Comparison of Beinaglutide Versus Metformin for Weight Loss in Overweight and Obese Non-diabetic Patients

Purpose We compared the efficacy and safety of beinaglutide, a glucagon-like peptide-1 (GLP-1) analogue with metformin in lowering the bodyweight of patients who were overweight/obese and non-diabetic. Patients and Methods Seventy-eight non-diabetic patients were randomly selected and beinaglutide or metformin was administered for 12 weeks. The primary endpoints were changes in body weight and the proportions of patients who lost≥5 and≥10% of their baseline body weights. Results A total of 64 patients completed the study; patients in the beinaglutide group exhibited more bodyweight loss than those in the metformin group [(9.5±0.8%; 9.1±0.9 kg) and (5.1±0.9%; 4.5±0.8 kg), respectively, corresponding to a difference of approximately 4.5 kg (95% confidence interval, 2.2–6.9 kg; P<0.01)]. In the beinaglutide group, 90.6 and 40.6% of the patients lost≥5 and≥10% of their body weight, respectively, whereas, in the metformin group, these rates were 46.9 and 12.5%, respectively (P<0.01 and P<0.05). Weight loss following beinaglutide treatment mainly resulted from the loss of fat mass. Compared to metformin, beinaglutide induced a greater decrease in the body mass index, weight circumference, percent body fat, and body fat mass (total, trunk, limb, android, and gynoid). Additionally, beinaglutide decreased serum insulin levels and ameliorated insulin resistance. Conclusions Beinaglutide is more efficient than metformin at reducing weight and fat mass in patients who are overweight/obese and non-diabetic. Beinaglutide may be a useful therapeutic option for overweight/obesity control in the Chinese population.

Association Between Body Weight Change In Late Life And Risk Of Dementia: A Population-based Cohort Study

Background: Adiposity in midlife is a modifiable risk factor for dementia. However, the effect of adiposity in late-life on dementia remains unclear. We investigated the association of body mass index (BMI) and weight changes after age 60 with the incident dementia. Methods: Within the Swedish National Study on Aging and Care-Kungsholmen, 1,673 dementia-free participants with data on BMI/weight both at baseline and the 6-year follow-up were followed to detect subsequent incident dementia cases. BMI change was assessed as the percentage of the difference between BMI at baseline and the initial 6-year follow-up and categorized into large (&gt;10%) or moderate (5–10%) loss, stable (≤5%), and moderate (5–10%) or large (&gt;10%) gain. Weight change (difference between weight at baseline and the 6-year follow-up) was categorized into large (&gt;7.5 kg) or moderate (2.5–7.5 kg) loss, stable (≤2.5 kg), and moderate (2.5–7.5 kg) or large (&gt; 7.5 kg) gain. Dementia was diagnosed following the DSM-IV criteria. Data were analyzed using Cox regression models. Results: During the follow-up (median 5.78 years), 102 incident dementia cases developed. BMI/weight change showed U-shaped associations with dementia. Compared with stable BMI, the hazard ratios (95% confidence intervals) of dementia were 2.93 (1.72−4.91) for large BMI loss and 2.61 (1.09−5.54) for large BMI gain. Similar results were observed for a large weight loss (2.92 [1.67−5.07]) or gain (2.95 [1.16−6.53]). These associations became stronger among participants carrying an ApoE ɛ4 allele. Conclusion: Both large bodyweight loss and gain are associated with a higher risk of dementia, especially among ApoE ɛ4 carriers.

Preclinical efficacy, safety, and immunogenicity of PHH-1V, a second-generation COVID-19 vaccine candidate based on a novel recombinant RBD fusion heterodimer of SARS-CoV-2.

Since the genetic sequence of SARS-CoV-2 became available in January 2020, new vaccines have been developed at an unprecedented speed. The current vaccines have been directly associated with a decline in new infection rates, prevention of severe disease and an outstanding decrease in mortality rates. However, the pandemic is still far from being over. New Variants of Concern (VoCs) are continuously evolving. Thus, it is essential to develop accessible second-generation COVID-19 vaccines against known and future VoCs to mitigate the current pandemic. Here, we provide preclinical data showing the immunogenicity, efficacy, and safety results in mice of a receptor-binding domain (RBD)-based recombinant protein vaccine candidate (PHH-1V) which consists of a novel RBD fusion heterodimer containing the B.1.1.7 (alpha) and B.1.351 (beta) variants of SARS-CoV-2, formulated with an oil-based adjuvant equivalent to MF59C.1. BALB/c and K18-hACE2 mice were immunized with different doses of recombinant RBD fusion heterodimer, following a two-dose prime-and-boost schedule. Upon 20 μg RBD fusion heterodimer/dose immunization, BALB/c mice produced RBD-binding antibodies with neutralising activity against the alpha, beta, gamma, and delta variants. Furthermore, vaccination elicited robust activation of CD4+ and CD8+ T cells with early expression of Th1 cytokines upon in vitro restimulation, along with a good tolerability profile. Importantly, vaccination with 10 μg or 20 μg RBD fusion heterodimer/dose conferred 100% efficacy preventing mortality and bodyweight loss upon SARS-CoV-2 challenge in K18-hACE2 mice. These findings demonstrate the feasibility of this novel recombinant vaccine strategy, allowing the inclusion of up to 2 different RBD proteins in the same vaccine. Most importantly, this new platform is easy to adapt to future VoCs and has a good stability profile, thus ensuring its global distribution.

Case Report: Newborns With Pseudohypoaldosteronism Secondary to Excessive Gastrointestinal Losses Through High Output Stoma

Life-threatening electrolyte imbalance is not uncommon in preemies. Differential diagnosis is important for immediate treatment. The syndrome of pseudohypoaldosteronism (PHA) is characterized by increased aldosterone secretion associated with clinical signs of hypoaldosteronism reflecting mineralocorticoid resistance. There are type I, type II, and secondary type of PHA. Most secondary PHA reported in the pediatric population result from urinary infection and obstructive uropathy and extremely rarely from gastrointestinal fluid loss. Seven preemies accepted jejunostomy or ileostomy, and they suffered from high output stoma. Electrolyte imbalance with bodyweight loss or cardiac event was noted. We found a high level of aldosterone and renin and diagnosed them with secondary PHA due to excessive gastrointestinal losses. After stomal reversal, aldosterone and renin level became normalized, and electrolyte was corrected. This study reports the finding of secondary pseudohyperaldosteronism (hyponatremia, hyperkalemia, and metabolic acidosis) in a series of cases with intestinal resection and ostomy of different causes. Early stomal reversal was recommended.

Neutralization of interleukin-38 exacerbates coxsackievirus B3-induced acute myocarditis in mice

Background Interleukin (IL)-38, a novel member of the IL-1 family, has been reported to be involved in several diseases associated with viral infection. However, the expression and functional role of IL-38 in acute viral myocarditis (AVMC) have not been investigated. Methods Male BALB/c mice were treated with intraperitoneal (i.p.) injection of coxsackievirus B3 (CVB3) for establishing AVMC models. On day 7 post-injection, the expression of IL-38 and IL-36R (IL-36 receptor) were measured. Mice were then treated with i.p. injection of mouse Anti-IL-38 Antibodies (Abs) for neutralization of IL-38. The survival, bodyweight loss, cardiac function, and myocarditis severity of mice were recorded. The percentages of splenic Th1 and Th17 cells, the expression levels of Th1/Th17-related master transcription factors (T-bet and RORγt) and cytokines were determined by flow cytometry, RT-qPCR, and ELISA, respectively. Cardiac viral replication was further detected. Results The mRNA and protein expression levels of IL-38 in myocardium and serum, as well as cardiac IL-36R mRNA levels were significantly elevated in mice with AVMC. Increased IL-38 levels were negatively correlated with the severity of AVMC. Neutralization of IL-38 exacerbated CVB3-induced AVMC, as verified by the lower survival rate, impaired cardiac function, continuous bodyweight loss, and higher values of HW/BW and cardiac pathological scores. In addition, neutralization of IL-38 suppressed Th1 cells differentiation while promoted Th17 cells differentiation, accompanied by decreased T-bet mRNA expression and increased RORγt expression. Down-regulation of IFN-γ and up-regulation of IL-17, TNF-α, and IL-6 mRNA and protein expression levels in myocardium and serum were also observed in the IL-38 neutralization group. Furthermore, neutralization of IL-38 markedly promoted cardiac viral replication. Conclusions Neutralization of IL-38 exacerbates CVB3-induced AVMC in mice, which may be attributable to the imbalance of Th1/Th17 cells and increased CVB3 replication. Thus, IL-38 can be considered as a potential therapeutic target for AVMC.

The Comparison of the Effects between Continuous and Intermittent Energy Restriction in Short-Term Bodyweight Loss for Sedentary Population: A Randomized, Double-Blind, Controlled Trial

Objective: To compare the effects of continuous energy restriction (CER) and intermittent energy restriction (IER) in bodyweight loss plan in sedentary individuals with normal bodyweight and explore the influence factors of effect and individual retention. Methods: 26 participants were recruited in this randomized controlled and double-blinded trial and allocated to CER and IER groups. Bodyweight (BW), body mass index (BMI), and resting metabolic rate (RMR) would be collected before and after a 4-week (28 days) plan which included energy restriction (CER or IER) and moderate-intensity exercise. Daily intake of three major nutrients (protein, carbohydrate, fat) and calories were recorded. Results: A significant decrease in BW and BMI were reported within each group. No statistically significant difference in the change of RMR in CERG. No statistically significant difference was reported in the effect between groups, neither as well the intake of total calories, three major nutrients, and individual plan retention. The influence factors of IER and CER are different. Conclusion: Both CER and IER are effective and safe energy restriction strategies in the short term. Daily energy intake and physical exercise are important to both IER and CER.

Scrutiny of human lung infection by SARS-CoV-2 and associated human immune responses in humanized mice

There is an urgent need for animal models of COVID-19 to study immunopathogenesis and test therapeutic intervenes. In this study we showed that NSG mice engrafted with human lung (HL) tissue (NSG-L) could be infected efficiently by SARS-CoV-2, and that live virus capable of infecting Vero cells was found in the HL grafts and multiple organs from infected NSG-L mice. RNA-seq examination identified a series of differentially expressed genes, which are enriched in viral defense responses, chemotaxis, interferon stimulation, and pulmonary fibrosis between HL grafts from infected and control NSG-L mice. Furthermore, when infecting humanized mice with human immune system (HIS) and autologous HL grafts (HISL mice), the mice had bodyweight loss and hemorrhage and immune cell infiltration in HL grafts, which were not observed in immunodeficient NSG-L mice, indicating the development of anti-viral immune responses in these mice. In support of this possibility, the infected HISL mice showed bodyweight recovery and lack of detectable live virus at the later time. These results demonstrate that NSG-L and HISL mice are susceptible to SARS-CoV-2 infection, offering a useful in vivo model for studying SARS-CoV-2 infection and the associated immune response and immunopathology, and testing anti-SARS-CoV-2 therapies.

Therapeutic Targeting of SGLT2: A New Era in the Treatment of Diabetes and Diabetic Kidney Disease

As the prevalence of diabetic kidney disease (DKD) continues to rise, so does the need for a novel therapeutic modality that can control and slow its progression to end-stage renal disease. The advent of sodium-glucose cotransporter-2 (SGLT2) inhibitors has provided a major advancement for the treatment of DKD. However, there still remains insufficient understanding of the mechanism of action and effectiveness of this drug, and as a result, its use has been very limited. Burgeoning evidence suggests that the SGLT2 inhibitors possess renal protective activities that are able to lower glycemic levels, improve blood pressure/hemodynamics, cause bodyweight loss, mitigate oxidative stress, exert anti-inflammatory and anti-fibrotic effects, reduce urinary albumin excretion, lower uric acid levels, diminish the activity of intrarenal renin-angiotensin-aldosterone system, and reduce natriuretic peptide levels. SGLT2 inhibitors have been shown to be safe and beneficial for use in patients with a GFR ≥30mL/min/1.73m2, associated with a constellation of signs of metabolic reprogramming, including enhanced ketogenesis, which may be responsible for the correction of metabolic reprogramming that underlies DKD. This article aims to provide a comprehensive overview and better understanding of the SGLT2 inhibitor and its benefits as it pertains to renal pathophysiology. It summarizes our recent understanding on the mechanisms of action of SGLT2 inhibitors, discusses the effects of SGLT2 inhibitors on diabetes and DKD, and presents future research directions and therapeutic potential.

Differential Impact of Severity and Duration of Status Epilepticus, Medical Countermeasures, and a Disease-Modifier, Saracatinib, on Brain Regions in the Rat Diisopropylfluorophosphate Model

Acute organophosphate (OP) toxicity poses a significant threat to both military and civilian personnel as it can lead to a variety of cholinergic symptoms including the development of status epilepticus (SE). Depending on its severity, SE can lead to a spectrum of neurological changes including neuroinflammation and neurodegeneration. In this study, we determined the impact of SE severity and duration on disease promoting parameters such as gliosis and neurodegeneration and the efficacy of a disease modifier, saracatinib (AZD0530), a Src/Fyn tyrosine kinase inhibitor. Animals were exposed to 4 mg/kg diisopropylfluorophosphate (DFP, s.c.) followed by medical countermeasures. We had five experimental groups: controls (no DFP), animals with no continuous convulsive seizures (CS), animals with ∼20-min continuous CS, 31-60-min continuous CS, and &gt; 60-min continuous CS. These groups were then assessed for astrogliosis, microgliosis, and neurodegeneration 8 days after DFP exposure. The 31-60-min and &gt; 60-min groups, but not ∼20-min group, had significantly upregulated gliosis and neurodegeneration in the hippocampus compared to controls. In the piriform cortex and amygdala, however, all three continuous CS groups had significant upregulation in both gliosis and neurodegeneration. In a separate cohort of animals that had ∼20 and &gt; 60-min of continuous CS, we administered saracatinib for 7 days beginning three hours after DFP. There was bodyweight loss and mortality irrespective of the initial SE severity and duration. However, in survived animals, saracatinib prevented spontaneous recurrent seizures (SRS) during the first week in both severity groups. In the ∼20-min CS group, compared to the vehicle, saracatinib significantly reduced neurodegeneration in the piriform cortex and amygdala. There were no significant differences in the measured parameters between the naïve control and saracatinib on its own (without DFP) groups. Overall, this study demonstrates the differential effects of the initial SE severity and duration on the localization of gliosis and neurodegeneration. We have also demonstrated the disease-modifying potential of saracatinib. However, its’ dosing regimen should be optimized based on initial severity and duration of CS during SE to maximize therapeutic effects and minimize toxicity in the DFP model as well as in other OP models such as soman.

An Ultrapotent Neutralizing Bispecific Antibody with Broad Spectrum Against SARS-CoV-2 Variants

Some variants of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are threatening our global efforts of herd immunity, novel and more efficacious agents are urgently needed. We have developed a bispecific antibody, 2022, which bonds with high affinity to two non-overlapping epitopes on the receptor-binding domain (RBD) simultaneously, blocks the binding of RBD to human angiotensin-converting enzyme 2 (ACE2), and potently neutralizes SARS-CoV-2 and all of the variants tested, including variants carrying mutations known to resist neutralizing antibodies approved under Emergency Use Authorization (EUA) and reduce the efficacy of existing vaccines. In a mouse model of SARS-CoV-2, 2022 showed strong prophylactic and therapeutic effects. A single administration of 2022 completely protected all mice from bodyweight loss, as compared with up to 20% loss of bodyweight in placebo treated mice, reduced the lung viral titers to undetectable in all mice treated with 2022 either prophylactically or therapeutically, as compared with around 1X105 pfu/g lung tissue in placebo treated mice. In summary, bispecific antibody 2022 showed potent binding and neutralizing activity across a variety of SARS-CoV-2 variants and could be an attractive weapon to combat the ongoing waves of the COVID-19 pandemic.