Ribosome biogenesis is essential for hemogenic endothelial cells to generate hematopoietic stem cells.

Undergoing endothelial-to-hematopoietic transition, a small fraction of embryonic aortic endothelial cells specializes into hemogenic endothelial cells (HECs) and eventually gives rise to hematopoietic stem cells (HSCs). Previously, we found that the activity of ribosome biogenesis (RiBi) is highly enriched in the HSC-primed HECs compared with adjacent arterial endothelial cells; however, whether RiBi is required in HECs for the generation of HSCs remains to be determined. Here, we have found that robust RiBi is markedly augmented during the endothelial-to-hematopoietic transition in mouse. Pharmacological inhibition of RiBi completely impeded the generation of HSCs in explant cultures. Moreover, disrupting RiBi selectively interrupted the HSC generation potential of HECs rather than T1 pre-HSCs, which was in line with its influence on cell cycle activity. Further investigation revealed that, upon HEC specification, the master transcription factor Runx1 dramatically bound to the loci of genes involved in RiBi, thereby facilitating this biological process. Taken together, our study provides functional evidence showing the indispensable role of RiBi in generating HSCs from HECs, providing previously unreported insights that may contribute to the improvement of HSC regeneration strategies.

Applications of Data Characteristic AI-Assisted Raman Spectroscopy in Pathological Classification.

Raman spectroscopy has been widely used for label-free biomolecular analysis of cells and tissues for pathological diagnosis in vitro and in vivo. AI technology facilitates disease diagnosis based on Raman spectroscopy, including machine learning (PCA and SVM), manifold learning (UMAP), and deep learning (ResNet and AlexNet). However, it is not clear how to optimize the appropriate AI classification model for different types of Raman spectral data. Here, we selected five representative Raman spectral data sets, including endometrial carcinoma, hepatoma extracellular vesicles, bacteria, melanoma cell, diabetic skin, with different characteristics regarding sample size, spectral data size, Raman shift range, tissue sites, Kullback-Leibler (KL) divergence, and significant Raman shifts (i.e., wavenumbers with significant differences between groups), to explore the performance of different AI models (e.g., PCA-SVM, SVM, UMAP-SVM, ResNet or AlexNet). For data set of large spectral data size, Resnet performed better than PCA-SVM and UMAP. By building data characteristic-assisted AI classification model, we optimized the network parameters (e.g., principal components, activation function, and loss function) of AI model based on data size and KL divergence etc. The accuracy improved from 85.1 to 94.6% for endometrial carcinoma grading, from 77.1 to 90.7% for hepatoma extracellular vesicles detection, from 89.3 to 99.7% for melanoma cell detection, from 88.1 to 97.9% for bacterial identification, from 53.7 to 85.5% for diabetic skin screening, and mean time expense of 5 s.

Risk factors for postoperative recurrent tricuspid regurgitation after concomitant tricuspid annuloplasty during left heart surgery and the association between tricuspid annular circumference and secondary tricuspid regurgitation.

BACKGROUND: To identify the association between tricuspid annular circumference and secondary tricuspid regurgitation and analyze the risk factors of recurrent tricuspid regurgitation after concomitant tricuspid annuloplasty during left heart surgery. METHODS: From October 2018 to June 2019, a total of 117 patients receiving concomitant tricuspid annuloplasty within left heart surgery were enrolled. Severity of tricuspid regurgitation was classified as 4 subtypes: normal, mild, moderate and severe. Perioperative data and mid-term outcome were collected. Tricuspid annular circumference (TAC) was measured under cardiac arrest during surgery procedure by cardioplegia. Optimal TAC and TAC index (TAC/body surface area, BSA) cutoffs of significant tricuspid annulus dilatation (moderate and severe) were obtained. Univariable and multivariable logistic regression analyses were performed to identify the risk factors of postoperative recurrent tricuspid regurgitation. The follow up period is 13-19 months (mean 15.5 ± 3.2 months). RESULTS: There was 1 patient was excluded who died after surgery. A total of 116 patients receiving tricuspid annuloplasty were included. Optimal cutoffs of significant tricuspid annulus dilatation were recommended (TAC 11.45 cm, Sensitivity 82.89%, Specificity 73.68%, AUC 0.915; TAC index 7.09 cm/m2, Sensitivity 73.68%, Specificity 85%, AUC 0.825, respectively). Based on findings of multivariable logistic regression, it has been showed that TAC index and postoperative atrial fibrillation were the independent risk factors of recurrent regurgitation after surgery. Optimal TAC index cutoff to predict recurrent tricuspid regurgitation was 7.86 cm/m2 CONCLUSIONS: The severity of secondary tricuspid regurgitation is associated with the tricuspid annular circumference. The cut-offs of significant tricuspid regurgitation (more than moderate) were TAC 11.45 cm and TAC index 7.09 cm/m2, respectively. Clinically, concomitant tricuspid annuloplasty is relative safe and effective. TAC index ≥ 7.86 cm/m2 and postoperative atrial fibrillation are the risk factors of recurrent significant tricuspid regurgitation after concomitant tricuspid annuloplasty during left heart surgery.

Area-selective atomic layer deposition of platinum using photosensitive polyimide.

Area-selective atomic layer deposition (AS-ALD) of platinum (Pt) was studied using photosensitive polyimide as a masking layer. The polyimide films were prepared by spin-coating and patterned using photolithography. AS-ALD of Pt using poly(methyl-methacrylate) (PMMA) masking layers was used as a reference. The results show that polyimide has excellent selectivity towards the Pt deposition, after 1000 ALD cycles less than a monolayer of Pt is deposited on the polyimide surface. The polyimide film could easily be removed after ALD using a hydrogen plasma, due to a combination of weakening of the polyimide resist during Pt ALD and the catalytic activity of Pt traces on the polyimide surface. Compared to PMMA for AS-ALD of Pt, polyimide has better temperature stability. This resulted in an improved uniformity of the Pt deposits and superior definition of the Pt patterns. In addition, due to the absence of reflow contamination using polyimide the nucleation phase during Pt ALD is drastically shortened. Pt patterns down to 3.5 µm were created with polyimide, a factor of ten smaller than what is possible using PMMA, at the typical Pt ALD processing temperature of 300 °C. Initial experiments indicate that after further optimization of the polyimide process Pt features down to 100 nm should be possible, which makes AS-ALD of Pt using photosensitive polyimide a promising candidate for patterning at the nanoscale.

Realization of efficient metal grating couplers for membrane-based integrated photonics.

Grating couplers are widely used to couple light between photonic integrated circuits and optical fibers. Here, we fabricate and characterize a device based on a buried metal grating. In contrast to dielectric gratings, simulations predict strongly reduced parasitic leakage of light to the substrate and are performance independent of the optical buffer thickness, while using standard fabrication processes with high yield. The gratings show a 3 dB bandwidth of 61 nm and chip-to-fiber coupling efficiency of 54%, which makes them attractive building blocks for on-wafer testing and dense optical interconnects.

Fullerene-assisted electron-beam lithography for pattern improvement and loss reduction in InP membrane waveguide devices.

In this Letter, we present a method to prepare a mixed electron-beam resist composed of a positive resist (ZEP520A) and C60 fullerene. The addition of C60 to the ZEP resist changes the material properties under electron beam exposure significantly. An improvement in the thermal resistance of the mixed material has been demonstrated by fabricating multimode interference couplers and coupling regions of microring resonators. The fabrication of distributed Bragg reflector structures has shown improvement in terms of pattern definition accuracy with respect to the same structures fabricated with normal ZEP resist. Straight InP membrane waveguides with different lengths have been fabricated using this mixed resist. A decrease of the propagation loss from 6.6 to 3.3 dB/cm has been demonstrated.

[Clinical Analysis of Reversible Posterior Encephalopathy Syndrome after Allogeneic Hematopoietic Stem Cell Transplantation in Children].

OBJECTIVE: To summarize the clinical features of reversible posterior encephalopathy syndrome (PRES) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children. METHODS: The clinical data of six children who developed PRES after undergoing allo-HSCT in the Department of Hematology of Wuhan Children's Hospital from June 2016 to December 2022 were retrospectively analyzed, and their clinical characteristics, imaging examination, laboratory examination, and treatment regression were summarized. RESULTS: Among 281 children underwent allo-HSCT, 6 cases (2.14%) developed PRES, with a median age of 5.1(1.5-9.7) years old. 4 cases underwent related haploidentical donor transplantation, and 2 cases underwent sibling allografting and unrelated donor allografting donor transplantation, respectively. All six children had an acute onset of illness, with clinical manifestations of nausea and vomiting, seizures, psychiatric disorders, visual disturbances. The five cases elevated blood pressure. All children with PRES were treated with oral immunosuppressive drugs during seizures, and 3 cases were combined with different degrees of graft-versus-host disease. Most of the children showed effective improvement in clinical symptoms and imaging after adjusting/discontinuing suspected medications (cyclosporine, etc.) and symptomatic supportive treatments (oral antihypertensive, diazepam for antispasmodic, mannitol to lower cranial blood pressure), and one of them relapsed more than 8 months after the first seizure. CONCLUSION: PRES is rare after hematopoietic stem cell transplantation in children, and its onset may be related to hypertension, cytotoxic drugs, graft-versus-host disease, etc. Most of them can be recovered after active treatment, but not completely reversible, and the prognosis of those who combined with TMA is poor.

[Clinical Analysis of Mitoxantrone Liposome in the Treatment of Children with High-Risk Acute Myeloid Leukemia].

OBJECTIVE: To investigate the safety and efficacy of mitoxantrone liposome in the treatment of children with high-risk acute myeloid leukemia (AML). METHODS: The children with high-risk AML who received the mitoxantrone liposome regimen at Wuhan Children's Hospital from January 2022 to February 2023 were collected as the observation group, and the children with high-risk AML who received idarubicin regimen were enrolled as controls, and their clinical data were analyzed. Time to bone marrow recovery, the complete remission rate of bone marrow cytology, the clearance rate of minimal residual disease, and treatment-related adverse reactions were compared between the two groups. RESULTS: The patients treated with mitoxantrone liposome showed shorter time to recovery of leukocytes(17 vs 21 day), granulocytes(18 vs 24 day), platelets(17 vs 24 day), and hemoglobin(20 vs 26 day) compared with those treated with idarubicin, there were statistical differences (P <0.05). The effective rate and MRD turning negative rate in the observation group were 90.9% and 72.7%, respectively, while those in the control group were 94.1% and 76.4%, with no statistical difference (P >0.05). The overall response rate of the two groups of patients was similar. CONCLUSION: The efficacy of mitoxantrone liposome is not inferior to that of idarubicin in children with high-risk AML, but mitoxantrone liposome allows a significantly shorter duration of bone marrow suppression and the safety is better.

Effects of hesperidin on the histological structure, oxidative stress, and apoptosis in the liver and kidney induced by NiCl2.

The aim of this study was to investigate the effect of hesperidin on the liver and kidney dysfunctions induced by nickel. The mice were divided into six groups: nickel treatment with 80 mg/kg, 160 mg/kg, 320 mg/kg hesperidin groups, 0.5% CMC-Na group, nickel group, and blank control group. Histopathological techniques, biochemistry, immunohistochemistry, and the TUNEL method were used to study the changes in structure, functions, oxidative injuries, and apoptosis of the liver and kidney. The results showed that hesperidin could alleviate the weight loss and histological injuries of the liver and kidney induced by nickel, and increase the levels of lactate dehydrogenase (LDH), alanine aminotransferase (GPT), glutamic oxaloacetic transaminase (GOT) in liver and blood urea nitrogen (BUN), creatinine (Cr) and N-acetylglucosidase (NAG) in kidney. In addition, hesperidin could increase the activities of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and glutathione peroxidase (GSH-Px) in the liver and kidney, decrease the content of malondialdehyde (MDA) and inhibit cell apoptosis. It is suggested that hesperidin could help inhibit the toxic effect of nickel on the liver and kidney.

Single-Stranded DNA Gap Accumulation Is a Functional Biomarker for USP1 Inhibitor Sensitivity.

Recent studies suggest that PARP and POLQ inhibitors confer synthetic lethality in BRCA1-deficient tumors by accumulation of single-stranded DNA (ssDNA) gaps at replication forks. Loss of USP1, a deubiquitinating enzyme, is also synthetically lethal with BRCA1 deficiency, and USP1 inhibitors are now undergoing clinical development for these cancers. Herein, we show that USP1 inhibitors also promote the accumulation of ssDNA gaps during replication in BRCA1-deficient cells, and this phenotype correlates with drug sensitivity. USP1 inhibition increased monoubiquitinated proliferating cell nuclear antigen at replication forks, mediated by the ubiquitin ligase RAD18, and knockdown of RAD18 caused USP1 inhibitor resistance and suppression of ssDNA gaps. USP1 inhibition overcame PARP inhibitor resistance in a BRCA1-mutated xenograft model and induced ssDNA gaps. Furthermore, USP1 inhibition was synergistic with PARP and POLQ inhibition in BRCA1-mutant cells, with enhanced ssDNA gap accumulation. Finally, in patient-derived ovarian tumor organoids, sensitivity to USP1 inhibition alone or in combination correlated with the accumulation of ssDNA gaps. Assessment of ssDNA gaps in ovarian tumor organoids represents a rapid approach for predicting response to USP1 inhibition in ongoing clinical trials. Significance: USP1 inhibitors kill BRCA1-deficient cells and cause ssDNA gap accumulation, supporting the potential of using ssDNA gap detection as a functional biomarker for clinical trials on USP1 inhibitors.

Nupr1 Negatively Regulates Endothelial to Hematopoietic Transition in the Aorta-Gonad-Mesonephros Region.

In the aorta of mid-gestational mouse embryos, a specialized endothelial subpopulation termed hemogenic endothelial cells (HECs) develops into hematopoietic stem and progenitor cells (HSPCs), through a conserved process of endothelial-to-hematopoietic transition (EHT). EHT is tightly controlled by multiple intrinsic and extrinsic mechanisms. Nevertheless, the molecular regulators restraining this process remain poorly understood. Here, it is uncovered that, one of the previously identified HEC signature genes, Nupr1, negatively regulates the EHT process. Nupr1 deletion in endothelial cells results in increased HSPC generation in the aorta-gonad-mesonephros region. Furthermore, single-cell transcriptomics combined with serial functional assays reveals that loss of Nupr1 promotes the EHT process by promoting the specification of hematopoiesis-primed functional HECs and strengthening their subsequent hematopoietic differentiation potential toward HSPCs. This study further finds that the proinflammatory cytokine, tumor necrosis factor α (TNF-α), is significantly upregulated in Nupr1-deficient HECs, and the use of a specific TNF-α neutralizing antibody partially reduces excessive HSPC generation in the explant cultures from Nupr1-deficient embryos. This study identifies a novel negative regulator of EHT and the findings indicate that Nupr1 is a new potential target for future hematopoietic stem cell regeneration research.

Effectiveness of lenvatinib plus immune checkpoint inhibitors in primary advanced hepatocellular carcinoma beyond oligometastasis.

BACKGROUND: Targeted therapy combined with immune checkpoint inhibitors is considered a promising treatment for primary advanced hepatocellular carcinoma (HCC). Nevertheless, the difference between synchronous and asynchronous treatment of lenvatinib with programmed death receptor-1 (PD-1) inhibitor in advanced HCC is still unclear. The aim of this investigation is to evaluate the effectiveness of synchronous and asynchronous of lenvatinib and PD-1 inhibitor on the advanced HCC beyond oligometastasis. METHODS: In this study, 213 patients from four institutions in China were involved. Patients were split into two collections: (1) lenvatinib plus PD-1 inhibitor were used synchronously (synchronous treatment group); (2) patients in asynchronous treatment group received PD-1 inhibitor after 3 months of lenvatinib treatment prior to tumour progression. To analyse progression-free survival (PFS), overall survival (OS), efficacy and safety of patients in both groups, we employed propensity score matching (PSM). RESULTS: The 6-, 12- and 24-month OS rates were 100%, 93.4% and 58.1% in the synchronous treatment group and 100%, 71.5% and 25.3% in the asynchronous treatment group, respectively. In contrast to the asynchronous treatment group, the group treated synchronously exhibited a substantially enhanced OS (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.30-0.66; p < .001). The 6-, 12- and 18-month PFS rates were 82.6%, 42.6% and 10.8% in the synchronous treatment group and 63.3%, 14.2% and 0% in the asynchronous treatment group, respectively. A significant difference was observed in the PFS rate (HR, 0.46; 95% CI, 0.33-0.63; p < .001) between the two collections. CONCLUSIONS: Patients with advanced HCC beyond oligometastasis, simultaneous administration of lenvatinib and PD-1 inhibitor led to significant improvements in survival.

A randomized trial of safety, acceptability and adherence of three rectal microbicide placebo formulations among young sexual and gender minorities who engage in receptive anal intercourse (MTN-035).

Efforts to develop a range of HIV prevention products that can serve as behaviorally congruent viable alternatives to consistent condom use and oral pre-exposure prophylaxis (PrEP) remain crucial. MTN-035 was a randomized crossover trial seeking to evaluate the safety, acceptability, and adherence to three placebo modalities (insert, suppository, enema) prior to receptive anal intercourse (RAI). If participants had no RAI in a week, they were asked to use their assigned product without sex. We hypothesized that the modalities would be acceptable and safe for use prior to RAI, and that participants would report high adherence given their behavioral congruence with cleansing practices (e.g., douches and/or enemas) and their existing use to deliver medications (e.g., suppositories; fast-dissolving inserts) via the rectum. Participants (N = 217) were sexual and gender minorities enrolled in five different countries (Malawi, Peru, South Africa, Thailand, and the United States of America). Mean age was 24.9 years (range 18-35 years). 204 adverse events were reported by 98 participants (45.2%); 37 (18.1%) were deemed related to the study products. The proportion of participants reporting "high acceptability" was 72% (95%CI: 65% - 78%) for inserts, 66% (95%CI: 59% - 73%) for suppositories, and 73% (95%CI: 66% - 79%) for enemas. The proportion of participants reporting fully adherent per protocol (i.e., at least one use per week) was 75% (95%CI: 69% - 81%) for inserts, 74% (95%CI: 68% - 80%) for suppositories, and 83% (95%CI: 77% - 88%) for enemas. Participants fully adherent per RAI-act was similar among the three products: insert (n = 99; 58.9%), suppository (n = 101; 58.0%) and enema (n = 107; 58.8%). The efficacy and effectiveness of emerging HIV prevention drug depends on safe and acceptable delivery modalities that are easy to use consistently. Our findings demonstrate the safety and acceptability of, and adherence to, enemas, inserts, and suppositories as potential modalities through which to deliver a rectal microbicide.

InAs/InP(100) quantum dot waveguide photodetectors for swept-source optical coherence tomography around 1.7 µm.

In this paper a study of waveguide photodetectors based on InAs/InP(100) quantum dot (QD) active material are presented for the first time. These detectors are fabricated using the layer stack of semiconductor optical amplifiers (SOAs) and are compatible with the active-passive integration technology. We investigated dark current, responsivity as well as spectral response and bandwidth of the detectors. It is demonstrated that the devices meet the requirements for swept-source optical coherent tomography (SS-OCT) around 1.7 µm. A rate equation model for QD-SOAs was modified and applied to the results to understand the dynamics of the devices. The model showed a good match to the measurements in the 1.6 to 1.8 µm wavelength range by fitting only one of the carrier escape rates. An equivalent circuit model was used to determine the capacitances which dominated the electrical bandwidth.

Decade-long mitral valve surgery trends and rheumatic heart disease: a review of mitral valve surgery in a large Chinese cardiovascular center.

BACKGROUND: Despite being one of the few chronic secondary heart diseases that can be prevented, current epidemiological data on rheumatic heart disease (RHD) in China are unavailable. This study examined mitral valve (MV) surgery trends in a large Chinese cardiovascular center over the last 10 years and provided insight into the distribution of RHDs and their changes. METHODS: Medical records of patients who underwent cardiac surgery, MV surgery, and MV surgery for rheumatic MV (rMV) disease at Beijing Anzhen Hospital between January 2010 and December 2019 were retrospectively reviewed. Patients' demographic and clinical characteristics were statistically analyzed among age groups. RESULTS: Overall, 7,736 patients underwent rMV surgery and 87.5% were aged 40-70 years. The proportion of patients aged >60 years increased annually (P<0.05), and the proportion of patients in all other age groups decreased. The proportion of patients with rMV diseases among those with cardiac or mitral valve diseases decreased each year, but the absolute number of patients with rMV disease remained stable. Approximately 90% of patients who underwent rMV surgery were from northern China. The incidence of rMV disease among patients with mitral valve disease moderately correlated with the per capita gross regional product (Per-GRP), an indicator of living standards (r=-0.517, P<0.05). CONCLUSIONS: RHD still exists in northern China and requires adequate resources for its management. The number of older patients with rMV disease presents a challenge for mitral valve surgery.

Short-Term Results on Leaflet Mobility in Patients Undergoing Rheumatic Mitral Valve Repair With an Efficient 4-Step Commissuroplasty Technique.

BACKGROUND: Mitral valve stenosis (MS) is the primary pathologic feature of rheumatic mitral valve disease, and the complex repair affects its clinical outcome. This study aimed to examine the efficacy of the 4-step commisuroplasty "SCORe" procedure by assessing changes in the mobility of mitral valve leaflets and its clinical effects. METHODS: From September 1, 2018, to January 13, 2019, patients with MS who underwent mitral valve repair with the SCORe procedure in the study center were analyzed in this prospective study. Mitral valve structure was assessed by transthoracic echocardiography pre- and postoperatively as well as during follow-up. RESULTS: In total, 60 consecutive patients were examined. In 56 patients (93.3%), mitral valve orifice area (MVOA) was less than 1.5 cm2, and mean (SD) MVOA for the whole cohort was 1.20 (0.34) cm2. The mobility of the anterior leaflet was improved (P < .001) during the cardiac cycle postsurgery, but that of the posterior leaflet was not (P = .591). The mean (SD) coaptation length was increased significantly from 6.69 (1.32) mm to 7.92 (1.24) mm (P < .001) postoperatively. Mean (SD) MVOAs increased to 2.24 (0.38) cm2 postoperatively (P < .001). During the 1-year follow-up, there were no deaths or reoperations. Follow-up echocardiography revealed minor or mild regurgitation in 98.3% of patients. CONCLUSION: These findings demonstrated that the SCORe procedure can effectively improve the mobility of mitral leaflets and enlarge the valve orifice area in patients with rheumatic MS in China, with minimal complications and promising results.

Lenvatinib Combined With a PD-1 Inhibitor as Effective Therapy for Advanced Intrahepatic Cholangiocarcinoma.

Background: Lenvatinib combined with a PD-1 inhibitor has obtained a satisfactory antitumor effect in several solid tumors. However, the efficacy and tumor response of lenvatinib with a PD-1 inhibitor in advanced intrahepatic cholangiocarcinoma still need further exploration. Methods: This is a single-arm study for the assessment of the efficacy and tolerability of lenvatinib with a PD-1 inhibitor in intrahepatic cholangiocarcinoma patients who had chemotherapy failure. Efficacy was evaluated based on the Response Evaluation Criteria in Solid Tumors RECIST Version 1.1 (RECIST 1.1). Results: A total of 40 patients with advanced intrahepatic cholangiocarcinoma were enrolled after the chemorefractory effect. The median progression-free survival was 5.83 ± 0.76 months. The 3-month and 6-month progression-free survival rates were 80.0% and 32.5%, respectively. The median overall survival was 14.30 ± 1.30 months. The 12-month and 18-month overall survival rates were 61.4% and 34.7%. The 3-month RECIST 1.1 evaluation was that seven patients (17.5%) showed partial response, 23 patients (57.5%) had stable disease, and 10 patients (25.0%) had progressive disease. The objective response rate was 17.5%, and the disease control rate was 75.0%. All the recorded any-grade adverse events inducing treatment termination were controllable, and there were no AE-related deaths. Conclusion: Our study showed that a combination of lenvatinib with the PD-1 inhibitor could be an effective treatment for advanced intrahepatic cholangiocarcinoma after the chemorefractory effect.

Acceptability of PC-1005 Gel Administered Rectally to HIV-1 Seronegative Adults at Three Different Volume Levels (MTN-037).

Multipurpose prevention technologies (MPT) have been increasingly researched for their dual-purpose preventative properties against HIV and other STIs. The acceptability of PC-1005, a topical MPT candidate, was explored among men and women participating in the MTN-037 Phase I trial at two U.S. sites (Pittsburgh, PA, and Birmingham, AL). We triangulated quantitative and qualitative assessments of the acceptability of three volumes (4 mL, 16 mL, 32 mL) of PC-1005 administered rectally (N = 12; 6 males, 6 females). Participants rated overall gel acceptability on a scale of 1-10, with a median of 7.17 (SD = 2.04) and had positive feelings about all three dose volumes, citing them to be very comfortable or comfortable (dose 1 = 91.7%; dose 2 = 91.7%; dose 3 = 83.3%). High acceptability of and comfort with all three dose volumes shows promise for PC-1005 as an MPT to prevent HIV and STIs, warranting future clinical development.

Outcomes of mitral valve repair compared with replacement for patients with rheumatic heart disease.

OBJECTIVE: Whether mitral valve repair is superior to replacement in the population with rheumatic heart disease has been debated. This study aims to compare outcomes of repair with replacement by the propensity score method. METHODS: This observational, prospective study enrolled patients with rheumatic heart disease who underwent mitral valve repair and replacement from January 2011 to April 2019. The propensity score method was used to select 2 groups with similar baseline characteristics. Baseline, clinical, and follow-up data were collected. Clinical outcomes included death from any cause, reoperation, and valve-related complications. RESULTS: The overall population before matching (N = 1644) included 612 patients who underwent repair and 1032 patients who underwent replacement. The propensity score analysis generated matches for 1058 patients (529 pairs). The median follow-up time was 4.12 years. Early mortality and death from any cause during follow-up were significantly lower in the repair group compared with the replacement group (hazard ratio, 0.19; 95% confidence interval [CI], 0.05-0.64; P = .003; hazard ratio, 0.38; 95% CI, 0.19-0.74; P = .003, respectively). Patients in the repair group had a lower risk of valve-related complications compared with patients in the replacement group (subhazard ratio, 0.44; 95% CI, 0.21-0.90; P = .025). In terms of reoperation, no significant difference was observed between the repair and replacement groups (subhazard ratio, 2.54; 95% CI, 0.89-7.22; P = .081). CONCLUSIONS: The results suggest that rheumatic mitral valve repair in select patients is superior to mitral valve replacement with regard to lower mortality and fewer valve-related complications; meanwhile, it has a comparable risk of reoperation compared with replacement.

Safety, uptake, and use of a dapivirine vaginal ring for HIV-1 prevention in African women (HOPE): an open-label, extension study.

BACKGROUND: Two phase 3 clinical trials showed that use of a monthly vaginal ring containing 25 mg dapivirine was well tolerated and reduced HIV-1 incidence in women by approximately 30% compared with placebo. We aimed to evaluate use and safety of the dapivirine vaginal ring (DVR) in open-label settings with high background rates of HIV-1 infection, an important step for future implementation. METHODS: We did a phase 3B open-label extension trial of the DVR (MTN-025/HIV Open-label Prevention Extension [HOPE]). Women who were HIV-1-negative and had participated in the MTN-020/ASPIRE phase 3 trial were offered 12 months of access to the DVR at 14 clinical research centres in Malawi, South Africa, Uganda, and Zimbabwe. At each visit (monthly for 3 months, then once every 3 months), women chose whether or not to accept the offer of the ring. Used, returned rings were tested for residual amounts of dapivirine as a surrogate marker for adherence. HIV-1 serological testing was done at each visit. Dapivirine amounts in returned rings and HIV-1 incidence were compared with data from the ASPIRE trial, and safety was assessed. This study is registered with ClinicalTrials.gov, NCT02858037. FINDINGS: Between July 16, 2016, and Oct 10, 2018, of 1756 women assessed for eligibility, 1456 were enrolled and participated in the study. Median age was 31 years (IQR 27-37). At baseline, 1342 (92·2%) women chose to take the DVR; ring acceptance was more than 79% at each visit up until 12 months and 936 (73·2%) of 1279 chose to take the ring at all visits. 12 530 (89·3%) of 14 034 returned rings had residual dapivirine amounts consistent with some use during the previous month (>0·9 mg released) and the mean dapivirine amount released was greater than in the ASPIRE trial (by 0·21 mg; p<0·0001). HIV-1 incidence was 2·7 per 100 person-years (95% CI 1·9-3·8, 35 infections), compared with an expected incidence of 4·4 per 100 person-years (3·2-5·8) among a population matched on age, site, and presence of a sexually transmitted infection from the placebo group of ASPIRE. No serious adverse events or grade 3 or higher adverse events observed were assessed as related to the DVR. INTERPRETATION: High uptake and persistent use in this open-label extension study support the DVR as an HIV-1 prevention option for women. With an increasing number of HIV-1 prophylaxis choices on the horizon, these results suggest that the DVR will be an acceptable and practical option for women in Africa. FUNDING: The Microbicide Trials Network and the National Institute of Allergy and Infectious Diseases, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health, all components of the US National Institutes of Health.