From both sides of the needle: Understanding effective interventions for facilitating non-national immunization program vaccine decision making in China.

Vaccination decisions are influenced by various psychological and practical factors. In China, non-National Immunization Program (non-NIP) vaccines, which are voluntary and self-paid, add uncertainty and autonomy to the decision-making process. Effective communication between providers and recipients is crucial but understudied. This study aims to integrate their perspectives, identify strategies for facilitating vaccination decisions, and analyze their mechanisms. From July to December 2023, semi-structured interviews were conducted with 17 caregivers and 12 vaccination providers across five Chinese provinces. Participants shared their experiences and decision-making processes regarding non-NIP vaccines. The Behaviour Change Wheel framework guided the analysis, utilizing iterative coding and directed content analysis. Thirteen Behavior Change Techniques were identified, with feedback, monitoring, and environmental restructuring being the most common. Key intervention functions included Persuasion, Education, and Training. We further mapped how these interventions influence non-NIP vaccine decisions. Capability was enhanced through education and effective communication, providing necessary knowledge and skills. Opportunity was increased via infrastructural improvements and societal support, making vaccines more accessible and endorsed by the community. Motivation was driven by clear communication of vaccination benefits and risks, reinforced by societal norms through public health messaging. By understanding the mechanisms influencing vaccination behaviors and interacting with stakeholders, tailored strategies can be developed. Healthcare providers can enhance service accessibility and offer evidence-based guidance with reminders, monitoring, and incentives to ensure compliance. For recipients, reliable information, sustained engagement, timely communication, and motivational opportunities are essential. A multi-dimensional approach involving multiple stakeholders is crucial for promoting non-NIP vaccine uptake.

Policy gaps in addressing market failures and intervention misalignments in tuberculosis control: prospects for improvement in China, India, and Indonesia.

India, Indonesia, and China are the top three countries with the highest tuberculosis (TB) burden. To achieve the end TB target, we analyzed policy gaps in addressing market failures as well as misalignments between National TB Programs (NTP) and health insurance policies in TB control in three countries. In India and Indonesia, we found insufficient incentives to engage private practitioners or to motivate them to improve service quality. In addition, ineffective supervision of practice and limited coverage of drugs or diagnostics was present in all three countries. The major policy misalignment identified in all three countries is that while treatment guidelines encourage outpatient treatment for drug-sensitive patients, the national health insurance scheme covers primarily inpatient services. We therefore advocate for better alignment of TB control programs and broader universal health coverage (UHC) programs to leverage additional resources from national health insurance programs to improve the effective coverage of TB care.

NIR-responsive copper nanoliposome composites for cascaded ferrotherapy via ferroptosis actived ICD and IFN-γ released.

Metallic biomaterials activate tumor ferroptosis by increasing oxidative stress, but their efficacy is severely limited in tumor microenvironment. Although interferon gamma (IFN-γ) can promote tumor ferroptosis sensitivity by inhibiting the antioxidant system and promoting lipid accumulation, this effect limited by the lack of IFN-γ accumulation in tumors. Herein, we report a near-infrared (NIR)-responsive HCuS nanocomposite (HCuS-PE@TSL-tlyp-1) that can stimulate immunogenic cell death (ICD)-mediated IFN-γ secretion through exogenous oxidative stress, thereby achieving cascaded ferrotherapy by mutually reinforcing ferroptosis and systemic immunity. Upon laser irradiation, the dissolution of the thermal coating, and the introduction of Cu ions and piperazine-erastin (PE) simultaneously induce oxidative stress by reactive oxygen species (ROS)/lipid peroxide (LPO) accumulation and deplete cystine-glutamate transporter (xCT)/GSH. The onset of oxidative stress-mediated ferroptosis is thus achieved, and ICD is triggered, significantly promoting cytotoxic T-cell (CTL) infiltration for IFN-γ secretion. Furthermore, IFN-γ induces immunogenic tumor ferroptosis by inhibiting xCT-antioxidant pathways and enhancing the ACSL4-fatty acid recruitment pathway, which further promotes sensitivity to ferroptosis in cells. These HCuS nanocomposites combined with aPD-L1 effectively in inhibiting tumor metastasis and recurrence. Importantly, these cascade ferrotherapy results broadens the application of HCuS biomaterials.

Clinical Outcomes On Tubridge Flow Diverter in Treatmenting Intracranial Aneurysms: a Retrospective Multicenter Registry Study.

PURPOSE: In China, the application of nitinol Tubridge flow diverter (TFD) has become popular for treating intracranial aneurysms (IAs). In this study, we investigated the safety outcomes of the application of TFD for treating IAs in real-world scenarios. METHODS: We retrospectively analyzed aneurysms treated with TFD in 235 centers throughout China between April 2018 and April 2020. The primary endpoint was the event-free survival rate at 12 months, defined as the occurrence of morbidity (spontaneous rupture, intraparenchymal hemorrhage (IPH), ischemic stroke, and permanent cranial neuropathy) or death. Univariate and multivariate analyses were performed to assess the risk factors. A good outcome was defined as a modified Rankin Score (mRS) of 0-2. RESULTS: We included 1281 unruptured aneurysms treated with TFD. The overall neurological morbidity and death rates after 12 months were 5.4 and 2.8%, respectively. Ischemic strokes were the most common complication (4.2%, P < 0.001). Cranial neuropathy, IPH, and spontaneous rupture occurred in 0.3%, 0.3%, and 0.5% of aneurysms, respectively. Univariate and multivariate analyses indicated that the male gender, older age, larger aneurysm diameter, and aneurysm located on BA were the independent risk factors for neurologic events. Aneurysm located on BA was the independent risk factor for ischemic strokes. Most patients (1222) had access to the mRS, and 93.2% of them achieved good outcomes. CONCLUSION: Treatment of IAs with TFD was associated with low morbidity and mortality, most of which were ischemic events. Large posterior aneurysms might be associated with a higher complication rate. TRIAL REGISTRATION: Retrospectively registered.

Decomposable Nanoagonists Enable NIR-Elicited cGAS-STING Activation for Tandem-Amplified Photodynamic-Metalloimmunotherapy.

Activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway has emerged as an efficient strategy to improve the therapeutic outcomes of immunotherapy. However, the "constantly active" mode of current STING agonist delivery strategies typically leads to off-target toxicity and hyperimmunity. To address this critical issue, herein a metal-organic frameworks-based nanoagonist (DZ@A7) featuring tumor-specific and near-infrared (NIR) light-enhanced decomposition is constructed for precisely localized STING activation and photodynamic-metalloimmunotherapy. The engineered nanoagonist enabled the generation of mitochondria-targeted reactive oxygen species under NIR irradiation to specifically release mitochondrial DNA (mtDNA) and inhibit the repair of nuclear DNA via hypoxia-responsive drugs. Oxidized tumor mtDNA serves as an endogenous danger-associated molecular pattern that activates the cGAS-STING pathway. Concurrently, NIR-accelerated zinc ions overloading in cancer cells further enhance the cGAS enzymatic activity through metalloimmune effects. By combining the synergistically enhanced activation of the cGAS-STING pathway triggered by NIR irradiation, the engineered nanoagonist facilitated the maturation of dendritic cells and infiltration of cytotoxic T lymphocytes for primary tumor eradication, which also established a long-term anti-tumor immunity to suppress tumor metastasis. Therefore, the developed nanoagonist enabled NIR-triggered, agonist-free, and tandem-amplified activation of the cGAS-STING pathway, thereby offering a distinct paradigm for photodynamic-metalloimmunotherapy.

Self-Reinforced Bimetallic Mito-Jammer for Ca2+ Overload-Mediated Cascade Mitochondrial Damage for Cancer Cuproptosis Sensitization.

Overproduction of reactive oxygen species (ROS), metal ion accumulation, and tricarboxylic acid cycle collapse are crucial factors in mitochondria-mediated cell death. However, the highly adaptive nature and damage-repair capabilities of malignant tumors strongly limit the efficacy of treatments based on a single treatment mode. To address this challenge, a self-reinforced bimetallic Mito-Jammer is developed by incorporating doxorubicin (DOX) and calcium peroxide (CaO2) into hyaluronic acid (HA) -modified metal-organic frameworks (MOF). After cellular, Mito-Jammer dissociates into CaO2 and Cu2+ in the tumor microenvironment. The exposed CaO2 further yields hydrogen peroxide (H2O2) and Ca2+ in a weakly acidic environment to strengthen the Cu2+-based Fenton-like reaction. Furthermore, the combination of chemodynamic therapy and Ca2+ overload exacerbates ROS storms and mitochondrial damage, resulting in the downregulation of intracellular adenosine triphosphate (ATP) levels and blocking of Cu-ATPase to sensitize cuproptosis. This multilevel interaction strategy also activates robust immunogenic cell death and suppresses tumor metastasis simultaneously. This study presents a multivariate model for revolutionizing mitochondria damage, relying on the continuous retention of bimetallic ions to boost cuproptosis/immunotherapy in cancer.

Repurposing Disulfiram to Combat Acute Respiratory Distress Syndrome with Targeted Delivery by LET-Functionalized Nanoplatforms.

Acute respiratory distress syndrome (ARDS) is a serious respiratory condition characterized by a damaged pulmonary endothelial barrier that causes protein-rich lung edema, an influx of proinflammatory cells, and treatment-resistant hypoxemia. Damage to pulmonary endothelial cells and inflammation are pivotal in ARDS development with a key role played by endothelial cell pyroptosis. Disulfiram (DSF), a drug that has long been used to treat alcohol addiction, has recently been identified as a potent inhibitor of gasdermin D (GSDMD)-induced pore formation and can thus prevent pyroptosis and inflammatory cytokine release. These findings indicate that DSF is a promising treatment for inflammatory disorders. However, addressing the challenge posed by its intrinsic physicochemical properties, which hinder intravenous administration, and effective delivery to pulmonary vascular endothelial cells are crucial. Herein, we used biocompatible liposomes incorporating a lung endothelial cell-targeted peptide (CGSPGWVRC) to produce DSF-loaded nanoparticles (DTP-LET@DSF NPs) for targeted delivery and reactive oxygen species-responsive release facilitated by the inclusion of thioketal (TK) within the liposomal structure. After intravenous administration, DTP-LET@DSF NPs exhibited excellent cytocompatibility and minor systemic toxicity, effectively inhibited pyroptosis, mitigated lipopolysaccharide (LPS)-induced ARDS, and prevented cytokine storms resulting from excessive immune reactions in ARDS mice. This study presents a straightforward nanoplatform for ARDS treatment that potentially paves the way for the clinical use of this nanomedicine.

Flow-diverter stents in intracranial aneurysm treatment: impact on covered cerebral artery branches.

OBJECTIVE: Flow diverter stents (FDSs) have attracted interest for intracranial aneurysm (IA) treatment; however, occlusion of side branches and related complications have been reported. This study aimed to investigate the effects of FDSs in IA management when different branches of intracranial arteries are covered. MATERIALS AND METHODS: A cross-sectional study was conducted using PUBMED, Embase, Web of Science, and Cochrane databases to include randomized or nonrandomized comparative-designed studies from January 2000 to August 2022 which reported outcomes of occlusion/narrowing of branches after IA treatment using FDSs. The PRISMA guidelines were used for our report. A random-effects meta-analysis was conducted to pool the outcomes, which included incidence rates of occlusion/narrowing of FDS-covered branches, branch occlusion-related symptoms, obliteration of IAs, and ideal clinical outcomes (modified Rankin Scale score ≤2). RESULTS: The authors identified 57 studies involving 3789 patients with IA managed by FDSs covering different branches. During the median imaging follow-up at 12 months, the IA obliteration rate was satisfactory (>70%) when covering the ophthalmic artery (OA), posterior communicating artery (PComA), anterior choroidal artery (AChoA) or anterior cerebral artery (ACA), but not the middle cerebral artery-M2 segment (MCA-M2; 69.5%; 95% CI: 60.8-77.5%) and posterior inferior cerebellar artery (PICA; 59.1%, 13/22). The overall ideal clinical outcome was observed in 97.4% of patients (95% CI: 95.5-98.9%). Higher rates of occlusion/narrowing of branches were identified when FDSs covered the ACA (66.6%; 95% CI: 45.1-85.3%), PComA (44.3%; 95% CI: 34.2-54.6%), or MCA-M2 (39.2%; 95% CI: 24.5-54.7%); the risks were lower when covering the OA (11.8%; 95% CI: 8.8-15.1%), PICA (6.8%; 95% CI: 1.5-14.5%), and AchoA (0.5%; 95% CI: 0.0-2.9%). The risk of branch occlusion-related complications was low (incidence rate <5%) for each of the six evaluated branches. CONCLUSIONS: Acceptable outcomes were identified following treatment of IAs when FDSs were placed across each of the six studied cerebral arteries. Treatment decisions regarding FDS placement across branch arteries should be made with the risk of complications from branch occlusion in mind.

Cost Drivers and Financial Burden for Cancer-Affected Families in China: A Systematic Review.

This systematic review examined cancer care costs, the financial burden for patients, and their economic coping strategies in mainland China. We included 38 quantitative studies that reported out-of-pocket payment for cancer care and patients' coping strategies in English or Chinese (PROSPERO: CRD42021273989). We searched PubMed, Embase, Ovid, Web of Science, Cochrane, CNKI, and Wanfang Data from 1 January 2009 to 10 August 2022. We referred to the standards for reporting observational studies to assess the methodological quality and transparent reporting of the included studies and reported the costs narratively. Annual mean medical costs (including inpatient and outpatient costs and fees for self-purchasing drugs) ranged from USD 7421 to USD 10,297 per patient. One study investigated medical costs for 5 years and indicated that inpatient costs accounted for 51.6% of the total medical costs, followed by self-purchasing drugs (43.9%). Annual medical costs as a percentage of annual household income ranged from 36.0% to 63.1% with a metaproportion of 51.0%. The common coping strategies included borrowing money and reduction of household expenses and expenses from basic health services. Costs of inpatient care and self-purchasing drugs are major drivers of medical costs for cancer care, and many affected households shoulder a very heavy financial burden.

Behavioral trigger factors for hemorrhagic stroke: a case-crossover study.

BACKGROUND: The role and extent of the effects of short-term behavioral factors on the risk of hemorrhagic stroke (HS) are unclear. This study aimed to assess and quantify behavioral trigger factors (BTFs) for HS and identify the differences in BTFs between Chinese and other populations. METHODS: A case-crossover study was performed from March 2021 to February 2022. New-onset HS patients were recruited from two university hospitals in China. The patients were interviewed to evaluate their exposure to 20 potential BTFs during the predefined risk and control periods and to estimate the odds ratios (ORs) and 95% confidence intervals (CIs). A comprehensive literature review was conducted to synthesize the evidence. RESULTS: A total of 284 patients with HS were included (150 with intracerebral hemorrhage and 134 with subarachnoid hemorrhage). Multivariate regression analysis showed that straining for defecation (OR: 3.06; 95% CI: 1.01-8.40), weightlifting (OR: 4.82; 95% CI: 1.02-22.83), overeating (OR: 4.33; 95% CI: 1.24-15.21), heavy physical exertion (OR: 3.02; 95% CI: 1.18-7.78), and chess/cards/mahjong games (OR: 2.51; 95% CI: 1.05-6.01) were associated with an increased risk within 2 hours before HS onset, and critical life events (OR: 3.81; 95% CI: 1.06-13.74) were associated with an increased risk 7 days before the onset of HS. Exposure to anger (OR: 3.17; 95% CI: 1.73-5.81) and heavy physical exertion (OR: 2.12; 95% CI: 1.65, 2.74) showed an increased risk of HS events after the pooled analysis. CONCLUSIONS: Several behavioral activities and mood modifications are associated with the onset of HS. In addition to the common BTFs, Chinese patients have specific BTFs due to their habits and customs distinct from those of different populations in other regions. Key messages What is already known on this topic It is known that several behavioral trigger factors (BTFs) are associated with the onset of hemorrhagic stroke (HS), such as vigorous physical exercise and anger. Evidence for other potential trigger factors was of less robustness. Which BTFs contribute to HS among the Chinese population is poorly understood, since individuals in different countries and regions have their own habits of life and customs. What this study adds Our study identified that two special behaviors, chess/card/mahjong games and critical life events, were associated with the onset of HS in Chinese populations, besides heavy physical exertion, weightlifting, overeating, and straining for defecation, which were previously reported in other populations. Heavy physical exertion and anger could potentially increase the risk of HS based on a comprehensive aggregation and evidence synthesis. How this study might affect research, practice, or policy Patients in different populations or regions may possess specific BTFs owing to their distinct habits and customs. Avoidance of these behaviors and regulation of emotions to maintain a steady mentality would help minimize exposure and prevent the disease for high-risk populations in China.

Haemorrhage risk of brain arteriovenous malformation during pregnancy and puerperium.

BACKGROUND: This study aimed to assess whether pregnancy and puerperium were associated with the risk of brain arteriovenous malformation (bAVM) haemorrhage. METHODS: A retrospective review was conducted in Xiangya Hospital, Central South University from January 2012 to December 2021. A case-crossover design was adopted to calculate the incidence density of bAVM-related haemorrhage among female patients in risk (pregnancy and puerperium) and control (non-pregnancy and non-puerperium) periods, according to four scenarios observed in different populations (scenario I: patients with haemorrhagic bAVM of all ages; scenario II: patients with haemorrhagic bAVM of all ages, with at least one previous pregnancy; scenario III: patients with haemorrhagic bAVM who are of reproductive age (15-45 years); scenario IV: patients with haemorrhagic bAVM of reproductive age (15-45 years), with at least one previous pregnancy. Next, a comprehensive literature aggregation (up to April 2022) was performed for evidence synthesis. RESULTS: Among the 311 female patients with haemorrhagic bAVM, a significant haemorrhage risk during pregnancy and puerperium was found in Scenarios I (relative risk [RR], 2.08; 95% CI, 1.28 to 3.39), II (RR, 3.21; 95% CI, 1.95 to 5.31) and IV (RR, 2.92; 95% CI, 1.73 to 4.93); however, a suggestive risk was found in scenario III (RR, 1.62; 95% CI, 0.99 to 2.67). Evidence synthesis revealed a consistent haemorrhage risk among patients of all ages (RR, 3.15; 95% CI, 1.93 to 5.15) and those of reproductive age (RR, 1.29; 95% CI, 0.89 to 1.86). CONCLUSION: Compared with most previous studies, a higher but relatively moderate risk for bAVM-related haemorrhage was identified during pregnancy and puerperium. Individualised prevention and treatment strategies should be preferred when neurosurgeons make clinical decisions.

NIR Activated Multimodal Therapeutics Based on Metal-Phenolic Networks-Functionalized Nanoplatform for Combating against Multidrug Resistance and Metastasis.

Multidrug resistance (MDR) and metastasis in cancer have become increasingly serious problems since antitumor efficiency is greatly restricted by a single therapeutic modality and the insensitive tumor microenvironment (TME). Herein, metal-phenolic network-functionalized nanoparticles (t-P@TFP NPs) are designed to realize multiple therapeutic modalities and reshape the TME from insensitive to sensitive under multimodal imaging monitoring. After a single irradiation, a near-infrared laser-activated multistage reaction occurs. t-P@TFP NPs trigger the phase transition of perfluoropentane (PFP) to release tannic acid (TA)/ferric ion (Fe3+ )-coated paclitaxel (PTX) and cause hyperthermia in the tumor region to efficiently kill cancer cells. Additionally, PTX is released after the disassembly of the TA-Fe3+ film by the abundant adenosine triphosphate (ATP) in the malignant tumor, which concurrently inhibits ATP-dependent drug efflux to improve sensitivity to chemotherapeutic agents. Furthermore, hyperthermia-induced immunogenic cell death (ICD) transforms "cold" tumors into "hot" tumors with the assistance of PD-1/PD-L1 blockade to evoke antitumor immunogenicity. This work carefully reveals the mechanisms underlying the abilities of these multifunctional NPs, providing new insights into combating the proliferation and metastasis of multidrug-resistant tumors.

Tumor-penetrating nanoplatform with ultrasound "unlocking" for cascade synergistic therapy and visual feedback under hypoxia.

BACKGROUND: Combined therapy based on the effects of cascade reactions of nanoplatforms to combat specific solid tumor microenvironments is considered a cancer treatment strategy with transformative clinical value. Unfortunately, an insufficient O2 supply and the lack of a visual indication hinder further applications of most nanoplatforms for solid tumor therapy. RESULTS: A visualizable nanoplatform of liposome nanoparticles loaded with GOD, H(Gd), and PFP and grafted with the peptide tLyP-1, named tLyP-1H(Gd)-GOD@PFP, was constructed. The double-domain peptide tLyP-1 was used to specifically target and penetrate the tumor cells; then, US imaging, starvation therapy and sonodynamic therapy (SDT) were then achieved by the ultrasound (US)-activated cavitation effect under the guidance of MR/PA imaging. GOD not only deprived the glucose for starvation therapy but also produced H2O2, which in coordination with 1O2 produced by H(Gd), enable the effects of SDT to achieve a synergistic therapeutic effect. Moreover, the synergistic therapy was enhanced by O2 from PFP and low-intensity focused ultrasound (LIFU)-accelerated redox effects of the GOD. The present study demonstrated that the nanoplatform could generate a 3.3-fold increase in ROS, produce a 1.5-fold increase in the maximum rate of redox reactions and a 2.3-fold increase in the O2 supply in vitro, and achieve significant tumor inhibition in vivo. CONCLUSION: We present a visualizable nanoplatform with tumor-penetrating ability that can be unlocked by US to overcome the current treatment problems by improving the controllability of the O2 supply, which ultimately synergistically enhanced cascade therapy.

Peptide Supramolecular Assembly-Instructed In Situ Self-Aggregation for Stratified Targeting Sonodynamic Therapy Enhancement of AIE Luminogens.

The emergence of aggregation-induced emission luminogens (AIEgens) has attracted substantial scientific attention. However, their antitumor efficacy in photodynamic therapy (PDT) is significantly restricted by the poor water solubility and limited treatment depth. Therefore, a novel AIEgens-involved therapeutic platform with good permeability and bioavailability is urgently required. Herein, supramolecular chemistry is combined with the AIEgen bis-pyrene (BP) to construct a peptide-AIEgen hybrid nanosystem (PAHN). After intravenous injection, the versatile nanoplatform not only improved the hydrophilicity of BP but also achieved stratified targeting from tumor to mitochondrial and induced mitochondrial dysfunction, thus activating caspase-3 upregulation. Then, sonodynamic therapy (SDT), an alternative modality with high tissue penetrability, is performed to evoke reactive oxygen species (ROS) generation for BP. More importantly, since the hydrophilic shell is separated from the nanosystem by the specific cleavage of caspase-3, the resulting decrease in hydrophilicity induced tight self-aggregation of PAHN residues in situ, further allowing more absorbed energy to be used for ROS generation under ultrasound irradiation and enhancing SDT efficacy. Moreover, severe oxidative stress resulting from ROS imbalance in the mitochondria initiates the immunogenic cell death process, thus evoking antitumor immunogenicity. This PAHN provides prospective ideas into AIE-involved antitumor therapy and design of peptide-AIEgens hybrids.

Associated genetic variants and potential pathogenic mechanisms of brain arteriovenous malformation.

BACKGROUND: The pathogenic mechanism of brain arteriovenous malformation (bAVM) is poorly understood. A growing body of evidence indicates that genetic factors play crucial roles in bAVM. This study examined genetic variants associated with bAVM through quantitative synthesis and qualitative description of literature. METHODS: Five databases were searched to gather potentially relevant articles published up to January 2022. STATA 14.0 software was used for statistical analyses. Pooled odds ratios and 95% confidence intervals were calculated with random effect models, and heterogeneity was assessed using the Cochran Q test and quantified with the I 2 test. Sensitivity and publication bias were analyzed to test the robustness of the associations. Variants identified in only one study or with great heterogeneity were not suitable for pooling association analysis, and therefore a qualitative systematic review was performed. RESULTS: In total, 30 papers were included in a systematic review involving 4709 cases and 7832 controls, where 17 papers were in a meta-analysis. A suggested association of bAVM was observed with ACVRL1 rs2071219 in the additive model and CDKN2B-AS1 rs1333040 in the recessive and additive models. Other variants of genes that could not be analyzed were summarized by qualitative description. These genes were mostly involved in bone morphogenic protein/transforming growth factor beta (BMP/TGF-ß), vascular endothelial growth factor/vascular endothelial growth factor receptor (VEGF/VEGFR), and RAS-mitogen activated protein kinase (MAPK) signaling and inflammation. CONCLUSIONS: According to our meta-analysis, ACVRL1 rs2071219 and CDKN2B-AS1 rs1333040 were potentially associated with bAVM. Multiple pathological signaling pathways could affect disease development. Future studies should aim to determine the interaction of candidate genes with environmental risk factors and to elucidate detailed mechanisms of action of variants and genes.1.

Factors affecting time to treatment initiation after diagnosis for multidrug-resistant/rifampicin-resistant tuberculosis patients: A mixed-methods study in Jakarta, Indonesia.

OBJECTIVE: To investigate the time to treatment initiation (TTI) for multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) patients after diagnosis in Indonesia and biological, psychological and social factors associated with the time interval. METHODS: This study was conducted in Persahabatan Hospital, Jakarta using a mixed-methods approach. Registry data and medical records of MDR/RR-TB patients were collected and matched (hospital dataset), and linked with psychosocial assessment results (linked dataset). Descriptive analysis was conducted to understand patient characteristics and the distribution of TTI after RR-TB diagnosis by GeneXpert. Generalised linear regression was used to analyse factors associated with delay duration, and logistic regression to explore factors associated with the delay longer than the median duration for both datasets (basic vs. extended model). In-depth interviews were conducted with patients and healthcare workers to understand the procedure of treatment initiation and how different factors led to delay. RESULTS: The hospital dataset included 275 patient-matched cases, and 188 were further linked with psychosocial assessment results. The median time interval was 24 days [interquartile range (IQR) 23.5] and 26 days (IQR 21.25), respectively. Regression analysis showed that in the extended model, comorbidities (exp [coefficient]= 1.93), unemployment (exp [coefficient] = 1.80) and poor knowledge of MDR/RR-TB (exp (coefficient) = 1.67) seemed to have the strongest effects on prolonging the time interval (p < 0.05). Unsuccessful TB treatment history was the only factor that significantly increased the risk of delay longer than the median duration (p < 0.05) in the basic model, while none of the factors were significant in the extended model. The qualitative study identified provider-side factors (centralised service provision and insufficient human resources) and patient-side factors (physical weakness, psychological stress and financial concern) associated with treatment delay. CONCLUSION: MDR/RR-TB patients in Persahabatan Hospital, Jakarta, Indonesia waited around 25 days for treatment initiation after RR-TB diagnosis. Health system solutions are needed to address challenges facing both MDR/RR-TB patients and healthcare providers to reduce delay in treatment initiation.

Nanoenabled Tumor Energy Metabolism Disorder via Sonodynamic Therapy for Multidrug Resistance Reversal and Metastasis Inhibition.

Cancer multidrug resistance (MDR) is an important reason that results in chemotherapy failure. As a main mechanism of MDR, overexpressed P-glycoprotein (P-gp) utilizes adenosine triphosphate (ATP) to actively pump chemotherapy drugs out of cells. In addition, metabolic reprogramming of drug-resistant tumor cells (DRTCs) exacerbates the specific hypoxic microenvironment and promotes tumor metastasis and recurrence. Therefore, we propose a novel sonodynamic therapy (SDT) paradigm to induce energy metabolism disorder and drug resistance change of DRTCs. A US-controlled "Nanoenabled Energy Metabolism Jammer" (TL@HPN) is designed using perfluoropentane (PFP) adsorbing oxygen in the core, and a targeting peptide (CGNKRTR) is attached to the liposome as the delivery carrier shell to incorporate hematoporphyrin monomethyl ether (HMME) and paclitaxel (PTX). The TL@HPN with ultrasonic/photoacoustic imaging (PAI/USI) precisely controlled the release of drugs and oxygen after being triggered by ultrasound (US), which attenuated the hypoxic microenvironment. SDT boosted the reactive oxygen species (ROS) content in tumor tissues, preferentially inducing mitochondrial apoptosis and maximizing immunogenic cell death (ICD). Persistently elevated oxidative stress levels inhibited ATP production and downregulated P-gp expression by disrupting the redox balance and electron transfer of the respiratory chain. We varied the effect of TL@HPN combined with PD-1/PD-L1 to activate autoimmunity and inhibit tumor metastasis, providing a practical strategy for expanding the use of SDT-mediated tumor energy metabolism.

Use of covered stents to treat complex cerebrovascular diseases: Expert consensus.

The treatment of complex cerebrovascular diseases (CCVDs) at the skull base, such as complex intracranial aneurysms, carotid-cavernous sinus fistulas, and intracranial artery traumatic injuries, is a difficult clinical problem despite advances in endovascular and surgical therapies. Covered stents or stent graft insertion is a new concept for endovascular treatment that focuses on arterial wall defect reconstruction, differing from endovascular lesion embolization or flow diverter therapies. In recent years, covered stents specifically designed for cerebrovascular treatment have been applied in the clinical setting, allowing thousands of patients with CCVDs to undergo intraluminal reconstruction treatment and achieving positive results, even in the era of flow diverters. Since there is no unified reference standard for the application of covered stents for treating CCVDs, it is necessary to further standardize and guide the clinical application of this technique. Thus, we organized authoritative experts in the field of neurointervention in China to write an expert consensus, which aims to summarize the results of covered stent insertion in the treatment of CCVDs and propose suitable standards for its application in the clinical setting. Based on the contents of this consensus, clinicians can use individualized intraluminal reconstruction treatment techniques for patients with CCVDs.