Efficacy of typhoid conjugate vaccine: final analysis of a 4-year, phase 3, randomised controlled trial in Malawian children.

BACKGROUND: Randomised controlled trials of typhoid conjugate vaccines among children in Africa and Asia have shown high short-term efficacy. Data on the durability of protection beyond 2 years are sparse. We present the final analysis of a randomised controlled trial in Malawi, encompassing more than 4 years of follow-up, with the aim of investigating vaccine efficacy over time and by age group. METHODS: In this phase 3, double-blind, randomised controlled efficacy trial in Blantyre, Malawi, healthy children aged 9 months to 12 years were randomly assigned (1:1) by an unmasked statistician to receive a single dose of Vi polysaccharide conjugated to tetanus toxoid vaccine (Vi-TT) or meningococcal capsular group A conjugate (MenA) vaccine. Children had to have no previous history of typhoid vaccination and reside in the study areas for inclusion and were recruited from government schools and health centres. Participants, their parents or guardians, and the study team were masked to vaccine allocation. Nurses administering vaccines were unmasked. We did surveillance for febrile illness from vaccination until follow-up completion. The primary outcome was first occurrence of blood culture-confirmed typhoid fever. Eligible children who were randomly assigned and vaccinated were included in the intention-to-treat analyses. This trial is registered at ClinicalTrials.gov, NCT03299426. FINDINGS: Between Feb 21, 2018, and Sept 27, 2018, 28 130 children were vaccinated; 14 069 were assigned to receive Vi-TT and 14 061 to receive MenA. After a median follow-up of 4·3 years (IQR 4·2-4·5), 24 (39·7 cases per 100 000 person-years) children in the Vi-TT group and 110 (182·7 cases per 100 000 person-years) children in the MenA group were diagnosed with a first episode of blood culture-confirmed typhoid fever. In the intention-to-treat population, efficacy of Vi-TT was 78·3% (95% CI 66·3-86·1), and 163 (129-222) children needed to be vaccinated to prevent one case. Efficacies by age group were 70·6% (6·4-93·0) for children aged 9 months to 2 years; 79·6% (45·8-93·9) for children aged 2-4 years; and 79·3% (63·5-89·0) for children aged 5-12 years. INTERPRETATION: A single dose of Vi-TT is durably efficacious for at least 4 years among children aged 9 months to 12 years and shows efficacy in all age groups, including children younger than 2 years. These results support current WHO recommendations in typhoid-endemic areas for mass campaigns among children aged 9 months to 15 years, followed by routine introduction in the first 2 years of life. FUNDING: Bill & Melinda Gates Foundation.

Safety and Efficacy of a Typhoid Conjugate Vaccine in Malawian Children.

BACKGROUND: Typhoid fever caused by multidrug-resistant H58 Salmonella Typhi is an increasing public health threat in sub-Saharan Africa. METHODS: We conducted a phase 3, double-blind trial in Blantyre, Malawi, to assess the efficacy of Vi polysaccharide typhoid conjugate vaccine (Vi-TCV). We randomly assigned children who were between 9 months and 12 years of age, in a 1:1 ratio, to receive a single dose of Vi-TCV or meningococcal capsular group A conjugate (MenA) vaccine. The primary outcome was typhoid fever confirmed by blood culture. We report vaccine efficacy and safety outcomes after 18 to 24 months of follow-up. RESULTS: The intention-to-treat analysis included 28,130 children, of whom 14,069 were assigned to receive Vi-TCV and 14,061 were assigned to receive the MenA vaccine. Blood culture-confirmed typhoid fever occurred in 12 children in the Vi-TCV group (46.9 cases per 100,000 person-years) and in 62 children in the MenA group (243.2 cases per 100,000 person-years). Overall, the efficacy of Vi-TCV was 80.7% (95% confidence interval [CI], 64.2 to 89.6) in the intention-to-treat analysis and 83.7% (95% CI, 68.1 to 91.6) in the per-protocol analysis. In total, 130 serious adverse events occurred in the first 6 months after vaccination (52 in the Vi-TCV group and 78 in the MenA group), including 6 deaths (all in the MenA group). No serious adverse events were considered by the investigators to be related to vaccination. CONCLUSIONS: Among Malawian children 9 months to 12 years of age, administration of Vi-TCV resulted in a lower incidence of blood culture-confirmed typhoid fever than the MenA vaccine. (Funded by the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT03299426.).

Development of small-molecular-based radiotracers for PET imaging of PD-L1 expression and guiding the PD-L1 therapeutics.

PURPOSE: Programmed cell death protein ligand 1 (PD-L1) is a crucial biomarker for immunotherapy. However, nearly 70% of patients do not respond to PD-L1 immune checkpoint therapy. Accurate monitoring of PD-L1 expression and quantification of target binding during treatment are essential. In this study, a series of small-molecule radiotracers were developed to assess PD-L1 expression and direct immunotherapy. METHODS: Radiotracers of [68Ga]Ga-D-PMED, [68Ga]Ga-D-PEG-PMED, and [68Ga]Ga-D-pep-PMED were designed based on a 2-methyl-3-biphenyl methanol scaffold and successfully synthesized. Cellular experiments and molecular docking assays were performed to determine their specificity for PD-L1. PD-L1 status was investigated via positron emission tomography (PET) imaging in MC38 tumor models. PET imaging of [68Ga]Ga-D-pep-PMED was performed to noninvasively quantify PD-L1 blocking using an anti-mouse PD-L1 antibody (PD-L1 mAb). RESULTS: The radiosyntheses of [68Ga]Ga-D-PMED, [68Ga]Ga-D-PEG-PMED, and [68Ga]Ga-D-pep-PMED were achieved with radiochemical yields of 87 ± 6%, 82 ± 4%, and 79 ± 9%, respectively. In vitro competition assays demonstrated their high affinities (the IC50 values of [68Ga]Ga-D-PMED, [68Ga]Ga-D-PEG-PMED, and [68Ga]Ga-D-pep-PMED were 90.66 ± 1.24, 160.8 ± 1.35, and 51.6 ± 1.32 nM, respectively). At 120 min postinjection (p.i.) of the radiotracers, MC38 tumors displayed optimized tumor-to-muscle ratios for all radioligands. Owing to its hydrophilic modification, [68Ga]Ga-D-pep-PMED had the highest target-to-nontarget (T/NT) ratio of approximately 6.2 ± 1.2. Interestingly, the tumor/liver ratio was hardly affected by different concentrations of the inhibitor BMS202. We then evaluated the impacts of dose and time on accessible PD-L1 levels in the tumor during anti-mouse PD-L1 antibody treatment. The tumor uptake of [68Ga]Ga-D-pep-PMED significantly decreased with increasing PD-L1 mAb dose. Moreover, after 8 days of treatment with a single antibody, the uptake of [68Ga]Ga-D-pep-PMED in the tumor significantly increased but remained lower than that in the saline group. CONCLUSION: PET imaging with [68Ga]Ga-D-pep-PMED, a small-molecule radiotracer, is a promising tool for evaluating PD-L1 expression and quantifying the target blockade of PD-L1 to assist in the development of effective therapeutic regimens.

Synchronous myopia development induced by bilateral form deprivation in chicks.

Form deprivation (FD) is a widely employed experimental paradigm, typically used to induce unilateral myopia in animal models. This model is weakened by potential influence upon the FD eye from vision in the freely-viewing contralateral eye, which could be eliminated by imposing FD in both eyes; but while a few previous studies have explored the feasibility of inducing bilateral FD in chicks, substantial discrepancies in treatment outcomes were noted. Consequently, this study aimed to establish a bilateral FD myopia model in chicks, with validation by investigating the associated ocular growth patterns, feeding, and social behavior. Six-day-old chicks were treated with bilateral (n = 21) or unilateral (n = 10) FD for 12 days; the fellow untreated eyes in the unilateral FD group served as controls. Refractive error, corneal power, and ocular axial dimensions were measured at 4-day intervals after the onset of form deprivation, with a Hartinger refractometer, a custom-made videokeratography system, and a high-resolution A-scan ultrasonographer, respectively. Body weight was monitored to assess the chick's physical development. Our results showed that birds treated with bilateral FD grew as robustly as the unilaterally form-deprived chicks, with similar or slightly heavier body weights and mortalities. Unilateral FD induced significantly higher myopia in the treated eye, with stronger corneal power, deeper anterior and vitreous chambers, and longer axial length. Moreover, either bilaterally or unilaterally FD eyes developed similar refractive error (bilateral FD, left: -28.03 ± 9.06 D, right: -28.44 ± 9.45 D; unilateral FD: -29.48 ± 8.26 D) and ocular biometric changes; but choroidal thickness was thicker in bilaterally FD eyes, rather than thinner as in unilaterally FD eyes. In addition to the highly synchronized (symmetrical, parallel) development reported previously in bilateral FD, we found in this study that the correlations between bilaterally form-deprived eyes were highest for ocular biometric parameters directly contributing to myopia development, including corneal power (r = 0.74 to 0.93), anterior chamber depth (r = 0.60 to 0.85), vitreous chamber depth (r = 0.92 to 0.94), and axial length (r = 0.90 to 0.96). The remarkably synchronized growth pattern confirmed the feasibility of the bilateral FD paradigm for future research on myopia.

Fulvic acid alleviates the stress of low nitrogen on maize by promoting root development and nitrogen metabolism.

The potential of fulvic acid (FA) to improve plant growth has been acknowledged, but its effect on plant growth and nutrient uptake under nutrient stress remains unclear. This study investigated the effects of different FA application rates on maize growth and nitrogen utilization under low nitrogen stress. The results showed that under low nitrogen stress, FA significantly stimulated maize growth, particularly root development, biomass, and nitrogen content. The enhanced activity levels of key enzymes in nitrogen metabolism were observed, along with differential gene expression in maize, which enriched nitrogen metabolism, amino acid metabolism and plant hormone metabolism. The application of FA regulated the hormones' level, reduced abscisic acid content in leaves and Me-JA content in roots, and increased auxin and zeatin ribose content in leaves. This study concludes that, by promoting root development, nitrogen metabolism, and hormone metabolism, an appropriate concentration of FA can enhance plant tolerance to low nitrogen conditions and improve nitrogen use efficiency.

A proof-of-concept study on bioorthogonal-based pretargeting and signal amplify radiotheranostic strategy.

BACKGROUND: Radiotheranostics differs from the vast majority of other cancer therapies in its capacity for simultaneous imaging and therapy, and it is becoming more widely implemented. A balance between diagnostic and treatment requirements is essential for achieving effective radiotheranostics. Herein, we propose a proof-of-concept strategy aiming to address the profound differences in the specific requirements of the diagnosis and treatment of radiotheranostics. RESULTS: To validate the concept, we designed an s-tetrazine (Tz) conjugated prostate-specific membrane antigen (PSMA) ligand (DOTA-PSMA-Tz) for 68Ga or 177Lu radiolabeling and tumor radiotheranostics, a trans-cyclooctene (TCO) modified Pd@Au nanoplates (Pd@Au-PEG-TCO) for signal amplification, respectively. We then demonstrated this radiotheranostic strategy in the tumor-bearing mice with the following three-step procedures: (1) i.v. injection of the [68Ga]Ga-PSMA-Tz for diagnosis; (2) i.v. injection of the signal amplification module Pd@Au-PEG-TCO; (3) i.v. injection of the [177Lu]Lu-PSMA-Tz for therapy. Firstly, this strategy was demonstrated in 22Rv1 tumor-bearing mice via positron emission tomography (PET) imaging with [68Ga]Ga-PSMA-Tz. We observed significantly higher tumor uptake (11.5 ± 0.8%ID/g) with the injection of Pd@Au-PEG-TCO than with the injection [68Ga]Ga-PSMA-Tz alone (5.5 ± 0.9%ID/g). Furthermore, we validated this strategy through biodistribution studies of [177Lu]Lu-PSMA-Tz, with the injection of the signal amplification module, approximately five-fold higher tumor uptake of [177Lu]Lu-PSMA-Tz (24.33 ± 2.53% ID/g) was obtained when compared to [177Lu]Lu-PSMA-Tz alone (5.19 ± 0.26%ID/g) at 48 h post-injection. CONCLUSION: In summary, the proposed strategy has the potential to expand the toolbox of pretargeted radiotherapy in the field of theranostics.

A Description of the Statistical Methods for the Vaccine Impact on Diarrhea in Africa (VIDA) Study.

BACKGROUND: Diarrheal diseases remain a health threat to children in low- and middle-income countries. The Vaccine Impact on Diarrhea in Africa (VIDA) study was a 36-month, prospective, matched case-control study designed to estimate the etiology, incidence, and adverse clinical consequences of moderate-to-severe diarrhea (MSD) in children aged 0-59 months. VIDA was conducted following rotavirus vaccine introduction at 3 censused sites in sub-Saharan Africa that participated in the Global Enteric Multicenter Study (GEMS) ∼10 years earlier. We describe the study design and statistical methods of VIDA and where they differ from GEMS. METHODS: We aimed to enroll 8-9 MSD cases every 2 weeks from sentinel health centers in 3 age strata (0-11, 12-23, 24-59 months) and 1 to 3 controls matched by age, sex, date of case enrollment, and village. Clinical, epidemiological, and anthropometric data were collected at enrollment and ∼60 days later. A stool specimen collected at enrollment was analyzed by both conventional methods and quantitative PCR for enteric pathogens. For the matched case-control study, we estimated the population-based, pathogen-specific attributable fraction (AF) and attributable incidence adjusted for age, site, and other pathogens, and identified episodes attributable to a specific pathogen for additional analyses. A prospective cohort study nested within the original matched case-control study allowed assessment of (1) the association between potential risk factors and outcomes other than MSD status and (2) the impact of MSD on linear growth. CONCLUSIONS: GEMS and VIDA together comprise the largest and most comprehensive assessment of MSD conducted to date in sub-Saharan Africa populations at highest risk for morbidity and mortality from diarrhea. The statistical methods used in VIDA have endeavored to maximize the use of available data to produce more robust estimates of the pathogen-specific disease burden that might be prevented by effective interventions.

Stunting Following Moderate-to-Severe Diarrhea Among Children Aged <5 Years in Africa Before and After Rotavirus Vaccine Introduction: A Comparison of the Global Enteric Multicenter Study and the Vaccine Impact on Diarrhea in Africa (VIDA) Study.

BACKGROUND: Studies conducted before rotavirus vaccine introduction found that moderate-to-severe diarrhea (MSD) in children aged <5 years was associated with stunting at follow-up. It is unknown whether the reduction in rotavirus-associated MSD following vaccine introduction decreased the risk of stunting. METHODS: The Global Enteric Multicenter Study (GEMS) and the Vaccine Impact on Diarrhea in Africa (VIDA) study, two comparable matched case-control studies, were conducted during 2007-2011 and 2015-2018, respectively. We analyzed data from 3 African sites where rotavirus vaccine was introduced after GEMS and before starting VIDA. Children with acute MSD (<7 days onset) were enrolled from a health center and children without MSD (diarrhea-free for ≥7 days) were enrolled at home within 14 days of the index MSD case. The odds of being stunted at a follow-up visit 2-3 months after enrollment for an episode of MSD was compared between GEMS and VIDA using mixed-effects logistic regression models controlling for age, sex, study site, and socioeconomic status. RESULTS: We analyzed data from 8808 children from GEMS and 10 579 from VIDA. Among those who were not stunted at enrollment in GEMS, 8.6% with MSD and 6.4% without MSD became stunted during the follow-up period. In VIDA, 8.0% with MSD and 5.5% children without MSD developed stunting. An episode of MSD was associated with higher odds of being stunted at follow-up compared with children without MSD in both studies (adjusted odds ratio [aOR], 1.31; 95% confidence interval [CI]: 1.04-1.64 in GEMS and aOR, 1.30; 95% CI: 1.04-1.61 in VIDA). However, the magnitude of association was not significantly different between GEMS and VIDA (P = .965). CONCLUSIONS: The association of MSD with subsequent stunting among children aged <5 years in sub-Saharan Africa did not change after rotavirus vaccine introduction. Focused strategies are needed for prevention of specific diarrheal pathogens that cause childhood stunting.

Moderate-to-Severe Diarrhea and Stunting Among Children Younger Than 5 Years: Findings From the Vaccine Impact on Diarrhea in Africa (VIDA) Study.

BACKGROUND: Stunting affects >20% of children <5 years old worldwide and disproportionately impacts underserved communities. The Vaccine Impact on Diarrhea in Africa (VIDA) Study examined the association between an episode of moderate-to-severe diarrhea (MSD) and the risk of subsequent stunting in children <5 years living in 3 sub-Saharan African countries. METHODS: In this prospective, matched, case-control study among children <5 years, data were collected over 36 months from 2 groups. "Children with MSD" visited a health center within 7 days of illness onset experiencing ≥3 loose stools/day plus sunken eyes, poor skin turgor, dysentery, intravenous rehydration, or hospitalization. "Children without MSD" were enrolled from the community within 14 days of the index MSD child; they were diarrhea-free during the previous 7 days and were matched to the index case by age, sex, and residence. Using generalized linear mixed-effects models, we estimated the effect of an MSD episode on odds of being stunted, defined as height-for-age z-scores <-2, at a follow-up visit 2-3 months post-enrollment. RESULTS: The proportion of stunting at enrollment was similar when 4603 children with MSD and 5976 children without MSD were compared (21.8% vs 21.3%; P = .504). Among children not stunted at enrollment, those with MSD had 30% higher odds of being stunted at follow-up than children without MSD after controlling for age, sex, study site, and socioeconomic status (adjusted OR: 1.30; 95% CI: 1.05-1.62: P = .018). CONCLUSIONS: Children <5 years in sub-Saharan Africa without stunting experienced an increased likelihood of stunting during 2-3 months following an episode of MSD. Strategies for control of early childhood diarrhea should be integrated into programs intended to reduce childhood stunting.

Clinical and Epidemiologic Features of Cryptosporidium-Associated Diarrheal Disease Among Young Children Living in Sub-Saharan Africa: The Vaccine Impact on Diarrhea in Africa (VIDA) Study.

BACKGROUND: As part of the Vaccine Impact on Diarrhea in Africa (VIDA) Study, we examined the prevalence, clinical presentation, and seasonality of Cryptosporidium in children to understand its relative burden after the introduction of rotavirus vaccine. METHODS: VIDA was a 3-year, age-stratified, matched case-control study of medically attended acute moderate-to-severe diarrhea (MSD) in children aged 0-59 months residing in censused populations at sites in Kenya, Mali, and The Gambia. Clinical and epidemiologic data were collected at enrollment, and a stool sample was tested for enteropathogens by quantitative PCR. An algorithm was created based on the organism's cycle threshold (Ct) and association with MSD to identify the subset of Cryptosporidium PCR-positive (Ct <35) cases most likely to be attributed to MSD. Clinical outcomes were assessed at 2-3 months after enrollment. RESULTS: One thousand one hundred six (22.9%) cases of MSD and 873 controls (18.1%) were PCR positive for Cryptosporidium; 465 cases (42.0%) were considered attributable to Cryptosporidium, mostly among children 6-23 months. Cryptosporidium infections peaked in The Gambia and Mali during the rainy season, while in Kenya they did not have clear seasonality. Compared with cases with watery MSD who had a negative PCR for Cryptosporidium, cases with watery MSD attributed to Cryptosporidium were less frequently dehydrated but appeared more severely ill using a modified Vesikari scale (38.1% vs 27.0%; P < 0.001), likely due to higher rates of hospitalization and intravenous fluid administration, higher prevalence of being wasted or very thin very thin (23.4% vs 14.7%; P < 0.001), and having severe acute malnutrition (midupper arm circumference <115 mm, 7.7% vs 2.5%; P < 0.001). On follow-up, Cryptosporidium-attributed cases had more prolonged and persistent episodes (43.2% vs 32.7%; P <0 .001) and linear growth faltering (change in height-for-age z score between enrollment and follow-up: -0.29 vs -0.17; P < 0.001). CONCLUSIONS: The burden of Cryptosporidium remains high among young children in sub-Saharan Africa. Its propensity to cause illness and further impact children longer term by compromising nutritional status early in life calls for special attention to enable appropriate management of clinical and nutritional consequences.

Epidemiology of Enteroaggregative, Enteropathogenic, and Shiga Toxin-Producing Escherichia coli Among Children Aged <5 Years in 3 Countries in Africa, 2015-2018: Vaccine Impact on Diarrhea in Africa (VIDA) Study.

BACKGROUND: To address knowledge gaps regarding diarrheagenic Escherichia coli (DEC) in Africa, we assessed the clinical and epidemiological features of enteroaggregative E. coli (EAEC), enteropathogenic E. coli (EPEC), and Shiga toxin-producing E. coli (STEC) positive children with moderate-to-severe diarrhea (MSD) in Mali, The Gambia, and Kenya. METHODS: Between May 2015 and July 2018, children aged 0-59 months with medically attended MSD and matched controls without diarrhea were enrolled. Stools were tested conventionally using culture and multiplex polymerase chain reaction (PCR), and by quantitative PCR (qPCR). We assessed DEC detection by site, age, clinical characteristics, and enteric coinfection. RESULTS: Among 4840 children with MSD and 6213 matched controls enrolled, 4836 cases and 1 control per case were tested using qPCR. Of the DEC detected with TAC, 61.1% were EAEC, 25.3% atypical EPEC (aEPEC), 22.4% typical EPEC (tEPEC), and 7.2% STEC. Detection was higher in controls than in MSD cases for EAEC (63.9% vs 58.3%, P < .01), aEPEC (27.3% vs 23.3%, P < .01), and STEC (9.3% vs 5.1%, P < .01). EAEC and tEPEC were more frequent in children aged <23 months, aEPEC was similar across age strata, and STEC increased with age. No association between nutritional status at follow-up and DEC pathotypes was found. DEC coinfection with Shigella/enteroinvasive E. coli was more common among cases (P < .01). CONCLUSIONS: No significant association was detected between EAEC, tEPEC, aEPEC, or STEC and MSD using either conventional assay or TAC. Genomic analysis may provide a better definition of the virulence factors associated with diarrheal disease.

Chronic Epstein-Barr virus infection: A potential junction between primary Sjögren's syndrome and lymphoma.

Primary Sjögren's syndrome (pSS) is an autoimmune disease that targets exocrine glands, leading to exocrine dysfunction. Due to its propensity to infect epithelial and B cells, Epstein-Barr virus (EBV) is hypothesized to be related with pSS. Through molecular mimicry, the synthesis of specific antigens, and the release of inflammatory cytokines, EBV contributes to the development of pSS. Lymphoma is the most lethal outcome of EBV infection and the development of pSS. As a population-wide virus, EBV has had a significant role in the development of lymphoma in people with pSS. In the review, we will discuss the possible causes of the disease.

Development of [177Lu]Lu-LNC1003 for radioligand therapy of prostate cancer with a moderate level of PSMA expression.

PURPOSE: Evans blue as an albumin binder has been widely used to improve pharmacokinetics and enhance tumor uptake of radioligands, including prostate-specific membrane antigen (PSMA) targeting agents. The goal of this study is to develop an optimal Evans blue-modified radiotherapeutic agent that could maximize the absolute tumor uptake and tumor absorbed dose thus the therapeutic efficacy to allow treatment of tumors even with moderate level of PSMA expression. METHODS: [177Lu]Lu-LNC1003 was synthesized based on PSMA-targeting agent and Evans blue. Binding affinity and PSMA targeting specificity were verified through cell uptake and competition binding assay in 22Rv1 tumor model that has moderate level of PSMA expression. SPECT/CT imaging and biodistribution studies in 22Rv1 tumor-bearing mice were performed to evaluate the preclinical pharmacokinetics. Radioligand therapy studies were conducted to systematically assess the therapeutic effect of [177Lu]Lu-LNC1003. RESULTS: LNC1003 showed high binding affinity (IC50 = 10.77 nM) to PSMA in vitro, which was comparable with that of PSMA-617 (IC50 = 27.49 nM) and EB-PSMA-617 (IC50 = 7.91 nM). SPECT imaging of [177Lu]Lu-LNC1003 demonstrated significantly improved tumor uptake and retention as compared with [177Lu]Lu-EB-PSMA and [177Lu]Lu-PSMA-617, making it suitable for prostate cancer therapy. Biodistribution studies further confirmed the remarkably higher tumor uptake of [177Lu]Lu-LNC1003 (138.87 ± 26.53%ID/g) over [177Lu]Lu-EB-PSMA-617 (29.89 ± 8.86%ID/g) and [177Lu]Lu-PSMA-617 (4.28 ± 0.25%ID/g) at 24 h post-injection. Targeted radioligand therapy results showed noteworthy inhibition of 22Rv1 tumor growth after administration of a single dose of 18.5 MBq [177Lu]Lu-LNC1003. There was no obvious antitumor effect after [177Lu]Lu-PSMA-617 treatment under the same condition. CONCLUSION: In this study, [177Lu]Lu-LNC1003 was successfully synthesized with high radiochemical purity and stability. High binding affinity and PSMA targeting specificity were identified in vitro and in vivo. With greatly enhanced tumor uptake and retention, [177Lu]Lu-LNC1003 has the potential to improve therapeutic efficacy using significantly lower dosages and less cycles of 177Lu that promises clinical translation to treat prostate cancer with various levels of PSMA expression.

Shared Genetic Architecture between Parkinson's Disease and Brain Structural Phenotypes.

BACKGROUND: Patients with Parkinson's disease (PD) have consistently demonstrated brain structure abnormalities, indicating the presence of shared etiological and pathological processes between PD and brain structures; however, the genetic relationship remains poorly understood. OBJECTIVE: The aim of this study was to investigate the extent of shared genetic architecture between PD and brain structural phenotypes (BSPs) and to identify shared genomic loci. METHODS: We used the summary statistics from genome-wide association studies to conduct MiXeR and conditional/conjunctional false discovery rate analyses to investigate the shared genetic signatures between PD and BSPs. Subsequent expression quantitative trait loci mapping in the human brain and enrichment analyses were also performed. RESULTS: MiXeR analysis identified genetic overlap between PD and various BSPs, including total cortical surface area, average cortical thickness, and specific brain volumetric structures. Further analysis using conditional false discovery rate (FDR) identified 21 novel PD risk loci on associations with BSPs at conditional FDR < 0.01, and the conjunctional FDR analysis demonstrated that PD shared several genomic loci with certain BSPs at conjunctional FDR < 0.05. Among the shared loci, 16 credible mapped genes showed high expression in the brain tissues and were primarily associated with immune function-related biological processes. CONCLUSIONS: We confirmed the polygenic overlap with mixed directions of allelic effects between PD and BSPs and identified multiple shared genomic loci and risk genes, which are likely related to immune-related biological processes. These findings provide insight into the complex genetic architecture associated with PD. © 2023 International Parkinson and Movement Disorder Society.

Plasmodium falciparum infection and disease in infancy associated with increased risk of malaria and anaemia in childhood.

BACKGROUND: Infants under 6 months of age are often excluded from malaria surveillance and observational studies. The impact of malaria during early infancy on health later in childhood remains unknown. METHODS: Infants from two birth cohorts in Malawi were monitored at quarterly intervals and whenever they were ill from birth through 24 months for Plasmodium falciparum infections and clinical malaria. Poisson regression and linear mixed effects models measured the effect of exposure to malaria in infancy on subsequent malaria incidence, weight-for-age z-scores (WAZ), and haemoglobin concentrations after 6 months. RESULTS: Infants with at least one P. falciparum infection during their first 6 months had increased incidence ratio (IRR) of P. falciparum infection (IRR = 1.27, 95% CI, 1.06-1.52) and clinical malaria (IRR = 2.37, 95% CI, 2.02-2.80) compared to infants without infection. Infants with clinical malaria had increased risk of P. falciparum infection incidence between 6 and 24 months (IRR = 1.64, 95% CI, 1.38-1.94) and clinical malaria (IRR = 1.85, 95% CI, 1.48-2.32). Exposure to malaria was associated with lower WAZ over time (p = 0.02) and lower haemoglobin levels than unexposed infants at every time interval (p = 0.02). CONCLUSIONS: Infants experiencing malaria infection or clinical malaria are at increased risk of subsequent infection and disease, have poorer growth, and lower haemoglobin concentrations.

Impact of ¡Míranos! on parent-reported home-based healthy energy balance-related behaviors in low-income Latino preschool children: a clustered randomized controlled trial.

BACKGROUND: Widespread establishment of home-based healthy energy balance-related behaviors (EBRBs), like diet, physical activity, sedentary behavior, screen time, and sleep, among low-income preschool-aged children could curb the childhood obesity epidemic. We examined the effect of an 8-month multicomponent intervention on changes in EBRBs among preschool children enrolled in 12 Head Start centers. METHODS: The Head Start (HS) centers were randomly assigned to one of three treatment arms: center-based intervention group (CBI), center-based plus home-based intervention group (CBI + HBI), or control. Before and following the intervention, parents of 3-year-olds enrolled in participating HS centers completed questionnaires about their child's at-home EBRBs. Adult-facilitated physical activity (PA) was measured by an index based on questions assessing the child's level of PA participation at home, with or facilitated by an adult. Fruit, vegetable, and added sugar intake were measured via a short food frequency questionnaire, and sleep time and screen time were measured using 7-day logs. A linear mixed effects model examined the intervention's effect on post-intervention changes in PA, intake of fruit, vegetable, and added sugar, sleep time, and screen time from baseline to post-intervention. RESULTS: A total of 325 parents participated in the study (CBI n = 101; CBI + HBI n = 101; and control n = 123). Compared to control children, CBI and CBI + HBI parents reported decreases in children's intake of added sugar from sugar-sweetened beverages. Both CBI and CBI + HBI parents also reported smaller increases in children's average weekday screen time relative to controls. In addition, CBI + HBI parents reported CBI + HBI parents reported increases in children's adult-facilitated PA, fruit and vegetable intake, and daily sleep time during weekdays (excluding weekends) and the total week from baseline to post-intervention, while children in the CBI increased sleep time over the total week compared to the children in the control group. CONCLUSIONS: Parent engagement strengthened the improvement in parent-reported EBRBs at home in young children participating in an evidence-based obesity prevention program in a childcare setting. Future studies should investigate equity-related contextual factors that influence the impact of obesity prevention in health-disparity populations. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03590834. Registered July 18, 2018, https://clinicaltrials.gov/ct2/show/NCT03590834.

Broadband UV-Excitation and Red/Far-Red Emission Materials for Plant Growth: Tunable Spectrum Conversion in Eu3+,Mn4+ Co-doped LaAl0.7Ga0.3O3 Phosphors.

Broadband ultraviolet (UV) excitation and red/far-red emission phosphors can effectively convert solar spectrum to enhance photosynthesis and promote morphogenesis in plants. Based on the above application requirements, Eu3+ single-doped LaAl1-yGayO3 solid solutions and Eu3+,Mn4+ codoped LaAl0.7Ga0.3O3 phosphors were designed and synthesized in this work. The LaAl0.7Ga0.3O3:0.05Eu3+ (LAG:Eu3+) phosphor exhibits a strong charge transfer band (CTB) excitation and characteristic 5D0 → 7F2 transition red emission (619 nm), which is very similar to the luminescence properties of Eu3+-organic ligand compound (EuL3). Rietveld refinement studies further revealed that the cation substitution disturbs the site symmetry. The optimal Eu3+, Mn4+ co-doped LaAl0.7Ga0.3O3 (LAG:Eu,Mn) phosphor possesses a dual-band excitation spectrum in broadband ultraviolet (UVA, UVB) area and a dual-band emission spectrum within red/far-red area. Under the sunlight radiation, the real-time spectrum of luminous laminated glasses fabricated by coating the LAG:Eu,Mn phosphor shows the percentage of radiant intensity in the red/far-red region significantly increases, suggesting that the phosphor can be a promising candidate for solar spectral conversion in plant cultivation. We believe this work provides a new idea for developing novel broadband ultraviolet excitation and red/far-red emission phosphors.

Quantitative DECT of Iodine in Chronic Subdural Hematoma as Surrogate of Membrane Exudation: A Pilot Feasibility Study.

OBJECTIVE: We explore the feasibility to estimate the exudation from chronic subdural hematoma (CSDH) membranes, by using dual-energy computed tomography (DECT) quantification of iodine leak and test if the derived quantitative variables and membrane morphology correlates with hematoma volume, internal architecture (homogeneous, laminar, separated, and trabecular types), and fractional hyperdense hematoma at presentation. METHODS: In this retrospective study, consecutive CSDH patients with postcontrast DECT head images from January 2020 and June 2021 were analyzed. Predictor variables derived from DECT were correlated with outcome variables followed by mixed-effects regression analysis. RESULTS: The study included 36 patients with 50 observations (mean age, 72.6 years; standard deviation, 11.6 years); 31 were men. Dual-energy CT variables that correlated with hematoma volume were external membrane volume (ρ, 0.37; P = 0.008) and iodine concentration (ρ, -0.29; P = 0.04). Variables that correlated with separated type of hematoma were total iodine leak (median [Q 1 , Q 3 ], 68.3 mg [48.5, 88.9] vs 38.8 mg [15.5, 62.9]; P = 0.001) and iodine leak per unit membrane volume (median [Q 1 , Q 3 ], 16.47 mg/mL [10.19, 20.65] vs 8.68 mg/mL [5.72, 11.41]; P = 0.002). Membrane grade was the only variable that correlated with fractional hyperdense hematoma (ρ, 0.28; P = 0.05). Regression analysis showed total iodine leak as the strongest predictor of separated type hematoma (odds ratio [95% confidence interval], 1.06 per mg [1.01, 1.1]). CONCLUSIONS: Dual-energy CT demonstrates iodine leak from CSDH membranes. The variables derived from DECT correlated with hematoma volume, internal architecture, and fractional hyperdense hematoma.

Tofacitinib in the treatment of primary Sjögren's syndrome-associated interstitial lung disease: study protocol for a prospective, randomized, controlled and open-label trial.

INTRODUCTION: Tofacitinib, a selective inhibitor of JAK1 and/or JAK3, is considered to alleviate the pulmonary condition of primary Sjögren's syndrome (pSS)-associated interstitial lung disease (ILD) through its anti-inflammatory and antifibrotic effects. METHODS AND ANALYSIS: This is a single-center, prospective, randomized, open-label trial. The trial will compare a 52-week course of oral tofacitinib with traditional therapy cyclophosphamide (CYC) combined with azathioprine (AZA) in the treatment of pSS-ILD. A total of 120 patients will be randomly assigned into two treatment groups with a 1:1 ratio and followed for 52 weeks from the first dose. The primary endpoint of the study is the increase of forced vital capacity (FVC) at 52 weeks. Secondary endpoints include high-resolution computed tomography (HRCT), diffusion capacity for carbon monoxide of the lung (DLCO), the Mahler dyspnea index, the health-related quality of life (HARQoL) score, the cough symptom score, EULAR Sjögren's syndrome disease activity index (ESSDAI), and safety. DISCUSSION: This study will be the first randomized controlled trial to investigate tofacitinib compared to the traditional regimen of CYC in combination with AZA in the treatment of pSS-ILD, which will provide data on efficacy and safety and further elucidate the role of the JAK-STAT signaling pathway in the development of pSS-ILD. ETHICS AND DISSEMINATION: Before starting the experiment, the research proposal, informed consent (ICF) and relevant documents in accordance with the ethical principles of the Helsinki Declaration and the relevant requirements of the local GCP rules for ethical approval shall be submitted to the ethics committee of the hospital. The ethical approval of this study is reviewed by the Ethics Committee of Tongji Hospital and the ethical approval number is 2021-LCYJ-007. When the experiment is completed, the results will also be disseminated to patients and the public through publishing papers in international medical journals. TRIAL REGISTRATION: The study was registered on the Chinese Clinical Trial Registry, www.chictr.org.cn ; ID ChiCTR2000031389.

Evaluating Social Determinants of Health in a Mobile Integrated Healthcare-Community Paramedicine Program.

In 2018, the University of Maryland Medical Center and the Baltimore City Fire Department implemented a community paramedicine program to help medically or socially complex patients transition from hospital to home and avoid hospital utilization. This study describes how patients' social determinants of health (SDoH) needs were identified, and measures the association between needs and hospital utilization. SDoH needs were categorized into ten domains. Multinomial logistic regression was used to measure association between identified SDoH domains and predicted risk of readmission. Poisson regression was used to measure association between SDoH domains and actual 30-day hospital utilization. The most frequently identified SDoH needs were in the Coordination of Healthcare (37.7%), Durable Medical Equipment (18.8%), and Medication (16.3%) domains. Compared with low-risk patients, patients with an intermediate risk of readmission were more likely to have needs within the Coordination of Healthcare (RRR [95% CI] 1.12 [1.01, 1.24], p = 0.032) and Durable Medical Equipment (RRR = 1.13 [1.00, 1.27], p = 0.046) domains. Patients with the highest risk for readmission were more likely to have needs in the Utilities domain (RRR = 1.76 [0.97, 3.19], p = 0.063). Miscellaneous domain needs, such as requiring a social security card, were associated with increased 30-day hospital utilization (IRR = 1.23 [0.96, 1.57], p = 0.095). SDoH needs within the Coordination of Healthcare, Durable Medical Equipment, and Utilities domains were associated with higher predicted 30-day readmission, while identification documentation and social services needs were associated with actual readmission. These results suggest where to allocate resources to effectively diminish hospital utilization.