Effects of (S)-3,4-DCPG, an mGlu8 receptor agonist, on hippocampal long-term potentiation at perforant pathway-dentate gyrus synapses in prenatal valproic acid-induced rat model of autism.

Autism spectrum disorder (ASD) is a pervasive neurodevelopmental condition characterized by social interaction deficits, communication impairments, repetitive behaviors, and sensory sensitivities. While the etiology of ASD is multifaceted, abnormalities in glutamatergic neurotransmission and synaptic plasticity have been implicated. This study investigated the role of metabotropic glutamate receptor 8 (mGlu8) in modulating long-term potentiation (LTP) in a rat model of ASD induced by prenatal valproic acid (VPA) exposure. To induce an animal model with autism-like characteristics, pregnant rats received an intraperitoneal injection of 500 mg/kg of sodium valproate (NaVPA) on embryonic day 12.5. High-frequency stimulation was applied to the perforant path-dentate gyrus (PP-DG) synapse to induce LTP, while the mGlu8 receptor agonist (S)-3,4-dicarboxyphenylglycine (DCPG) was administered into the DG. The results revealed that VPA-exposed rats exhibited reduced LTP compared to controls. DCPG had contrasting effects, inhibiting LTP in controls and enhancing it in VPA-exposed rats. Moreover, reduced social novelty preference index (SNPI) in VPA-exposed rats was reversed by intra-DG administration of S-3,4-DCPG. In conclusion, our study advances our understanding of the complex relationship between glutamatergic neurotransmission, synaptic plasticity, and VPA-induced autism model. The findings suggest that mGlu8 receptor dysfunction plays a role in the impaired synaptic plasticity seen in ASD.

Disparity in Treatment Receipt by Race and Treatment Guideline Revision Years for Stage 1A Non-Small Cell Lung Cancer Patients in the US.

INTRODUCTION: Treatment guideline revision introduced by the National Comprehensive Cancer Network (NCCN) is referred to by about 95% of the United States (US) oncologists in treatment decision-making for stage 1A non-small cell lung cancer. It is vital to account for this factor that affects the standard treatment receipt among stage 1A patients, with about a 75% survival rate if treated on time. The first choice for medically fit patients is lobectomy; however, over the decades since the initial guidelines were published, several medical advances have introduced trends in treatment receipt along with other sociodemographic factors that could help identify survival outcomes associated with treatment receipt. Establishing the role of treatment guideline revision years is important to determine a close to true causal relationship in racial treatment disparities. METHODS: US national cancer registry data for all US counties and historical Area Health Resource Files for the study period 1988-2015 were utilized. Logistic regression analysis was adjusted for clustering of standard errors at the state level and for time-invariant unobserved factors for the year of diagnosis and county. The time-invariant unobservable for each year of diagnosis and county specificity were accounted for by including their dummy variables in the regression model with standard errors clustered at the state level. RESULTS: Black patients, Medicaid beneficiaries, large fringe metropolitan residents, and those diagnosed post-2007 treatment revisions years are less likely to receive lobectomy, which is the standard treatment guideline for medically fit patients. CONCLUSION: The study concludes that there exists a difference in treatment type received among stage 1A NSCLC patients in the US by race, socioeconomic status, and treatment guideline revisions.

Effect of intrahippocampal microinjection of VU0155041, a positive allosteric modulator of mGluR4, on long term potentiation in a valproic acid-induced autistic male rat model.

The precise cause of autism spectrum disorder (ASD) is not fully understood. Despite the involvement of glutamatergic dysregulation in autism, the specific contribution of mGlu4 receptors to synaptic plasticity remains unclear. Using the positive allosteric modulator VU0155041, we aimed to restore long-term potentiation (LTP) in the perforant path-dentate gyrus (PP-DG) pathway in VPA-induced autistic rat model. High-frequency stimulation was applied to the PP-DG synapse to induce LTP, while the VU0155041 was administered into the DG. Unexpectedly, VU0155041 failed to alleviate the observed LTP reduction in VPA-exposed rats, further resulting in a significant decrease in population spike LTP. This unexpected outcome prompts discussion on the complex nature of mGlu4 receptor modulation, highlighting potential interference with physiological processes underlying synaptic plasticity.

Correction: Intestinal microbiome profiles in broiler chickens raised without antibiotics exhibit altered microbiome dynamics relative to conventionally raised chickens.

[This corrects the article DOI: 10.1371/journal.pone.0301110.].

Exosomes encapsulated in hydrogels for effective central nervous system drug delivery.

The targeted delivery of pharmacologically active molecules, metabolites, and growth factors to the brain parenchyma has become one of the major challenges following the onset of neurodegeneration and pathological conditions. The therapeutic effect of active biomolecules is significantly impaired after systemic administration in the central nervous system (CNS) because of the blood-brain barrier (BBB). Therefore, the development of novel therapeutic approaches capable of overcoming these limitations is under discussion. Exosomes (Exo) are nano-sized vesicles of endosomal origin that have a high distribution rate in biofluids. Recent advances have introduced Exo as naturally suitable bio-shuttles for the delivery of neurotrophic factors to the brain parenchyma. In recent years, many researchers have attempted to regulate the delivery of Exo to target sites while reducing their removal from circulation. The encapsulation of Exo in natural and synthetic hydrogels offers a valuable strategy to address the limitations of Exo, maintaining their integrity and controlling their release at a desired site. Herein, we highlight the current and novel approaches related to the application of hydrogels for the encapsulation of Exo in the field of CNS tissue engineering.

S-3,4-DCPG, a potent orthosteric agonist for the mGlu8 receptor, facilitates extinction and inhibits the reinstatement of morphine-induced conditioned place preference in male rats.

The limbic system, particularly the NAc, shows a high concentration of metabotropic glutamate receptors (mGluRs). Recent evidence suggests the significant involvement of mGluRs in mental disorders, including substance abuse and addiction. The objective of this study was to examine the involvement of mGlu8 receptors in the NAc in the mechanisms underlying the extinction and reinstatement of conditioned place preference (CPP) induced by morphine. Male Wistar rats underwent surgical implantation of bilateral cannulas in the NAc and were assessed in a CPP protocol. In study 1 at the same time as the extinction phase, the rats were given varying doses of S-3,4-DCPG (0.03, 0.3, and 3 µg/0.5 µl). In study 2, rats that had undergone CPP extinction were given S-3,4-DCPG (0.03, 0.3, and 3 µg/0.5 µl) five minutes prior to receiving a subthreshold dose of morphine (1 mg/kg) in order to reactivate the previously extinguished morphine response. The findings demonstrated that administering S-3,4-DCPG directly into the accumbens nucleus resulted in a decrease in the duration of the CPP extinction phase. Moreover, dose-dependent administration of S-3,4-DCPG into the NAc inhibited CPP reinstatement. The observations imply that microinjection of S-3,4-DCPG as a potent orthosteric agonist with high selectivity for the mGlu8 receptor into the NAc promotes the process of extinction while concurrently exerting inhibitory effects on the reinstatement of morphine-induced CPP. This effect may be associated with the modulation of glutamate engagement within the NAc and the plasticity of reward pathways at the synaptic level.

Fabricating pentaazatetraethylene modified sulfonated polyacrylamide for dye adsorption from aqueous media: isotherms and kinetics models.

In this study, pentaazatetraethylene-modified sulfonated polyacrylamide (PAm-SO3-N5) was synthesized and used as a novel efficient adsorbent to remove calmagite from aqueous media. To this end, a central composite design (CCD) was applied to reduce the number of reaction variables (i.e., adsorbent concentration, temperature, initial concentration, and pH) on calmagite removal. The results showed that calmagite was entirely adsorbed by the PAm-SO3-N5 within 30 min. In addition, a pseudo-second-order (PSO) model was prepared as the optimum formula to fit the kinetics information. The modeling results revealed that film diffusion and adsorption are rate-limiting stages to remove the dyes. Using a Langmuir isotherm to fit the equilibrium data, the highest equilibrium adsorption was calculated to be 1732.5 mg/g. In the present study, the ΔH value indicates that the adsorption is of chemical type. Also, the negative sign of ΔS° shows that PAm-SO3-N5 removes calmagite during a relatively stable process with randomness in the system. The increase in ΔG° values with increasing temperature indicates a descending trend in the feasibility degree of calmagite adsorption. Eventually, recycling the adsorbent for 7 cycles to adsorb calmagite dye showed no remarkable activity loss.

IUPHAR review: Navigating the role of preclinical models in pain research.

Chronic pain is a complex and challenging medical condition that affects millions of people worldwide. Understanding the underlying mechanisms of chronic pain is a key goal of preclinical pain research so that more effective treatment strategies can be developed. In this review, we explore nociception, pain, and the multifaceted factors that lead to chronic pain by focusing on preclinical models. We provide a detailed look into inflammatory and neuropathic pain models and discuss the most used animal models for studying the mechanisms behind these conditions. Additionally, we emphasize the vital role of these preclinical models in developing new pain-relief drugs, focusing on biologics and the therapeutic potential of NMDA and cannabinoid receptor antagonists. We also discuss the challenges of TRPV1 modulation for pain treatment, the clinical failures of neurokinin (NK)- 1 receptor antagonists, and the partial success story of Ziconotide to provide valuable lessons for preclinical pain models. Finally, we highlight the overall success and limitations of current treatments for chronic pain while providing critical insights into the development of more effective therapies to alleviate the burden of chronic pain.

The effects of carvacrol and p-cymene on Aß1-42 -induced long-term potentiation deficit in male rats.

AIMS: Alzheimer's disease (AD) is the most common type of dementia in which oxidative stress plays an important role. In this disease, learning and memory and the cellular mechanism associated with it, long-term potentiation (LTP), are impaired. Considering the beneficial effects of carvacrol (CAR) and p-cymene against AD, their effect was assessed on in vivo hippocampal LTP in the perforant pathway (PP)-dentate gyrus (DG) pathway in an Aß1-42 -induced rat model of AD. METHODS: Male Wistar rats were randomly assigned to five groups: sham: intracerebroventricular (ICV) injection of phosphate-buffered saline, Aß: ICV Aß1-42 injections, Aß + CAR (50 mg/kg), Aß + p-cymene (50 mg/kg), and Aß + CAR + p-cymene. Administration of CAR and p-cymene was done by gavage daily 4 weeks before and 4 weeks after the Aß injection. The population spike (PS) amplitude and field excitatory postsynaptic potentials (fEPSP) slope were determined in DG against the applied stimulation to the PP. RESULTS: Aß-treated rats exhibited impaired LTP induction in the PP-DG synapses, resulting in significant reduction in both fEPSP slope and PS amplitude compared to the sham animals. Aß-treated rats consumed either CAR or p-cymene separately (but not their combination), and showed an enhancement in fEPSP slope and PS amplitude of the DG granular cells. CONCLUSIONS: These data indicate that CAR or p-cymene can ameliorate Aß-associated changes in synaptic plasticity. Surprisingly, the combination of CAR and p-cymene did not yield the same effect, suggesting a potential interaction between the two substances.

Association of MGLL Intronic C>T Single Nucleotide Polymorphism (rs782440) with Borderline Personality Disorder: A Case-Control Study.

OBJECTIVE: From the perspective of etiology, borderline personality disorder (BPD) is a multifactorial and complex disorder, hence our understanding about the molecular basis and signaling of this disorder is extremely limited. The purpose of this study was evaluating the relationship between BPD and the Monoacylglycerol lipase (MGLL) polymorphism rs782440 in the population of Hamadan, Iran. MATERIALS AND METHODS: In this case-control study, 106 participants including 53 patients with BPD and 53 healthy control subjects were selected by psychiatrists in the Department of Psychiatry at Farshchian Sina Hospital in Hamadan. The BPD patients were selected based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) form for diagnosing BPD patients. For genotyping, polymerase chain reaction (PCR) was used to amplify the desired region including the (MGLL) intronic C>T single nucleotide polymorphism (SNP) (rs782440) and afterward the amplicon was sequenced using the Sanger sequencing method. To determine the genotype of these patients, their sequences were aligned with the reference sequence of MGLL through the CLC genomic workbench software. RESULTS: The results indicated that the frequency of TT in comparison to the CC genotype was significantly different (P=0.003) and the risk of BPD in change from the TT genotype to CC genotype was increased by 6.679%. Regarding the frequency of allele in this group, no significant difference was observed. CONCLUSION: This paper, has studied and reports for the first time, the association between MGLL SNP (rs782440) with BPD. The findings of the current research revealed that the TT genotype increases the risk of BPD compared to the CC genotype. Considering the lack of a suitable diagnostic biomarker for BPD, using this potential biomarker in the near future can be promising.

Corrigendum: Effects of in ovo inoculation of multi-strain lactobacilli on cytokine gene expression and antibody-mediated immune responses in chickens.

[This corrects the article DOI: 10.3389/fvets.2020.00105.].

Provision of chaplaincy services in U.S. hospitals: A strategic conformity perspective.

BACKGROUND: Increasingly, hospitals are expected to provide patient-centered care that attends to patients' health needs, including spiritual care needs. Chaplaincy services help to meet patients' spiritual care needs, which have been shown to have a positive impact on health outcomes. Variation in the provision of chaplaincy services suggests hospitals do not uniformly conform to the expectation of making chaplaincy services available. PURPOSE: The aim of this study was to examine the availability and factors that influence hospitals' provision of chaplaincy services. METHODOLOGY: Data were combined from the American Hospital Association annual surveys with the Area Health Resource File at the county level from 2010 to 2019. Observations on general, acute-care community hospitals were analyzed (45,384 hospital-year observations) using logistic regression that clustered standard errors at the hospital level. RESULTS: Hospitals with Joint Commission accreditation, more staffed beds, nonprofit and government ownership, teaching status, one or more intensive care units, a higher percentage of Medicare inpatient days, church affiliation, and system membership were more likely to provide chaplaincy services than their counterparts. Certification as a trauma hospital and market competition showed no influence on the provision of chaplaincy services. CONCLUSION: The lack of chaplaincy services in many hospitals may be due to limited resources, workforce shortage, or a lack of consensus on scope and nature of chaplaincy services. PRACTICE IMPLICATIONS: Chaplaincy services are an underutilized resource that influences patient experience, clinician burnout and turnover, and the goal of ensuring care is patient-centered. Administrators should consider stronger partnerships where services are provided; researchers and policymakers should consider how the lack of these services in some hospitals may reinforce existing health disparities.

Mitochondrial biogenesis and apoptosis as underlying mechanisms involved in the cardioprotective effects of Gallic acid against D-galactose-induced aging.

BACKGROUND: Aging is a main risk factor for the development of cardiovascular diseases (CVDs). Gallic acid (GA) is a phenolic compound derived from a wide range of fruits. GA has a wide spectrum of pharmacological properties, including anti-oxidative, anti-inflammatory, and cardioprotective effects. This research was conducted to determine the cardioprotective effect of GA on cardiac hypertrophy in aged rats. METHODS AND RESULTS: Following histological evaluation and through observing the heart, we found that GA improved the cardiac hypertrophy induced by D-galactose (D-GAL) in cardiac cells. To clarify the causes for this anti-aging effect, we evaluated the malonic dialdehyde levels and antioxidant enzyme activity in rat cardiac tissue. The levels of lactate dehydrogenase (LDH) and creatine kinase (CK-MB) in serum were measured. The levels of genes related to mitochondrial biogenesis, mitophagy, and apoptosis in cardiac tissue were surveyed. The findings represented that GA ameliorated antioxidant enzyme activity while significantly decreasing the malonic dialdehyde levels. Real-time PCR analysis proposed that GA effectively improved mitochondrial biogenesis in the heart via regulating the expression levels of Sirtuin 1 (SIRT1), PPARγ coactivator 1α (PGC1-α), nuclear factor erythroid 2-related factor 2 (Nrf2), and mitochondrial transcription factor A (TFAM). GA also mitigated apoptosis in the heart by modulating the expression levels of B-cell lymphoma protein 2 (Bcl-2) and Bcl-2-associated X (Bax). In addition, GA improved serum LDH and CK-MB levels. CONCLUSIONS: GA may alleviate aging-induced cardiac hypertrophy via anti-oxidative, mitoprotective, and anti-apoptotic mechanisms.

Examining the relationship between long working hours and the use of prescription sedatives among U.S. workers.

OBJECTIVES: The prevalence of long working hours has been accompanied by a corresponding rise in sleep disorders. Sedative-hypnotic agents (SHAs), have been reported as the second most commonly misused drug class in the U.S. The key objective of this study was to examine the relationship between working hours on the use of sleep aids and medications with sedative properties. METHODS: The 2010-2019 Medical Expenditure Panel Survey data was utilized. SHAs and medications with sedative related properties (MSRPs) were identified. Furthermore, we employed different regression models ranging from multivariable linear regression, Tobit regression, Heckman regression, and multivariable logistic regression, to ensure consistency, robustness, and reliability of associations. RESULTS: Overall, a sample of 81,518 observations of full-time workers was analyzed. Working 56hours or more per week was significantly associated (p < 0.05) with an increased odds of using SHAs and MSRPs by 13% (Adjusted Odds Ratio, aOR =1.13, 95% Confidence Interval, CI=1.01:1.26) and 9% (aOR=1.09, 95% CI=1.03:1.16), respectively more than that among those who worked fewer hours. Females in our study had a higher likelihood (aOR=1.11, 95% CI=1.05:1.19) of using SHAs when compared to males. Also, professional services had the highest likelihood (aOR=1.31, 95% CI=1.14:1.50) of using SHAs. CONCLUSION: We found that long working hours were significantly associated with an elevated use of SHAs and MSRPs among U.S. workers. Specifically, female workers and individuals working in professional services had the highest likelihood of using sleep medications.

COVID-19 infection and mortality among non-pregnant indigenous adults in Mexico 2020-2022: Impact of marginalisation.

Background: Indigenous individuals have higher rates of mortality and poverty in Mexico and more than half are marginalised, and COVID-19 pandemic aggravated the existing burden of health disparities. We aimed to analyse the effects of being indigenous and marginalised on coronavirus (COVID-19) infection fatality in Mexico. Methods: We identified 3 424 690 non-pregnant, COVID-19 positive adults ≥19 years in the Mexico national COVID-19 database with known date of symptom. We used demographic information, indigenous status, marginalisation status, and co-morbidities in binary logistic regression to predict mortality, adjusting for covariates, including hospitalisation, admission to the intensive care unit (ICU), and mechanical ventilation use. We also assessed the interaction between indigenous status and marginalisation. Results: Marginalisation was much higher among indigenous (53.7%) compared to non-indigenous individuals (4.8%). COVID-19 fatalities were approximately 20 years older (64.4 and 63.0 years) than survivors (44.7 and 41.2 years) among indigenous vs non-indigenous individuals, respectively. The unadjusted risk of COVID-19 fatality among indigenous individuals was nearly two-fold (odds ratio (OR) = 1.92)) compared to non-indigenous individuals (OR = 1.05). COVID-19 fatality was higher among highly marginalised individuals (upper quartile) (OR = 1.51; 95% confidence interval (CI) = 1.49-1.54). Marginalised indigenous individuals had a significantly lower likelihood of ICU admission compared to non-indigenous non-marginalised individuals. The likelihood of mechanical ventilation for indigenous individuals was 4% higher compared to non-indigenous individuals. Indigenous marginalised individuals had a significantly lower probability of mechanical ventilation compared to non-indigenous non-marginalised individuals. COVID-19 comorbidity risks of fatality significantly differed between the two groups in the Cox survival analysis. In the fully adjusted model, indigenous individuals were 4% more likely to die from COVID-19 compared to non-indigenous. Conclusions: Indigenous, marginalised individuals with COVID-19 had higher risk of hospitalisation and ICU admission than non-indigenous patients. Marginalised, indigenous individuals were less likely to receive mechanical ventilation compared to non-indigenous, but had a higher risk of COVID-19. Indigenous individuals had a 4% higher COVID-19 mortality risk COVID-19 compared to non-indigenous individuals. Improved community medical care and augmented health services in rural hospitals could mitigate barriers to health care access in indigenous, marginalised populations.

Maternal high-intensity interval training as a suitable approach for offspring's heart protection in rat: evidence from oxidative stress and mitochondrial genes.

Considerable scientific evidence suggests that the intrauterine environment plays a crucial role in determining the long-term health of offspring. The present study aims to investigate the effects of high-intensity interval training in maternal rats before and during pregnancy on the antioxidant status, mitochondrial gene expression, and anxiety-like behavior of their offspring. A total of thirty-two female rats were assigned to four maternal groups based on the timing of exercise: before pregnancy, before and during pregnancy, during pregnancy, and sedentary. The female and male offspring were allocated to groups that matched their mothers' exercise regimen. Anxiety-like behavior in the offspring was evaluated using the open-field and elevated plus-maze tests. Our findings indicate that maternal HIIT does not have any detrimental effect on the anxiety-related behavior of offspring. Also, maternal exercise before and during pregnancy could improve the general activity of the offspring. Furthermore, our results demonstrate that female offspring exhibit more locomotion activity than males. Besides, maternal HIIT leads to a reduction in the levels of TOS and MDA, while TAC levels increase, and significantly upregulate the gene expression of PGC1-α, NFR1, and NRF2 in both sexes in the heart. Therefore, our study suggests that maternal HIIT is a beneficial maternal behavior and serves as a cardioprotective agent to enhance the health of the next generations.

Biodegradable Piezoelectric Polymers: Recent Advancements in Materials and Applications.

Recent materials, microfabrication, and biotechnology improvements have introduced numerous exciting bioelectronic devices based on piezoelectric materials. There is an intriguing evolution from conventional unrecyclable materials to biodegradable, green, and biocompatible functional materials. As a fundamental electromechanical coupling material in numerous applications, novel piezoelectric materials with a feature of degradability and desired electrical and mechanical properties are being developed for future wearable and implantable bioelectronics. These bioelectronics can be easily integrated with biological systems for applications, including sensing physiological signals, diagnosing medical problems, opening the blood-brain barrier, and stimulating healing or tissue growth. Therefore, the generation of piezoelectricity from natural and synthetic bioresorbable polymers has drawn great attention in the research field. Herein, the significant and recent advancements in biodegradable piezoelectric materials, including natural and synthetic polymers, their principles, advanced applications, and challenges for medical uses, are reviewed thoroughly. The degradation methods of these piezoelectric materials through in vitro and in vivo studies are also investigated. These improvements in biodegradable piezoelectric materials and microsystems could enable new applications in the biomedical field. In the end, potential research opportunities regarding the practical applications are pointed out that might be significant for new materials research.

Geraniol improves passive avoidance memory and hippocampal synaptic plasticity deficits in a rat model of Alzheimer's disease.

Alzheimer's disease (AD) is the most progressive and irreversible neurodegenerative disease that leads to synaptic loss and cognitive decline. The present study was designed to evaluate the effects of geraniol (GR), a valuable acyclic monoterpene alcohol, with protective and therapeutic effects, on passive avoidance memory, hippocampal synaptic plasticity, and amyloid-beta (Aß) plaques formation in an AD rat model induced by intracerebroventricular (ICV) microinjection of Aß1-40. Seventy male Wistar rats were randomly into sham, control, control-GR (100 mg/kg; P.O. (orally), AD, GR-AD (100 mg/kg; P.O.; pretreatment), AD-GR (100 mg/kg; P.O.; treatment), and GR-AD-GR (100 mg/kg; P.O.; pretreatment & treatment). Administration of GR was continued for four consecutive weeks. Training for the passive avoidance test was carried out on the 36th day and a memory retention test was performed 24 h later. On day 38, hippocampal synaptic plasticity (long-term potentiation; LTP) was recorded in perforant path-dentate gyrus (PP-DG) synapses to assess field excitatory postsynaptic potentials (fEPSPs) slope and population spike (PS) amplitude. Subsequently, Aß plaques were identified in the hippocampus by Congo red staining. The results showed that Aß microinjection increased passive avoidance memory impairment, suppressed of hippocampal LTP induction, and enhanced of Aß plaque formation in the hippocampus. Interestingly, oral administration of GR improved passive avoidance memory deficit, ameliorated hippocampal LTP impairment, and reduced Aß plaque accumulation in the Aß-infused rats. The results suggest that GR mitigates Aß-induced passive avoidance memory impairment, possibly through alleviation of hippocampal synaptic dysfunction and inhibition of Aß plaque formation.

Motivating non-physician health workers to reduce the behavioral risk factors of non-communicable diseases in the community: a field trial study.

BACKGROUND: Non-communicable diseases behavioral risk factors can be improved if effective interventions are designed considering the health system's capabilities and local resources. This study evaluated the effectiveness of interventions that aimed at increasing non-physician community health workers' motivation in reducing non-communicable diseases behavioral risk factors in the community. METHODS: A randomized field trial study was conducted in 32 community health centers in 4 Iranian districts after a baseline population survey on the status of NCDs of 30-70-year-old individuals (n = 1225). The interventions were performed to improve insufficient physical activity, insufficient fruit consumption, insufficient vegetable consumption, high salt intake, and tobacco use. Four intervention packages were implemented in 24 community health centers; the other 8 centers were used as control groups. The non-physician community health workers performed the interventions. The packages additively included goal-setting, evidence-based education, operational planning, and incentive payments. A second survey was conducted 1 year after the start of the interventions to identify the effects on an independent random sample of 30-70-year-old individuals (n = 1221). Difference-in-difference method was used to quantify the interventions' effects. RESULTS: The average age of participants in both surveys was about 49 years. Also, about half of the participants were female, and about 43% were illiterate or had a primary school education. The interventions had statistically significant effects only on decreasing the prevalence of insufficient physical activity. The package with all the intervention components decreased the odds of insufficient physical activity to 0.24 (95% CI, 0.08, 0.72). The package with operational planning but no performance-based financing did not change the odds of insufficient physical activity. CONCLUSIONS: This study highlighted the importance of components, design, and implementation details of interventions intended to reduce NCDs behavioral risk factors. Some risk factors, such as insufficient physical activity, seem more easily modifiable with limited low-cost interventions in a one-year horizon. However, risk factors related to healthy food consumption and tobacco use need more extensive interventions. TRIAL REGISTRATION: This trial was registered on the Iranian Registry of Clinical Trials (IRCT20081205001488N2) on 3 June 2018 ( https://en.irct.ir/trial/774 ).