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Nature Medicine Jun 2024There are more than 10,000 individual rare diseases and most are without therapy. Personalized genetic therapy represents one promising approach for their treatment. We...
There are more than 10,000 individual rare diseases and most are without therapy. Personalized genetic therapy represents one promising approach for their treatment. We present a road map for individualized treatment of an ultra-rare disease by establishing a gene replacement therapy developed for a single patient with hereditary spastic paraplegia type 50 (SPG50). Through a multicenter collaboration, an adeno-associated virus-based gene therapy product carrying the AP4M1 gene was created and successfully administered intrathecally to a 4-year-old patient within 3 years of diagnosis as part of a single-patient phase 1 trial. Primary endpoints were safety and tolerability, and secondary endpoints evaluated efficacy. At 12 months after dosing, the therapy was well tolerated. No serious adverse events were observed, with minor events, including transient neutropenia and Clostridioides difficile gastroenteritis, experienced but resolved. Preliminary efficacy measures suggest a stabilization of the disease course. Longer follow-up is needed to confirm the safety and provide additional insights on the efficacy of the therapy. Overall, this report supports the safety of gene therapy for SPG50 and provides insights into precision therapy development for rare diseases. Clinical trial registration: NCT06069687 .
PubMed: 38942994
DOI: 10.1038/s41591-024-03078-4 -
International Urogynecology Journal Jun 2024The objective was to examine the outcomes of posterior tibial nerve stimulation (PTNS) on bladder, bowel, and sexual health-related quality of life among a cohort of...
INTRODUCTION AND HYPOTHESIS
The objective was to examine the outcomes of posterior tibial nerve stimulation (PTNS) on bladder, bowel, and sexual health-related quality of life among a cohort of patients with multiple sclerosis (MS) with refractory lower urinary tract symptoms (LUTS).
METHODS
Patients with MS and refractory LUTS were recruited for a prospective, observational study using PTNS to treat their symptoms. Patients underwent 12 weekly 30-min PTNS sessions and bladder, bowel, and sexual symptoms were evaluated at baseline, 3, 12, and 24 months with voiding diaries, visual analog scales (VAS), and validated patient-reported questionnaires, including the American Urological Association Symptom Score (AUA-SS), Neurogenic Bladder Symptom Score (NBSS), Michigan Incontinence Symptom Index (M-ISI), Health Status Questionnaire, Sexual Satisfaction Scale, and Bowel Control Scale.
RESULTS
A total of 23 patients were recruited: 18 started PTNS and 14 completed 3 months of PTNS. Of the 18 who started PTNS, the mean age was 52 years (SD 12), 61% were female, 83% were white, and most patients had relapsing remitting (39%) MS. Baseline (n=18) and 3-month voiding (n=11) outcomes showed no significant change in number of voids or incontinence episodes. The median VAS symptom improvement was 49 (IQR 26.5, 26) and 9 (53%) patients elected for monthly maintenance PTNS. On paired analysis, there was a significant improvement in median change in NBSS, AUA-SS, and M-ISI. There was no significant change in bowel or sexual dysfunction.
CONCLUSIONS
This prospective, observational study of PTNS in patients with MS with refractory LUTS shows improvement in patient-reported bladder outcomes, but not in number of voids per day or bowel or bladder function.
PubMed: 38942931
DOI: 10.1007/s00192-024-05836-x -
Oncogene Jun 2024Clinical outcome for patients suffering from HPV-negative head and neck squamous cell carcinoma (HNSCC) remains poor. This is mostly due to highly invasive tumors that...
Clinical outcome for patients suffering from HPV-negative head and neck squamous cell carcinoma (HNSCC) remains poor. This is mostly due to highly invasive tumors that cause loco-regional relapses after initial therapeutic intervention and metastatic outgrowth. The molecular pathways governing the detrimental invasive growth modes in HNSCC remain however understudied. Here, we have established HNSCC patient derived organoid (PDO) models that recapitulate 3-dimensional invasion in vitro. Single cell mRNA sequencing was applied to study the differences between non-invasive and invasive conditions, and in a collective versus single cell invading PDO model. Differential expression analysis under invasive conditions in Collagen gels reveals an overall upregulation of a YAP-centered transcriptional program, irrespective of the invasion mode. However, we find that collectively invading HNSCC PDO cells show elevated levels of YAP transcription targets when compared to single cell invasion. Also, collectively invading cells are characterized by increased nuclear translocation of YAP within the invasive strands, which coincides with Collagen-I matrix alignment at the invasive front. Using gene set enrichment analysis, we identify immune cell-like migratory pathways in the single cell invading HNSCC PDO, while collective invasion is characterized by overt upregulation of adhesion and migratory pathways. Lastly, based on clinical head and neck cancer cohorts, we demonstrate that the identified collective invasion signature provides a candidate prognostic platform for survival in HNSCC. By uncoupling collective and single cell invasive programs, we have established invasion signatures that may guide new therapeutic options.
PubMed: 38942893
DOI: 10.1038/s41388-024-03091-4 -
Scientific Reports Jun 2024A novel interval valued p,q Rung orthopair fuzzy (IVPQ-ROF) multiple attribute group decision making (MAGDM) method for sustainable supplier selection (SSS) is proposed...
A novel interval valued p,q Rung orthopair fuzzy (IVPQ-ROF) multiple attribute group decision making (MAGDM) method for sustainable supplier selection (SSS) is proposed in this paper. This study mainly contains two research points: (1) tackling the interrelation between attributes; and (2) describing the psychological state and risk attitude of decision makers (DMs). For the first research point, we introduce the Archimedean operation rules for interval valued p,q Rung orthopair fuzzy sets (IVPQ-ROFSs), then the generalized interval valued p, q Rung orthopair fuzzy Maclaurin symmetric mean (GIVPQ-ROFMSM) operator and the generalized interval valued p, q Rung orthopair fuzzy weighted Maclaurin symmetric mean (GIVPQ-ROFWMSM) operator are defined to reflect the correlation between attributes. For the second research point, we introduce the positive ideal degree (PID) and negative ideal degree (NID) based on projection of IVPQ-ROFSs, and modified regret theory. Both of them consider the best alternative and worst alternative, so as to reflect the psychological state and risk attitude of DMs. Finally, a SSS problem is presented to manifest the effectiveness of the designed method. We also provide sensitivity analysis and comparative analysis to further demonstrate the rationality and validity of the proposed method.
PubMed: 38942771
DOI: 10.1038/s41598-024-64765-3 -
Clinical Therapeutics Jun 2024Penicillin allergy is the most common drug allergy among hospitalized patients. Traditionally, aztreonam is recommended for patients labeled with penicillin allergy...
PURPOSE
Penicillin allergy is the most common drug allergy among hospitalized patients. Traditionally, aztreonam is recommended for patients labeled with penicillin allergy (PLWPA) in our institutional empirical antibiotic guidelines. Due to a global aztreonam shortage in December 2022, the antimicrobial stewardship unit recommended ceftazidime as a substitute. There is a paucity of real-world data on the safety profile of ceftazidime in PLWPA. Hence, we evaluated tolerability outcomes of ceftazidime use in PLWPA.
METHODS
This retrospective cohort study compared PLWPA in Singapore General Hospital who received aztreonam (October 2022-December 2022) or ceftazidime (December 2022-February 2023). Patients were stratified according to their risk of allergic reaction (AR) based on history of penicillin allergy. The severity of AR was based on the Delphi study grading system. The primary outcome was development of AR after initiation of aztreonam or ceftazidime. The secondary tolerability outcomes include hepatotoxicity and neurotoxicity.
FINDINGS
There were 168 patients in the study; 69 were men (41.1%) and the median age was 69 years (interquartile range: 59-76 years). Incidence of AR was statistically similar in both arms: 1 of 102 patients (0.98%) in the aztreonam arm vs 2 of 66 patients (3.03%) in the ceftazidime arm (P = 0.33). The patient in the aztreonam arm was deemed at medium risk of having an AR and developed localized rashes (grade 1). Both patients in the ceftazidime arm were deemed at high risk of AR and developed localized skin reaction (grade 1). Hepatotoxicity was observed in 1 patient prescribed aztreonam. No patients in the ceftazidime arm developed adverse events.
IMPLICATIONS
Ceftazidime appears to be better tolerated and cheaper compared with aztreonam in PLWPA, and serves as an antimicrobial stewardship strategy to conserve broader-spectrum antibiotics use.
PubMed: 38942719
DOI: 10.1016/j.clinthera.2024.05.007 -
Human Reproduction Update Jun 2024Chemotherapy-associated ovarian damage (CAOD) is one of the most feared short- and long-term side effects of anticancer treatment in premenopausal women. Accumulating...
BACKGROUND
Chemotherapy-associated ovarian damage (CAOD) is one of the most feared short- and long-term side effects of anticancer treatment in premenopausal women. Accumulating detailed data show that different chemotherapy regimens can lead to disturbance of ovarian hormone levels, reduced or lost fertility, and an increased risk of early menopause. Previous studies have often focused on the direct effects of chemotherapeutic drugs on ovarian follicles, such as direct DNA damage-mediated apoptotic death and primordial follicle burnout. Emerging evidence has revealed an imbalance in the ovarian microenvironment during chemotherapy. The ovarian microenvironment provides nutritional support and transportation of signals that stimulate the growth and development of follicles, ovulation, and corpus luteum formation. The close interaction between the ovarian microenvironment and follicles can determine ovarian function. Therefore, designing novel and precise strategies to manipulate the ovarian microenvironment may be a new strategy to protect ovarian function during chemotherapy.
OBJECTIVE AND RATIONALE
This review details the changes that occur in the ovarian microenvironment during chemotherapy and emphasizes the importance of developing new therapeutics that protect ovarian function by targeting the ovarian microenvironment during chemotherapy.
SEARCH METHODS
A comprehensive review of the literature was performed by searching PubMed up to April 2024. Search terms included 'ovarian microenvironment' (ovarian extracellular matrix, ovarian stromal cells, ovarian interstitial, ovarian blood vessels, ovarian lymphatic vessels, ovarian macrophages, ovarian lymphocytes, ovarian immune cytokines, ovarian oxidative stress, ovarian reactive oxygen species, ovarian senescence cells, ovarian senescence-associated secretory phenotypes, ovarian oogonial stem cells, ovarian stem cells), terms related to ovarian function (reproductive health, fertility, infertility, fecundity, ovarian reserve, ovarian function, menopause, decreased ovarian reserve, premature ovarian insufficiency/failure), and terms related to chemotherapy (cyclophosphamide, lfosfamide, chlormethine, chlorambucil, busulfan, melphalan, procarbazine, cisplatin, doxorubicin, carboplatin, taxane, paclitaxel, docetaxel, 5-fluorouraci, vincristine, methotrexate, dactinomycin, bleomycin, mercaptopurine).
OUTCOMES
The ovarian microenvironment shows great changes during chemotherapy, inducing extracellular matrix deposition and stromal fibrosis, angiogenesis disorders, immune microenvironment disturbance, oxidative stress imbalances, ovarian stem cell exhaustion, and cell senescence, thereby lowering the quantity and quality of ovarian follicles. Several methods targeting the ovarian microenvironment have been adopted to prevent and treat CAOD, such as stem cell therapy and the use of free radical scavengers, senolytherapies, immunomodulators, and proangiogenic factors.
WIDER IMPLICATIONS
Ovarian function is determined by its 'seeds' (follicles) and 'soil' (ovarian microenvironment). The ovarian microenvironment has been reported to play a vital role in CAOD and targeting the ovarian microenvironment may present potential therapeutic approaches for CAOD. However, the relation between the ovarian microenvironment, its regulatory networks, and CAOD needs to be further studied. A better understanding of these issues could be helpful in explaining the pathogenesis of CAOD and creating innovative strategies for counteracting the effects exerted on ovarian function. Our aim is that this narrative review of CAOD will stimulate more research in this important field.
REGISTRATION NUMBER
Not applicable.
PubMed: 38942605
DOI: 10.1093/humupd/dmae020 -
Human Reproduction (Oxford, England) Jun 2024Can pregnancy outcomes following fresh elective single embryo transfer (eSET) in gonadotropin-releasing hormone (GnRH) antagonist protocols increase using a gonadotropin...
A modified flexible GnRH antagonist protocol using antagonist early cessation and a gonadotropin step-down approach improves live birth rates in fresh cycles: a randomized controlled trial.
STUDY QUESTION
Can pregnancy outcomes following fresh elective single embryo transfer (eSET) in gonadotropin-releasing hormone (GnRH) antagonist protocols increase using a gonadotropin (Gn) step-down approach with cessation of GnRH antagonist on the day of hCG administration (hCG day) in patients with normal ovarian response?
SUMMARY ANSWER
The modified GnRH antagonist protocol using the Gn step-down approach and cessation of GnRH antagonist on the hCG day is effective in improving live birth rates (LBRs) per fresh eSET cycle.
WHAT IS KNOWN ALREADY
Currently, there is no consensus on optimal GnRH antagonist regimens. Studies have shown that fresh GnRH antagonist cycles result in poorer pregnancy outcomes than the long GnRH agonist (GnRHa) protocol. Endometrial receptivity is a key factor that contributes to this phenomenon.
STUDY DESIGN, SIZE, DURATION
An open label randomized controlled trial (RCT) was performed between November 2021 and August 2022. There were 546 patients allocated to either the modified GnRH antagonist or the conventional antagonist protocol at a 1:1 ratio.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Both IVF and ICSI cycles were included, and the sperm samples used were either fresh or frozen from the partner, or from frozen donor ejaculates. The primary outcome was the LBRs per fresh SET cycle. Secondary outcomes included rates of implantation, clinical and ongoing pregnancy, miscarriage, and ovarian hyperstimulation syndrome (OHSS), as well as clinical outcomes of ovarian stimulation.
MAIN RESULTS AND THE ROLE OF CHANCE
Baseline demographic features were not significantly different between the two ovarian stimulation groups. However, in the intention-to-treat (ITT) population, the LBRs in the modified antagonist group were significantly higher than in the conventional group (38.1% [104/273] vs. 27.5% [75/273], relative risk 1.39 [95% CI, 1.09-1.77], P = 0.008). Using a per-protocol (PP) analysis which included all the patients who received an embryo transfer, the LBRs in the modified antagonist group were also significantly higher than in the conventional group (48.6% [103/212] vs. 36.8% [74/201], relative risk 1.32 [95% CI, 1.05-1.66], P = 0.016). The modified antagonist group achieved significantly higher implantation rates, and clinical and ongoing pregnancy rates than the conventional group in both the ITT and PP analyses (P < 0.05). The two groups did not show significant differences between the number of oocytes retrieved or mature oocytes, two-pronuclear zygote (2PN) rates, the number of embryos obtained, blastocyst progression and good-quality embryo rates, early miscarriage rates, or OHSS incidence rates (P > 0.05).
LIMITATIONS, REASONS FOR CAUTION
A limitation of our study was that the subjects were not blinded to the treatment allocation in the RCT trial. Only women under 40 years of age who had a good prognosis were included in the analysis. Therefore, use of the modified antagonist protocol in older patients with a low ovarian reserve remains to be investigated. In addition, the sample size for Day 5 elective SET was small, so larger trials will be required to strengthen these findings.
WIDER IMPLICATIONS OF THE FINDINGS
The modified GnRH antagonist protocol using the Gn step-down approach and cessation of GnRH antagonist on hCG day improved the LBRs per fresh eSET cycle in normal responders.
STUDY FUNDING/COMPETING INTEREST(S)
This project was funded by grant 2022YFC2702503 from the National Key Research & Development Program of China and grant 2021140 from the Beijing Health Promotion Association. The authors declare no conflicts of interest.
TRIAL REGISTRATION NUMBER
The RCT was registered in the Chinese Clinical Trial Registry; Study Number: ChiCTR2100053453.
TRIAL REGISTRATION DATE
21 November 2021.
DATE OF FIRST PATIENT’S ENROLLMENT
23 November 2021.
PubMed: 38942602
DOI: 10.1093/humrep/deae145 -
The Science of the Total Environment Jun 2024Since the discovery of antibiotics, penicillin has remained the top choice in clinical medicine. With continuous advancements in biotechnology, penicillin production has... (Review)
Review
Since the discovery of antibiotics, penicillin has remained the top choice in clinical medicine. With continuous advancements in biotechnology, penicillin production has become cost-effective and efficient. Genetic engineering techniques have been employed to enhance biosynthetic pathways, leading to the production of new penicillin derivatives with improved properties and increased efficacy against antibiotic-resistant pathogens. Advances in bioreactor design, media formulation, and process optimization have contributed to higher yields, reduced production costs, and increased penicillin accessibility. While biotechnological advances have clearly benefited the global production of this life-saving drug, they have also created challenges in terms of waste management. Production fermentation broths from industries contain residual antibiotics, by-products, and other contaminants that pose direct environmental threats, while increased global consumption intensifies the risk of antimicrobial resistance in both the environment and living organisms. The current geographical and spatial distribution of antibiotic and penicillin consumption dramatically reveals a worldwide threat. These challenges are being addressed through the development of novel waste management techniques. Efforts are aimed at both upstream and downstream processing of antibiotic and penicillin production to minimize costs and improve yield efficiency while lowering the overall environmental impact. Yield optimization using artificial intelligence (AI), along with biological and chemical treatment of waste, is also being explored to reduce adverse impacts. The implementation of strict regulatory frameworks and guidelines is also essential to ensure proper management and disposal of penicillin production waste. This review is novel because it explores the key remaining challenges in antibiotic development, the scope of machine learning tools such as Quantitative Structure-Activity Relationship (QSAR) in modern biotechnology-driven production, improved waste management for antibiotics, discovering alternative path to reducing antibiotic use in agriculture through alternative meat production, addressing current practices, and offering effective recommendations.
PubMed: 38942308
DOI: 10.1016/j.scitotenv.2024.174236 -
Journal of Vascular and Interventional... Jun 2024
PubMed: 38942285
DOI: 10.1016/j.jvir.2024.06.019 -
Journal of Clinical Epidemiology Jun 2024To map whether and how systematic reviews (SRs) with network meta-analysis (NMA) use presentation formats to report (a) structured evidence summaries - here defined as...
OBJECTIVE
To map whether and how systematic reviews (SRs) with network meta-analysis (NMA) use presentation formats to report (a) structured evidence summaries - here defined as reporting of effects estimates in absolute effects with certainty ratings and with a method to rate interventions across one or more outcome(s) - and (b) NMA results in general.
STUDY DESIGN AND SETTING
We conducted a systematic survey, searching MEDLINE (Ovid) for SRs with NMA published between January 1, 2020, and December 31, 2021. We planned to include a random sample of publications, with predefined mechanisms in place for saturation, and included SRs that met pre-specified quality criteria and extracted data on presentation formats that reported: (a) estimates of effects, (b) certainty of the evidence, or (c) rating of interventions.
RESULTS
The 200 eligible SRs, from 158 unique Journals, utilized 1133 presentation formats. We found structured evidence summaries in 10 publications (5.0%), with three (1.5%) reporting structured evidence summaries across all outcomes, including benefits and harms. Sixteen of the 133 SRs (11.7%) reporting dichotomous outcomes included estimates of absolute effects. Seventy-six SRs (38.0%) reported both benefits and harms and 26 SRs (13.0%) reported certainty ratings in presentation formats, 20 (76.9%) used Grading of Recommendations Assessment, Development and Evaluation (GRADE) and six (23.1%) used Confidence In Network Meta-analysis (CINeMA). Surface Under the Cumulative Ranking Curve (SUCRA) was the most common method to rate interventions (69 SRs, 34.5%). NMA results were most often reported using forest plots (108 SRs, 54.0%) and league tables (93 SRs, 46.5%).
CONCLUSION
Most SRs with NMA do not report structured evidence summaries and only rarely do such summaries include reporting of both benefits and harms. Those that do offer effective user-friendly communication and provide models for optimal NMA presentation practice.
PubMed: 38942177
DOI: 10.1016/j.jclinepi.2024.111445