BMC Medicine最新文献

Background: During the COVID-19 pandemic, diverse vaccine strategies were applied globally, yet most relied on immunogenicity evaluations and bridging trials rather than retrospective assessment through real-world infections. This limited understanding of protective mechanisms under natural variant exposure.

Methods: A retrospective cohort study of real-world BA.5 infections was used to analyze the protective efficacy of Ad5-nCoV booster vaccination (A-A). Multi-layered immune profiling was performed, including neutralizing antibodies (NAbs), single-cell BCR sequencing (BCR usage), transcriptomic profiling (RNA-seq), antibody-dependent cellular cytotoxicity (ADCC), natural killer (NK) cell cytotoxicity, and virus-specific T cell immunity. These were integrated to dissect A-A-induced protection mechanisms.

Results: The A-A conferred 48% effectiveness against symptomatic BA.5 infection (115/239) compared to the three doses of inactivated vaccine (I-I-I), which showed 10% effectiveness (4/39). Specifically, in the A-A group, 52% (124/239) of individuals experienced symptomatic infection, 38% (90/239) had asymptomatic infection, and 10% (25/239) remained uninfected. Compared to I-I-I, A-A induced significantly higher NAbs against BA.5 (GMT = 180 vs. I-I-I GMT = 54) and comparable anti-WT NAbs (GMT = 358 vs. 226), despite lower anti-S IgG levels (GMT = 6441 vs. 12,228) at 2 months post BA.5 infection. Single-cell BCR analysis revealed broader neutralizing antibody clone types in A-A, dominated by IGHV4-39 usage with elevated somatic mutation frequency. Additionally, transcriptomic and functional assays demonstrated an enhanced NK cell-mediated ADCC response and cytotoxicity against K562 target cells in A-A.

Conclusions: Ad5-nCoV booster vaccination confers enhanced protection against symptomatic BA.5 infection through cross-reactive NAbs with expanded epitope breadth and NK cell-mediated innate immunity enhancement. This retrospective study provides insights into the immunogenicity and molecular mechanisms of two vaccination strategies against real-world BA.5 infection, highlighting Ad5-based technology's efficacy. It provides guidance for future vaccination strategies against emerging Disease X, emphasizing the value of retrospective real-world analyses in vaccine development.

Background: Healthcare workers (HCWs) face high occupational exposure to SARS-CoV-2 and are a priority group for vaccination. Both natural infection and vaccination-individually or combined as hybrid immunity-confer protection against SARS-CoV-2 infection. This study aimed to evaluate the protection conferred by hybrid, infection-induced, and booster vaccine-induced immunity against laboratory-confirmed SARS-CoV-2 infections in HCWs during the circulation of three pandemic and one post-pandemic Omicron sublineages.

Methods: We conducted a prospective cohort study of HCWs from 18 hospitals across nine European countries. Participants underwent RT-PCR testing at enrolment and during weekly or fortnightly follow-ups. The study period was divided based on dominant Omicron sublineage circulation: BA.1/2 (Dec 16, 2021-Jun 1, 2022), BA.4/5/BQ.1 (Jun 2-Dec 31, 2022), BA.2/XBB (Jan 1-May 2, 2023), and post-pandemic XBB.1.5/BA.2.86 (Sep 1, 2023-May 21, 2024). Participants were classified into four groups: hybrid (prior infection and recent booster vaccination 7-179 days), infection-induced (prior infection, no recent vaccination), vaccine-induced immunity (recent booster vaccination, no prior infection), and a reference group (no prior infection, no recent booster vaccination). Adjusted hazard ratios (aHRs) for infection were estimated using Cox regression, adjusting for hospital, age, sex, chronic condition, and patient-facing role.

Results: A total of 3 133 HCWs were included: 2572 (82%) female, 1734 (55%) aged 40-59, and 563 (29%) with ≥ 1 chronic condition. Hybrid immunity showed significant protection during BA.1/2 (aHR = 0.37, 95%CI 0.21-0.63), BA.4/5/BQ.1 (aHR = 0.36, 95%CI 0.22-0.58), and XBB.1.5/BA.2.86 (aHR = 0.53, 95%CI 0.37-0.74) periods. Infection-induced immunity was protective across all periods, most during BA.1/2 (aHR = 0.26, 95%CI 0.12-0.53), and least during BA.2/XBB (aHR = 0.66, 95%CI 0.36-1.22). Vaccine-induced immunity alone offered limited protection during BA.1/2 (aHR = 0.72, 95%CI 0.49-1.06) and BA.4/5/BQ.1 (aHR = 0.77, 95%CI 0.50-1.19), with wide confidence intervals suggesting low statistical significance.

Conclusions: Hybrid and infection-induced immunity groups were more protected against infection caused by earlier Omicron sub-lineages and more protected than vaccination alone, which had no significant protective effect. These findings highlight the need for adaptive public health strategies, including timely vaccine updates and understanding of prior SARS-CoV-2 infection to inform COVID-19 vaccination policies for HCWs in the post-pandemic era.

Background: Growth of head circumference is critically associated with neurodevelopmental outcomes. Extrauterine growth restriction of head circumference from birth to term-equivalent age is linked to impaired neurodevelopment. This study examined whether a proinflammatory state and metabolic dysregulation characterize the association between delayed feeding progression and extrauterine restricted head growth in extremely preterm infants.

Methods: This cohort study included infants born ≤ 28 weeks' gestation between 2019 and 2021. Feeding progression trajectories, categorized as improvement or delayed improvement based on daily enteral feeding milk volumes during the first 8 weeks, were analyzed using kmlShape. Plasma metabolomics were assessed at 36 weeks postmenstrual age, and head growth and brain MRI were evaluated at term-equivalent age.

Results: Among the 98 extremely preterm infants, 62 (63%) demonstrated improvement in feeding progression, while 36 (37%) had delayed improvement. Compared to the feeding improvement group, the delayed feeding improvement group had higher rates of gastrointestinal morbidities, including necrotizing enterocolitis (NEC) of Bell stage II or higher (17% vs. 2%, p = 0.009) and abdominal surgery for non-NEC events (25% vs. 8%, p = 0.021) during admission, and a significantly increased risk of extrauterine growth restriction in head circumference by term-equivalent age (47% vs. 23%, p = 0.021). The multivariable analysis showed delayed feeding improvement was also a significant risk associated with the delta z-scores below - 1.5 in head circumference (adjusted odds ratio [aOR]: 5.26 [95% CI 1.66-16.65]). MRI examinations revealed significantly smaller residual brain volumes involving total brain tissue volume, brainstem, and cerebellum in the delayed improvement group. Untargeted plasma metabolomics showed elevated levels of hydroxyeicosatetraenoic acid, leukotriene B4, prostaglandins, bile acids and immune markers, and reduced levels of L-tyrosine, phenylpyruvic acid, L-tryptophan metabolism, and L-carnitine biosynthesis were found in the delayed improvement group compared to that in the improvement group.

Conclusions: Proinflammatory and dysregulated metabolic state following early delayed feeding progression were associated with impaired extrauterine head growth, highlighting the potential role of the immature gut-brain axis in preterm infants.

Background: Gut microbial dysbiosis is common in the intensive care unit and certain derangements, like expansion of Enterobacteriaceae and other potential pathogens (pathobionts), are associated with increased morbidity. In other populations, dysbiosis is improved by enteral nutrition supplemented with prebiotic short-chain fructooligosaccharides (scFOS-EN). The impact of scFOS-EN on the microbiota in critical illness is unknown and difficult to predict in a dysbiotic environment. Thus, we conducted a pilot randomized control trial (RCT) in critically ill trauma patients to evaluate the effects of scFOS-EN versus a fiber-free enteral formula (NF-EN) on gut microbial dynamics.

Methods: In this single-center, prospective, double-blind RCT, mechanically ventilated trauma ICU patients received scFOS-EN or a similar fiber-free formula (NF-EN). Microbial communities in longitudinally collected stool samples were characterized using 16S rRNA gene sequencing. We used linear mixed-effects models to assess microbial dynamics in the 10-day study period after scFOS-EN or NF-EN initiation, as well as a time-informed dimensionality reduction method to identify patient-specific temporal responses and clinical correlates and network approaches for microbe:microbe interactions.

Results: A total of 57 stool samples were analyzed from 17 patients (7 NF-EN, 10 scFOS-EN). All participants had profound baseline dysbiosis and received broad-spectrum antibiotics. Compared to NF-EN, scFOS-EN was associated with an accelerated loss of Bifidobacterium (- 0.6%/day p = .026) and Firmicutes (3.5%/day, p < .001) and greater increases in several Bacteroidaceae members, with expansion of pathobiont Enterobacteriaceae (0.3%/day, p = .003) unique to scFOS-EN participants. Detrimental microbial responses to scFOS-EN, including high Enterobacteriaceae burden, were dictated by pre-existing and ongoing antibiotic exposure and associated with enhanced microbial competition.

Conclusions: In the dysbiotic gut of critically ill trauma patients, the effect of scFOS-EN is context-dependent. Prior exposure to anaerobic antibiotics appears to modify the microbial response from beneficial to detrimental. These findings challenge a universal approach to prebiotic therapy and underscore the need for personalized nutritional strategies in the ICU.

Trial registration: The trial was prospectively registered at ClinicalTrials.gov (Identifier: NCT03153397; first posted May 15, 2017) prior to participant enrollment and approved by the Duke Health Institutional Review Board (IRB Pro00081414).

Background: Compulsory admissions to psychiatric hospitals have been rising in England and some other higher-income countries. Patients and families often find such admissions distressing, disempowering and traumatising. Evidence on how to prevent compulsory admissions is still very limited. Collaborative crisis planning currently appears to be the most promising way of reducing compulsory readmissions, but can be challenging to implement.

Methods: The overall aim of the FINCH (Feasibility trial of an INtervention to reduce Compulsory Hospitalisation) study was to develop a crisis planning and monitoring intervention to prevent repeat compulsory admissions, and to investigate the feasibility and acceptability of testing it through a randomised controlled trial. Drawing on a promising intervention developed in Switzerland and on qualitative interviews with service users and carers, a team including researchers, service users, carers and clinicians co-designed an intervention. This included formulating personalised plans for preventing and managing crises, with follow-up contacts over a year to support participants in implementing these. We carried out a feasibility randomised controlled trial of the intervention, with 80 participants recruited towards the end of compulsory hospital admissions in three areas of England.

Results: Eighty participants were recruited within our target timeframe, 40 (as planned) from ethnic groups at disproportionately high risk of compulsory admission. Data were obtained for 86% of participants on compulsory admission, identified as a potential primary outcome for a full trial, but only for 51% on secondary outcomes measured at interview. Twenty-five of the 38 experimental group participants (66%) received at least three intervention sessions and developed a crisis plan of some kind. Qualitative data obtained from participating service users and carers suggested the intervention was acceptable and feasible, but that a high level of persistence and flexibility and considerable time were needed to deliver it.

Conclusions: We were readily able to recruit for this study, including from ethnic groups who are at high risk of compulsory admission, and delivery of our study intervention was feasible at least in a minimum form. Given the high financial and human costs of compulsory admission, there is an ethical and practical requirement for more research in this area: larger-scale research based on a refined version of our intervention has the potential to contribute.

Trial registration: ISRCTN, ISRCTN11627644. Registered prospectively 25th May 2022,  https://www.isrctn.com/ISRCTN11627644 .

Background: The presence and role of endogenous digoxin-like cardiotonic steroids (CTS) in humans is controversial. This study utilises a novel pipeline to quantify CTS and examines their interaction with digoxin within a randomised trial.

Methods: The RAte control Therapy Evaluation in permanent Atrial Fibrillation (RATE-AF) trial randomised patients with permanent AF and symptoms of heart failure to low-dose digoxin or beta-blocker therapy; clinicaltrials.gov NCT02391337. Circulating CTS were detected and quantified using a new ultra-high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS) pipeline.

Results: All 160 participants of the RATE-AF trial were included, with mean age 76 years (SD 8) and 46% women. Endogenous CTS detected and quantified in baseline samples included digoxigenin and digitoxigenin, plus low or unquantifiable levels of ouabain, telocinobufagin, cinobufagin, marinobufagenin, bufalin, cinobufotalin, dihydroouabain, and ouabagenin. Compared to beta-blockers, patients randomised to digoxin had better functional outcomes at 12 months for heart failure (- 0.57 New York Heart Association class, 95% CI - 0.82 to - 0.32; p < 0.001) and atrial fibrillation (odds ratio 2.24 for a two-class improvement in modified European Heart Rhythm Association class, 95% CI 1.43-3.84; p < 0.001), with lower NT-pro-B-type natriuretic peptide (geometric mean ratio 0.78, 95% CI 0.61 to 0.99; p = 0.006). No interactions were observed for any baseline CTS with each outcome. Digoxin was associated with fewer adverse events (odds ratio 0.16, 95% CI 0.07-0.34; p < 0.001), again without any interaction from circulating CTS. Digoxin levels by LC-MS/MS were strongly correlated with measurement by a clinical immunoassay (r = 0.87; p < 0.001), and treatment with digoxin did not affect CTS concentrations at 6-month follow-up.

Conclusions: A range of CTS are detected in the circulation of patients with atrial fibrillation and heart failure. Within this randomised trial but limited by low circulating levels, CTS do not appear to interact with the ability of digoxin to improve wellbeing compared to conventional first-line treatment with beta-blockers.

Background: A firm understanding of SARS-CoV-2 hybrid immunity is crucial for our ongoing efforts to protect people from severe and fatal disease and assess population vulnerability to emerging novel variants. As many components of the immune response are unobserved and complex to investigate, some ambiguities and unanswered questions remain about hybrid immunity to COVID-19, such as the duration of the antibody response in individuals.

Methods: To address this, we evaluated longitudinal data that spanned up to 21 months from 52 SARS-CoV-2 naive individuals and 88 SARS-CoV-2 recovered individuals. We further separated individuals according to whether they received an mRNA or non-mRNA vaccine for their primary two-dose vaccinations. A hierarchical Bayesian framework was used to fit the parameters of mono-phasic exponential decay and bi-phasic exponential decay models to the observed data to estimate the magnitude and half-life of the spike-specific and receptor-binding domain (RBD)-specific IgG responses.

Results: Results from both our mono-phasic and bi-phasic exponential decay models estimate that the median half-life of the spike-specific and RBD-specific IgG response in individuals with hybrid immunity is almost double that of naive individuals who were only vaccinated. Recovered mRNA recipients were estimated through the mono-phasic decay model to have a median IgG response half-life of 448 days (95% CrI: [375.08, 547.54]) to spike antigen, compared to an estimated 222 days (95% CrI: [179.90, 286.62]) for naive mRNA recipients. Posterior estimates from the bi-phasic exponential decay model show that recovered individuals who received mRNA vaccinations had a median IgG response half-life of 810 days (95% CrI: [650.91, 1031.63]) to spike antigen, compared to 451 days (95% CrI: [336.81, 618.14]) for naive mRNA recipients. A similar pattern is seen in non-mRNA vaccine recipients, with IgG response half-lives differing slightly. Our results show that, across different model assumptions, individuals with hybrid immunity have an IgG response half-life that is considerably greater than that of individuals with only infection- or vaccine-induced immunity.

Conclusions: Our work provides important insight into the longevity of the IgG response to SARS-CoV-2 in individuals with hybrid immunity and can guide effective immunisation approaches to maintain and improve population-level protection.

Background: Ischemic leg ulcers (ILU) represent a severe manifestation of chronic limb-threatening ischemia (CLTI), characterized by high recurrence and amputation rates. This study evaluated the efficacy and safety of tibial periosteal distraction (TPD) for treating ILU through a combination of animal experiments and clinical trials.

Methods: Nine Beagle dogs were randomly allocated into TPD group, tibial soft tissue distraction (TSD) group, and control group. Standardized 15-mm circular wounds were created on the foot, followed by periosteal distraction at a rate of 0.5 mm/day for 11 days. Parameters assessed included wound healing rates, serum VEGF levels, histopathological changes, and CT angiography/perfusion parameters. A multicenter retrospective cohort study was conducted from June 2019 to January 2024, enrolling 103 ILU patients treated with TPD compared with 127 patients receiving conventional treatment. Primary endpoints included ulcer healing rates at 3 and 6 months, amputation rates, and recurrence within 1 year. Secondary endpoints comprised complications and safety assessments.

Results: In animal study, the TPD group demonstrated accelerated wound healing compared to both control and TSD groups, with residual wound area of 2.08 ± 1.68% on day 16, versus 5.46 ± 1.98% in the control group and 12.49 ± 2.97% in the TSD group. Serum VEGF levels were markedly elevated in the TPD group from days 8 to 16 (peak: 27.25 ± 2.16 pg/ml vs. 17.90 ± 1.72 pg/ml in controls, P < 0.01). CT angiography revealed enhanced collateral circulation in the distraction region with increased tissue perfusion parameters (equivalent blood volume and arterial flow). In clinical study, the TPD group achieved superior healing rates compared to controls: 90.3% vs. 77.2% at 3 months (P = 0.008) and 94.2% vs. 85.8% at 6 months (P = 0.039). Major amputation rate was reduced in the TPD group (2.9% vs. 9.5%, P = 0.046), while minor amputation rates showed no significant difference (38.8% vs. 44.1%, P = 0.421). Recurrence within 1 year was markedly decreased (8.7% vs. 19.7%, P = 0.020). Complications included pin tract infection in 7 cases (6.8%) and pain intolerance requiring distraction rate adjustment in 9 cases (8.7%), all successfully managed with conservative treatment.

Conclusions: TPD offers a promising therapeutic option for CLTI patients, particularly those unsuitable for vascular reconstruction. Further prospective randomized trials are warranted to establish standardized protocols and optimize treatment parameters.

Background: To explore the associations between clustering of cardiometabolic risk factors, physical activity (PA), and digital exclusion with depressive symptoms trajectories, and to assess whether PA and digital exclusion mediate these associations.

Methods: This study included 8999 participants from the Health and Retirement Study (HRS, n = 4380) and the English Longitudinal Study of Ageing (ELSA, n = 4519). Cardiometabolic risk factors included waist circumference, high-density lipoprotein (HDL) cholesterol, systolic and diastolic blood pressure, type 2 diabetes mellitus, glycated hemoglobin (HbA1c), and C-reactive protein (CRP). Depressive symptoms, PA, and digital exclusion were assessed via self-report. Statistical analyses used multinomial logistic regression and the Karlson-Holm-Breen (KHB) method.

Results: We identified three clustering of cardiometabolic risk factors and four depressive symptoms trajectories. Compared to participants classified as healthy obesity, those in the obesity-hypertension group had an OR of 1.26 (95% CI: 1.09-1.46) for the moderately severe depressive symptom trajectory, while those in the complex cardiometabolic group had an OR of 1.31 (95% CI: 1.08-1.58), 1.79 (95% CI: 1.45-2.23), or 2.19 (95% CI: 1.66-2.90) for the moderate, moderately severe, or severe depressive symptom trajectory, respectively. Compared to those with PA insufficiency and digital exclusion, among PA sufficient participants, the OR of being in the moderate, moderately severe, or severe depressive symptom trajectory was 0.74 (95% CI: 0.65-0.84), 0.57 (95% CI: 0.50-0.66), or 0.35 (95% CI: 0.20-0.61), respectively; among digitally engaged participants, the OR of being in the moderately severe or severe trajectory was 0.63 (95% CI: 0.53-0.75) or 0.42 (95% CI: 0.33-0.54), respectively. Compared with the healthy obesity group, those with sufficient PA or digital inclusion in obesity-hypertension and complex cardiometabolic groups had lower odds of depressive symptoms trajectories. Mediation analysis showed that PA and digital inclusion accounted for 12.5% and 6.67% of the association between clustering of cardiometabolic risk factors and the severe depressive symptom trajectory, respectively.

Conclusions: The obesity-hypertension was only associated with increased odds of the moderately severe depressive symptom trajectory, while the complex cardiometabolic pattern was associated with increased odds of depressive symptoms trajectories; in contrast, sufficient PA and digital inclusion were associated with reduced odds.

Background: Patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC) face limited treatment options and poor outcomes. Preclinical evidence supports chemoimmunotherapy as a conversion therapy; therefore, this study aims to evaluate the efficacy and safety of preoperative camrelizumab with paclitaxel and nedaplatin.

Methods: Patients received a combination of camrelizumab (200 mg), paclitaxel (155 mg/m²), and nedaplatin (80 mg/m²) every 3 weeks. An efficacy assessment was performed every two cycles using the RECIST v1.1 criteria, and patients in the resected group underwent surgery 4-6 weeks after the last dose. The primary endpoint was 1-year overall survival (OS) rate, while secondary endpoints included surgical conversion rates, pathological response rates, objective response rate (ORR), disease-free survival (DFS), and safety.

Results: This trial enrolled 141 patients with unresectable ESCC (132 locally advanced [M0], 9 metastatic [M1]) with a median follow-up of 32.2 months. Post-induction ORR was 56.7%. The intention-to-treat (ITT) conversion rate reached 48.9% overall and 50.0% (66/132) in M0 patients (R0: 100%; pathological complete response (pCR): 20.9%; major pathological response: 55.2%). One-year OS was 78.7%. Surgical conversion significantly improved survival overall (median OS: not reached (NR) vs. 14.1 months; hazard ratio (HR) = 0.22; 95% CI, 0.13-0.37; P < 0.0001), with further benefit in objective responders (median OS: NR vs. 20.9 months; HR = 0.30; 95% CI, 0.14-0.61; P < 0.001). Approximately 75.9% of patients experienced treatment-related adverse events (TRAEs), predominantly mild to moderate. Pan-lactylation levels were significantly elevated in non-pCR ESCC compared to pCR tissues. A peritumoral radiomic features-derived model effectively stratified patients into distinct groups with significantly different OS and DFS.

Conclusions: The chemoimmunotherapy regimen shows promising efficacy as a conversion therapy in improving surgical resectability and survival outcomes with manageable TRAEs, and does not delay surgery.

Trial registration number: ChiCTR2100046355.