医学最新文献

Objective: The purpose of this systematic review and meta-analysis is to assess the association of handgrip strength (HGS) in subjects with high-normal or mildly elevated and low-normal serum uric acid (SUA) reported by quartiles.

Methods: The research protocol was registered at PROSPERO (CRD420251050351). We searched four databases to obtain relevant articles reporting HGS by SUA quartiles in subjects without gout. Outcomes were compared by combining the third and fourth SUA (higher) quartiles versus the first and second (low) quartiles. The risk of bias was assessed using the Newcastle‒Ottawa Scale, and heterogeneity with the I² test. The results are reported as the mean difference (MD), standardized MD (SMD), or odds ratio (OR).

Results: Seven cross-sectional studies, including 18,765 adult subjects with higher SUA quartiles showed significant higher HGS (SMD: 0.21, 95% confidence interval [CI]: 0.03, 0.39), body mass index (MD: 1.02 kg/m², 95% CI: 0.48, 1.55), total cholesterol (SMD: 0.14, 95% CI: 0.05, 0.24), LDL-cholesterol SMD: 0.13, 95% CI: 0.09, 0.17), and triglycerides (SMD: 0.26, 95% CI: 0.11, 0.41) than those with lower SUA quartiles. HDL-cholesterol was significantly reduced in subjects with higher SUA (SMD: -0.13, 95% CI: -0.20, -0.07). High SUA levels were associated with a drinking history (OR: 1.21, 95% CI: 1.10, 1.34) and hypertension (OR: 1.51, 95% CI: 1.15, 1.99).

Conclusions: Subjects with higher normal SUA levels showed higher HGS compared to those with lower normal levels.

Alterations in the gut microbiota, known as gut dysbiosis, are associated with inflammatory bowel disease (IBD). There is a need for model systems that can recapitulate the IBD gut microbiome to better understand the mechanistic impact of differences in microbiota composition and its functional consequences in a controlled laboratory setting. To this end, we introduced fecal samples from patients with Crohn's disease (CD) and ulcerative colitis (UC), as well as from healthy control subjects, to miniature bioreactor arrays (MBRAs) and analyzed the microbial communities over time. We then performed two functional assessments. First, we evaluated the colitogenic potential of the CD microbiotas in genetically susceptible germ-free IL-10-deficient mice and found that colitogenic capacity was preserved in a bioreactor-cultivated CD microbiota. Second, we tested impaired colonization resistance against Clostridioides difficile in UC microbiotas using the MBRA system and found that UC microbiotas were innately susceptible to C. difficile colonization while healthy microbiotas were resistant, consistent with what is seen clinically. Overall, our results demonstrate that IBD microbiotas perform comparably to healthy donor microbiotas in the MBRA system, successfully recapitulating microbial structure while preserving IBD-specific functional characteristics. These findings establish a foundation for further mechanistic research into the IBD microbiota using MBRAs.

Background: Premature ovarian insufficiency (POI) significantly impairs female fertility and poses substantial health risks; however, its pathogenesis is incompletely understood, and effective therapeutic interventions are limited. Although gut bacteriome has been closely associated with ovarian dysfunction, the role and therapeutic potential of gut viruses, which far outnumber bacteria, remain largely unexplored.

Results: Therefore, we recruited 60 healthy reproductive-aged women and recently diagnosed POI patients and investigated these concerns using various techniques, including whole-genome shotgun sequencing of virus-like particle (VLP) and fecal virome transplantation (FVT) in CTX-induced POI rats. We found considerable interindividual variability in the gut virome. The virome of POI patients exhibited significant dysbiosis, characterized by a marked reduction in virulent phage, significant changes in predominant phages, and a notable increase in horizontal gene transfer of resistance genes and virulence factors. Furthermore, gut VLPs from the healthy reproductive-aged women significantly improved the condition of POI rats. Conversely, gut VLPs from POI patients markedly impaired the ovarian function and reproductive capacity of healthy rats. The above regulatory effect is primarily due to modulations of gut bacteriome, specifically the estrobolome, and intestinal barrier integrity, which subsequently affect hypothalamic-pituitary-ovarian axis hormone levels and regulate ovarian oxidative stress and inflammation, thereby influencing ovarian function.

Conclusions: Our findings demonstrate the critical roles of the gut virome in regulating ovarian function and provide new insights into the pathogenesis of POI. This study also underscores the therapeutic potential of the gut virome in improving ovarian dysfunction and female infertility including POI.

Nanobodies have emerged as promising tools for many biotechnological applications due to their small size, high stability and remarkable binding specificity. Next-Generation Sequencing (NGS) enables deep profiling of large nanobody libraries and panning campaigns; however, the scale and diversity of nanobody NGS datasets presents a significant bioinformatic challenge. To this end, we have developed alpseq, an optimized, open-source software pipeline designed specifically for the efficient and accurate processing of NGS data from nanobody libraries and panning campaigns. alpseq is also paired with a PCR-free sequencing library preparation protocol to allow researchers to easily generate their own data while avoiding biases. The alpseq software pipeline is composed of two parts: a pre-processing module written in Nextflow efficiently handles raw nanobody reads in a single line of code. These results are then fed into the analysis module, which contains a comprehensive suite of functions for quality control, diversity analysis, identification of enriched sequences and clustering. alpseq also creates a user-friendly interactive report which empowers scientists to explore their data without the need for extensive bioinformatic experience. Sophisticated panning campaign designs are supported, such as replicates and comparisons between different pans to find cross-binding leads. alpseq thus generates insights into the nanobody selection process and delivers a list of lead candidates for further experimental validation and downstream applications. alspeq is available at https://github.com/kzeglinski/alpseq.

Although numerous drugs have been developed for intravaginal administration, the implementation of personalized intravaginal treatment options is limited. The MedRing overactive bladder (OAB) system is a medical device for intravaginal oxybutynin administration via patient-controlled schedules. The primary aim was to assess the feasibility, tolerability, and safety of intravaginal oxybutynin administration via the MedRing OAB system. Second, the functioning of the MedRing OAB system, user satisfaction and quality of life (QoL) were assessed. Female OAB patients were included to receive the MedRing OAB system. Treatment was divided into three periods with increasing dosing flexibility: 2 mg at three fixed timepoints daily, 2 mg at three patient-defined timepoints daily, and flexible dosing up to 6 mg/day of 1 or 2 mg doses. Feasibility, tolerability, satisfaction, and QoL were assessed via questionnaires, safety via treatment-emergent adverse events (TEAEs), device deficiencies (DDs) and physical examination and functioning via pharmacokinetics and MedRing logs. Thirteen patients were enrolled, of whom three patients discontinued the study prematurely. Most patients reported low user burden, found the system practical and expressed positive opinions. The TEAEs were consistent with known oxybutynin effects and local TEAEs were comparable to other intravaginal devices. Most DDs were synchronization difficulties, which improved after a software update. After 10 minutes, oxybutynin levels were detected in 12 of the 13 patients. This study showed that the MedRing OAB system appears to be a feasible, tolerable and safe alternative intravaginal oxybutynin administration for 28 days in OAB patients, offering a potential alternative to existing treatment options and introducing personalized patient care.

The instability of liposomes in blood samples during clinical drug research and drug monitoring results in the inability to accurately determine the actual drug concentrations in the body at the time of collection, mainly due to lipid deterioration, particle fusion or aggregation, and phase separation degradation, resulting in payload leakage. To improve drug monitoring accuracy, we developed a cryopreservation strategy in this study by innovatively combining cryoprotective agents (CPAs), such as L-proline, sucrose, and polyvinyl alcohol (PVA), to prevent liposomal leakage and maintain stability for reliable drug monitoring and clinical drug research applications. Doxorubicin liposomes were prepared, and the CPAs were tested at various concentrations and under different freeze‒thaw protocols in biological matrices, with the stability and leakage of the liposomes assessed. Each CPA contributes distinct stabilization mechanisms, with L-proline's osmoprotective ability, sucrose's hydrogen bonding, and PVA's steric hindrance to form a protective barrier. The optimized CPA combination demonstrated superior performance at 85% (v/v) by preserving liposomal integrity, offering the best cryoprotective effect for liposomes in plasma stored at -20 °C, achieving about 90% entrapment efficiency, compared to about 60% in the control group without CPAs. Mechanistic investigations confirmed that CPAs protect liposomes against mechanical stress, prevent membrane disruption, and reduce ice damage by inhibiting recrystallization and adjusting bilayer hydration. These findings offer practical solutions for accurate pharmacokinetic assessments and reliable personalized dosing, safer alternative for liposomal drug research, biobanking, and real-world therapeutic monitoring.

Purpose: This study focused on how adults with cerebral palsy successfully confronted ableism during encounters with others and successfully coped with ableism in general.

Methods: Adults with cerebral palsy led this critical participatory action research project, in which ten adults with cerebral palsy shared their experiences (via an online survey or interview) of successfully confronting ableism (situations, actions taken, and outcomes) and coping with ableism.

Results: Participants had difficulty recalling successful confrontations due to failing to recognise ableism, ignoring it, or being unsure whether confrontations were successful. Of the 23 situations described, common forms of ableism were denial of privacy, perceived helplessness, and spread effect. Actions taken in successful confrontations were educating perpetrators, being independent, self-advocating or requesting advocacy, attempting to make perpetrators feel uncomfortable, and disengaging with perpetrators (and encouraging others to do similar). Outcomes were changed perpetrator behaviour, apparent changed perpetrator perceptions, actions to prevent recurrence of ableism, disengagement, changed thinking, and feeling successful. Adults coped with ableism through changing their own thinking about disability and ableism, engaging in everyday activities, seeking social support, and making efforts to change society.

Conclusions: Harnessing this knowledge may assist people with cerebral palsy to challenge the social oppression they face.

Bispecific antibodies are used for the treatment of hematological malignancies as well as solid tumors. One of their main effector mechanisms is the recruitment of effector cells such as CD8⁺ T cells and CD16A⁺ NK cells to tumor cells. Bispecific innate cell engagers (ICE®) harnessing CD16A⁺ NK cells have been shown to induce significant tumor cell lysis in preclinical models, translating to promising signs of clinical activity together with a well-managed safety profile. However, how killing of tumor cells by NK cells influences other innate immune cells in the tumor microenvironment, such as dendritic cells (DCs), instrumental in bridging innate and adaptive tumor immunity, is largely unknown. Thus, we here analyzed whether antibody-dependent cell-mediated cytotoxicity by NK cells affected human DC subpopulations. We could show that killing of tumor cells leads to a strong activation of human conventional DCs type 1 (cDC1), DC2, and DC3 with enhanced expression of co-stimulatory molecules as well as the secretion of proinflammatory cytokines. Further, DC subpopulations as well as surviving tumor cells showed increased expression of the immunoregulatory molecule PD-L1 that is known to dampen T-cell immunity. Nevertheless, ADCC boosted the capacity of cDC1 and DC2 to prime naïve T cell responses but not of DC3. Thus, our data suggests that the therapy with bispecific antibodies targeting NK cells may have the potential to facilitate adaptive antitumor immune responses via activation of cDC1 and DC2.

Antibody-drug conjugates (ADCs) and other biopharmaceuticals require robust analytical methods to assess biotransformation in biological matrices. Current approaches often require off-line enrichment and extensive chromatographic separation, limiting throughput and complicating data processing. We developed a native affinity liquid chromatography-mass spectrometry (aLC-MS) method using POROS CaptureSelect FcXL columns combined with optimized solvents and MS parameters for direct analysis (1D aLC-MS) of ADCs and other antibody-derived formats in complex sample matrices, such as serum. The method was evaluated using stability studies and concentration series in mouse serum. Direct analysis enabled accurate determination of drug-antibody ratio (DAR), drug-load distribution (DLD) and relative drug abundance across samples without chromatographic peak integration. Stability studies revealed distinct ADC biotransformation profiles in serum versus PBS, including maleimide hydrolysis and disulfide exchange at under-conjugated cysteine sites. The aLC-MS method achieved excellent linearity (R² = 0.99) over 125-2000 µg/mL in serum and demonstrated sensitivity to 31.25 µg/mL. This rapid, selective aLC-MS method enables high-throughput monitoring of ADC quality attributes in complex matrices with minimal sample preparation, supporting biopharmaceutical product development and bioanalysis applications. The method is exclusively based on MS results, which makes data processing and reporting fast and easy to automate.

Background: Renal denervation (RDN) has emerged as a potential therapeutic option for resistant hypertension (HT), which remains a major clinical challenge due to poor blood pressure (BP) control despite optimized pharmacotherapy. This study aimed to assess the safety and effectiveness of catheter-based RDN in resistant hypertension patients, based on our center's experience.

Methods: This retrospective, single-center study included 120 patients with resistant HT who were eligible for RDN and underwent the procedure using the Symplicity Spyral system between January 2023 and December 2024. Office systolic and diastolic BP were assessed at baseline and 6 months after RDN. The primary endpoint was the reduction in BP, while secondary endpoints included changes in the number of antihypertensive medications.

Results: At 6 months, office systolic BP decreased significantly from 156 ± 7.7 mmHg to 143 ± 3.7 mmHg, while diastolic BP declined from 93.5 ± 5.5 mmHg to 90 ± 3.9 mmHg (both p < 0.001). Median per-patient reductions were 13 mmHg systolic and 3.5 mmHg diastolic. The mean number of antihypertensive medications decreased from 4.88 ± 0.9 to 4.47 ± 1.1 (p < 0.001). Minor adverse events included acute kidney injury in two patients (1.7%) and femoral artery injury in one patient (0.8%).

Conclusion: Catheter-based RDN using the Symplicity Spyral system was safe and effective in reducing BP and medication burden in patients with resistant HT. These results support RDN as a potential therapeutic option in appropriately selected patients.