Citations

AbstractAsparagine‐linked glycosylation 1 protein is a β‐1,4‐mannosyltransferase, is encoded by the ALG1 gene, which catalyzes the first step of mannosylation in N‐glycosylation. Pathogenic variants in ALG1 cause a rare autosomal recessive disorder termed as ALG1‐CDG. We performed a quantitative proteomics and N‐glycoproteomics study in fibroblasts derived from patients with one homozygous and two compound heterozygous pathogenic variants in ALG1. Several proteins that exhibited significant upregulation included insulin‐like growth factor II and pleckstrin, whereas hyaluronan and proteoglycan link protein 1 was downregulated. These proteins are crucial for cell growth, survival and differentiation. Additionally, we observed a decrease in the expression of mitochondrial proteins and an increase in autophagy‐related proteins, suggesting mitochondrial and cellular stress. N‐glycoproteomics revealed the reduction in high‐mannose and complex/hybrid glycopeptides derived from numerous proteins in patients explaining that defect in ALG1 has broad effects on glycosylation. Further, we detected an increase in several short oligosaccharides, including chitobiose (HexNAc2) trisaccharides (Hex‐HexNAc2) and novel tetrasaccharides (NeuAc‐Hex‐HexNAc2) derived from essential proteins including LAMP1, CD44 and integrin. These changes in glycosylation were observed in all patients irrespective of their gene variants. Overall, our findings not only provide novel molecular insights into understanding ALG1‐CDG but also offer short oligosaccharide‐bearing peptides as potential biomarkers.

Abstract Elevated 1,25-dihydroxyvitamin D (1,25(OH)2D) is a rare cause of non–parathyroid hormone (PTH)–mediated hypercalcemia seen in granulomatous disease, malignancy (most often lymphoma), or genetic mutations. Therapeutic options are limited. We report the case of a 67-year-old White man with nonmalignant, nongranulomatous, 1,25(OH)2D-mediated hypercalcemia treated successfully with cinacalcet. At presentation, he had hypercalcemia, hypercalciuria with recurrent nephrolithiasis, low PTH, elevated 1,25(OH)2D, and normal 25-hydroxyvitamin D. The 1,25(OH)2D levels were inappropriate in the setting of hypercalcemia with low PTH. Evaluations for sarcoidosis, tuberculosis, and malignancy were negative. Genetic testing showed biallelic variants in the CYP24A1 gene. Cinacalcet was trialed and showed normalization of calcium levels. On cinacalcet, biochemical indices showed a slight increase in 1,25(OH)2D and 24-hour urine calcium and mild decrease in PTH. He briefly experienced symptomatic hypocalcemia that resolved after reducing cinacalcet dose. Due to limited symptomatic benefit, he opted to stop cinacalcet. Additional follow-up showed intermittently elevated serum calcium levels after stopping cinacalcet, most recently 10.3 mg/dL. Cinacalcet may be a therapeutic option in nonmalignant, 1,25(OH)2D-mediated hypercalcemia. Further study is necessary to confirm efficacy, understand risks and benefits, and elucidate mechanism(s) of action.

Objective To investigate the optimal number of induction chemotherapy cycles needed to achieve a pathological response in patients with clinically lymph node‐positive (cN+) bladder cancer (BCa) who received three or four cycles of induction chemotherapy followed by consolidative radical cystectomy (RC) with pelvic lymph node dissection. Patients and Methods We included 388 patients who received three or four cycles of cisplatin/gemcitabine or (dose‐dense) methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), followed by consolidative RC for cTanyN1–3M0 BCa. We compared pathological complete (pCR = ypT0N0) and objective response (pOR = yp ≤T1N0) between treatment groups. Predictors of pCR and/or pOR were assessed using uni‐ and multivariable logistic regression analysis. The secondary endpoints were overall (OS) and cancer‐specific survival (CSS). We evaluated the association between the number of induction chemotherapy cycles administered and survival outcomes on multivariable Cox regression. Results Overall, 101 and 287 patients received three or four cycles of induction chemotherapy, respectively. Of these, 72 (19%) and 128 (33%) achieved pCR and pOR response, respectively. The pCR (20%, 18%) and pOR (40%, 31%) rates did not differ significantly between patients receiving three or four cycles ( P > 0.05). The number of cycles was not associated with pCR or pOR on multivariable logistic regression analyses. The 2‐year OS estimates were 63% (95% confidence interval [CI] 0.53–0.74) and 63% (95% CI 0.58–0.7) for patients receiving three or four cycles, respectively. Receiving three vs four cycles was not associated with OS and CSS on uni‐ or multivariable Cox regression analyses. Conclusion Pathological response and survival outcomes did not differ between administering three or four induction chemotherapy cycles in patients with cN+ BCa. A fewer cycles (minimum three) may be oncologically sufficient in patients with cN+ BCa, while decreasing the wait for definitive local therapy in those patients who end up without a response to chemotherapy. This warrants further validation.

A liver-specific Alb-FlpO mouse line was generated. By coupling it with other existing CreERT or Cre lines, the dual recombinase approach can enable sequential gene modifications within the same cell or across various cell types in an organism for liver research through temporal and spatial gene manipulations.

Abstract Rheumatoid arthritis (RA) causes immunological and metabolic imbalances in tissue, exacerbating inflammation in affected joints. Changes in immunological and metabolic tissue homeostasis at different stages of RA are not well understood. Herein, the changes in the immunological and metabolic profiles in different stages in collagen induced arthritis (CIA), namely, early, intermediate, and late stage is examined. Moreover, the efficacy of the inverse‐vaccine, paKG(PFK15+bc2) microparticle, to restore tissue homeostasis at different stages is also investigated. Immunological analyses of inverse‐vaccine‐treated group revealed a significant decrease in the activation of pro‐inflammatory immune cells and remarkable increase in regulatory T‐cell populations in the intermediate and late stages compared to no treatment. Also, glycolysis in the spleen is normalized in the late stages of CIA in inverse‐vaccine‐treated mice, which is similar to no‐disease tissues. Metabolomics analyses revealed that metabolites UDP‐glucuronic acid and L‐Glutathione oxidized are significantly altered between treatment groups, and thus might provide new druggable targets for RA treatment. Flux metabolic modeling identified amino acid and carnitine pathways as the central pathways affected in arthritic tissue with CIA progression. Overall, this study shows that the inverse‐vaccines initiate early re‐establishment of homeostasis, which persists through the disease span.

AbstractIntroductionInvasive neuromodulation interventions such as deep brain stimulation (DBS) and vagal nerve stimulation (VNS) are important treatments for movement disorders and epilepsy, but literature focused on young patients treated with DBS and VNS is limited. This retrospective study aimed to examine naturalistic outcomes of VNS and DBS treatment of epilepsy and dystonia in children, adolescents, and young adults.MethodsWe retrospectively assessed patient demographic and outcome data that were obtained from electronic health records. Two researchers used the Clinical Global Impression scale to retrospectively rate the severity of neurologic and psychiatric symptoms before and after patients underwent surgery to implant DBS electrodes or a VNS device. Descriptive and inferential statistics were used to examine clinical effects.ResultsData from 73 patients were evaluated. Neurologic symptoms improved for patients treated with DBS and VNS (p < .001). Patients treated with DBS did not have a change in psychiatric symptoms, whereas psychiatric symptoms worsened for patients treated with VNS (p = .008). The frequency of postoperative complications did not differ between VNS and DBS groups.ConclusionYoung patients may have distinct vulnerabilities for increased psychiatric symptoms during treatment with invasive neuromodulation. Child and adolescent psychiatrists should consider a more proactive approach and greater engagement with DBS and VNS teams that treat younger patients.

Background: Managing patients with recurrent anterior shoulder instability and glenoid bony deficiency remains a challenge. Multiple graft options, including iliac crest, distal clavicle, coracoid, and distal tibia allograft have been used. There is a growing body of evidence that supports distal tibia allograft for glenoid restoration in patients with shoulder instability due to its ability to restore the articular surface as well as the glenoid depth and curvature. Indications: Surgical indications for anterior glenoid reconstruction with distal tibia allograft combined with open capsular shift include patients with recurrent shoulder instability and glenoid bone loss. Technique Description: A deltopectoral interval is utilized and the subscapularis is split in lines with its fibers. The subscapularis and capsule are split together in a horizontal fashion and tagged together. Any prior hardware is then removed utilizing appropriate removal sets, a burr, and a broken screw set if necessary. The anterior glenoid is then prepared and the defect is measured. Bone marrow aspirate is then harvested from the proximal humerus using a vortex needle. The distal tibia allograft is then cut to size and prepared utilizing pulsed lavage, pressurized sterile carbon dioxide, and the bone marrow aspirate. The allograft is then fixed with solid stainless steel 3.5-mm cortical screws with washers. The medial, glenoid based capsular repair it completed by placing 1.8-mm knotless FiberTak anchor at the bottom of the distal tibia allograft. A free needle is utilized to place a horizontal mattress stitch from the anchor to the inferior capsule, which is then loaded onto a shuttling suture, to repair it to the anterior inferior glenoid. A knotless anchor is then placed right off the chondral margin of the humeral head, and this is used to repair both the capsule and subscapularis in the correct position by passing through both inferior and superior leaflets. This is then loaded onto the knotless anchor and reduced, which shifts the subscapularis and capsule laterally. The remainder of the subscapularis split is then closed. Patients are then placed in a sling with an abduction pillow with no shoulder range of motion for 6 weeks. They can then progress their therapy with a goal of returning to sport at 6 months. Results: Several large systemic reviews have shown that return to sport rates after anterior glenoid reconstruction range between 80% and 90%, with returning to the same level of play in the 70% range. Discussion: Anterior glenoid reconstruction utilizing distal tibia allograft combined with an open capsular shift is a durable surgical option for patients presenting with shoulder instability and glenoid bone loss. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication.

Background. Pancreas transplant biopsy practices for the diagnosis of rejection or other pathologies are not well described. Methods. We conducted a survey of staff at US pancreas transplant programs (March 22, 2022, to August 22, 2022) to assess current program practices and perceptions about the utility and challenges in the performance and interpretation of pancreas allograft biopsies. Results. Respondents represented 65% (76/117) of active adult pancreas transplant programs, capturing 66% of recent pancreas transplant volume in the United States. Participants were most often nephrologists (52%), followed by surgeons (46%), and other staff (4%). Pancreas allograft biopsies were performed mostly by interventional radiologists (74%), followed by surgeons (11%), nephrologists (8%), and gastroenterologists (1%). Limitations in the radiologist’s or biopsy performer’s comfort level or expertise to safely perform a biopsy, or to obtain sufficient/adequate samples were the two most common challenges with pancreas transplant biopsies. Pancreas transplant biopsies were read by local pathologists at a majority (86%) of centers. Challenges reported with pancreas biopsy interpretation included poor reliability, lack of reporting of C4d staining, lack of reporting of rejection grading, and inconclusive interpretation of the biopsy. Staff at a third of responding programs (34%) stated that they rarely or never perform pancreas allograft biopsies and treat presumed rejection empirically. Conclusions. This national survey identified significant variation in clinical practices related to pancreas allograft biopsies and potential barriers to pancreas transplant utilization across the United States. Consideration of strategies to improve program experience with percutaneous pancreas biopsy and to support optimal management of pancreas allograft rejection informed by histology is warranted.

Abstract Aims To compare weight loss outcomes between patients starting semaglutide who had previously been on another anti‐obesity medication (AOM) compared to those who were AOM‐naïve. Materials and Methods We performed a retrospective study in patients with overweight or obesity taking semaglutide for weight loss for a duration of 3 to 12 months. Our primary endpoint was assessment of percentage of total body weight loss (TBWL) in patients who started semaglutide as their first AOM (AOM‐naïve) compared to those who started semaglutide and had previously taken another AOM (non‐AOM‐naïve). The secondary outcome was a comparison of the proportions of patients achieving ≥5%, ≥10%, ≥15% and ≥20% TBWL between the groups. Our endpoints were analysed using independent t ‐tests and ANOVA/ANCOVA for continuous variables and Pearson's test for categorical variables. Results This study included 305 patients. Outcomes of semaglutide treatment were superior in AOM‐naïve patients ( n = 231) compared to non‐AOM‐naïve patients ( n = 74) at 3 (6.3% vs. 3.8%), 6 (10.6% vs. 6.7%), 9 (14.0% vs. 9.1%) and 12 months (14.3% vs. 10.6%; p < 0.0001 at 3, 6 and 9 months, and p = 0.01 at 12 months). A greater proportion of patients in the AOM‐naïve group achieved a TBWL ≥ 15% (48% vs 21%; p = 0.02) and ≥20% (27% vs 4% p < 0.01) at 12 months. Conclusion The use of semaglutide in patients with previous intake of other AOMs was associated with inferior weight loss outcomes in comparison to patients who were AOM‐naïve.