't include loss of wages to the analysis, which may further underestimate the costs. Despite concerns over billing, reimbursement, and state licensure, virtual care is being established as a critical part of medicine moving forward. 1. Doolittle, G.C. and A.O. Spaulding, Providing Access to Oncology Care for Rural Patients via Telemedicine. Journal of Oncology Practice, 2006. 2(5): p. 228-230. 2. Internal Revenue Service. Standard mileage rates for 2021. Available at: https://www.irs.gov/tax-professionals/standard-mileage-rates 3. US General Services Administration. Per diem rates. Available at: https://www.gsa.gov/travel/plan-book/per-diem-rates/per-diem-rates-results?action=perdiems_report&fiscal_year=2021&state=AZ&city=&zip=85054

Introduction: Intussusception is a common finding among children. Conversely, it is infrequent in adults. Colonic lipomas are generally clinically silent making them a very rare etiology of intussusception. Presentation of case: The authors present a case of a 48-year-old male who presented to the emergency department suffering from severe abdominal pain. Following examination and investigations, a giant lipoma (GL) in the transverse colon was identified via ultrasound which showed the classical “target sign”. Clinical discussion: Intussusception among adults is unusual as it accounts for only 1% of bowel obstruction cases. Being colo-colonic makes it even more unlikely since it occurs only in 17% of intestinal obstruction cases. GLs exceeding 5 cm in size can present with a variety of symptoms. Intussusception is an uncommon presentation of a GL. Preoperative diagnosis of GL-induced intussusception is highly improbable and surgical resection is the treatment of choice. Conclusion: Despite the dominance of the asymptomatic presentation of lipomas, considering its diagnosis in the case of an intussusception-induced acute abdomen should cross physicians’ minds.

Abstract Brain metabolism perturbation can contribute to traits and diseases. We conducted the first large-scale CSF and brain genome-wide association studies, which identified 219 independent associations (59.8% novel) for 144 CSF metabolites and 36 independent associations (55.6% novel) for 34 brain metabolites. Most of the novel signals (97.7% and 70.0% in CSF and brain) were tissue specific. We also integrated MWAS-FUSION approaches with Mendelian Randomization and colocalization to identify causal metabolites for 27 brain and human wellness phenotypes and identified eight metabolites to be causal for eight traits (11 relationships). Low mannose level was causal to bipolar disorder and as dietary supplement it may provide therapeutic benefits. Low galactosylglycerol level was found causal to Parkinson’s Disease (PD). Our study expanded the knowledge of MQTL in central nervous system, provided insights into human wellness, and successfully demonstrates the utility of combined statistical approaches to inform interventions.

Background: Ganglion cysts are benign soft-tissue tumors that are most commonly found in the wrist. Within the wrist, 60% to 70% of ganglion cysts occur on the dorsal side and 20% to 30% occur on the volar side 1 . Although ganglia arise from multiple sites over the dorsal wrist, dorsal ganglia most commonly originate at the scapholunate joint 2,3 . Open excision is the standard surgical treatment for dorsal wrist ganglia. This procedure is considered when symptoms such as pain and range-of-motion deficits begin to impact activities of daily living. Description: Open excision of a dorsal wrist ganglion is commonly performed with the patient under general anesthesia or a regional block. The patient is placed in the supine position, and a tourniquet is applied on the affected upper limb. After outlining the periphery of the palpable ganglion, the surgeon makes a transverse or longitudinal incision over the ganglion. The surgeon then begins a deep dissection, dissecting through the subcutaneous tissue and isolating the ganglion while avoiding any rupture, if possible. Once the cyst has been identified, extensor tendons surrounding the cyst are retracted and the cyst and stalk are mobilized. The cyst and stalk are subsequently excised, and the wound is closed 4 . Alternatives: Alternative treatments for dorsal wrist ganglia include nonoperative interventions such as observation, aspiration, controlled rupture, and injection. Operative treatments include arthroscopic and open dorsal wrist ganglion resections. Rationale: Although nonoperative treatment can produce successful outcomes, the various modalities have been associated with recurrence rates ranging from 15% to 90% 4 . As a result, surgical excision remains the gold standard of treatment and is typically indicated when weakness, pain, and limited range of motion interfere with activities of daily living. Among surgical interventions, arthroscopic excision is a minimally invasive procedure that has become more common because of the reduced scarring and faster recovery 5 . However, open excision, which does not involve complex equipment, is regarded as the standard among surgical treatments. Although the rates of recurrence for arthroscopic versus open dorsal ganglion excision are similar, arthroscopic excision is less effective with regard to pain relief 5,6 . This difference in pain relief could potentially be the result of the neurectomy of the posterior interosseous nerve in an open excision. In contrast, an arthroscopic procedure may provide less relief of pain from the posterior interosseous nerve stump attaching to the scarred capsule 5 . Expected Outcomes: Open excision of a dorsal wrist ganglion is a safe, reliable procedure. The recurrence rate after open excision is similar to that after arthroscopic excision and significantly lower recurrence than that after ganglion cyst aspiration 6,7 . Additionally, not all ganglion cysts can be aspirated. In a retrospective study assessing the risk of recurrence after open excision of ganglion cysts in 628 patients, researchers reported a recurrence rate of 4.1% among the 341 who underwent open dorsal ganglion excision. Furthermore, the authors reported male sex and less surgeon experience as significant risk factors for cyst recurrence 8 . In a study assessing outcomes of open dorsal ganglion excision in 125 active-duty military personnel, researchers reported a recurrence rate of 9%. More notably, the researchers found persistent pain at 4 weeks postoperatively in 14% of the participants. The authors recommended that patients whose daily activities require forceful wrist extension, such as athletes and military personnel, should be counseled on the potential functional limitations and residual pain from open dorsal wrist ganglion excision 9 . Important Tips: When conducting an open excision, it is beneficial to identify the stalk of the cyst, allowing the surgeon to excise the complete ganglion complex and prevent recurrence. For large cysts that adhere to the surrounding soft tissue, it is helpful to rupture the ganglion in order to facilitate an easier deep dissection. Excising the scapholunate interosseous ligament could possibly lead to scapholunate dissociation and instability. The posterior interosseous nerve courses past the 4th dorsal compartment and may be resected during the deep dissection.

Background: An open Achilles tendon repair is performed in patients who have suffered an acute rupture. All patients with this injury should be counseled on their treatment options, which include open operative repair and functional rehabilitation. We prefer the use of an open repair in high-level athletes and those who have delayed presentation. Typically, this injury—and the resulting open repair—are seen in young or middle-aged patients as well as athletes. Operative repair of a ruptured Achilles tendon is associated with a much faster return to activity/sport when compared with nonoperative alternatives. This surgical procedure is especially useful in allowing this patient population to return to their previous activity level and functional capacity as quickly as possible. Description: Open repair of a ruptured Achilles tendon begins with a 6 to 8-cm incision over the posteromedial aspect of the lower leg. Superficial and deep dissections are performed until the 2 ends of the ruptured tendon are identified. Adhesions are debrided to adequately mobilize and define the proximal and distal segments of the tendon. With use of a fiber tape suture, a modified locking Bunnell stitch is utilized to secure both ends. The fiber tape is tied securely, and the repair is reinforced with Vicryl suture (Ethicon). Once the tendon is repaired, the paratenon layer is identified and repaired with a running 0 or 2-0 Vicryl suture. This is an important step to minimize postoperative wound complications. The wound is then closed, and the extremity is splinted in maximum plantar flexion. Alternatives: Alternative treatments include minimally invasive surgical techniques such as percutaneous Achilles tendon repair and nonoperative treatment with functional rehabilitation, which can provide excellent outcomes but can also lead to a slight decrease in explosiveness as the patient returns to sport 1,2 . Rationale: Nonoperative and operative treatment of Achilles tendon rupture can both result in excellent patient outcomes. Appropriate patient selection is critical. Younger patients hoping to return to more highly competitive athletics should consider operative repair 3 . Possible differences have been identified in peak torque when comparing operative versus nonoperative treatment, with patients who had undergone operative repair having greater peak torque (i.e., explosiveness) 2 . Otherwise, findings are similar between treatment options as long as the patients meet the criteria for nonoperative treatment. Expected Outcomes: Overall, the scientific literature demonstrates that the functional outcomes following operative repair are good to excellent. In a study by Hsu et al. 4 , 88% of patients were able to return to their baseline level of activity by 5 months postoperatively, with a complication rate of 10.6% and no reruptures. In a recent meta-analysis by Meulenkamp et al. 5 , the authors found that operative repair of Achilles tendon rupture was associated with a reduced risk of rerupture compared with primary immobilization (i.e., conventional cast immobilization with delayed weight-bearing for at least 6 weeks only). However, open surgical repair, minimally invasive repair, and functional rehabilitation all had similar risk of rerupture 5 . In a review by Ochen et al. 6 that analyzed 29 studies with a total of 15,862 patients, operative repair was associated with a significantly lower risk of rerupture compared with nonoperative treatment (2.3% versus 3.9%, respectively). However, operative treatment was also associated with a significantly higher complication rate compared with nonoperative treatment (4.9% versus 1.6%, respectively) 6 . Finally, in a meta-analysis by Soroceanu et al. 7 , the authors found that if early range-of-motion protocols and functional rehabilitation were utilized, operative and nonoperative treatment resulted in similar outcomes and equivalent rates of rerupture. Important Tips: To prevent rerupture of an Achilles tendon, remind patients to engage in adequate stretching and warming prior to physical activity. Palpate and locate the tendon defect prior to making the first incision. Immobilize the ankle joint in a splint for 2 weeks postoperatively in maximum plantar flexion. Pitfalls include: ○ Poor suture management leading to tangling in the repair. ○ Undertensioning or overtensioning of the repair, which can be avoided by sterilely draping out both legs and checking resting tension intraoperatively. ○ Failure to close the paratenon, causing scarring of the skin or surrounding tissues, which can be avoided by making a relieving incision on the deep surface of the paratenon. ○ Leaving suture knots on the dorsal side of the repair that may aggravate the skin. Acronyms & Abbreviations: MRI = magnetic resonance imaging ESU = electrosurgical unit

Background: Open trigger finger release is an elective surgical procedure that serves as the gold standard treatment for trigger digits. The aim of this procedure is to release the A1 pulley in a setting in which the pulley is completely visible, ultimately allowing the flexor tendons that were previously impinged on to glide more easily through the tendon sheath. Although A1—or the first annular pulley—is the site of triggering in nearly all cases, alternative sites include A2, A3, and the palmar aponeurosis 1 . Description: Typically, the surgical procedure can be conducted in an outpatient setting and can vary in duration from a few minutes to half an hour. The surgical procedure involves the patient lying in the supine position with the operative hand positioned to the side. A small incision, ranging from 1 to 1.5 cm, is made on the volar side of the hand, just proximal to the A1 pulley in the skin crease in order to minimize scarring. Once the underlying neurovascular structures are exposed, the A1 pulley is released longitudinally at least to the level of the A2 pulley, followed by decompression of the flexor tendons that were previously impinged on. In order to confirm the release, the patient is asked to flex and extend the affected finger. The wound is irrigated and closed once the release is confirmed by both the patient and surgeon. Alternatives: Aside from an open release, trigger finger can be treated nonoperatively with use of splinting and corticosteroid injection. Alternative operative treatments include a percutaneous release, which involves the use of a needle to release the A1 pulley 2 . Trigger finger can initially be treated nonoperatively. If unsuccessful, surgical intervention is considered the ultimate remedy 2 . Rationale: Because of their efficacious nature, corticosteroid injections are indicated preoperatively, particularly in non-diabetic patients 3 . Splinting is often an appropriate treatment option in patients who wish to avoid a corticosteroid injection 1 . However, if nonoperative treatment modalities fail to resolve pain and symptoms, surgical intervention is indicated 2 . In comparison with a percutaneous trigger finger release, an open release provides enhanced exposure and may be safer with respect to avoiding iatrogenic neurovascular injury 2 . However, in a randomized controlled trial, Gilberts et al. found no difference in the rates of recurrence when comparing open versus percutaneous trigger finger release 4 . Expected Outcomes: With reported success rates ranging from 90% to 100%, the open release of the A1 pulley is considered a common procedure associated with minimal complications 2 . Complications of the procedure were assessed in a retrospective analysis of 43 patients who underwent 78 open trigger releases performed by 1 surgeon. In that study, the authors reported a minor complication rate of 28% and a major complication rate of 3% 5 . Specifically, the 2 major complications noted by the authors were a synovial fistula and a proximal interphalangeal joint arthrofibrosis. In a larger study that included 543 patients who underwent 795 open trigger releases, the authors reported a minor complication rate of 9.6% and major complication rate of 2.4% 6 . Furthermore, the most common complications involved persistent stiffness, swelling, or pain. In that analysis, the authors suggested that sedation, male gender, and general anesthesia may be associated with greater risk 6 . Important Tips: At the discretion of the surgeon, a longitudinal, transverse, or oblique incision is made directly on top of the tendon at the level of the metacarpophalangeal joint, which is the preferred incision site because it provides maximal accessibility to the A1 pulley. Local anesthesia is preferred because it allows the patient and surgeon to confirm the release immediately. If conducting an open trigger release on the thumb, the surgeon should identify and protect the radial digital nerve, which courses directly over the A1 pulley. Acronyms and Abbreviations: MCP = metacarpophalangeal

Zika virus (ZIKV) pandemic and its implication in congenital malformations and severe neurological disorders had created serious threats to global health. ZIKV is a mosquito-borne flavivirus which spread rapidly and infect a large number of people in a shorter time-span. Due to the lack of effective therapeutics, this had become paramount urgency to discover effective drug molecules to encounter the viral infection. Various anti-ZIKV drug discovery efforts during the past several years had been unsuccessful to develop an effective cure. The NS2B-NS3 protein was reported as an attractive therapeutic target for inhibiting viral proliferation, due to its central role in viral replication and maturation of non-structural viral proteins. Therefore, the current in silico drug exploration aimed to identify the novel inhibitors of Zika NS2B-NS3 protease by implementing an e-pharmacophore-based high-throughput virtual screening. A 3D e-pharmacophore model was generated based on the five-featured (ADPRR) pharmacophore hypothesis. Subsequently, the predicted model is further subjected to the high-throughput virtual screening to reveal top hit molecules from the various small molecule databases. Initial hits were examined in terms of binding free energies and ADME properties to identify the candidate hit exhibiting a favourable pharmacokinetic profile. Eventually, molecular dynamic (MD) simulations studies were conducted to evaluate the binding stability of the hit molecule inside the receptor cavity. The findings of the in silico analysis manifested affirmative evidence for three hit molecules with −64.28, −55.15 and −50.16 kcal/mol binding free energies, as potent inhibitors of Zika NS2B-NS3 protease. Hence, these molecules holds the promising potential to serve as a prospective candidates to design effective drugs against ZIKV and related viral infections.

Purpose To investigate the characteristics of shoulder and elbow fellowship directors (FDs). Methods FDs for shoulder and elbow fellowship programs in the United States were identified. Demographic, educational, and professional background data were collected from available curricula vitarum, institutional biographies, and the Scopus database. Data collected included age, sex, race/ethnicity, training locations, graduation years, advanced degrees, current institutional information, and personal research H‐index. Results Thirty current orthopaedic shoulder and elbow FDs were identified. The mean Scopus H‐index was 25.5. The mean age of FDs was 52.1 years. In total, 29 FDs (96.7%) were male and 1 (3.3%) was female. In addition, 25 of the 30 (83.3%) were White (83.3%), 4 were Asian, and 1 (3.3%) was Hispanic. Two (6.7%) had a military affiliation. Mean time from fellowship training graduation to FD appointment was 13.5 years. Mean number of years as FD was 6.1 years, whereas the number of years tenure with an FD‐affiliated institution was 13.0 years. Mean calendar years for completion of orthopaedic residency training and fellowship training were 1998 and 2000, respectively. The residencies that produced the most future FDs were Hospital of the University of Pennsylvania (n = 2) and University of Nebraska Medical Center/Creighton University Health Foundation (n = 2). The fellowship that produced the most future FDs was Columbia University (n = 6). Moderate correlation was found between age and Scopus H‐index (r = 0.48; P = .04) and years as FD and Scopus H‐index (r = 0.42; P = .03). Conclusions Women and minorities are under‐represented in leadership positions in shoulder and elbow surgery. Shoulder and elbow FDs have the highest H‐index of any subspecialty reported in the orthopaedic literature. Research productivity is an important qualification when considering the characteristics of shoulder and elbow FDs. Clinical Relevance Fellowship directors can have a profound influence on current and future orthopaedic surgeons. It is important to identify the traits that characterize current fellowship directors to have a better understanding of who we choose as leaders in our field.

OBJECTIVES: We designed this study to test whether clazakizumab, a direct interleukin-6 inhibitor, benefits patients hospitalized with severe or critical COVID-19 disease accompanied by hyperinflammation. DESIGN: Multicenter, randomized, double-blinded, placebo-controlled, seamless phase II/III trial. SETTING: Five U.S. medical centers. PATIENTS: Adults inpatients with severe COVID-19 disease and hyperinflammation. INTERVENTIONS: Eighty-one patients enrolled in phase II, randomized 1:1:1 to low-dose (12.5 mg) or high-dose (25 mg) clazakizumab or placebo. Ninety-seven patients enrolled in phase III, randomized 1:1 to high-dose clazakizumab or placebo. MEASUREMENTS AND MAIN RESULTS: The primary outcome was 28-day ventilator-free survival. Secondary outcomes included overall survival, frequency and duration of intubation, and frequency and duration of ICU admission. Per Data Safety and Monitoring Board recommendations, additional secondary outcomes describing clinical status and status changes, as measured by an ordinal scale, were added. Bayesian cumulative proportional odds, logistic, and Poisson regression models were used. The low-dose arm was dropped when the phase II study suggested superiority of the high-dose arm. We report on 152 patients, 74 randomized to placebo and 78 to high-dose clazakizumab. Patients receiving clazakizumab had greater odds of 28-day ventilator-free survival (odds ratio [OR] = 3.84; p [OR > 1] 99.9%), as well as overall survival at 28 and 60 days (OR = 1.75; p [OR > 1] 86.5% and OR = 2.53; p [OR > 1] 97.7%). Clazakizumab was associated with lower odds of intubation (OR = 0.2; p [OR] < 1; 99.9%) and ICU admission (OR = 0.26; p [OR < 1] 99.6%); shorter durations of ventilation and ICU stay (risk ratio [RR] < 0.75; p [RR < 1] > 99% for both); and greater odds of improved clinical status at 14, 28, and 60 days (OR = 2.32, p [OR > 1] 98.1%; OR = 3.36, p [OR > 1] 99.6%; and OR = 3.52, p [OR > 1] 99.8%, respectively). CONCLUSIONS: Clazakizumab significantly improved 28-day ventilator-free survival, 28- and 60-day overall survival, as well as clinical outcomes in hospitalized patients with COVID-19 and hyperinflammation.

136 Background: Intensification of initial treatment of in patients with metastatic castration-sensitive prostate cancer (mCSPC) with androgen pathway inhibition (API) in addition to docetaxel (DOC) and androgen deprivation therapy (ADT) has shown promise to improve clinical outcomes. Thus, we synthesize the data from modern clinical trials to estimate overall estimates of progression and survival outcomes. Methods: A systematic search of electronic databases (MEDLINE and EMBASE) was conducted to include phase III randomized controlled trials (RCTs) evaluating triplet therapy (API+DOC+ADT) against doublet therapy (DOC+ADT) in mCSPC. Outcomes of interest included overall survival (OS) and radiographic progression-free survival (rPFS). A DerSimonian-Laird random-effects meta-analysis was performed to pool precomputed hazard ratios (HRs) and confidence intervals (CIs) after logarithmic transformation using inverse-variance weighting approach. Cochran’s Q statistical test was used to assess statistically significant heterogeneity not explained by chance, while I2 statistical test was used to quantify the total observed variability, due to between-study heterogeneity. I2 values >50% indicated substantial heterogeneity. A summary of findings table was constructed to translate relative estimates to absolute risks. Results: A total of 1,531 patients in four RCTs with direct comparative data between triplet and doublet therapies, were included in this meta-analysis. PEACE-1 was the only RCT directly assessing this question (AAP+DOC+ADT). ENZA+DOC+ADT was evaluated as a subgroup in two RCTs (ENZAMET; ARCHES), APA+DOC+ADT was evaluated as a subgroup in one (TITAN). To be able to pool studies, the relative efficacy of control arm in ENZAMET (first generation bicalutamide + ADT) was considered equivalent to ADT based on prior literature. A total of 672 rPFS events were observed (34%; 261 events in triplet therapy, 54%; 411 events in doublet therapy). The difference was statistically significant (HR: 0.49; 95% CI: 0.42-0.58; I2: 0%). Similarly, 469 OS events were observed (28%; 217 events in triplet therapy, 33%; 252 events in doublet therapy). The difference was statistically significant (HR: 0.80; 95% CI: 0.67-0.96; I2: 0%). The summary of findings is outlined in the table. Conclusions: The results of this meta-analysis support an improvement in rPFS and OS in favor of triplet therapy over doublet therapy for mCRPC. However, comparative effectiveness of different triplet regimens may be different and needs further exploration.[Table: see text]