Citations

Background: Most people with coronavirus disease 2019 (COVID-19) experience resolution of symptoms within days to weeks following initial infection. In a subset of individuals, symptoms persist longer than 4 weeks, known as ‘Long COVID’. Many gastrointestinal (GI) symptoms persist as part of this syndrome; yet, an approach to treatment remains unclear. Prior studies have demonstrated the efficacy of complementary and alternative medicine (CAM) for the treatment of acute COVID-19 infections, but little data exist regarding the potential use of CAM in the treatment of Long COVID. Objectives: Identify CAM approaches useful in treating the GI symptoms of Long COVID. Design: A systematic review of studies reporting on the use of CAM for the treatment of GI symptoms of Long COVID was performed. Data Sources and Methods: Five electronic databases were searched from January 2019 to November 2022. Studies describing the use of CAM to treat GI symptoms of Long COVID were included and assessed by two independent reviewers. Studies not reporting on GI symptoms or using CAM were excluded. Studies chosen for final review underwent quality and bias assessment using predetermined criteria. The extracted data were synthesized utilizing a framework derived from the National Center of Complementary and Integrative Health categories. Results: The initial search yielded 396 articles. After applying the eligibility criteria, a total of four studies (three case reports and one case series) were included for final review. Two studies used nutritional supplements and two studies used traditional Chinese medicine. Reductions in nausea, loss of appetite, diarrhea, acid reflux, epigastric pain, and bloating were reported. Conclusion: This is the first systematic review to explore the role of CAM in treating GI manifestations of Long COVID. The review identified four studies, all reporting reductions in the GI symptoms of Long COVID. Despite the positive studies included in this review, the overall search yielded few results, all of which were non-experimental. As the post-infectious sequelae of COVID-19 become better recognized in the wake of the pandemic, higher-quality clinical studies are needed.

Abstract Extracellular vesicles (EVs) have emerged as critical mediators of intercellular communication and promising biomarkers and therapeutics in the central nervous system (CNS). Human brain‐derived EVs (BDEVs) provide a comprehensive snapshot of physiological changes in the brain's environment, however, the isolation of BDEVs and the comparison of different methods for this purpose have not been fully investigated. In this study, we compared the yield, morphology, subtypes and protein cargo composition of EVs isolated from the temporal cortex of aged human brains using three established separation methods: size‐exclusion chromatography (SEC), phosphatidylserine affinity capture (MagE) and sucrose gradient ultracentrifugation (SG‐UC). Our results showed that SG‐UC method provided the highest yield and collected larger EVs compared to SEC and MagE methods as assessed by transmission electron microscopy and nanoparticle tracking analysis (NTA). Quantitative tandem mass‐tag (TMT) mass spectrometry analysis of EV samples from three different isolation methods identified a total of 1158 proteins, with SG‐UC showing the best enrichment of common EV proteins with less contamination of non‐EV proteins. In addition, SG‐UC samples were enriched in proteins associated with ATP activity and CNS maintenance, and were abundant in neuronal and oligodendrocytic molecules. In contrast, MagE samples were more enriched in molecules related to lipoproteins, cell‐substrate junction and microglia, whereas SEC samples were highly enriched in molecules related to extracellular matrix, Alzheimer's disease and astrocytes. Finally, we validated the proteomic results by performing single‐particle analysis using the super‐resolution microscopy and flow cytometry. Overall, our findings demonstrate the differences in yield, size, enrichment of EV cargo molecules and single EV assay by different isolation methods, suggesting that the choice of isolation method will have significant impact on the downstream analysis and protein discovery.

AbstractPropulsion of contents in the gastrointestinal tract requires coordinated functions of the extrinsic nerves to the gut from the brain and spinal cord, as well as the neuromuscular apparatus within the gut. The latter includes excitatory and inhibitory neurons, pacemaker cells such as the interstitial cells of Cajal and fibroblast-like cells, and smooth muscle cells. Coordination between these extrinsic and enteric neurons results in propulsive functions which include peristaltic reflexes, migrating motor complexes in the small intestine which serve as the housekeeper propelling to the colon the residual content after digestion, and mass movements in the colon which lead to defecation.

Abstract Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by life-threatening infections and inflammatory conditions. Hematopoietic cell transplantation (HCT) is the definitive treatment for CGD, but questions remain regarding patient selection and impact of active disease on transplant outcomes. We performed a multi-institutional retrospective and prospective study of 391 patients with CGD treated either conventionally (non-HCT) enrolled from 2004 to 2018 or with HCT from 1996 to 2018. Median follow-up after HCT was 3.7 years with a 3-year overall survival of 82% and event-free survival of 69%. In a multivariate analysis, a Lansky/Karnofsky score <90 and use of HLA-mismatched donors negatively affected survival. Age, genotype, and oxidase status did not affect outcomes. Before HCT, patients had higher infection density, higher frequency of noninfectious lung and liver diseases, and more steroid use than conventionally treated patients; however, these issues did not adversely affect HCT survival. Presence of pre-HCT inflammatory conditions was associated with chronic graft-versus-host disease. Graft failure or receipt of a second HCT occurred in 17.6% of the patients and was associated with melphalan-based conditioning and/or early mixed chimerism. At 3 to 5 years after HCT, patients had improved growth and nutrition, resolved infections and inflammatory disease, and lower rates of antimicrobial prophylaxis or corticosteroid use compared with both their baseline and those of conventionally treated patients. HCT leads to durable resolution of CGD symptoms and lowers the burden of the disease. Patients with active infection or inflammation are candidates for transplants; HCT should be considered before the development of comorbidities that could affect performance status. This trial was registered at www.clinicaltrials.gov as #NCT02082353.

PURPOSE Increased awareness of the distinct tumor biology for adolescents and young adults (AYAs) with cancer has led to improvement in outcomes for this population. However, in cholangiocarcinoma (CCA), a paucity of data exist on the AYA population. To our knowledge, we present the largest study to date on AYA disease biology, treatment patterns, and survival outcomes in CCA. METHODS A multi-institutional cohort of patients with CCA diagnosed with intrahepatic cholangiocarcinoma (ICC) or extrahepatic cholangiocarcinoma (ECC) was used for analysis. Retrospective chart review was conducted on patients who were 50 years old and younger (young; n = 124) and older than 50 years (older; n = 723). RESULTS Among 1,039 patients screened, 847 patients met eligibility (72% ICC, 28% ECC). Young patients had a larger median tumor size at resection compared with older patients (4.2 v 3.6 cm; P = .048), more commonly had N1 disease (65% v 43%; P = .040), and were more likely to receive adjuvant therapy (odds ratio, 4.0; 95% CI, 1.64 to 9.74). Tumors of young patients were more likely to harbor an FGFR2 fusion, BRAF mutation, or ATM mutation ( P < .05 for each). Young patients were more likely to receive palliative systemic therapy (96% v 69%; P < .001), targeted therapy (23% v 8%; P < .001), and treatment on a clinical trial (31% v 19%; P = .004). Among patients who presented with advanced disease, young patients had a higher median overall survival compared with their older counterparts (17.7 v 13.5 months; 95% CI, 12.6 to 22.6 v 11.4 to 14.8; P = .049). CONCLUSION Young patients with CCA had more advanced disease at resection, more commonly received both adjuvant and palliative therapies, and demonstrated improved survival compared with older patients. Given the low clinical trial enrollment and poor outcomes among some AYA cancer populations, data to the contrary in CCA are highly encouraging.

Significance Statement Segmentation of multiple structures in cross-sectional imaging is time-consuming and impractical to perform manually, especially if the end goal is clinical implementation. In this study, we developed, validated, and demonstrated the capability of a deep learning algorithm to segment individual medullary pyramids in a rapid, accurate, and reproducible manner. The results demonstrate that cortex volume, medullary volume, number of pyramids, and mean pyramid volume is associated with patient clinical characteristics and microstructural findings and provide insights into the mechanisms that may lead to CKD. Background The kidney is a lobulated organ, but little is known regarding the clinical importance of the number and size of individual kidney lobes. Methods After applying a previously validated algorithm to segment the cortex and medulla, a deep-learning algorithm was developed and validated to segment and count individual medullary pyramids on contrast-enhanced computed tomography images of living kidney donors before donation. The association of cortex volume, medullary volume, number of pyramids, and mean pyramid volume with concurrent clinical characteristics (kidney function and CKD risk factors), kidney biopsy morphology (nephron number, glomerular volume, and nephrosclerosis), and short- and long-term GFR <60 or <45 ml/min per 1.73 m 2 was assessed. Results Among 2876 living kidney donors, 1132 had short-term follow-up at a median of 3.8 months and 638 had long-term follow-up at a median of 10.0 years. Larger cortex volume was associated with younger age, male sex, larger body size, higher GFR, albuminuria, more nephrons, larger glomeruli, less nephrosclerosis, and lower risk of low GFR at follow-up. Larger pyramids were associated with older age, female sex, larger body size, higher GFR, more nephrons, larger glomerular volume, more nephrosclerosis, and higher risk of low GFR at follow-up. More pyramids were associated with younger age, male sex, greater height, no hypertension, higher GFR, lower uric acid, more nephrons, less nephrosclerosis, and a lower risk of low GFR at follow-up. Conclusions Cortex volume and medullary pyramid volume and count reflect underlying variation in nephron number and nephron size as well as merging of pyramids because of age-related nephrosclerosis, with loss of detectable cortical columns separating pyramids.

Background: As the number of primary total hip arthroplasty procedures performed each year continues to rise, so too do the number of complications, including periprosthetic femoral fracture 1–9 . Vancouver B2 and B3 periprosthetic femoral fractures are difficult to treat because they require the surgeon to simultaneously manage a femoral fracture and gain new implant fixation. Fluted tapered stems have advanced the treatment of periprosthetic femoral fractures by providing immediate axial and rotational implant fixation distal to the fracture 10–18 . Modular fluted tapered stems provide the added practical advantage of allowing length and anteversion adjustment after implantation of the distal fixation portion of the stem. Description: In this technique, a modified extended trochanteric osteotomy incorporating the fracture is utilized to gain access to the loose femoral implant and femoral diaphyseal canal. The femoral diaphyseal canal is then sequentially reamed in 1-mm increments. A fluted tapered stem with the appropriate length, diameter, and axial and rotational stability is inserted into the canal. A proximal body is then chosen that establishes the appropriate leg length, femoral offset, and version. The final proximal body is engaged into the fluted tapered stem. Finally, the fracture is fixed around the implant with a combination of cables or wires. Alternatives: Historically, implants such as extensively porous coated stems were utilized to treat Vancouver B2 or B 3 periprosthetic femoral fractures. Unfortunately, these implants were associated with high rates of failure and revision 7,9 . Rationale: The introduction of a fluted tapered stem provided a more reliable implant that achieves immediate axial and rotational stability. In addition, utilizing a fluted tapered stem allowed for a more soft-tissue-preserving approach to these complex injuries, in turn allowing the fracture to be reduced around the implant proximally with cerclage cables and or wires. Modular fluted tapered stems provide the additional advantage of allowing the surgeon to modify leg length, offset, and femoral version, independently of the fluted tapered stem. As a result of these unique advantages, these stems were introduced several years ago for the treatment of Vancouver B 2 or B 3 periprosthetic femoral fractures. Expected Outcomes: Contemporary series have demonstrated that the use of a modular fluted tapered stem leads to improved implant survivorship and clinical outcomes with lower complication rates for Vancouver B2 and B 3 periprosthetic femoral fractures 1,10–12,14–19 . Important Tips: Template both the fluted tapered stem and proximal body preoperatively. The proximal body should be templated at the ideal hip center of rotation that appropriately restores leg lengths and offset. Template the fluted tapered stem so that it provides appropriate isthmic fit and bypasses the most distal extent of the fracture by at least 2 cortical diameters. Utilize a modified extended trochanteric osteotomy for your exposure in order to facilitate visualization of the fracture and to provide direct access to the femoral canal. Place a prophylactic cable prior to preparing the femur for the implant in order to help prevent iatrogenic fracture. Place a trial stem and obtain intraoperative anteroposterior and lateral radiographs in order to assess the position of the implants and the risk of anterior cortical perforation. When placing the final implants, be sure the fluted tapered stem has both axial and rotational stability. Reduce and fix the fracture after the final implants are placed and the hip is reduced. Acronyms and Abbreviations: AP = anteroposterior MFT = modular fluted tapered (stem) ETO = extended trochanteric osteotomy THA = total hip arthroplasty CT = computed tomography PJI = periprosthetic joint infection

Background: Removal of well-fixed femoral components during revision total hip arthroplasty (THA) can be difficult and time-consuming 1 , leading to numerous complications, such as femoral perforation, bone loss, and fracture. Extended trochanteric osteotomies (ETOs), which provide wide exposure and direct access to the femoral canal under controlled conditions, have become a popular method to circumvent these challenges. ETOs were popularized by Wagner (i.e., the anterior-based osteotomy), and later modified by Paprosky (i.e., the lateral-based osteotomy) 2 . Description: The decision to utilize the laterally based Paprosky ETO versus the anteriorly based Wagner ETO is primarily based on surgeon preference, the location and type of in situ implants, and the osseous anatomy. Typically, a laterally based ETO is most facile in conjunction with a posterior approach and an anteriorly based ETO is most commonly paired with a lateral or anterolateral approach. Attention must be paid to maintaining vascularity to the osteotomy fragment, including minimizing stripping of the vastus lateralis from the osteotomy fragment and maintaining abductor attachments to the osteotomy fragment. When utilizing a laterally based ETO, the posterior border of the vastus lateralis must be carefully elevated to provide exposure for performance of the osteotomy. When an anteriorly based osteotomy is performed, the surgeon may instead extend the abductor tenotomy proximally with use of a longitudinal split of the vastus lateralis distally, which helps to keep the anterior and posterior sleeves of soft tissue in continuity. In either approach, dissection of the vastus lateralis involves managing several large vascular perforators. We prefer performing careful blunt dissection to identify the perforators and prophylactically controlling them, with ligation of large vessels and electrocautery of smaller vessels. Vascular clips are also available in case difficult-to-control bleeding is encountered. In general, an oscillating saw (with preference for a thin blade) is utilized to complete the posterior longitudinal limb of the ETO, extending approximately 12 to 16 cm distally from the tip of the greater trochanter. Although a 12 to 16-cm zone is required to maintain maximum vascularity to the osteotomized fragment, the osteotomy length must ultimately be determined by (1) the length of the femoral component to be removed; (2) the presence of distal bone ingrowth, ongrowth, or cement; and (3) the presence of distal hardware or stemmed knee components. A smaller oscillating saw is then utilized to complete the transverse limb at the previously identified distal extent. A high-speed pencil-tip burr is utilized to complete the corners of the osteotomy in a rounded configuration, and a combination of saws and pencil-tip burrs is utilized to create partial proximal and distal anterior longitudinal limbs of the osteotomy to the extent allowed by the soft-tissue attachments. The anterior longitudinal limb may be further weakened in a controlled fashion with use of serial drill holes. The anterior longitudinal limb then undergoes controlled fracture by placement of 2 to 4 broad straight osteotomes in the posterior longitudinal limb. These osteotomes are carefully levered anteriorly in unison with a gentle, steady force. After the ETO is completed, intramedullary prostheses, hardware, and cement are removed; the acetabulum is addressed as needed; and a final femoral stem is implanted, if appropriate. After completion of the osteotomy, the osteotomized fragment must be retracted gently, with care taken to avoid a fracture and maintain vascularity. To this end, debridement of the endosteum of the osteotomized fragment, including any cement removal, should be avoided until the end of the procedure, when the osteotomy is ready to be closed. Our preferred method for closure is to place 1 prophylactic cable 1 cm distal to the osteotomy, 1 to 2 cables along the diaphyseal segment of the osteotomy, and 1 Luque wire above the less trochanter. A Luque wire is our specific choice for the location above the lesser trochanter because it sits in the effective joint space; however, the use of Luque wires distal to the lesser trochanter is also acceptable. A strut allograft or locking plate can be utilized to reinforce the osteotomy in rare cases or to bridge interprosthetic stress risers. Trochanteric implants are typically avoided because of the low rate of clinically relevant trochanteric migration with this closure technique and because of the high rate of symptomatic implants with trochanteric claws or plates. Alternatives: An alternative osteotomy of similar exposure is the transfemoral osteotomy. Additionally, a variety of non-extended trochanteric osteotomies, such as trochanteric slide osteotomies, offer more limited exposure. Rationale: Femoral surgical exposure for revision THA can be aided by performing transfemoral osteotomies, but these provide less precise control of the separate proximal femoral osteotomized segment(s), and healing and fixation can be less reliable. Less invasive osteotomies such as non-extended trochanteric osteotomies typically do not provide adequate exposure in challenging cases for which ETO is being considered. Expected Outcomes: ETOs have high union rates, and notable trochanteric migration is infrequent. The most common complications are fracture of the osteotomy fragment intraoperatively or postoperatively. Radiographic and clinical union is achieved in 98% of patients. The mean proximal trochanteric osteotomy fragment migration prior to union is 3 mm. ETO fragment migration of >1 cm occurs in just 7% of hips. Postoperative greater trochanter fractures occur in 9% of hips. The 10-year survivorship free of revision for aseptic femoral loosening, free of femoral or acetabular component removal or revision for any reason, and free of reoperation for any reason is 97%, 91%, and 82%, respectively 3 . Important Tips: Attention should be paid to patient anatomy, deformity, surgical approach, and implant type when choosing to perform a laterally based Paprosky or anteriorly based Wagner ETO. Appropriate length of the posterior longitudinal limb of the ETO is approximately 12 to 16 cm distally from the tip of the greater trochanter. Attention must be paid to maintaining vascularity to the osteotomy fragment, including minimizing stripping of the vastus lateralis from the osteotomy fragment and maintaining abductor attachments to the osteotomy fragment. A high-speed pencil-tip burr should be utilized to complete the corners of the osteotomy in a rounded configuration in order to avoid stress risers. The anterior longitudinal limb is completed by controlled fracture of the remaining intervening segment in order to maintain vastus lateralis attachments and vascular supply to the osteotomy fragment. The ETO is closed with use of cerclage cables and/or double-stranded Luque wires, typically utilizing a total of 3 to 4 in order to obtain secure fixation without compromising local biology. Acronyms and Abbreviations: MFT = modular fluted tapered