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掌跖蕈样肉芽肿病

掌跖蕈样肉芽肿病

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测试京东医生

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230人

以下内容来源于：NEJM。

Chen Li, M.D.

Wen-Hui Wang, M.D.

Peking University Third Hospital

Beijing, China

wwh0608@ 126 . com

This article was published on November 30,

2024, at NEJM.org.

A 38-year-old man presented to the dermatology clinic with a 15-year history of a waxing and waning rash on his palms and soles, which had spread to his forearms over the past year. A skin biopsy that had been performed 5 years before presentation had shown nonspecific inflammation. The rash had not abated with treatments for possible palmoplantar pustulosis. Physical

examination was notable for diffuse erythema of the palms and proximal forearms with overlying scabs and scaling (Panel A). A nodule on the volar aspect of the right forearm was also detected on palpation (Panel A, arrow). The soles showed patchy erythema and desquamation (Panel B). Palpable axillary and inguinal lymphadenopathy was also present. Skin biopsies of the palms, soles, and forearm were performed. Histopathological analysis of a tissue sample stained with hematoxylin and eosin showed a dense lymphocytic infiltration of the superficial and middle dermis with atypical lymphocytes migrating among epidermal keratinocytes — a finding known as epidermotropism (Panel C). The lymphocytes also formed intraepidermal aggregates known as Pautrier’s microabscesses (Panel C, arrows). Immunophenotyping identified the atypical lymphocytes as being positive for CD4 and negative for CD8, with down-regulation of CD7. Clonal T-cell receptor (TCR) gene rearrangement was also identified in the biopsy specimens. No abnormal cells or clonal TCR gene rearrangements were detected in the peripheral blood. A diagnosis of mycosis fungoides of the palms and soles was made. Treatment with subcutaneous interferon and topical glucocorticoids was given. After 6 months of treatment, the rash and the nodule had abated.

DOI:10.1056/NEJMicm2401673

Copyright © 2024 Massachusetts Medical Society.

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文章神经元FAM171A2介导α-突触核蛋白纤维摄取并驱动帕金森病

以下内容来源于Science。 Editor’s summary One of the major causes of neurodegeneration in patients with Parkinson’s disease (PD) is the intracellular accumulation of α-synuclein in neurons. Wu et al. investigated the mechanisms mediating the uptake of α-synuclein in neurons using in vitro and in vivo models. The product of the recently identified PD-risk gene FAM171A2 was found to be the neuronal receptor for α-synuclein fibrils, mediating their internalization through endocytosis. In silico screening identified an approved drug, bemcentinib, that is able to inhibit α-synuclein internalization in vitro and in vivo by blocking its binding to FAM171A2. The results provide insights into PD pathogenesis and identify a potential therapeutic target. —Mattia Maroso. Abstract Neuronal accumulation and spread of pathological α-synuclein (α-syn) fibrils are key events in Parkinson's disease (PD) pathophysiology. However, the neuronal mechanisms underlying the uptake of α-syn fibrils remain unclear. In this work, we identified FAM171A2 as a PD risk gene that affects α-syn aggregation. Overexpressing FAM171A2 promotes α-syn fibril endocytosis and exacerbates the spread and neurotoxicity of α-syn pathology. Neuronal-specific knockdown of FAM171A2 expression shows protective effects. Mechanistically, the FAM171A2 extracellular domain 1 interacts with the α-syn C terminus through electrostatic forces, with >1000 times more selective for fibrils. Furthermore, we identified bemcentinib as an effective blocker of FAM171A2–α-syn fibril interaction with an in vitro binding assay, in cellular models, and in mice. Our findings identified FAM171A2 as a potential receptor for the neuronal uptake of α-syn fibrils and, thus, as a therapeutic target against PD.

测试京东医生

主任医师

京东互联网医院

文章诱导化疗后小范围放疗对比常规范围放疗治疗鼻咽癌：一项开放标签、非劣效性、多中心、随机3期临床试验

Abstract Background Nearly 90% locoregionally advanced nasopharyngeal carcinoma (LANPC) responds to induction chemotherapy (IC) with significant tumor volume shrinkage. Radiotherapy always follows IC, and reduced volume has been proposed. However, the efficacy and safety of reduced-volume radiotherapy is uncertain. Methods In this multi-center, noninferiority, randomized, controlled trial, patients with LANPC who completed IC were randomly assigned (1:1) to receive reduced-volume radiotherapy based on post-IC tumor volume (Post-IC group) or conventional volume radiotherapy based on pre-IC tumor volume (Pre-IC group). The primary endpoint was locoregional relapse-free survival, with a noninferiority margin of 8%. Secondary endpoints comprised adverse events, and quality of life (QoL). Results Between August 7, 2020, and May 27, 2022, 445 patients were randomly assigned to Post-IC (n = 225) or Pre-IC (n = 220) groups. The average volume receiving radical dose was 66.6 cm3 in Post-IC group versus 80.9 cm3. After a median follow-up of 40.4 months, the 3-year locoregional relapse-free survival was 91.5% in the Post-IC group versus 91.2%, with a difference of 0.3% (95% confidence interval −4.9% to 5.5%). The incidence of grade 3-4 radiation-related toxicity was lower in the Post-IC group including: acute mucositis (19.8% vs 34.1%), late otitis media (9.5% vs 20.9%) and late dry month (3.6% vs 9.5%). The Post-IC group had better QoL for global health status, physical functioning, emotional functioning, dry mouth and sticky saliva. Conclusions In this trial, reduced-volume radiotherapy was noninferior to conventional volume radiotherapy in locoregional relapse-free survival, and was associated with lower toxicities and improved QoL. (ClinicalTrials.gov identifier NCT04384627). INTRODUCTION Induction chemotherapy (IC) followed by concurrent chemoradiotherapy is the standard of care for locoregionally advanced nasopharyngeal carcinoma. Nearly 90% patients respond, with an average tumor volume shrinkage from 20.1% to 54.7%. For decades, full radical dose coverage, calculated based on the pre-IC tumor volume, has been recommended, regardless of the response to IC and concurrent chemoradiotherapy.This results in high-dose exposure to the surrounding functional structures, represented by the inner ear, parotid gland and temporal lobe, resulting in high proportions of hearing impairment (72%),dry mouth (57%),and temporal lobe injury (12%)and reducing patients' quality of life (QoL) far beyond the end of treatment. Reduced-volume radiotherapy with a full dose only to the residual tumors after the completion of IC may achieve comparable outcomes with less associated toxicities. Properly designed trials regarding the safety of reduced-volume radiotherapy and its benefit to QoL are needed. Therefore, we designed this multicenter, phase 3 trial to test the hypothesis that reduced-volume radiotherapy based on post-IC tumor volume (the post-IC group) would be noninferior to conventional-volume radiotherapy based on pre-IC tumor volume (the pre-IC group) in patients with locoregional, advanced nasopharyngeal carcinoma who receive IC. MATERIALS AND METHODS Trial design and participants This multicenter, noninferiority, open-label, phase 3, randomized controlled trial was conducted in three Chinese medical centers (see Supporting Information Supporting Methods, p 13). The key eligibility criteria comprised patients who had: newly diagnosed, histologically confirmed, nonkeratinizing nasopharyngeal carcinoma, stage III–IVA disease (according to the 8th edition American Joint Committee on Cancer/Union for International Cancer Control staging system); aged 18–70 years; a Karnofsky performance status score ≥70; and adequate hematologic function. Patients had to be treatment-naive, and all patients were required to have completed three cycles of IC with gemcitabine plus cisplatin before enrolment. The key exclusion criteria included: tumor progression after IC; previous receipt of chemotherapy, radiotherapy, or surgery (except diagnostic) to the nasopharynx or neck; a history of cancer; lactation or pregnancy; severe coexisting illness; or requiring palliative treatment. The trial protocol was approved by the institutional ethics committee at each participating center. All participants provided written informed consent. Patient consent could be withdrawn post-enrolment at any time for any reason. Comprehensive details of the trial are provided in the protocol (see Supporting Information : Supporting Materials). Randomization and masking Eligible patients were randomly assigned to receive reduced-volume radiotherapy (in the post-IC group) or conventional-volume radiotherapy (in the pre-IC group), at a 1:1 ratio in blocks of four and stratified by trial center and disease stage (III or IVA). Centralized randomization was performed at the Clinical Trials Center of Sun Yat-sen University Cancer Center (Guangzhou, China). Random assignment was generated by using a computerized, randomized list generator. Treatment group assignment was not masked to the patients or physician, although it was masked to the Central Imaging Review Committee (CIRC) and the statisticians. The block structure was known only to the statistician and the study coordinator, who were not involved clinically in the trial. Rigorous quality-control measures were implemented to ensure the scientific integrity of the trial (see Supporting Information Supporting Methods, p. 11–12). Procedures Intensity-modulated radiotherapy was required for all patients. The definition of radiotherapy target volumes was done according to the International Commission on Radiation Units and Measurements (ICRU) reports 50 and 62.The gross tumor volume (GTV) contained the primary tumor (GTVnx) and the involved cervical lymph nodes (GTVnd) that would receive the full prescribed radical dose of irradiation and was delineated according to the allocation group. In the post-IC group, the GTVnx was delineated based on post-IC magnetic resonance imaging (MRI), which included only the residual soft tissue mass of the nasopharynx for patients without initial bony structural invasion. However, in patients with initial bony structural invasion, the involved bony structures were delineated based on pre-IC imaging to ensure that all initial disease within the bone was encompassed regardless of signal changes after induction, although the soft tissue component of the GTVnx was still delineated based on postinduction MRI. The GTVnd was delineated based on post-IC imaging. In patients without bone invasion, if no tumor signal was detected after induction, as confirmed by the CIRC, the GTVnx would not be delineated for the post-IC group. The GTVnd would not be delineated for any lymph node with complete resolution on the post-IC MRI for the post-IC group. Instead, the high-risk clinical target volume (CTV) covered the originally involved fat space. In the pre-IC group, the GTV would be delineated based on pre-IC MRI and should include all structures that tumor involved before IC, even if they are no longer grossly involved. And pre-treatment 18F-fluorodeoxyglucose examination was also used for delineation when available. Detailed delineation methods, including skull base invasion, paranasal sinus invasion, parapharyngeal muscle invasion, etc., are shown in Figures The high-risk CTV was defined as the GTVnx plus a margin of 5–10 mm (2–3 mm posteriorly if adjacent to the brainstem or spinal cord) and the GTVnd plus a margin of 3–5 mm. In addition, in the post-IC group, the volume should encompass all tumor volume before IC. The low-risk CTV was defined as the high-risk CTV plus a margin of 5–10 mm (2–3 mm posteriorly if adjacent to the brainstem or spinal cord). The planning target volume was defined as the GTV or CTV plus a margin of 3–5 mm. The prescribed doses were 70 grays (Gy) to the primary tumor, 66–70 Gy to the cervical lymph nodes, 60–62 Gy to the high-risk CTV, and 54–56 Gy to the low-risk CTV in 30–33 fractions (once daily, five fractions every week). To ensure the quality of the trial, the research team at the Sun Yat-sen University Cancer Center reviewed all radiotherapy plans. During radiotherapy, two or three cycles of concurrent cisplatin were administered intravenously at a dose of 100 mg/m2 every 3 weeks. Details of the radiotherapy and chemotherapy are provided in Supporting Information: Supporting Methods (p. 3–8). In this trial, essential baseline evaluations were required within 2 weeks before IC (see Supporting Information Supporting Methods, p. 3). At day 7 after IC completion, and at week 16 after chemoradiotherapy, nasopharyngoscopy was used to assess the primary tumor. Acute toxicity was assessed using the National Cancer Institute’s Common Toxicity Criteria, version 4.0, and radiation-related late toxicities were assessed according to the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer (EORTC) late-radiation morbidity scoring scheme. The EORTC Quality-of-Life Core 30-item questionnaire (QLQ-C30), version 3.0, and the Quality-of-Life Head and Neck 35-item questionnaire (QLQ-H&N35), version 1.0, were used to evaluate QoL during follow-up. Patients were followed at 3-month intervals for the first 3 years and then at 6 month intervals until death (see Supporting Information : Supporting Methods, p. 8–9). The initial radiologic examination and Epstein–Barr virus DNA test were performed 3 months after the completion of treatment. Subsequently, these tests were conducted at least once every 6 months for the next 3 years and annually thereafter. Physical examinations were scheduled every 3 months during the first 3 years and every 6 months thereafter. Whenever possible, histology was used to confirm distant or locoregional relapses. In patients for whom histologic confirmation was medically contraindicated or technically infeasible, the CIRC confirmed relapses while blinded to treatment assignment by using at least two imaging methods. For those patients who were lost to follow-up, mortality information was obtained from their death certificates. Outcomes The primary end point was locoregional relapse-free survival, defined as the time from randomization to either documented local and/or regional relapse or death from any cause (except for metastasis), whichever occurred first. Secondary end points were overall survival, distant metastasis-free survival, failure-free survival, radiation-related toxicity profile, and QoL (see Supporting Information : Supporting Methods, p. 9–10). If a patient's first relapse event was a locoregional relapse, they were censored for distant metastasis analysis, and vice versa. If both distant and locoregional relapses occurred simultaneously, patients were designated as having events for both distant metastasis-free survival and locoregional relapse-free survival analyses. Patients were censored at the last follow-up visit if they remained alive without any treatment failure or if they were lost to follow-up. Statistical analysis This trial was designed to determine whether reduced-volume radiotherapy would be noninferior in terms of 3-year locoregional relapse-free survival compared with conventional-volume radiotherapy. In both groups, locoregional relapse-free survival at 3 years was assumed to be 92% on the basis of previous data. We set the noninferiority margin at 8% based on expert consensus, institutional experience, and published studies. Consequently, to demonstrate noninferiority, the lower boundary of the 95% confidence interval (CI) for the difference in 3-year locoregional relapse-free survival rate between the two groups must not exceed −8%. With 80% power and a 5% one-sided type I error, at least 435 patients were required to allow for a 5% loss to follow-up or dropout. Efficacy analyses were performed in the intention-to-treat population and were repeated in the per-protocol population. The safety analyses were done in the safety population. All patients who started the randomly assigned treatment were included in the per-protocol and safety populations. An independent data monitoring committee was assembled in this trial and reviewed the efficacy and safety data to determine whether the trial design should be modified every 6 months. No protocol-mandated interim analysis was done in our trial for noninferiority. The Kaplan–Meier method was used to calculate time-to-event outcomes with log-rank tests for comparisons between groups. The results were stratified according to disease stage and trial center. Patients were censored at the last follow-up visit if they remained alive without any treatment failure or were lost to follow-up. A z test was used to estimate the difference in the 3-year survival rate between the two groups. The hazard ratios (HRs) and 95% CIs were calculated with a stratified Cox proportional hazards model (using treatment as a single covariate), in which the assumptions of proportional hazards were confirmed using Schoenfeld residuals. A Cox proportional hazards model further evaluated treatment-by-covariate interaction based on the intention-to-treat population to ascertain whether the treatment effect was different among the prespecified patient subgroups; interactions with age, sex, tumor categories, lymph node categories, and disease stages. A Cox proportional hazard model was also used for multivariable analyses to identify significant independent factors. We summarized acute and late toxicities according to frequency and severity. Analyses of QoL were performed in patients who were without disease relapse or metastasis in the safety population. The Supporting Information : Supporting Methods (p. 10) detail the analytical methods used for patient-reported outcomes. Post-hoc analyses of locoregional relapse-free survival were conducted between patients with or without baseline plasma Epstein–Barr virus DNA testing and between those with or without baseline 18F-fluorodeoxyglucose PET/CT examination. In addition, a post-hoc analysis also was done to test the primary hypothesis in patients who had different baseline Epstein–Barr virus DNA levels (with a cutoff of 2000 copies/mL chosen based on our previous study ). SPSS (version 27.0; IBM Corporation) or R (version 4.3.0; R Foundation for Statistical Computing) software were used for all analyses. A one-sided statistical test was used for a noninferiority test of locoregional relapse-free survival, with p values < .05 indicating statistical significance. All other statistical tests were two-sided, with the same significant p value. The key raw data underlying this study were uploaded to the Research Data Deposit public platform (RDDA2025934346). This study is registered with ClinicalTrials.gov, NCT04384627. RESULTS Participants and treatment Between August 7, 2020, and May 27, 2022, we enrolled and randomly assigned 445 patients to the post-IC group (n = 225) or the pre-IC group (n = 220; Figure ). Baseline characteristics were well balanced between the groups (Table 1). Most patients (n = 354; 80%) were treated with a volumetric-modulated arc therapy technique. All patients underwent daily guided imaging with either cone-beam computed tomography (n = 319; 72%) or kilovoltage orthogonal imaging (n = 126; 28%). The proportions of those who underwent volumetric-modulated arc therapy and an image-guided modality did not differ between the study groups (see Table ).

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文章异种移植猪肾治疗终末期肾病

以下内容来源于：NEJM。 Summary Xenotransplantation offers a potential solution to the organ shortage crisis. A 62-year-old hemodialysis-dependent man with long-standing diabetes, advanced vasculopathy, and marked dialysis-access challenges received a gene-edited porcine kidney with 69 genomic edits, including deletion of three glycan antigens, inactivation of porcine endogenous retroviruses, and insertion of seven human transgenes. The xenograft functioned immediately. The patient’s creatinine levels decreased promptly and progressively, and dialysis was no longer needed. After a T-cell–mediated rejection episode on day 8, intensified immunosuppression reversed rejection. Despite sustained kidney function, the patient died from unexpected, sudden cardiac causes on day 52; autopsy revealed severe coronary artery disease and ventricular scarring without evident xenograft rejection. (Funded by Massachusetts General Hospital and eGenesis.) Kidney transplantation has become the ideal standard of care for end-stage kidney disease, but organ shortage remains critical. One promising approach to address this critical shortage is xenotransplantation of porcine organs. Advances in CRISPR–Cas9 gene editing have enabled porcine kidney xenografts to survive for more than 2 years in nonhuman primates. We treated a 62-year-old man with long-standing diabetes and advanced vasculopathy who had lost nearly all viable hemodialysis-access options. His chance of receiving a transplant within 5 years was only 16%, with a 76% likelihood of dying or becoming too ill to receive a transplant, according to the decision-aid calculator for kidney transplantation of the Scientific Registry of Transplant Recipients. With no living donor available, we pursued a gene-edited pig kidney transplant under a single-patient, expanded-access authorization. The patient’s candidacy underwent rigorous evaluation by an independent psychiatrist, the Optimum Care Ethics Committee at Massachusetts General Hospital, and external transplant experts. After iterative protocol review by the Food and Drug Administration and final approval by the institutional review board at Massachusetts General Hospital, we transplanted a gene-edited porcine kidney with deletion of three major glycan xenoantigens (3KO), inactivation of porcine endogenous retroviruses, and insertion of seven human transgenes. Methods Pig Kidney Xenograft A Yucatan miniature pig was engineered to carry 69 genomic edits, eliminating three major glycan antigens, overexpressing seven human transgenes (TNFAIP3, HMOX1, CD47, CD46, CD55, THBD, and EPCR), and inactivating porcine endogenous retroviruses (Fig. S1 in the , available with the full text of this article at NEJM.org). Recipient Evaluation The patient was a 62-year-old man with end-stage kidney disease caused by type 2 diabetes mellitus who had exhausted nearly all viable vascular access for dialysis. His history included myocardial infarction, severe vasculopathy, heart failure, total parathyroidectomy, and receipt of a deceased-donor kidney in 2018. After having graft failure in May 2023 associated with BK virus infection and recurrent diabetic nephropathy, he returned to receiving hemodialysis. Comprehensive evaluation by the multidisciplinary team at Massachusetts General Hospital, along with ethical assessments conducted by an independent psychiatrist and ethics committee, are detailed in the and in Table S1. Transplant Procedure and Immunosuppression Protocol The transplant procedures are detailed in the and the , available at NEJM.org. The immunosuppressive regimen was based on our preclinical studies in nonhuman primates and included antithymocyte globulin (rabbit), rituximab, Fc-modified anti-CD154 monoclonal antibody (tegoprubart), and anti-C5 antibody (ravulizumab) in combination with maintenance immunosuppression with tacrolimus, mycophenolic acid, and prednisone Figure 1 Immunosuppressive Regimen and Post-Transplantation Clinical Course. Disease Surveillance, Histopathological Review, and Transcript Analysis Extensive microbiologic testing of the donor swine herd and the specific porcine donor was conducted before transplantation. Post-transplantation monitoring for both human and porcine pathogens and pathological analyses of biopsy samples are detailed in Tables S2, S3, and S4. Results Early Postoperative Period The transplantation procedure was completed with a cold ischemic time of 4 hours 38 minutes. The xenograft produced urine within 5 minutes after implantation and more than 6 liters in the first 48 hours. Thereafter, urine output stabilized at 1.5 to 2 liters per day (Fig. S2). The patient’s plasma creatinine level dropped from 11.8 to 2.2 mg per deciliter by day 6 The patient recovered from the transplantation procedure. Aside from chills and fever after the first infusion of antithymocyte globulin, he did not have overt problems with the immunosuppressive regimen. Because the patient’s T cells were sufficiently depleted after the initial dose of antithymocyte globulin (Fig. S3), a second dose was not administered. Immunosuppression with anti-CD154 monoclonal antibody resulted in serum trough levels exceeding 1000 μg per milliliter on day 0, after which levels were consistently above 800 μg per milliliter. Tacrolimus trough levels were maintained below 4 ng per milliliter during the first week after transplantation , combined with a lowered dose of 360 mg of mycophenolic acid twice daily owing to concern about overimmunosuppression with lymphocyte depletion, intensive immunosuppression, and his history of BK virus nephropathy. Xenograft Rejection Episode On day 8, the patient’s plasma creatinine level increased from 2.2 (day 7) to 2.9 mg per deciliter, accompanied by fever, allograft tenderness, and decreased urine output. An infectious disease workup was negative. Empirical therapy with glucocorticoid pulse (500 mg of methylprednisolone) and monoclonal antibody against interleukin-6 receptor (tocilizumab at a dose of 8 mg per kilogram of body weight) was initiated for suspected antibody-mediated rejection. A pretreatment, same-day biopsy confirmed acute T-cell–mediated rejection, Banff grade 2A, without evidence of thrombotic microangiopathy or antibody-mediated rejection and Table S5; ; and Fig. S4A, S4B, and S4C). Two glucocorticoid pulses (500 mg each) and antithymocyte globulin (1.5 mg per kilogram) were administered on days 9 and 10, and the doses of tacrolimus and mycophenolic acid were increased. Given the C3 deposition in the biopsy sample (Fig. S5), we administered pegcetacoplan, a targeted C3 and C3b inhibitor. Since the biopsy sample showed no evidence of antibody-mediated rejection, no additional doses of tocilizumab were administered. After these interventions, the patient’s urine output increased, and the plasma creatinine level started to decline. The patient was discharged on day 18 with a plasma creatinine level of 2.5 mg per deciliter. Figure 2 Pathological Analyses of Biopsy Samples Obtained from the Kidney Xenograft. Table 1 Banff Scores on Xenograft Biopsy Samples. On day 34, another xenograft biopsy was performed because of an increase in the creatinine level (to 2.65 from 1.9 mg per deciliter), which showed resolution of the T-cell–mediated rejection but with C3 deposition, focal interstitial fibrosis, and tubular atrophy without evidence of antibody-mediated rejection or thrombotic microangiopathy ; Fig. S4D and S4F; and Fig. S5). The plasma creatinine level decreased to 1.57 mg per deciliter with hydration on day 36. Antiporcine antibody titers remained lower than values in human serum controls (Fig. S6). No new anti-HLA antibodies were detected, and levels of preexisting anti-HLA antibodies were reduced (Fig. S7). Kidney Function, Hemodynamics, and Fluid-Electrolyte Balance Although the plasma creatinine levels occasionally fluctuated with the patient’s volume status, baseline levels ranged from 1.5 to 2.0 mg per deciliter, with an estimated glomerular filtration rate (eGFR) of 40 to 50 ml per minute per 1.73 m2 of body-surface area . The measurement of 24-hour urine creatinine clearance on days 7 and 28 after transplantation was 37 and 59 ml per minute per 1.73 m2, respectively. The mean blood pressure was 131/70 mm Hg (Fig. S8), and a loop diuretic (furosemide) was used to maintain euvolemia. The electrolyte levels remained mostly within normal limits (Figs. S9 and S10). However, the plasma total calcium level was low (Fig. S11) in association with the patient’s previous parathyroidectomy with undetectable levels of parathyroid hormone, which was managed with vitamin D and calcium supplementation. Plasma phosphate levels were elevated throughout the clinical course, necessitating the addition of phosphate binders. There was no hematuria or albuminuria, with a urine albumin-to-creatinine ratio (with both measured in grams) in the range of 0 to 0.2. Although the patient’s hemoglobin levels remained stable, erythropoietin was initiated on day 15 after transplantation because of the low reticulocyte count with appropriate iron stores. Infectious Complications On day 25, a subcutaneous wound infection led to a partial surgical opening of the incision and initiation of antibiotics (linezolid and meropenem). A retroperitoneal fluid collection, positive for Pseudomonas aeruginosa, was drained through percutaneous drain placement. The surgical incision was successfully closed on day 37. After 2 weeks of negative cultures and resolution of the fluid collection confirmed by abdominal computed tomography, the drain was removed on day 51. Cardiac Complication The patient was also evaluated in the outpatient clinic on day 51 after transplantation. He reported low fluid intake, and the plasma creatinine level of 2.7 mg per deciliter was relatively elevated, despite tacrolimus trough levels within target range. He had no symptoms of congestive heart failure or worrisome findings on physical examination, and kidney ultrasonography showed no abnormalities. The overall presentation was similar to a previous episode of an elevated creatinine level on day 34, which had resolved with hydration. Intravenous magnesium (2 g) and a 500-ml bolus of normal saline were administered over a 30-minute period to address hypomagnesemia and presumed volume depletion. The patient’s blood pressure, heart rate, and respiratory rate were all normal. Later that evening, the patient had respiratory distress and rapidly became unresponsive. Despite resuscitative efforts, he died. Autopsy revealed an enlarged heart with severe, diffuse coronary artery disease, diffuse left ventricular fibrosis, and a remote posterior infarct with a subacute ischemic extension, all of which were considered to have been caused by diabetic and ischemic cardiomyopathy (Fig. S12). There was no evidence of acute myocardial infarction, pulmonary embolism, pneumonia, inflammation in other organs, or drug toxicity. We concluded that the patient had probable sudden cardiac death caused by dysrhythmia in the context of severe ischemic cardiomyopathy. The xenograft showed focal fibrosis (attributed to sequelae of the episode of T-cell–mediated rejection) and no histologic evidence of active T-cell– or antibody-mediated rejection or thrombotic microangiopathy ; and Fig. S4G, S4H, and S4I). No porcine pathogens were detected in cultures, on nucleic acid testing, or on metagenomic assays during the clinical course. Retrospective transcriptomic analyses of biopsy samples are shown and discussed in Figure S13 and Table S4. Discussion This report documents the transplantation of a 3KO kidney xenograft with seven human transgenes into a patient with end-stage kidney disease, which built on our preclinical studies. Tegoprubart, an Fc-modified anti-CD154 monoclonal antibody in phase 2 trials for kidney allotransplantation, was part of the immunosuppressive regimen. This agent has shown potent inhibition of antibody production,as well as suppression of innate immune responses by blocking CD11b, another receptor of CD154. The pattern and timing of rejection in this patient suggested that early subtherapeutic levels of tacrolimus and mycophenolic acid may have contributed to the development of T-cell–mediated rejection, which was successfully treated with standard antirejection therapy. On biopsy, there was no evidence of antibody-mediated rejection, a common complication observed in the preclinical and decedent models of kidney xenotransplantation. Thrombotic microangiopathy has been a frequent cause of xenograft loss in previous studies in nonhuman primates. This condition can arise from incompatibilities between porcine endothelial cells and the human complement system. Therefore, we included an anti-C5 monoclonal antibody, ravulizumab, in the patient’s regimen, and no thrombotic microangiopathy was observed in the xenograft. Upon encountering T-cell–mediated rejection with C3 deposition and inflammation on biopsy, we also added pegcetacoplan to inhibit the proximal complement pathway. Our intention was to cautiously taper the use of anticomplement agents while closely monitoring for the development of thrombotic microangiopathy through protocol biopsies, as the clinical necessity for these agents remains to be fully established. Comprehensive monitoring for zoonotic pathogens was performed with the use of targeted nucleic acid testing and metagenomic sequencing. No porcine-derived pathogens were detected throughout the clinical course. Certain physiological differences between porcine and human kidney function remain to be elucidated. In studies involving nonhuman primates, porcine renin did not efficiently cleave angiotensin I from angiotensinogen, resulting in a dysfunctional renin–angiotensin–aldosterone system (RAAS). Given the incompatibility of primate antidiuretic hormone in nonhuman primates that have received xenografts, dehydration accompanied by elevated creatinine levels often develops. In our patient, blood pressure was well maintained at an average of 131/70 mm Hg, with stable plasma sodium levels and the use of diuretics to maintain euvolemia. Although reversible kidney dysfunction was observed on day 34 and improved with hydration, additional studies are needed to clarify potential differences in the hemodynamic regulation of glomerular filtration by porcine kidneys transplanted to humans. Whether this diuretic requirement in our patient stemmed from the propensity for sodium reabsorption of the porcine kidney or the patient’s preexisting heart disease (cardiorenal syndrome) is unclear and warrants further investigation in future xenotransplant recipients. In contrast with the hypercalcemia and hypophosphatemia that are observed in nonhuman primate recipients, our patient had hypocalcemia and hyperphosphatemia, findings that potentially could be attributed to the patient’s previous parathyroidectomy. Finally, although the 155-g kidney xenograft obtained from a 75-kg pig donor was relatively small for the 100-kg patient, the average creatinine level was 1.85 mg per deciliter after recovery from the rejection episode — a level that was reasonable for kidney function, given the size difference. The patient died from unanticipated, sudden cardiac causes, despite a functioning kidney xenograft. An autopsy revealed severe coronary artery disease with diffuse ventricular scarring but no evidence of acute thrombi, and we surmise that the cause of death was probably due to ventricular dysrhythmia. With such severe ischemic heart disease, the risk of sudden death from dysrhythmia remains substantial in any patient, 14 especially after a major surgical procedure. However, we cannot exclude the possibility that frequent fluctuations in intravascular volume, possibly caused by a dysfunctional RAAS in the pig kidney, may have increased the risk of cardiac dysrhythmia in a patient with severe ischemic heart disease. Despite the short observation period, this case demonstrated that a genetically modified kidney xenograft with human transgenes provided life-supporting kidney function in a living human patient. This outcome supports the feasibility of using genetically modified pig kidney xenografts to expand transplant access for patients with end-stage kidney disease. Although the identification of suitable candidates for kidney xenotransplantation is complex and debated, a small, pilot clinical trial for well-informed dialysis patients who face a high risk of dying while awaiting a human transplant may be a logical next step. Despite stable kidney function, our study patient who had undergone kidney xenotransplantation died from apparent sudden cardiac causes on day 52. The autopsy revealed severe coronary artery disease and ventricular scarring but no evidence of xenograft rejection.

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文章房颤导管消融术对脑类淋巴系统功能及认知功能的影响

以下内容来源于：Eur Heart J。 Abstract Background and Aims It remains unknown whether the brain glymphatic system, which is driven by the heartbeat-driven pulsation of arteries and is responsible for cerebral waste clearance, is impaired in atrial fibrillation (AF) and mediates cognitive dysfunction related to AF. The aim of this study was to assess brain glymphatic alterations in AF, their role in cognitive function, and whether catheter ablation can improve glymphatic activity. Methods In this case-control and prospective before–and–after study, patients with AF and healthy controls (HCs) were enrolled. Participants underwent brain magnetic resonance imaging and a comprehensive neuropsychological battery. Glymphatic activity was quantified by diffusion tensor image analysis along the perivascular space (DTI-ALPS) index. Magnetic resonance imaging was repeated after surgery in patients who underwent ablation. Results Overall, 87 patients with AF and 44 HCs were enrolled. Compared with HCs, patients with AF had a lower ALPS index (P = .016). Nonparoxysmal AF patients showed lower ALPS index than both HCs (P = .002) and paroxysmal AF patients (P = .044). A lower ALPS index was associated with worse scores of Trail Making Test, Digit Symbol Substitution Test, Digit Span Test, and Stroop Colour and Word Test (all P < .05). Mediation analyses revealed that glymphatic activity was a mediator between AF and cognitive decline. Among the 50 patients who underwent ablation therapy, DTI-ALPS index was improved after surgery (P = .015). Conclusions Brain glymphatic function measured by DTI-ALPS index was impaired in patients with AF, mediates the association between AF and cognitive decline, and was improved after ablation therapy. Structured Graphical Abstract The brain glymphatic activity is impaired in patients with atrial fibrillation (AF), correlates with cognitive function, and mediates the relationship between AF and cognitive decline. Glymphatic activity was improved after catheter ablation in patients with AF. HCs, health controls; PAF, paroxysmal AF; nPAF, nonparoxysmal AF; DTI-ALPS, diffusion tensor image analysis along the perivascular space.

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文章《手术开始》专题直播栏目互动问答

各位老师好，《手术开始》直播栏目互动问答整理如下，我们将定期更新，供您查阅。温馨提示：每个QA已标明期数，当期内容请在栏目专区《往期回顾》查看。【第1期】 Q1：手术机器人在手术配合上有精确的计算程序吗? A1：不用将手术机器人看得过高。机器人的确是个很好的工具，看得更清楚、机械臂也更灵活，手术医生轻松一点但最好不要对机器人产生依赖。 Q2：手术窗口期的判断很难，如何判断? A2：基于医生经验，需术前检查、肛门指诊、盆腔磁共振，必要时膀胱镜，甚至诊断性电切。主要怕侵犯直肠、膀胱输尿管，影响切除或并发症比较严重。我自己一般肿瘤不侵犯双侧输尿管，指诊没有明显黏连，就可考虑手术。 Q3：术后序贯治疗吗？ A3：术后一般还是要辅助内分泌治疗1~2年。 Q4：请问专家，术后这个导尿管留置多少天比较合适？ A4：术后一般保留导尿两周，我一般喜欢用f18的3腔导尿管，术后务必保持导尿通畅，如果观察严密，有条件，一般保留导尿一周就很安全。 Q5：术后常规膀胱冲洗吗？ A5：术后一般不需要膀胱冲洗，必须要保证导尿通畅，如果有堵塞，可以临时冲一下。如果有出血，要加用止血药，如果有必要可以持续冲洗。一般尿色清畅的话，导尿就比较安全。 Q6：5/8线缝合有无优势？ A6：使用什么针我觉得看术者的方便和熟练程度，针不要太大，不要太粗，不要太细，一般3-0可吸收线就可以了。针的弧度不重要。【第2-3期】 Q1：术后需要服用抗凝药物吗?抗凝多长时间? A1：高凝状态像肿瘤患者、凝血因子异常、血栓史、重度肥胖、行走闲难者等及年龄超过75岁老人，这些都需要预防性抗凝。 Q2：术后需要绷带加压吗？加压多长时间？ A2：偏心弹力绷带包扎3天，术后第四天起拆除绷带穿二级弹力袜2-4周，根据病情而定 Q3：硬化剂不是已经注射了吗？刚在侧枝循环的位置打的，现在是追加硬化剂吗？ A3：血管鞘内注射硬化剂。未能覆盖的侧支再另打。 Q4：远端需要离断吗？ A4：不需要。 Q5：老师是否有出版的静脉曲张手术书籍和配套视频？ A5：可以查看我的发表文献和视频号。 Q6：术后会出现后遗症吗？ A6：淤青、水肿等症状较常见。血栓、神经损伤等罕见。

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文章利用ExGRS预测不同祖源人群的高度近视

以下内容来源于： Commun Med 。 Abstract Background: High myopia (HM), characterized by a severe myopic refractive error, stands as a leading cause of visual impairment and blindness globally. HM is a multifactorial ocular disease that presents high genetic heterogeneity. Employing a genetic risk score (GRS) is useful for capturing genetic susceptibility to HM. Methods: This study assesses the effectiveness of these strategies via incorporating rare variations into the GRS assessment. This study enrolled two independent cohorts: 12,600 unrelated individuals of Han Chinese ancestry from Myopia Associated Genetics and Intervention Consortium (MAGIC) and 8682 individuals of European ancestry from UK Biobank (UKB). Results: Here, we first estimate the heritability of HM resulting in 0.53 (standard error, 0.06) in the MAGIC cohort and 0.21 (standard error, 0.10) in the UKB cohort by using whole-exome sequencing (WES) data. We generate, optimize, and validate an exome-wide genetic risk score (ExGRS) for HM prediction by combining rare risk genotypes with common variant GRS (cvGRS). ExGRS improved the AUC from 0.819 (cvGRS) to 0.856 for 1219 Han Chinese individuals of an independent testing dataset. Individuals with a top 5% ExGRS confer a 15.57-times (95% CI, 5.70-59.48) higher risk for developing HM compared to the remaining 95% of individuals in MAGIC cohort. Conclusions: Our study suggests that rare variants are a major source of the missing heritability of HM and that ExGRS provides enhanced accuracy for HM prediction in Han Chinese ancestry, shedding new light on research and clinical practice. Plain language summary High Myopia (HM) is a disease of the eyes frequently caused by one’s inherited genes. Mathematical equations can be used to predict disease risk based on a person’s genetic make-up (profile). This calculation, called a genetic risk score (GRS), doesn’t include rare genetic changes and it is challenging to consider these in the calculations. Here, we test whether combining rare genetic changes can help to predict HM risk. Our calculations not only outperformed existing methods used for HM risk, they also allow us to estimate an individual’s risk of HM, showing how important including rare genetic changes are in accurately predicting risk of this disorder. © 2024. The Author(s). PubMed Disclaimer Conflict of interest statement Competing interests: The authors declare no competing interests. Figures

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文章哺乳动物不同类型运动纤毛中轴突结构的多样性

以下内容来源于： Nature Portfolio 。 Abstract Reproduction, development and homeostasis depend on motile cilia, whose rhythmic beating is powered by a microtubule-based molecular machine called the axoneme. Although an atomic model of the axoneme is available for the alga Chlamydomonas reinhardtii 1, structures of mammalian axonemes are incomplete 1,2,3,4,5. Furthermore, we do not fully understand how molecular structures of axonemes vary across motile-ciliated cell types in the body. Here we use cryoelectron microscopy, cryoelectron tomography and proteomics to resolve the 96-nm modular repeat of axonemal doublet microtubules (DMTs) from both sperm flagella and epithelial cilia of the oviduct, brain ventricles and respiratory tract. We find that sperm DMTs are the most specialized, with epithelial cilia having only minor differences across tissues. We build a model of the mammalian sperm DMT, defining the positions and interactions of 181 proteins including 34 newly identified proteins. We elucidate the composition of radial spoke 3 and uncover binding sites of kinases associated with regeneration of ATP and regulation of ciliary motility. We discover a sperm-specific, axoneme-tethered T-complex protein ring complex (TRiC) chaperone that may contribute to construction or maintenance of the long flagella of mammalian sperm. We resolve axonemal dyneins in their prestroke states, illuminating conformational changes that occur during ciliary movement. Our results illustrate how elements of chemical and mechanical regulation are embedded within the axoneme, providing valuable resources for understanding the aetiology of ciliopathy and infertility, and exemplifying the discovery power of modern structural biology. Similar content being viewed by others In situ cryo-electron tomography reveals the asymmetric architecture of mammalian sperm axonemes Article Open access 02 January 2023 In-cell structural insight into the stability of sperm microtubule doublet Article Open access 21 November 2023 Native doublet microtubules from Tetrahymena thermophila reveal the importance of outer junction proteins Article Open access 15 April 2023 Main Motile cilia are used by unicellular and multicellular organisms either to propel themselves through fluid or to move fluid across their surfaces. Ciliary motility is driven by a microtubule-based supramolecular assembly known as the axoneme, which consists of nine doublet microtubules (DMTs) surrounding a central apparatus of two singlet microtubules. DMTs are patterned into repeating 96-nm units by two rows of dynein arms (outer dynein arms (ODAs) and inner dynein arms (IDAs)), up to three T-shaped mechanoregulatory complexes called radial spokes (RSs), the nexin–dynein regulatory complex (N-DRC) that links neighbouring DMTs and a network of coiled coils that regulates the docking and periodicity of the aforementioned complexes. In addition, the DMT lumen is extensively decorated with microtubule inner proteins (MIPs) that bind in varying multiples of the 8-nm tubulin repeat, but with an overall periodicity of 48 nm that is in coherent register with the external 96-nm repeat. Over the past 20 years, cryoelectron tomography (cryo-ET) and cryoelectron microscopy (cryo-EM) have brought our understanding of the axoneme to the molecular level, culminating in a recent atomic model of the 96-nm modular repeat from the green alga C hlamydomonas reinhardtii 1,6. However, corresponding models of mammalian axonemes are incomplete 1,2,3,4,5. For instance, the model of a human DMT from respiratory cilia 1 lacks RS3, a prominent complex present in most ciliated organisms but absent from Chlamydomonas, and does not account for many enzymes or regulatory kinases thought to be anchored to the axoneme 7. Cryo-EM and cryo-ET have also shown marked variation in axonemal subcomplexes across species and cell types 1,2,3,8,9,10,11,12. This variation reflects the diversity of ciliary form and function in nature, and even within an organism; for instance, ependymal cilia in brain ventricles drive the flow of watery cerebrospinal fluid, whereas respiratory cilia in the trachea propel viscous mucus along the airway surface. Epithelial cilia and sperm flagella have distinct waveforms 13 and vary greatly in length, ranging from a few microns in the respiratory tract to tens or even hundreds of microns in sperm. They also respond differently to mutations in proteins that they are proposed to share. However, the lack of high-resolution structures of axonemes from different mammalian cell types prevents a full understanding of how differences in individual proteins or protein complexes contribute to ciliary diversity in normal function and in disease. Comparison of epithelial and sperm DMTs To shed light on the structural diversity of axonemes across different mammalian motile-ciliated cell types, we used single-particle analysis (SPA) cryo-EM to reconstruct the native 96-nm repeat of DMTs from disintegrated axonemes of sperm flagella (Bos taurus) and epithelial cilia isolated from either the oviduct (B. taurus and Homo sapiens) or brain ventricles (Sus scrofa) (Fig. 1, Extended Data Fig. 1a–d, Supplementary Figs. 1–7, Supplementary Tables 1, 2 and Methods). Separately, we reconstructed the 96-nm repeat from intact porcine (S. scrofa) oviduct cilia using cryo-ET and subtomogram averaging, showing consistency with our SPA structures, especially near the microtubule surfaces (Extended Data Fig. 1e–g and Methods). By comparison of these reconstructions with published maps of human respiratory cilia 1, we define how the structure of the axoneme varies across motile-ciliated cell types of the mammalian body. Fig. 1: Cryo-EM reconstructions of the 96-nm axonemal repeat of motile cilia from different mammalian cell types. Each panel shows a longitudinal and cross-sectional view of a composite cryo-EM map of a 96-nm repeat unit of a doublet microtubule from bovine sperm flagella (a), bovine oviductal cilia (b), porcine brain ventricle cilia (c) and human respiratory cilia (d). The reconstruction in d is EMD-35888 (ref. 1). Each major axonemal complex is given a unique colour with the doublet microtubule in grey. IJ, inner junction; MAP, microtubule-associated protein; OJ, outer junction. Full size image Our work demonstrates that the DMTs of multiciliated epithelial cells are almost structurally indistinguishable, with differences restricted to the intraluminal tektin bundle and associated proteins RIBC1/2 (Extended Data Fig. 2). The overall similarity of epithelial DMTs reflects the similarity of epithelial cilia in general—they are all approximately 5–10 µm long, consist of an axoneme sheathed by a ciliary membrane and have similar waveform dynamics. Nevertheless, the absence of obvious structural specializations in DMTs from epithelial cilia is somewhat unexpected considering their roles in propelling liquids of very different viscosity, and the different sensitivities of tissues to ciliopathic mutations. For example, genetic ablation of the β-tubulin isotype TUBB4B causes severe loss of tracheal and oviductal cilia in mice, but has no apparent effect on the number, length or beat frequency of brain ependymal cilia 14. Our structural and proteomic data confirm that TUBB4B is the main β-tubulin isotype of pig ependymal DMTs—as it is in all motile cilia examined (Supplementary Tables 3 and 4)—suggesting that differential sensitivity to TUBB4B depletion cannot be explained solely by gross differences in DMT structure. In contrast to the relatively homogeneous structures of epithelial DMTs, direct comparison of bovine DMTs from three different tissues shows that sperm DMTs have an additional layer of complexity (Fig. 1) that extends to the MIPs that decorate the lumen of axonemal DMTs 2,3 (Extended Data Fig. 2). Our structures further show that ciliary microtubule-associated proteins (CIMAPs) bound close to the external surface of the DMT 2,15 are ubiquitous features of mammalian axonemes but have cilium-specific distribution (Extended Data Fig. 3a,b). For example, CIMAP3 is present in all mammalian axonemes hitherto studied, yet CIMAP2, which binds the same protofilament cleft, is found only in sperm (Extended Data Fig. 3b). These structural observations are supported by both proteomics (Supplementary Table 4) and expression data 16.

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文章谷固醇血症合并眶周黄色肉芽肿

以下内容来源于：NEJM 。

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文章随机临床试验：急性脑损伤患者的限制性输血策略与宽松输血策略对比

以下内容来源于：JAMA 。 Abstract Importance: Blood transfusions are commonly administered to patients with acute brain injury. The optimal hemoglobin transfusion threshold is uncertain in this patient population. Objective: To assess the impact on neurological outcome of 2 different hemoglobin thresholds to guide red blood cell transfusions in patients with acute brain injury. Design, setting, and participants: Multicenter, phase 3, parallel-group, investigator-initiated, pragmatic, open-label randomized clinical trial conducted in 72 intensive care units across 22 countries. Eligible patients had traumatic brain injury, aneurysmal subarachnoid hemorrhage, or intracerebral hemorrhage; hemoglobin values below 9 g/dL within the first 10 days after injury; and an expected intensive care unit stay of at least 72 hours. Enrollment occurred between September 1, 2017, and December 31, 2022. The last day of follow-up was June 30, 2023. Interventions: Eight hundred fifty patients were randomly assigned to undergo a liberal (transfusion triggered by hemoglobin <9 g/dL; n = 408) or a restrictive (transfusion triggered by hemoglobin <7 g/dL; n = 442) transfusion strategy over a 28-day period. Main outcomes and measures: The primary outcome was occurrence of an unfavorable neurological outcome, defined as a Glasgow Outcome Scale Extended score between 1 and 5, at 180 days following randomization. There were 14 prespecified serious adverse events, including occurrence of cerebral ischemia after randomization. Results: Among 820 patients who completed the trial (mean age, 51 years; 376 [45.9%] women), 806 had available data on the primary outcome, 393 in the liberal strategy group and 413 in the restrictive strategy group. The liberal strategy group received a median of 2 (IQR, 1-3) units of blood, and the restrictive strategy group received a median of 0 (IQR, 0-1) units of blood, with an absolute mean difference of 1.0 unit (95% CI, 0.87-1.12 units). At 180 days after randomization, 246 patients (62.6%) in the liberal strategy group had an unfavorable neurological outcome compared with 300 patients (72.6%) in the restrictive strategy group (absolute difference, -10.0% [95% CI, -16.5% to -3.6%]; adjusted relative risk, 0.86 [95% CI, 0.79-0.94]; P = .002). The effect of the transfusion thresholds on neurological outcome at 180 days was consistent across prespecified subgroups. In the liberal strategy group, 35 (8.8%) of 397 patients had at least 1 cerebral ischemic event compared with 57 (13.5%) of 423 in the restrictive strategy group (relative risk, 0.65 [95% CI, 0.44-0.97]). Conclusions and relevance: Patients with acute brain injury and anemia randomized to a liberal transfusion strategy were less likely to have an unfavorable neurological outcome than those randomized to a restrictive strategy. Trial registration: ClinicalTrials.gov Identifier: NCT02968654. PubMed Disclaimer Conflict of interest statement Conflict of Interest Disclosures: Dr Gouvêa Bogossian reported receipt of grants from Fonds National de Recherche Scientifique–Wallonie Bruxelles and a Clinical Research Award 2021 from the European Society of Intensive Care Medicine (ESICM) outside the submitted work. Dr Chabanne reported receipt of personal fees from SOPHYSA outside the submitted work and being a member of the executive committee of the Neurocritical Care and Neuro Anesthesiology French Speaking Society. No other disclosures were reported.

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文章一名九岁儿童的胸部巨大肿块病例

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