The dual amylin and calcitonin receptor agonist KBP-336 elicits a unique combination of weight loss, antinociception and bone protection - a novel disease-modifying osteoarthritis drug.

BACKGROUND: Despite the extensive research to provide a disease-modifying osteoarthritis drug (DMOAD), there is still no approved DMOAD. Dual amylin and calcitonin receptor agonists (DACRA) can provide metabolic benefits along with antinociceptive and potential structural preserving effects. In these studies, we tested a DACRA named KBP-336 on a metabolic model of OA in meniscectomised (MNX) rats. METHODS: We evaluated KBP-336's effect on pain-like symptoms in Sprague Dawley (SD) rats on high-fat diet (HFD) that underwent meniscectomy using the von Frey test to measure the 50% paw withdrawal threshold (PWT) and analyzed using one-way ANOVA. Short in vivo studies and in vitro cell receptor expression systems were used to illustrate receptor pharmacology. RESULTS: After 30 weeks on HFD, including an 8-week treatment, female MNX animals receiving KBP-336 4.5 nmol/Kg/72 h had lower body weight and smaller adipose tissues than their vehicle-treated counterparts. After 20 weeks on HFD, including an 8-week treatment, male rats receiving KBP-336 had lower body weight than the vehicle group. In both the female and male rats, the MNX groups on KBP-336 treatment had a higher PWT than the vehicle-treated MNX group. Aiming to identify the receptor influencing pain alleviation, KBP-336 was compared to the long-acting human calcitonin (hCTA). Single-dose studies on 12-week-old male rats showed that hCTA lowers CTX-I without affecting food intake, confirming its calcitonin receptor selectivity. On the metabolic OA model with 18 weeks of HFD, including 6-week treatment, hCTA at 100 nmol/Kg/24 h and KBP-336 at 0.5, 1.5, and 4.5 nmol/Kg/72 h produced significantly higher PWT in MNX animals compared to MNX animals on vehicle treatment. hCTA and KBP-336 at 0.5 nmol/Kg did not affect body weight and fat tissues. CONCLUSION: Overall, KBP-336 improved the pain observed in the metabolic OA model. Calcitonin receptor activation proved to be essential in this antinociceptive effect.

Patient actor training improves preexposure prophylaxis delivery for adolescent girls and young women in Kenya: a cluster randomized trial.

OBJECTIVE: To evaluate effectiveness of a standardized patient actor (SP) training intervention to improve quality of preexposure prophylaxis (PrEP) services for adolescent girls and young women (AGYW) in Kenya. DESIGN: Cluster randomized trial and mystery shopper evaluation. METHODS: Twelve of 24 maternal child health and family planning facilities were randomized to SP training. Providers at intervention facilities participated in 2-day training in adolescent health, PrEP guidelines, values clarification, and communication skills, followed by role-playing and de-briefing with trained actors. Control facilities received standard national training. The primary outcome was quality of care, assessed by unannounced SPs (USPs) or "mystery shoppers" blinded to intervention arm. Quality was measured in two domains: guideline adherence and communication skills. Intent to treat analysis compared postintervention quality scores by randomization arm, clustering on facility, and adjusting for baseline scores and USP. RESULTS: Overall, 232 providers consented to USP visits, and 94 providers completed the training. Following training, USPs posed as AGYW seeking PrEP in 142 encounters (5-6 encounters per site). The mean quality score was 73.6% at intervention sites and 58.4% at control sites [adjusted mean difference = 15.3, 95% confidence interval (CI): 9.4-21.1, P  < 0.001]. Mean guideline adherence scores were 57.2% at intervention sites and 36.2% at control sites (adjusted mean difference = 21.0, 95% CI: 12.5-29.4, P  < 0.001). Mean communication scores were 90.0% at intervention sites and 80.5% at control sites (adjusted mean difference = 9.5, 95% CI: 5.5-13.6, P  < 0.001). CONCLUSIONS: SP training significantly improved quality of PrEP care for AGYW in Kenya. Incorporating SP training and unannounced SP evaluation could improve PrEP uptake among AGYW.

The enduring metabolic improvement of combining dual amylin and calcitonin receptor agonist and semaglutide treatments in a rat model of obesity and diabetes.

Long-acting dual amylin and calcitonin receptor agonists (DACRAs) are novel candidates for the treatment of type 2 diabetes and obesity due to their beneficial effects on body weight, glucose control, and insulin action. However, how the metabolic benefits are maintained after long-lasting treatment is unknown. This study investigates the long-term anti-obesity and anti-diabetic treatment efficacy of the DACRA KBP-336 alone and combined with the GLP-1 analog semaglutide. Zucker diabetic Sprague Dawley (ZDSD) rats with obesity and diabetes received KBP-336 (4.5 nmol/kg Q3D), semaglutide (50 nmol/kg Q3D), or the combination for 7 months, and the treatment impact on body weight, food intake, glucose control, and insulin action was evaluated. Furthermore, serum levels of the cardiac fibrosis biomarker endotrophin were evaluated. KBP-336, semaglutide and the combination lowered body weight significantly compared to the vehicle, with the combination inducing a larger and more sustained weight loss than either monotherapy. All treatments resulted in reduced fasting blood glucose levels and HbA1c levels, and improved glucose tolerance compared to vehicle-treated rats. Further, all treatments protected against lost insulin secretory capacity and improved insulin action. Serum levels of endotrophin were significantly lowered by KBP-336 compared to vehicle. This study shows the benefit of combining KBP-336 and semaglutide to obtain significant and sustained weight loss and improved glucose control. Further, KBP-336-driven reductions in circulating endotrophin indicate a clear reduction in the risk of complications. Altogether, KBP-336 is a promising candidate for the treatment of obesity and type 2 diabetes both alone and in combination with GLP-1 analogs.

DACRA induces profound weight loss, satiety control, and increased mitochondrial respiratory capacity in adipose tissue.

BACKGROUND AND OBJECTIVES: Dual amylin and calcitonin receptor agonists (DACRAs) are therapeutic candidates in the treatment of obesity with beneficial effects on weight loss superior to suppression of food intake. Hence, suggesting effects on energy expenditure by possibly targeting mitochondria in metabolically active tissue. METHODS: Male rats with HFD-induced obesity received a DACRA, KBP-336, every third day for 8 weeks. Upon study end, mitochondrial respiratory capacity (MRC), - enzyme activity, - transcriptional factors, and -content were measured in perirenal (pAT) and inguinal adipose tissue. A pair-fed group was included to examine food intake-independent effects of KBP-336. RESULTS: A vehicle-corrected weight loss (23.4 ± 2.8%) was achieved with KBP-336, which was not observed to the same extent with the food-restricted weight loss (12.4 ± 2.8%) (P < 0.001). Maximal coupled respiration supported by carbohydrate and lipid-linked substrates was increased after KBP-336 treatment independent of food intake in pAT (P < 0.01). Moreover, oligomycin-induced leak respiration and the activity of citrate synthase and ß-hydroxyacetyl-CoA-dehydrogenase were increased with KBP-336 treatment (P < 0.05). These effects occurred without changes in mitochondrial content in pAT. CONCLUSIONS: These findings demonstrate favorable effects of KBP-336 on MRC in adipose tissue, indicating an increased energy expenditure and capacity to utilize fatty acids. Thus, providing more mechanistic insight into the DACRA-induced weight loss.

Readiness for mHealth interventions in Jordan: Refugee camp and urban community survey.

Jordan hosts one of the largest populations of refugees in the world. This study evaluated the capacity, infrastructure, and interest in mobile health interventions to address unmet mental health needs among refugees and non-refugees in Jordan. We surveyed 209 (141 refugees) adults and youth in urban, rural, and refugee camp settings. Survey results indicated that mobile device ownership was lower among refugees than non-refugees (71 % vs. 100 %, respectively). Refugee phone users had less access to smartphones than non-refugees (75 % vs. 96 %, respectively). Refugees and non-refugees reported using mobile devices for diverse activities including calling (83 % vs. 100 %, respectively), texting (28 % vs. 87 %, respectively) social media (45 % vs. 94 %, respectively), watching videos (23 % vs. 90 %, respectively), and studying (34 % vs. 72 %, respectively). Most respondents had reliable access to electricity (75 % vs. 99 %, respectively) and to mobile-cellular service (67 % vs. 97 %, respectively). Refugees and non-refugees differed substantially in their access to WiFi (14 % vs. 91 %, respectively). Both groups identified anger, anxiety, depression, traumatic memories, and eating problems as the most common mental health problems in their communities. Approximately half of refugees (44 %) and non-refugees (50 %) reported that their communities had insufficient or no access to mental health resources. Most refugees (78 %) and non-refugee (87 %) believed that using mobile devices to provide support for people with mental health conditions would be helpful. Overall, both groups' reported access to mobile technologies and openness to digital mental health treatment options suggest that mHealth interventions may be feasible and welcomed in these communities.

Combining mHealth Technology and Pharmacotherapy to Improve Mental Health Outcomes and Reduce Human Rights Abuses in West Africa: Intervention Field Trial.

Background: In West Africa, healers greatly outnumber trained mental health professionals. People with serious mental illness (SMI) are often seen by healers in "prayer camps" where they may also experience human rights abuses. We developed "M&M," an 8-week-long dual-pronged intervention involving (1) a smartphone-delivered toolkit designed to expose healers to brief psychosocial interventions and encourage them to preserve human rights (M-Healer app), and (2) a visiting nurse who provides medications to their patients (Mobile Nurse). Objective: We examined the feasibility, acceptability, safety, and preliminary effectiveness of the M&M intervention in real-world prayer camp settings. Methods: We conducted a single-arm field trial of M&M with people with SMI and healers at a prayer camp in Ghana. Healers were provided smartphones with M-Healer installed and were trained by practice facilitators to use the digital toolkit. In parallel, a study nurse visited their prayer camp to administer medications to their patients. Clinical assessors administered study measures to participants with SMI at pretreatment (baseline), midtreatment (4 weeks) and post treatment (8 weeks). Results: Seventeen participants were enrolled and most (n=15, 88.3%) were retained. Participants had an average age of 44.3 (SD 13.9) years and 59% (n=10) of them were male. Fourteen (82%) participants had a diagnosis of schizophrenia and 2 (18%) were diagnosed with bipolar disorder. Four healers were trained to use M-Healer. On average, they self-initiated app use 31.9 (SD 28.9) times per week. Healers watched an average of 19.1 (SD 21.2) videos, responded to 1.5 (SD 2.4) prompts, and used the app for 5.3 (SD 2.7) days weekly. Pre-post analyses revealed a significant and clinically meaningful reduction in psychiatric symptom severity (Brief Psychiatric Rating Scale score range 52.3 to 30.9; Brief Symptom Inventory score range 76.4 to 27.9), psychological distress (Talbieh Brief Distress Inventory score range 37.7 to 16.9), shame (Other as Shamer Scale score range 41.9 to 28.5), and stigma (Brief Internalized Stigma of Mental Illness Scale score range 11.8 to 10.3). We recorded a significant reduction in days chained (1.6 to 0.5) and a promising trend for reduction in the days of forced fasting (2.6 to 0.0, P=.06). We did not identify significant pre-post changes in patient-reported working alliance with healers (Working Alliance Inventory), depressive symptom severity (Patient Health Questionnaire-9), quality of life (Lehman Quality of Life Interview for the Mentally Ill), beliefs about medication (Beliefs about Medications Questionnaire-General Harm subscale), or other human rights abuses. No major side effects, health and safety violations, or serious adverse events occurred over the course of the trial. Conclusions: The M&M intervention proved to be feasible, acceptable, safe, and clinically promising. Preliminary findings suggest that the M-Healer toolkit may have shifted healers' behaviors at the prayer camp so that they commit fewer human rights abuses.

Investigating the impact of feed-induced, subacute ruminal acidosis on rumen epimural transcriptome and metatranscriptome in young calves at 8- and 17-week of age.

Introduction: With the goal to maximize intake of high-fermentable diet needed to meet energy needs during weaning period, calves are at risk for ruminal acidosis. Using the calves from previously established model of feed-induced, ruminal acidosis in young calves, we aimed to investigate the changes in rumen epimural transcriptome and its microbial metatranscriptome at weaning (8-week) and post-weaning (17-week) in canulated (first occurred at 3 weeks of age) Holstein bull calves with feed-induced subacute ruminal acidosis. Methods: Eight bull calves were randomly assigned to acidosis-inducing diet (Treated, n = 4; pelleted, 42.7% starch, 15.1% neutral detergent fiber [NDF], and 57.8% nonfiber carbohydrates), while texturized starter was fed as a control (Control, n = 4; 35.3% starch, 25.3% NDF, and 48.1% nonfiber carbohydrates) starting at 1 week through 17 weeks. Calves fed acidosis-inducing diet showed significantly less (p < 0.01) body weight over the course of the experiment, in addition to lower ruminal pH (p < 0.01) compared to the control group. Rumen epithelial (RE) tissues were collected at both 8 weeks (via biopsy) and 17 weeks (via euthanasia) and followed for whole transcriptome RNA sequencing analysis. Differentially expressed genes (DEGs) analysis was done using cufflinks2 (fold-change ≥2 and p < 0.05) between treated and control groups at 8-week of age, and between 8- and 17-week for the treated group. Results: At 8-week of age, DEGs between treatment groups showed an enrichment of genes related to the response to lipopolysaccharide (LPS) (p < 0.005). The impact of prolonged, feed-induced acidosis was reflected by the decreased expression (p < 0.005) in genes involved in cell proliferation related pathways in the RE at 17-week of age in the treated group. Unique sets of discriminant microbial taxa were identified between 8-and 17-week calves in the treated group and the treatment groups at 8-week, indicating that active microbial community changes in the RE are an integral part of the ruminal acidosis development and progression.

Are insulin sensitizers the new strategy to treat Type 1 diabetes? A long-acting dual amylin and calcitonin receptor agonist improves insulin-mediated glycaemic control and controls body weight.

BACKGROUND AND PURPOSE: Insulin therapies for Type 1 diabetes (T1D) have limitations, such as glucose fluctuations, hypoglycaemia, and weight gain. Only pramlintide is approved with insulin. However, its short half-life limits efficacy, requiring multiple daily injections and increasing hypoglycaemia risk. New strategies are needed to improve glycaemic control. Dual amylin and calcitonin receptor agonists are potent insulin sensitizers developed for Type 2 diabetes (T2D) as they improve glucose control, reduce body weight, and attenuate hyperglucagonemia. However, it is uncertain if they could be used to treat T1D. EXPERIMENTAL APPROACH: Sprague Dawley rats received a single intravenous injection of streptozotocin (STZ) (50 mg·kg-1) to induce T1D. Humulin (1 U/200 g·day-1 or 2 U/200 g·day-1) was continuously infused, while half of the rats received additional KBP-336 (4.5 nmol·kg-1 Q3D) treatment. Bodyweight, food intake, and blood glucose were monitored throughout the study. An oral glucose tolerance test was performed during the study. KEY RESULTS: Treatment with Humulin or Humulin + KBP-336 improved the health of STZ rats. Humulin increased body weight in STZ rats, but KBP-336 attenuated these increases and maintained a significant weight loss. The combination exhibited greater blood glucose reductions than Humulin-treated rats alone, reflected by improved HbA1c levels and glucose control. The combination prevented hyperglucagonemia, reduced amylin levels, and increased pancreatic insulin content, indicating improved insulin sensitivity and beta-cell preservation. CONCLUSION AND IMPLICATIONS: The insulin sensitizer KBP-336 lowered glucagon secretion while attenuating insulin-induced weight gain. Additionally, KBP-336 may prevent hypoglycaemia and improve insulin resistance, which could be a significant advantage for individuals with T1D seeking therapeutic benefits.

Mental Health Priorities in the Arab World: Insights From Jordan.

War, geopolitical instability, and natural disasters have contributed to enormous unmet mental health needs in the Middle East and North Africa. Jordan is a middle-income country that needs internal and international stakeholder engagement and support to effectively provide mental health services to its citizens and to the millions of immigrants and refugees who reside there. This column presents a snapshot of the state of mental health care in Jordan and outlines areas for future investment. Potentially high-yield areas for development include digital health technology, integrated care, and youth-focused interventions.

Digital Mental Health Approaches to Improve Well-Being of Refugee Families.

Refugee populations face disproportionately high risk for mental health challenges because of their exposure to geopolitical conflict, persecution, violence, and human rights violations. Dedicated, sustained psychological services are scarce in refugee contexts. Access to mental health treatment is limited by stigma and discrimination, linguistic and cultural barriers, and lack of privacy and confidentiality. Digital health approaches can increase access to mental health services in refugee contexts where need is high, mobile device infrastructure is common, and digital options may transcend contextual barriers. Tailored digital mental health interventions that may overcome barriers to mental health treatment among refugee populations are outlined.

Liver microbial community and associated host transcriptome in calves with feed induced acidosis.

Introduction: In the dairy industry, calves are typically fed diets rich in highly fermentable carbohydrates and low in fibrous feeds to maximize ruminal papillae and tissue development. Calves on such diets are vulnerable at developing ruminal acidosis. Prevalent in cattle, liver abscess (LA) is considered a sequela to ruminal acidosis. LAs can cause significant liver function condemnation and decreased growth and production. Currently, we know little about the liver microbiome in calves with feed-induced acidosis. Methods: Using our established model of ruminal acidosis, where young calves were fed an acidosis-inducing (AC) or -blunting (control) diet starting at birth until 17-week of age, we investigated microbial community changes in the liver resultant from ruminal acidosis. Eight calves were randomly assigned to each diet, with four animals per treatment. Rumen epithelium and liver tissues were collected at 17 weeks of age right after euthanasia. Total RNAs were extracted and followed by whole transcriptome sequencing. Microbial RNA reads were enriched bioinformatically and used for microbial taxonomy classification using Kraken2. Results: AC Calves showed significantly less weight gain over the course of the experiment, in addition to significantly lower ruminal pH, and rumen degradation comparison to the control group (p < 0.05). In the liver, a total of 29 genera showed a significant (p < 0.05) abundance change (> 2-fold) between the treatments at 17-week of age. Among these, Fibrobacter, Treponema, Lactobacillus, and Olsenella have been reported in abscessed liver in cattle. Concurrent abundance changes in 9 of the genera were observed in both the liver and rumen tissues collected at 17-week of age, indicating potential crosstalk between the liver and rumen epithelial microbial communities. Significant association was identified between host liver gene and its embedded microbial taxa. Aside from identifying previously reported microbial taxa in cattle abscessed liver, new repertoire of actively transcribed microbial taxa was identified in this study. Discussion: By employing metatranscriptome sequencing, our study painted a picture of liver microbiome in young calves with or without feed induced acidosis. Our study suggested that liver microbiome may have a critical impact on host liver physiology. Novel findings of this study emphasize the need for further in-depth analysis to uncover the functional roles of liver resident microbiome in liver metabolic acidosis resultant from feed-related ruminal acidosis.

Dual amylin and calcitonin receptor agonist treatment reduces biomarkers associated with kidney fibrosis in diabetic rats.

Dual amylin and calcitonin receptor agonists (DACRAs) are effective treatments for obesity and type 2 diabetes (T2D). They provide beneficial effects on body weight, glucose control, and insulin action. However, whether DACRAs protect against diabetes-related kidney damage remains unknown. We characterize the potential of long-acting DACRAs (KBP-A, Key Bioscience Peptide-A) as a treatment for T2D-related pathological alterations of the kidney extracellular matrix (ECM) in Zucker diabetic fatty rats (ZDF). We examined levels of endotrophin (profibrotic signaling molecule reflecting collagen type VI formation) and tumstatin (matrikine derived from collagen type IVα3) in serum and evaluated kidney morphology and collagen deposition in the kidneys. We included a study in obese Sprague-Dawley rats to further investigate the impact of KBP-A on ECM biomarkers. In ZDF vehicles, levels of endotrophin and tumstatin increased, suggesting disease progression along with an increase in blood glucose levels. These rats also displayed damage to their kidneys, which was evident from the presence of collagen formation in the medullary region of the kidney. Interestingly, KBP-A treatment attenuated these increases, resulting in significantly lower levels of endotrophin and tumstatin than the vehicle. Levels of endotrophin and tumstatin were unchanged in obese Sprague-Dawley rats, supporting the relation to diabetes-related kidney complications. Furthermore, KBP-A treatment normalized collagen deposition in the kidney while improving glucose control. These studies confirm the beneficial effects of DACRAs on biomarkers associated with kidney fibrosis. Moreover, these antifibrotic effects are likely associated with improved glucose control, highlighting KBP-A as a promising treatment of T2D and its related late complications.NEW & NOTEWORTHY These studies describe the beneficial effects of using a dual amylin and calcitonin receptor agonist (DACRA) for diabetes-related kidney complications. DACRA treatment reduced levels of serological biomarkers associated with kidney fibrosis. These reductions were further reflected by reduced collagen expression in diabetic kidneys. In general, these results validate the use of serological biomarkers while demonstrating the potential effect of DACRAs in treating diabetes-related long-term complications.

Liver and Muscle Transcriptomes Differ in Mid-Lactation Cows Divergent in Feed Efficiency in the Presence or Absence of Supplemental Rumen-Protected Choline.

Improving dairy cow feed efficiency is critical to the sustainability and profitability of dairy production, yet the underlying mechanisms that contribute to individual cow variation in feed efficiency are not fully understood. The objectives of this study were to (1) identify genes and associated pathways that are altered in cows with high- or low-residual feed intake (RFI) using RNA sequencing, and (2) determine if rumen-protected choline supplementation during mid-lactation would influence performance or feed efficiency. Mid-lactation (134 ± 20 days in milk) multiparous Holstein cows were randomly assigned to either supplementation of 0 g/d supplementation (CTL; n = 32) or 30 g/d of a rumen-protected choline product (RPC; 13.2 g choline ion; n = 32; Balchem Corp., New Hampton, NY, USA). Residual feed intake was determined as dry matter intake regressed on milk energy output, days in milk, body weight change, metabolic body weight, and dietary treatment. The 12 cows with the highest RFI (low feed efficient; LE) and 12 cows with the lowest RFI (high feed efficient; HE), balanced by dietary treatment, were selected for blood, liver, and muscle analysis. No differences in production or feed efficiency were detected with RPC supplementation, although albumin was greater and arachidonic acid tended to be greater in RPC cows. Concentrations of ß-hydroxybutyrate were greater in HE cows. Between HE and LE, 268 and 315 differentially expressed genes in liver and muscle tissue, respectively, were identified through RNA sequencing. Pathway analysis indicated differences in cell cycling, oxidative stress, and immunity in liver and differences in glucose and fatty acid pathways in muscle. The current work indicates that unique differences in liver and muscle post-absorptive nutrient metabolism contribute to sources of variation in feed efficiency and that differences in amino acid and fatty acid oxidation, cell cycling, and immune function should be further examined.

Dual amylin and calcitonin receptor agonist treatment improves insulin sensitivity and increases muscle-specific glucose uptake independent of weight loss.

Dual amylin and calcitonin receptor agonists (DACRAs) are known to induce significant weight loss as well as improve glucose tolerance, glucose control, and insulin action in rats. However, to what extent DACRAs affect insulin sensitivity beyond that induced by weight loss and if DACRAs affect glucose turnover including tissue-specific glucose uptake is still unknown. Hyperinsulinemic glucose clamp studies were carried out in pre-diabetic ZDSD and diabetic ZDF rats treated with either the DACRA KBP or the long-acting DACRA KBP-A for 12 days. The glucose rate of disappearance was assessed using 3-3H glucose and tissue-specific glucose uptake was evaluated using 14C-2-deoxy-D-glucose (14C-2DG). In diabetic ZDF rats, KBP treatment significantly reduced fasting blood glucose and improved insulin sensitivity independent of weight loss. Furthermore, KBP increased the rate of glucose clearance, likely by increasing glucose storage, but without altering the endogenous glucose production. This was confirmed in pre-diabetic ZDSD rats. Direct assessment of tissue-specific glucose uptake showed, that both KBP and KBP-A significantly increased glucose uptake in muscles. In summary, KBP treatment significantly improved insulin sensitivity in diabetic rats and markedly increased glucose uptake in muscles. Importantly, in addition to their well-established weight loss potential, the KBPs have an insulin-sensitizing effect independent of weight loss, highlighting DACRAs as promising agents for the treatment of type 2 diabetes and obesity.

Treatment sequencing using the dual amylin and calcitonin receptor agonist KBP-336 and semaglutide results in durable weight loss.

OBJECTIVE: Long-acting dual amylin and calcitonin receptor agonists (DACRAs) hold great promise as potential treatments for obesity and its associated comorbidities. These agents have demonstrated beneficial effects on body weight, glucose control, and insulin action mirroring the effects observed with glucagon-like peptide-1 (GLP-1) agonist treatment. Strategies aimed at enhancing and prolonging treatment efficacy include treatment sequencing and combination therapy. Here, we sought to investigate the impact of switching between or combining treatment with the DACRA KBP-336 and the GLP-1 analog semaglutide in fed rats with obesity induced by a high-fat diet (HFD). METHODS: Two studies were performed in which HFD-induced obese Sprague Dawley rats were switched between treatment with KBP-336 (4.5 nmol/kg, Q3D) and semaglutide (50 nmol/kg, Q3D) or a combination of the two. Treatment efficacy on weight loss and food intake was evaluated, and glucose tolerance was assessed by oral glucose tolerance tests. RESULTS: KBP-336 and semaglutide monotherapy resulted in a similar reduction in body weight and food intake. Treatment sequencing resulted in continuous weight loss and all monotherapies resulted in similar weight loss independent of the treatment regimen (P < 0.001 compared to vehicle). The combination of KBP-336 and semaglutide significantly improved the weight loss compared to either monotherapy alone (P < 0.001), which was evident in the adiposity at the study end. All treatments improved glucose tolerance, with the KBP-effect on insulin sensitivity as the dominant response. CONCLUSIONS: These findings highlight KBP-336 as a promising anti-obesity therapy both alone, in treatment sequencing, and in combination with semaglutide or other incretin-based therapies.

Risks of adverse perinatal outcomes in relation to maternal depressive symptoms: A prospective cohort study in Kenya.

BACKGROUND: Evidence gaps remain regarding the influence of prenatal psychosocial factors on adverse pregnancy outcomes. OBJECTIVE: The objective of this study is to evaluate relationships between psychosocial factors and adverse perinatal outcomes among Kenyan women. METHODS: We analysed data from a prospective cohort study enrolling HIV-negative women in pregnancy (NCT03070600) in 20 antenatal clinics in Western Kenya. Study nurses assessed depressive symptoms using the Center for Epidemiologic Studies Depression Scale (CESD-10), social support using the Medical Outcomes Survey scale (MOS-SSS), intimate partner violence (IPV) with the Hurt, Insult, Threaten, Scream scale (HITS), and pregnancy outcomes at 6 weeks postpartum. Cox proportional hazards models were used to evaluate relationships between depressive symptoms (moderate-to-severe [MSD, CESD-10 ≥10] and mild-to-severe [Mild-SD, CESD-10 ≥5]), low social support (MOS-SSS <72), and IPV (HITS ≥10) with adverse perinatal outcomes of pregnancy loss, stillbirth, preterm birth (PTB), small for gestational age, and neonatal mortality. We also estimated the population attributable risk. RESULTS: Among 4153 women, 23.9% (n = 994) had MSD, 54.7% (n = 2273) mild-SD, 37.3% (n = 1550) low social support, and 7.8% (n = 323) experienced IPV. Pregnancy loss was 5-fold higher among women with MSD (adjusted hazard ratio [HR] 5.04, 95% confidence interval [CI] 2.44, 10.42); 37.4% of losses were attributable to MSD. Mild-SD was associated with PTB (HR 1.39, 95% CI 1.03, 1.87). Stillbirth risk more than doubled among women reporting low social support (HR 2.37, 95% CI 1.14, 4.94). CONCLUSIONS: Adverse perinatal outcomes were common and associated with prenatal depressive symptoms and low social support in this large cohort of Kenyan mother-infant pairs.

COVID-19 vaccine hesitancy among pregnant and postpartum Kenyan women.

OBJECTIVE: The authors evaluated factors contributing to coronavirus disease 2019 (COVID-19) vaccine hesitancy among pregnant and postpartum women to inform vaccine scale-up strategies. METHODS: This observational study utilized data from pregnant and postpartum women attending four public maternal child health (MCH) clinics in Western Kenya. From October 2020 to July 2022, nurses assessed COVID-19 vaccine hesitancy, defined as reporting "unlikely" or "very unlikely" to the question, "If a vaccine for COVID-19 were available today, what is the likelihood that you would get vaccinated?" RESULTS: Among 1023 women (235 pregnant, 788 postpartum), 20% reported worsened MCH care during the pandemic and most (92%) perceived themselves or family members to be at risk for COVID-19, yet 54% of women reported COVID-19 vaccine hesitancy. Vaccine hesitancy was more frequent among women reporting worsened MCH care (P < 0.001) since the pandemic and those who did not trust the government as a source of COVID-19 information (P = 0.016). Over the 2-year period, willingness to receive the vaccine almost doubled (38% to 71%, P < 0.001). CONCLUSIONS: Our findings suggest that sustaining access to quality MCH services may decrease COVID-19 vaccine hesitancy. Willingness to receive the vaccine doubled over the 2-year period in our cohort, suggesting increased trust for use and acceptance in the unique context of the pregnancy/postpartum period.

Comparing depression screening tools (CESD-10, EPDS, PHQ-9, and PHQ-2) for diagnostic performance and epidemiologic associations among postpartum Kenyan women: Implications for research and practice.

BACKGROUND: Identifying optimal depression screening tools for use in maternal health clinics could improve maternal and infant health. We compared four tools for diagnostic performance and epidemiologic associations. METHODS: This study was nested in a cluster-randomized trial in Kenya. Women in 20 maternal health clinics were evaluated at 6 weeks postpartum with Center for Epidemiologic Studies Depression Scale (CESD-10), Edinburgh Postnatal Depression Scale (EPDS), Patient Health Questionnaire-9 and -2 (PHQ-9, PHQ-2) for moderate-to-severe depressive symptoms (MSD) [CESD-10 ≥ 10, EPDS≥13, PHQ-9 ≥ 10, or PHQ-2 ≥ 3]. We assessed area under the curve (AUC) per scale (CESD-10, EPDS) against probable major depressive disorder (MDD) using the PHQ-9 scoring algorithm. Associations between MSD and intimate partner violence (IPV) were compared between scales. RESULTS: Among 3605 women, median age was 24 and 10 % experienced IPV. Prevalence of MSD symptoms varied by tool: 13 % CESD-10, 9 % EPDS, 5 % PHQ-2, 3 % PHQ-9. Compared to probable MDD, the CESD-10 (AUC:0.82) had higher AUC than the EPDS (AUC:0.75). IPV was associated with MSD using all scales: EPDS (RR:2.5, 95%CI:1.7-3.7), PHQ-2 (RR:2.3, 95%CI:1.6-3.4), CESD-10 (RR:1.9, 95%CI:1.2-2.9), PHQ-9 (RR:1.8, 95%CI:0.8-3.8). LIMITATIONS: Our study did not include clinical diagnosis of MDD by a specialized clinician, instead we used provisional diagnosis of probable MDD classified by the PHQ-9 algorithm as a reference standard in diagnostic performance evaluations. CONCLUSION: Depression screening tools varied in detection of postpartum MSD. The PHQ-2 would prompt fewer referrals and showed strong epidemiologic association with a cofactor.

Dose-Dependent Effects of Supplementing a Two-Strain Bacillus subtilis Probiotic on Growth Performance, Blood Parameters, Fecal Metabolites, and Microbiome in Nursery Pigs.

This experiment was conducted to evaluate the effects of dietary supplementation level of a two-strain Bacillus subtilis probiotic on growth performance, blood parameters, fecal metabolites, and microbiome in nursery pigs. A total of 54 weaned piglets were allotted to three treatments in three replicate pens with six pigs/pen for a 28 d feeding trial. The treatments were as follows: control: no probiotic supplementation; Pro1x: B. subtilis supplementation at 1.875 × 105 CFU/g diet; and Pro10x: B. subtilis supplementation at 1.875 × 106 CFU/g diet. Body weight at d 14 postweaning (p = 0.06) and average daily gain for d 0 to 14 postweaning (p < 0.05) were greater in the Pro1x treatment than in the other treatments. Blood glucose levels were greater in both probiotic treatments than in the control treatment at d 14 postweaning (p < 0.05). In the fecal short-chain fatty acid (SCFA) concentrations, the butyrate concentrations were greater in the Pro1x treatment than in the other treatments (p < 0.05), and the acetate, propionate, and total SCFA concentrations were greater in the Pro1x treatment than in the Pro10x treatment (p < 0.05). The beta diversity of fecal microbiome composition at d 14 postweaning based on Unweighted Unifrac analysis was dissimilar between the Pro1x and Pro10x treatments (p < 0.05). In conclusion, dietary B. subtilis supplementation of two strains selected to reduce effects of pathogenic Escherichia coli to nursery diets at 1.875 × 105 CFU/g diet improved the growth rate in the early postweaning period, increased fecal SCFA concentrations and altered the fecal microbial community composition. A higher dose of B. subtilis did not improve the performance parameters over those of the control piglets.