Modest Reduction Research Articles

The impact of metformin on weight and metabolic parameters in patients with obesity: A systematic review and meta-analysis of randomized controlled trials.

There are conflicting data on the weight-reducing potential of metformin (MTF) in nondiabetic patients with obesity. The purpose of this systematic review and meta-analysis was to evaluate the effect of MTF on weight and cardiometabolic parameters in adults with overweight/obesity with or without nonalcoholic fatty liver disease (NAFLD) (CRD42018085512). We included randomized controlled trials (RCTs) in adults without diabetes mellitus, with mean body mass index (BMI) ≥ 25 kg/m2, with or without NAFLD, comparing MTF to placebo/control, lifestyle modification (LSM) or a US Food and Drug Administration-approved anti-obesity drug, reporting on weight or metabolic parameters, and extending over at least 3 months. We conducted a systematic search in MEDLINE, EMBASE, PubMed and the Cochrane Library without time limitation (until March 2022). We screened and selected eligible articles, abstracted relevant data, and assessed the risk of bias. All steps were in duplicate and independently. We conducted a random-effects model meta-analysis using Review Manager version 5.3, with prespecified subgroup analyses in case of heterogeneity. We identified 2650 citations and included 49 trials (55 publications). Compared to placebo, MTF was associated with a significant reduction in BMI (mean difference [MD] -0.56 [-0.74, -0.37] kg/m2; p < 0.0001), at doses ranging from 500 to 2550 mg/day, and with a significant percentage change in BMI of -2.53% (-2.90, -2.17) at the dose 1700 mg/day. There was no interaction by baseline BMI, MTF dose or duration, nor presence or absence of NAFLD. There was no significant difference between MTF and LSM. Orlistat was more effective than MTF (at doses of 1000-1700 mg/day) in terms of weight loss, with an MD in BMI of -3.17 (-5.88; -0.47) kg/m2, favouring the former. Compared to placebo/control, MTF improved insulin parameters, while no effect was detected when compared to LSM. A few small trials showed heterogenous effects on liver parameters in patients with NAFLD treated with MTF compared to placebo/control. There was a large variability in the expression of outcome measures and RCTs were of low quality. In conclusion, MTF was associated with a modest weight reduction in obese nondiabetic patients. Further high-quality and better powered studies are needed to examine the impact of MTF in patients with insulin resistance and NAFLD.

Fishing for the evidence on community water fluoridation: a commentary on the CATFISH study.

Goodwin M, Emsley R, Kelly M P et al. Evaluation of water fluoridation scheme in Cumbria: the CATFISH prospective longitudinal cohort study. Southampton: National Institute for Health and Care Research, 2022. This longitudinal, prospective cohort study, recruited two populations - a birth cohort and older school cohort - assessing the effects of community water fluoridation (CWF) over a five-year period. The control group received non-fluoridated drinking water in the East of Cumbria, while the intervention group received fluoridated drinking water in the West of Cumbria. The primary outcome measures were the presence or absence of decay into dentine in primary and permanent teeth. Cost effectiveness was assessed by quality-adjusted life-years. Birth Cohort: Modest beneficial effect (17.4% with decay, 21.4% in control). Adjusted Odd Ratios (AOR): 0.74 (95% CI: 0.56 to 0.98). Older Cohort: Insufficient evidence of difference (19.1% with decay and 21.9% in control). AOR: 0.80 (95% CI: 0.58 to 1.09). The authors concluded that CWF was effective in the birth cohort and that the modest absolute reduction in caries should be considered in the context of other preventive measures. A longer follow-up period was recommended to fully understand the benefits and risks of CWF in contemporary low-prevalence populations.

Effectiveness of Endoscopic Screening on Esophageal Cancer Incidence and Mortality: A 9-Year Report of the Endoscopic Screening for Esophageal Cancer in China (ESECC) Randomized Trial.

To evaluate the effectiveness of endoscopic screening against incidence of and mortality from esophageal squamous cell carcinoma (ESCC). From January 2012 to September 2016, we conducted a community-based cluster randomized controlled trial involving permanent residents age 45-69 years in a high-risk region for ESCC in northern China. A total of 668 targeted villages were randomly assigned in a 1:1 ratio to the screening group (offered Lugol's chromoendoscopy) or control group (no screening). Intention-to-treat and per-protocol analyses were performed to compare esophageal cancer (EC) incidence and mortality between the two groups. The per-protocol analysis adjusted for nonadherence to the screening procedure. A total of 33,847 participants were included in the analysis: 17,104 in the screening group, 15,165 (88.7%) of whom underwent screening, and 16,743 in the control group. During a maximum follow-up of 9 years, EC incidence in the screening and control groups were 60.9 and 72.5 per 100,000 person-years, respectively; mortality in the screening and control groups were 29.7 and 32.4 per 100,000 person-years, respectively. Compared with the control group, the incidence and mortality of the screening group reduced by 19% (adjusted hazard ratio [aHR], 0.81 [95% CI, 0.60 to 1.09]) and 18% (aHR, 0.82 [95% CI, 0.53 to 1.26]), respectively, in the intention-to-treat analysis; and by 22% (aHR, 0.78 [95% CI, 0.56 to 1.10]) and 21% (aHR, 0.79 [95% CI, 0.49 to 1.30]), respectively, in the per-protocol analysis. With a 9-year follow-up, our trial suggests that chromoendoscopic screening induces modest reductions in EC incidence and mortality. A more efficient strategy for EC screening and subsequent patient management should be established to guarantee the effectiveness of endoscopic screening.

Suppressed IgG4 class switching in dupilumab- and TNF inhibitor-treated patients after mRNA vaccination.

The noninflammatory immunoglobulin G4 (IgG4) is linked to tolerance and is unique to humans. Although poorly understood, prolonged antigenic stimulation and IL-4-signaling along the T helper 2-axis may be instrumental in IgG4 class switching. Recently, repeated SARS-CoV-2 mRNA vaccination has been linked to IgG4 skewing. Although widely used immunosuppressive drugs have been shown to only moderately affect humoral responses to SARS-CoV-2 mRNA vaccination, the effect on IgG4 switching has not been investigated. Here we study the impact of such immunosuppressive drugs, including the IL-4 receptor-blocking antibody dupilumab, on IgG4 skewing upon repeated SARS-CoV-2 mRNA vaccination. Receptor-binding domain (RBD) specific antibody responses were longitudinally measured in 600 individuals, including patients with immune-mediated inflammatory diseases treated with a TNF inhibitor (TNFi) and/or methotrexate (MTX), dupilumab, and healthy/untreated controls, after repeated mRNA vaccination. We observed a substantial increase in the proportion of RBD-specific IgG4 antibodies (median 21%) in healthy/untreated controls after third vaccination. This IgG4 skewing was profoundly reduced in dupilumab-treated patients (<1%). Unexpectedly, an equally strong suppression of IgG4 skewing was observed in TNFi-treated patients (<1%), whereas MTX caused a modest reduction (7%). RBD-specific total IgG levels were hardly affected by these immunosuppressive drugs. Minimal skewing was observed, when primary vaccination was adenoviral vector-based. Our results imply a critical role for IL-4/IL-13 as well as TNF invivo IgG4 class switching. These novel findings advance our understanding of IgG4 class switch dynamics, and may benefit humoral tolerance induction strategies, treatment of IgG4 pathologies and mRNA vaccine optimization.

Change in upper eyelid position after teprotumumab treatment for thyroid eye disease

ABSTRACT Purpose Despite the high prevalence, treatment challenges, and significant impact of eyelid retraction on vision and quality of life among patients with thyroid eye disease, the effects of teprotumumab on eyelid retraction are not fully understood. This study evaluated change in upper eyelid position after teprotumumab. Methods A retrospective study of all patients who completed eight teprotumumab infusions at one institution from January 1 2020 to December 31 2022. Primary outcome was change in upper eyelid position immediately after treatment and at most recent follow-up compared to pre-treatment. Results Among 234 eyes of 118 patients, average margin reflex distance-1 (MRD1) pre-treatment was 5.25 mm (range 0–10.0, SD 1.75), 4.66 mm (1.0–9.0, SD 1.32) immediately post-treatment (p < 0.001), and 4.50 mm (0–10.0, SD 1.52) at most recent follow-up (mean follow-up duration 10.60 months). In total, 136 (58.12%) eyes of 88 patients had MRD1 reduction immediately post-treatment, averaging 1.49 mm (0.5–5.0 mm, SD 0.97). Every 1-mm increase in pre-treatment MRD1 increased the odds of MRD1 reduction by 15.03% (CI 10.52–19.72, p < 0.001) and increased the reduction amount by 0.48 mm (CI 0.39–0.57, p < 0.001). Of 154 eyes of 78 patients with most recent follow-up, 107 (69.48%) eyes had stable or further improved retraction at most recent follow-up compared to immediately post-treatment. Conclusions This study found a modest but significant reduction in MRD1 in approximately 60% of eyes, independent of proptosis change, which was sustained by most patients over longer-term follow-up. Higher pre-treatment MRD1 corresponded with greater improvement. These results suggest an overall mild benefit of teprotumumab for upper eyelid retraction.

Differences in femoral fracture localizations in men and women in Switzerland between 1998 and 2021-reversal of the secular trend?

Long-term incidence trends for femoral fractures by individual localizations are unknown. Annual absolute number of hospitalizations and median age at hospital admission between 1998 and 2021 were extracted from the medical database of the Swiss Federal Office of Statistics by sex and 10-year age groups for the following 10th International Classification of Diseases (ICD-10) codes: femoral neck (ICD-10 S72.0), pertrochanteric (S72.1), subtrochanteric (S72.2), and femoral shaft fractures (S72.3). Age-standardized incidence rates (ASI) and corresponding trends were calculated. Over 24years, the number of femoral neck fractures increased in men (+ 45%) but decreased in women (- 7%) with ASI significantly decreasing by 20% and 37% (p < 0.001 for trend for both), respectively. By contrast, the number of pertrochanteric fractures increased by 67% and 45% in men and women, respectively, corresponding to a horizontal ASI-trend in men (n.s.) and a modest significant decreasing ASI-trend in women (p < 0.001). The number of subtrochanteric fractures increased in both sexes with corresponding modest significant reductions in ASI-trends (p = 0.015 and 0.002, respectively). Femoral shaft fractures almost doubled in men (+ 71%) and doubled in women (+ 100%) with corresponding significant increases in ASI-trends (p = 0.001 and p < 0.001, respectively). Age at admission increased for all fracture localizations, more so in men than in women and more so for subtrochanteric and shaft fractures than for "typical" hip fractures. Incidence changes of pertrochanteric fractures and femoral shaft fractures deserve increased attention, especially in men. Pooling diagnostic codes for defining hip fractures may hide differing patterns by localization and sex.

Effects of Electron-Withdrawing and Electron-Donating Groups on Aromaticity in Cyclic Conjugated Polyenes.

Determining the aromaticity of various fluorinated benzenes is challenging as easily obtained experimental aromaticity [Δδ(Houter - Hinner)] necessitates the chemical shifts of inner and outer protons. This issue was addressed in porphyrinoids by replacing the electron-withdrawing (E.W.) groups at the meso-positions of porphyrins and allyliporphyrins. Electronic effects on aromaticity in porphyrinoids have not been thoroughly examined in the literature. In porphyrins, the effect of E.W. groups is minimal, making it difficult to establish a clear relationship between the aromaticity strength and E.W. groups. Conversely, in allyliporphyrins, stronger E.W. groups, such as indandione (IND) derivatives, significantly reduce the aromaticity of the parent structure. The IND derivatives disrupted the aromatic pathway of allyliporphyrin more effectively than those attached to porphyrins. This is attributed to the absence of β-carbons in allyliporphyrins. The effect of electron-donating (E.D.) groups on porphyrins and allyliporphyrins was further investigated. Contrary to the initial assumption that the E.D. groups might enhance aromaticity owing to their ability to increase electron density, as the strength of the E.D. groups increased, the aromaticity of the porphyrinoids decreased. Despite the modest reduction in aromaticity, any form of electron perturbation reduces aromaticity. The aromaticity of various fluorinated benzenes is expected to parallel our observations of porphyrinoids as representative aromatic polyenes.

Novel roles of cardiac-derived erythropoietin in cardiac development and function

The role of erythropoietin (EPO) has extended beyond hematopoiesis to include cytoprotection, inotropy, and neurogenesis. Extra-renal EPO has been reported for multiple tissue/cell types, but the physiological relevance remains unknown. Although the EPO receptor is expressed by multiple cardiac cell types and human recombinant EPO increases contractility and confers cytoprotection against injury, whether the heart produces physiologically meaningful amounts of EPO in vivo is unclear. We show a distinct circadian rhythm of cardiac EPO mRNA expression in adult mice and increased mRNA expression during embryogenesis, suggesting physiological relevance to cardiac EPO production throughout life. We then generated constitutive, cardiomyocyte-specific EPO knockout mice driven by the Mlc2v promoter (EPOfl/fl:Mlc2v-cre+/−; EPOΔ/Δ-CM). During cardiogenesis, cardiac EPO mRNA expression and cellular proliferation were reduced in EPOΔ/Δ-CM hearts. However, in adult EPOΔ/Δ- CM mice, total heart weight was preserved through increased cardiomyocyte cross-sectional area, indicating the reduced cellular proliferation was compensated for by cellular hypertrophy. Echocardiography revealed no changes in cardiac dimensions, with modest reductions in ejection fraction, stroke volume, and tachycardia, whereas invasive hemodynamics showed increased cardiac contractility and lusitropy. Paradoxically, EPO mRNA expression in the heart was elevated in adult EPOΔ/Δ-CM, along with increased serum EPO protein content and hematocrit. Using RNA fluorescent in situ hybridization, we found that Epo RNA colocalized with endothelial cells in the hearts of adult EPOΔ/Δ-CM mice, identifying the endothelial cells as a cell responsible for the EPO hyper-expression. Collectively, these data identify the first physiological roles for cardiomyocyte-derived EPO. We have established cardiac EPO mRNA expression is a complex interplay of multiple cell types, where loss of embryonic cardiomyocyte EPO production results in hyper-expression from other cells within the adult heart.

Stand structure is more important for forest productivity stability than tree, understory plant and soil biota species diversity

IntroductionThe stability of forest productivity is an important management goal in order to sustain ecosystem services for an expanding human population and in the face of global climate change. Evidence from theoretical, observational, and experimental studies has demonstrated that higher biodiversity promotes stability of forest productivity. However, the majority of these studies have focused solely on tree diversity and have neglected the potentially important role of understory plant and soil biodiversity.MethodsIn this study, we explain the effect of tree, understory woody and herbaceous plant, and soil biota (fauna, fungi, and bacteria) species diversity on forest productivity and its stability over time (2000–2020) across an area of Northeast China covering 145 million hectares. We explore the eight stand structure variables for stability of forest productivity and the relationship between productivity stability and tree, understory plant, and soil biota species diversity.ResultsOur results show no significant, direct impact of understory plant, soil fungi, and bacteria species diversity on the stability of the forest ecosystem. Tree species diversity indirectly affects productivity stability by directly influencing stand structure, whereas soil fauna species diversity indirectly influences stability through its relationship with tree species diversity. Stand structure is more important than tree and soil fauna species diversity for forest productivity stability. Specifically, increasing crown height (CH) from its minimum to maximum value leads to a substantial gain of 20.394 in forest productivity stability. In contrast, raising tree species diversity (α-Tree) and soil fauna species diversity (α-Fauna) from their minimum to maximum values results in a modest reduction of only 0.399 and 0.231 in forest productivity stability, respectively.DiscussionTo increase the stability of forest productivity in response to climate change, we should adjust the stand structure more in the process of management rather than just considering biodiversity. Overall, this study highlights the ecological risks associated with large-scale biotic homogenization under future climate change and management practices.

On the role of interconnected mini-grids in net-zero emissions electricity system: insights from Nigeria

As developing countries like Nigeria strive to reduce carbon emissions while expanding energy access, mini-grids’ role has gained recognition. However, limited analysis exists regarding the role of interconnected mini-grids (IMGs) in the transition to net-zero emissions electricity generation systems. Here, we employ a bottom-up energy system optimization modeling framework to explore the techno-economic implications of deploying IMGs in net-zero emissions electricity systems, using Nigeria as a case study. We find that IMGs can contribute to modest system-level cost reductions in net-zero emissions electricity systems. IMGs can help minimize stranded electricity generation assets and decrease the reliance on negative emissions technologies in scenarios aiming for net-zero emissions electricity systems by 2050. In scenarios where the net-zero target is delayed until 2070, the widespread deployment of comparatively affordable cleaner generators and the phaseout of fossil fuel power plants may render negative emission technologies unnecessary. The model results further indicate that IMGs can help reduce the use of captive diesel/gasoline gen-sets quickly, and nuclear power has a role in the electricity generation mix in all net-zero emissions scenarios. Moreover, in order to achieve the median per capita electricity consumption observed in high-income countries by the year 2050, Nigeria must undertake a formidable expansion of its current electricity generation capacity at a rate approximately six times greater than that dictated by a business-as-usual trajectory. The study also provides recommendations to address the policy, regulatory, and financial considerations crucial for implementing IMGs successfully.

The higher dietary inflammation is associated with a higher burden of multimorbidity of cardio-metabolic and mental health disorders in an urbanizing community of southern India: A cross-sectional analysis for the APCAPS cohort

Background & aimsHabitual dietary pattern has been shown to be a major modulator of systemic inflammation and is considered a modifiable risk factor for cardio-metabolic diseases (CMDs) and mental health disorders. We examined whether dietary-inflammation is associated with the multimorbidity of CMDs and mental health disorders in urbanizing-villages in southern India. We hypothesized that the participants with higher dietary-inflammation would have a higher burden of multimorbidity. Materials & methodsWe conducted a cross-sectional analysis of 5984 adults (53% male) participating in the Andhra Pradesh Children and Parents' Study. We assessed dietary-inflammation using dietary inflammatory index (DII®) based on intake of 27 micro- and macro-nutrients which were measured using a validated food-frequency-questionnaires. The CMDs and mental health disorders were assessed using standardized clinical procedures and validated questionnaires. ‘Multimorbidity’ was defined as a co-existence of one or more CMDs (hypertension, diabetes, myocardial infarction, heart failure, angina and stroke) and one or more mental health disorders (depression and anxiety). The association of multimorbidity with dietary-inflammation was examined using robust Poisson regression. ResultsThe prevalence of multimorbidity was 3.5% and ∼75% of participants were consuming a pro-inflammatory diet (DII >0.0). As compared to the 1st DII-quartile (least dietary-inflammatory group), the adjusted prevalence ratio (95% confidence interval) for the presence of multimorbidity was 1.46(0.87, 2.46) for 2nd, 1.75(1.05, 2.89) for 3rd, and 1.77(1.06, 2.96) for 4th DII-quartile (p-trend = 0.021). There was no evidence of an interaction between DII and sex on multimorbidity. ConclusionsDietary-inflammation had a positive linear association with the multimorbidity, which suggest that even modest reduction in dietary-inflammation may reduce the multimorbidity burden.

Dapagliflozin and Blood Pressure in Patients with Chronic Kidney Disease and Albuminuria

Background and AimsSodium–glucose cotransporter 2 inhibitors decrease blood pressure in patients with type 2 diabetes, but the consistency and magnitude of blood pressure lowering with dapagliflozin in patients with chronic kidney disease (CKD) is unknown. We conducted a prespecified analysis of the DAPA-CKD trial to investigate the effect of dapagliflozin on systolic blood pressure (SBP) in patients with CKD, with and without type 2 diabetes. MethodsA total of 4304 adults with baseline estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73m2 and urinary albumin-to-creatinine ratio (UACR) 200-5000 mg/g were randomized to either dapagliflozin 10 mg or placebo once daily; median follow-up was 2.4 years. The primary endpoint was a composite of sustained ≥50% eGFR decline, end-stage kidney disease, or death from a kidney or cardiovascular cause. Change in SBP was a prespecified outcome. ResultsBaseline mean (SD) SBP was 137.1 mmHg (17.4). By Week 2, dapagliflozin compared to placebo reduced SBP by 3.6 mmHg (95% CI 2.8-4.4 mmHg), an effect maintained over the duration of the trial (2.9 mmHg, 2.3-3.6 mmHg). Time-averaged reductions in SBP were 3.2 mmHg (2.5-4.0 mmHg) in patients with diabetes and 2.3 mmHg (1.2-3.4 mmHg) in patients without diabetes. The time-averaged effect of dapagliflozin on diastolic blood pressure (DBP) was 1.0 mmHg (0.6-1.4 mmHg); 0.8 mmHg (0.4-1.3 mmHg) in patients with diabetes and 1.4 mmHg (0.7-2.1 mmHg) in patients without diabetes. Benefits of dapagliflozin on the primary composite and secondary endpoints were evident across the spectrum of baseline SBP and DBP. ConclusionIn patients with CKD and albuminuria, randomization to dapagliflozin was associated with modest reductions in systolic and diastolic BP.

Smoking, Drinking, and Dietary Risk Factors for Head and Neck Cancer in Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Participants

There is a paucity of large-scale prospective studies evaluating the risk of developing head and neck cancer (HNC) associated with smoking, drinking, and dietary habits. To determine the association of smoking, drinking, and dietary habits with the risk of developing HNC. A nested cohort survival analysis of Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial participants was performed. Participants were between 55 and 74 years of age and recruited at 10 centers across the US from November 1993 to July 2001. Participants who developed HNC were matched with controls based on demographics and family history of HNC for analysis of smoking habits; for the analysis of drinking and dietary habits, matching was performed on smoking status and duration in addition to demographics and family history of HNC. Data analysis was performed from January to November 2023. Smoking, drinking, and dietary habits. Diagnosis of HNC. In total, 139 926 participants (51% female; mean [SD] age, 62.6 [5.4] years) were included in the analysis of smoking habits with a median (IQR) follow-up time of 12.1 (10.3-13.6) years, 571 of whom developed HNC. HNC risk associated with smoking increased the closer the proximity of the head and neck subsite to the lungs, with the greatest risk associated with smoking observed in laryngeal cancer (current smoker hazard ratio [HR], 9.36; 95% CI, 5.78-15.15 compared to a nonsmoker). For analysis of drinking and dietary habits, 94 466 participants were included in the analysis of smoking habits with a median (IQR) follow-up time of 12.2 (10.5-13.6) years, 264 of whom developed HNC. HNC risk increased with heavy drinking (HR, 1.85; 95% CI, 1.44-2.38) and decreased with consumption of whole grains (HR, 0.78; 95% CI, 0.64-0.94/oz per day), whole fruits (HR, 0.90; 95% CI, 0.82-0.98/cup per day), and overall healthy eating, as scored by Healthy Eating Index 2015 (HR, 0.87; 95% CI, 0.78-0.98/10 points). In this nested cohort study, the risk of HNC associated with smoking was higher for subsites that were closer to the lungs; heavy drinking was associated with greater HNC risk, while healthy eating was associated with a modest reduction in HNC risk.

Demonstration of a robust high cell density transient CHO platform yielding mAb titers of up to 2 g/L without medium exchange.

Biopharmaceuticals like therapeutic monoclonal antibodies (mAbs) and other derived proteins are popular for treating various diseases. Transient gene expression (TGE) is typically used as a fast yet efficient method to generate moderate amounts of material. It has been used to support early stage research and discovery processes. Introduction of a robust high yielding and predictive TGE platform in Chinese hamster ovary (CHO) is crucial. It maintains the consistency in cell lines and processes throughout the early drug discovery and downstream manufacturing processes. This helps researchers to identify the issues at an early stage for timely resolution. In this study, we have demonstrated a simple high-titer platform for TGE in CHO based on a dilution process of seeding cells. We achieved titers ranging from 0.8 to 1.9 g/L for eight model mAbs at three scales (1, 30, 100 mL) in 10 days using our new platform. The ability to seed by dilution significantly streamlined the process and dramatically enhanced platform throughput. We observed a modest reduction in titer ranging from 11% to 28% when cells were seeded using dilution compared to when cells were seeded using medium exchange. Further studies revealed that carry over of spent medium into transfection negatively affected the DNA uptake and transcription processes, while the translation and secretion was minimally impacted. In summary, our transient CHO platform using cells prepared by dilution at high densities can achieve high titers of up to 1.9 g/L, which can be further improved by targeting the bottlenecks of transfection and transcription.

Enterococcus mundtii A2 biofilm and its anti-adherence potential against pathogenic microorganisms on stainless steel 316L.

Pathogenic bacterial biofilms present significant challenges, particularly in food safety and material deterioration. Therefore, using Enterococcus mundtii A2, known for its antagonistic activity against pathogen adhesion, could serve as a novel strategy to reduce pathogenic colonization within the food sector. This study aimed to investigate the biofilm-forming ability of E. mundtii A2, isolated from camel milk, on two widely used stainless steels within the agri-food domain and to assess its anti-adhesive properties against various pathogens, especially on stainless steel 316L. Additionally, investigations into auto-aggregation and co-aggregation were also conducted. Plate count methodologies revealed increased biofilm formation by E. mundtii A2 on 316L, followed by 304L. Scanning electron microscopy (SEM) analysis revealed a dense yet thin biofilm layer, playing a critical role in reducing the adhesion of L. monocytogenes CECT 4032 and Staphylococcus aureus CECT 976, with a significant reduction of ≈ 2 Log CFU/cm2. However, Gram-negative strains, P. aeruginosa ATCC 27853 and E. coli ATCC 25922, exhibit modest adhesion reduction (~ 0.7 Log CFU/cm2). The findings demonstrate the potential of applying E. mundtii A2 biofilms as an effective strategy to reduce the adhesion and propagation of potentially pathogenic bacterial species on stainless steel 316L.

Enhancing Pre-Treatment Motivation Improves Forensic Mental Health Outcomes.

Despite evidence that psychological treatments benefit from pre-treatment intervention, there remains no published research on the value of including a pre-treatment intervention in forensic mental health settings. The present study aimed to address this gap by examining the effects of adding a brief motivational preparatory program (MPP) to standard forensic psychiatric care. The MPP was based on hope theory and motivational interviewing within a cognitive-behavioral therapy approach. MPP participants and a waitlist control group completed a battery of self-report measures of hope and motivation to change, which were compared with respect to risk, demographic, offence history, and outcome variables. There was a significant increase in client motivation for change after completing the MPP. Additionally, those who completed the MPP evidenced modest reductions in aggressive behavior, but significantly increased engagement in subsequent forensic treatment and programming.

Safety and efficacy of malaria vaccine candidate R21/Matrix-M in African children: a multicentre, double-blind, randomised, phase 3 trial

Recently, we found that a new malaria vaccine, R21/Matrix-M, had over 75% efficacy against clinical malaria with seasonal administration in a phase 2b trial in Burkina Faso. Here, we report on safety and efficacy of the vaccine in a phase 3 trial enrolling over 4800 children across four countries followed for up to 18 months at seasonal sites and 12 months at standard sites. We did a double-blind, randomised, phase 3 trial of the R21/Matrix-M malaria vaccine across five sites in four African countries with differing malaria transmission intensities and seasonality. Children (aged 5-36 months) were enrolled and randomly assigned (2:1) to receive 5 μg R21 plus 50 μg Matrix-M or a control vaccine (licensed rabies vaccine [Abhayrab]). Participants, their families, investigators, laboratory teams, and the local study team were masked to treatment. Vaccines were administered as three doses, 4 weeks apart, with a booster administered 12 months after the third dose. Half of the children were recruited at two sites with seasonal malaria transmission and the remainder at standard sites with perennial malaria transmission using age-based immunisation. The primary objective was protective efficacy of R21/Matrix-M from 14 days after third vaccination to 12 months after completion of the primary series at seasonal and standard sites separately as co-primary endpoints. Vaccine efficacy against multiple malaria episodes and severe malaria, as well as safety and immunogenicity, were also assessed. This trial is registered on ClinicalTrials.gov, NCT04704830, and is ongoing. From April 26, 2021, to Jan 12, 2022, 5477 children consented to be screened, of whom 1705 were randomly assigned to control vaccine and 3434 to R21/Matrix-M; 4878 participants received the first dose of vaccine. 3103 participants in the R21/Matrix-M group and 1541 participants in the control group were included in the modified per-protocol analysis (2412 [51·9%] male and 2232 [48·1%] female). R21/Matrix-M vaccine was well tolerated, with injection site pain (301 [18·6%] of 1615 participants) and fever (754 [46·7%] of 1615 participants) as the most frequent adverse events. Number of adverse events of special interest and serious adverse events did not significantly differ between the vaccine groups. There were no treatment-related deaths. 12-month vaccine efficacy was 75% (95% CI 71-79; p<0·0001) at the seasonal sites and 68% (61-74; p<0·0001) at the standard sites for time to first clinical malaria episode. Similarly, vaccine efficacy against multiple clinical malaria episodes was 75% (71-78; p<0·0001) at the seasonal sites and 67% (59-73; p<0·0001) at standard sites. A modest reduction in vaccine efficacy was observed over the first 12 months of follow-up, of similar size at seasonal and standard sites. A rate reduction of 868 (95% CI 762-974) cases per 1000 children-years at seasonal sites and 296 (231-362) at standard sites occurred over 12 months. Vaccine-induced antibodies against the conserved central Asn-Ala-Asn-Pro (NANP) repeat sequence of circumsporozoite protein correlated with vaccine efficacy. Higher NANP-specific antibody titres were observed in the 5-17 month age group compared with 18-36 month age group, and the younger age group had the highest 12-month vaccine efficacy on time to first clinical malaria episode at seasonal (79% [95% CI 73-84]; p<0·001) and standard (75% [65-83]; p<0·001) sites. R21/Matrix-M was well tolerated and offered high efficacy against clinical malaria in African children. This low-cost, high-efficacy vaccine is already licensed by several African countries, and recently received a WHO policy recommendation and prequalification, offering large-scale supply to help reduce the great burden of malaria in sub-Saharan Africa. The Serum Institute of India, the Wellcome Trust, the UK National Institute for Health Research Oxford Biomedical Research Centre, and Open Philanthropy.

Inhibition of Receptor-Interacting Protein Kinase1 in Chronic Plaque Psoriasis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study.

Receptor-interacting protein kinase1 (RIPK1), a key mediator of inflammation through necroptosis and proinflammatory cytokine production, may play a role in the pathogenesis of immune-mediated inflammatory diseases such as chronic plaque psoriasis. An experimental medicine study of RIPK1 inhibition with GSK2982772 immediate-release formulation at doses up to 60mg three times daily in mild to moderate plaque psoriasis indicated that efficacy may be improved with higher trough concentrations of GSK2982772. This multicenter, randomized, double-blind, placebo-controlled, repeat-dose study (NCT04316585) assessed the efficacy, safety, pharmacokinetics, and pharmacodynamics of 960mg GSK2982772 (once-daily modified-release formulation) in patients with moderate to severe plaque psoriasis. Twenty-nine patients were randomized 2:1 to GSK2982772 (N = 19) or placebo (N = 10) for 12weeks. GSK2982772 was well tolerated with trough concentrations greater than tenfold higher than the previous phase1 study with immediate release. Despite near complete RIPK1 target engagement in blood and modest reduction in circulating inflammatory cytokines, the proportion of patients achieving 75% improvement from baseline in Psoriasis Area Severity Index score at week12 was similar between GSK2982772 and placebo (posterior median 1.8% vs 4.9%, respectively), with an estimated median treatment difference of - 2.3%. This analysis incorporated historical placebo data through the use of an informative prior distribution on the placebo arm. Week4 changes in skin biopsy gene expression suggested sufficient local drug exposure to elicit a pharmacodynamic response. Administration of the RIPK1 inhibitor GSK2982772 to patients with moderate to severe plaque psoriasis did not translate into meaningful clinical improvements.

Associations of the utilization of household water treatment devices with mortality

This study aimed to investigate the relationship between the utilization of household water treatment devices (UHWTD) and both overall and cause-specific mortality, addressing the lack of comprehensive prospective research in this area. The study was a population-based prospective cohort study using data from the US National Health and Nutrition Examination Survey (NHANES 1999–2010). Among the 30,322 participants included in the study, the group without UHWTD (No UHWTD) was younger but reported worse baseline health compared to the UHWTD group. During an average follow-up period of 14.3 years, 6811 participants died. After adjusting for age, sex, and other covariates, No UHWTD was significantly associated with a higher risk of overall (adjusted hazard ratio [aHR]: 1.221, 95% Confidence Interval [CI]: 1.147–1.300), heart (aHR: 1.405, 95% CI: 1.241–1.589), cancer (aHR: 1.176, 95% CI: 1.003–1.379), Alzheimer’s disease (aHR: 1.404, 95% CI: 1.027–1.919), and nephrosis (aHR: 1.613, 95% CI: 1.026–2.537) mortality compared to UHWTD. Moreover, those main association almost remained after further adjustment for water source. Additionally, we observed a lower detection rate of bromoform, chloroform, bromodichloromethane, and dibromochloromethane in tap water when household water treatment devices was used compared to No UHWTD. The utilization of household water treatment devices in this prospective cohort was associated with modest reductions in the risk of overall, heart, cancer, Alzheimer’s disease, and nephrosis mortality. These findings suggest that the use of household water treatment devices may have the potential to influence health outcomes and extend life expectancy.

Evaluating and Enhancing Snow Compaction Process in the Noah‐MP Land Surface Model

AbstractThe accuracy of snow density in land surface model (LSM) simulations impacts the accuracy of simulated terrestrial water and energy budgets. However, there has been little research that has focused on enhancing snow compaction in operationally used LSMs. A baseline snow simulation with the widely used Noah‐MP LSM systematically overestimates snow depth by 55 mm even after removing daily snow water equivalent (SWE) biases. To reduce uncertainties associated with snow compaction, we enhance the most sensitive Noah‐MP snow compaction parameter—the empirical parameter for compaction due to overburden (Cbd)—such that Cbd is calculated as a function of surface air temperature as opposed to a fixed value in the baseline simulation. This enhancement improves accuracy in simulated snow compaction across the majority of western U.S. (WUS) SNOTEL test sites (biases reduced at 88% of test sites), with modest bias reductions in cooler accumulation periods (biases reduced at 70% of test sites) and substantial improvements during warmer ablation periods (biases reduced at 99% of test sites). Relatively larger improvements during warm conditions are attributable to the default Cbd value being reasonable for cold temperatures (≤−5°C). Improvements in simulated snow depth and density with observations outside of the training sites and optimization periods support that the snow compaction enhancement is transferable in space and time. Differences between enhanced and baseline gridded simulations across the total WUS support that the enhancement can have important impacts on snowpack evolution, snow albedo feedback, and snow hydrology.