Mucocoele of the appendix.

Introduction: Mucocoele of the appendix occurs in 0.2-0.7% of people in the world without any well-defined clinical symptoms. It occurs when there is an accumulation of mucous in the lumen of the appendix. Case Presentation: We present three cases: a 48-year-old male admitted to the emergency room with a one-day history of right iliac fossa pain. Abdominal examination was suggestive of acute appendicitis. The initial abdominal computerised tomography scan was reported as being unremarkable. At surgery, a firm tumour of the appendix was found, and a limited right hemicolectomy was done. Histopathology confirmed a mucocoele of the appendix with borderline mucinous histology.The second case is a 63-year-old man who presented with a one-year history of abdominal distension and weight loss. Previous abdominal ultrasound was suggestive of liver cirrhosis with significant ascitic fluid. Abdominal magnetic resonance imaging found an appendix mucocoele with infiltration of the omentum and scalloping of the liver surface suggestive of pseudomyxoma peritonei. A percutaneous biopsy of the omental mass confirmed metastatic mucinous adenocarcinoma of the appendix.The third case is a 68-year-old man who, during an annual medical check-up, had an incidental finding of a cystic right iliac fossa mass on ultrasound, confirmed on abdominopelvic computerised tomography scan to be an appendix mucocele. He had laparoscopic appendicectomy. The histopathological diagnosis confirmed a mucinous cystadenoma of the appendix. Conclusion: Preoperative diagnosis of appendiceal mucocoele is difficult and commonly discovered intraoperatively. The prognosis is good for the histologically benign type, but it is poor when malignant or peritoneal lesions are present. Funding: None declared.

L-type calcium channel regulation of depression, anxiety and anhedonia-related behavioral phenotypes following chronic stress exposure.

Exposure to chronic and unpredictable stressors can precipitate mood-related disorders in humans, particularly in individuals with pre-existing mental health challenges. L-type calcium channels (LTCCs) have been implicated in numerous neuropsychiatric disorders, as LTCC encoding genes have been identified as candidate risk factors for neuropsychiatric illnesses. In these sets of experiments, we sought to examine the ability of LTCC blockade to alter depression, anxiety, and anhedonic-related behavioral responses to chronic unpredictable stress (CUS) exposure in female and male rats. Rats first underwent either 21 days of CUS or no exposure to chronic stressors, serving as home cage controls (HCC). Then rats were examined for anhedonia-related behavior, anxiety and depression-like behavioral responses as measured by the sucrose preference test (SPT), elevated plus maze (EPM), and forced swim test (FST). CUS exposed females and males showed anhedonic and anxiogenic-like behavioral responses on the SPT and EPM, respectively, when compared to HCCs. In female and male rats, systemic administration of the LTCC blocker isradipine (0.4 mg/kg and 1.2 mg/kg, I.P.) attenuated the CUS-induced decrease in sucrose preference and reversed the CUS-induced decrease in open arm time. In the FST, systemic isradipine decreased immobility time across all groups, consistent with an antidepressant-like response. However, there were no significant differences in forced swim test immobility time between HCC and CUS exposed animals. Taken together, these data point to a role of LTCCs in the regulation of mood disorder-related behavioral phenotype responses to chronic stress exposure.

Impact of vanilla flavor on nicotine taste, choice, intake, and seeking behaviors.

RATIONALE: Flavors can alter the orosensory properties of tobacco products. Specifically, flavors can serve as an oral cue for smokeless tobacco products. OBJECTIVES: We aimed to investigate the impact of oral vanillin, the principal chemical of vanilla flavor in tobacco products, on nicotine's taste, and nicotine choice, intake, and seeking behaviors. METHODS: Experiments were performed in young adult Sprague Dawley rats. We employed a two-bottle free-choice test (2BC) to measure the preference for different concentrations of vanillin and its effect on nicotine preference. To explore the long-term effects of early exposure to sweetened vanillin, we utilized a combined 2BC and intraoral self-administration (IOSA) model. We assessed the nicotine taking and seeking behaviors in the presence or absence of vanillin. We performed a taste reactivity test (TRT) to quantify liking (ingestive) and disliking (aversive) taste responses to oral nicotine with or without vanillin. RESULTS: In 2BC, female rats preferred vanillin containing solutions more than their male counterparts. In IOSA, vanillin alone and in combination with nicotine led to greater IOSA compared to water. Female rats self-administered vanillin plus nicotine more than male rats. Vanillin increased motivation to nicotine taking, but only in females. In TRT, vanillin increased nicotine's ingestive responses but blocked aversive responses in both sexes. CONCLUSIONS: These results indicate that vanilla flavor can increase oral nicotine intake. It can also increase liking and decrease disliking of nicotine's taste. Furthermore, the impact of vanilla flavor on nicotine taste and nicotine choice, intake, and seeking behaviors is concentration and sex dependent.

Towards Understanding the Microepidemiology of Lymphatic Filariasis at the Community Level in Ghana.

Studies on the distribution of lymphatic filariasis (LF) have mostly focused on reporting prevalence at the community level and distribution at the district levels. Understanding the distribution patterns at community levels may help in designing surveillance strategies. This study aimed to characterize the spatial distribution of LF infections in four hotspot communities in Ghana. The research, involving 252 participants, collected demographic data, mass drug administration (MDA) information, household GPS coordinates, and antigen detection test results. The LF prevalence varied significantly among the communities, with Asemda having the highest (33.33%) and Mempeasem having the lowest (4.44%). Females had lower odds of infection than males (OR = 2.67, p = 0.003 CI: 1.39-5.13). Spatial analysis using kernel density, Anselin Local Moran's, Getis-Ord Gi models, Ordinary Least Squares, and Geographic Weighted Regression revealed mixed patterns of spatial autocorrelation. This study identified LF hotspots, indicating clusters of high or low prevalence with some areas showing disparities between MDA coverage and LF positivity rates. Despite these hotspots, the overall distribution of LF appeared random, suggesting the importance of purposeful sampling in surveillance activities. These findings contribute valuable insights into the micro-epidemiology of LF, emphasizing the need for community-specific investigations to understand the factors influencing the effectiveness of MDA programs in controlling filarial infections. The study highlights the importance of refining surveillance strategies based on community-level distribution patterns.

Exploring racial and secondary substance use differences in route of administration of opioid drugs: Analysis of the 2015-2019 treatment admission data.

INTRODUCTION: The opioid crisis continues to evolve with increasing opioid-related overdose deaths among under-represented minorities. A better understanding of substance use differences in the route of administration for people using heroin and other opioids can lead to targeted strategies and interventions. METHODS: Using the 2015-2019 Treatment Episode Data Set - Admissions (TEDS-A), a multinomial logistic regression model examined the relationship between race/ethnicity and secondary substance use with route of administration in a subset of 591,078 admissions. RESULTS: For individuals reporting heroin as their primary substance, minoritized clients were both more likely to smoke (NH Blacks RR: 2.28, 95 % CI 2.16-2.41; Hispanic RR: 1.80, 95 % CI: 1.74, 1.87; Other RR: 2.09, 95 % CI: 2.00, 2.20) or inhale heroin (Hispanic RR: 1.82, 95 % CI 1.78-1.85; Other RR: 1.30, 95 % CI 1.25, 1.34) compared to non-Hispanic (NH) Whites. NH Black clients were nearly seven and a half times more likely to report inhaling (RR: 7.45, 95 % CI 7.28, 7.62) heroin over injecting it. Clients were more likely to smoke heroin compared to injection if they reported secondary drug use of methamphetamines (RR: 2.28, 95 % CI 2.21, 2.35) and other opioids (RR: 1.21, 95 % CI 1.15, 1.28). For clients reporting other opioids as their primary substance, Hispanic (RR: 1.33, 95 % CI 1.19, 1.47) and other racial/ethnic minority clients (RR: 2.50, 95 % CI 2.23, 2.79) were more likely to smoke opioids vs take it orally compared to their NH White counterparts. Individuals who reported methamphetamine use as a secondary substance were significantly more than three times as likely to smoke (RR: 3.07, 95 % CI 2.74, 3.45) or inject (RR: 3.36, 95 % CI 3.17, 3.57) compared to orally ingesting opioids, while those who reported cocaine or crack cocaine use were more than twice as likely to inject (RR: 2.22, 95 % CI 2.09-2.36) opioids than taking them orally. CONCLUSION: Findings demonstrate significant racial and ethnic differences in the route of administration. This work expands on the understanding of the complex nature of polysubstance use in the evolving opioid crisis and the secondary substance use of clients on routes of administration of opioids and heroin, highlighting the need for tailored interventions to address the treatment needs of under-represented minorities.

Targeting the Actions of Muscarinic Receptors on Dopamine Systems: New Strategies for Treating Neuropsychiatric Disorders.

Cholinergic regulation of dopamine (DA) signaling has significant implications for numerous disorders, including schizophrenia, substance use disorders, and mood-related disorders. The activity of midbrain DA neurons and DA release patterns in terminal regions are tightly regulated by cholinergic neurons found in both the striatum and the hindbrain. These cholinergic neurons can modulate DA circuitry by activating numerous receptors, including muscarinic acetylcholine receptor (mAChR) subtypes. This review specifically focuses on the complex role of M2, M4, and M5 mAChR subtypes in regulating DA neuron activity and DA release and the potential clinical implications of targeting these mAChR subtypes.

Ventral Tegmental Area M5 Muscarinic Receptors Mediate Effort-Choice Responding and Nucleus Accumbens Dopamine in a Sex-Specific Manner .

Optimization of effort-related choices is impaired in depressive disorders. Acetylcholine (ACh) and dopamine (DA) are linked to depressive disorders, and modulation of ACh tone in the ventral tegmental area (VTA) affects mood-related behavioral responses in rats. However, it is unknown if VTA ACh mediates effort-choice behaviors. Using a task of effort-choice, rats can choose to lever press on a fixed-ratio 5 (FR5) schedule for a more-preferred food or consume freely available, less-preferred food. VTA administration of physostigmine (1 µg and 2 µg/side), a cholinesterase inhibitor, reduced FR5 responding for the more-preferred food while leaving consumption of the less-preferred food intact. VTA infusion of the M5 muscarinic receptor negative allosteric modulator VU6000181 (3 µM, 10 µM, 30 µM/side) did not affect lever pressing or chow consumption. However, VU6000181 (30 µM/side) coadministration with physostigmine (2 µg/side) attenuated physostigmine-induced decrease in lever pressing in female and male rats and significantly elevated lever pressing above vehicle baseline levels in male rats. In in vivo voltammetry experiments, VTA infusion of combined physostigmine and VU6000181 did not significantly alter evoked phasic DA release in the nucleus accumbens core (NAc) in female rats. In male rats, combined VTA infusion of physostigmine and VU6000181 increased phasic evoked DA release in the NAc compared with vehicle, physostigmine, or VU6000181 infusion alone. These data indicate a critical role and potential sex differences of VTA M5 receptors in mediating VTA cholinergic effects on effort choice behavior and regulation of DA release. SIGNIFICANCE STATEMENT: Effort-choice impairments are observed in depressive disorders, which are often treatment resistant to currently available thymoleptics. The role of ventral tegmental area (VTA) acetylcholine muscarinic M5 receptors, in a preclinical model of effort-choice behavior, is examined. Using the selective negative allosteric modulator of the M5 receptor VU6000181, we show the role of VTA M5 receptors on effort-choice and regulation of dopamine release in the nucleus accumbens core. This study supports M5 receptors as therapeutic targets for depression.

Chronic oral nicotine exposure decreases aversive taste of nicotine, increases nicotine withdrawal and reinstatement, but cherry flavor does not alter nicotine's effects in adolescent rats.

Although e-cigarette use among youth is recognized as an epidemic, there is limited understanding regarding nicotine's orosensory and chronic use effects in youth, and how fruit e-cigarette flavorings may influence nicotine's effects. We aimed to characterize the orosensory and chronic use effects of nicotine in adolescent rats. We also determined the acute and chronic effects of benzaldehyde, a cherry/berry/almond flavoring, on nicotine's taste, consumption, withdrawal, and reinstatement. Rats were examined for their acute taste responses to the different nicotine concentrations. The effects of chronic exposure on nicotine's taste, withdrawal, and reinstatement were also determined. In addition, impact of benzaldehyde on these nicotine use behaviors was evaluated. While taste responses to low nicotine concentrations did not differ from water, high nicotine concentrations induced aversion. Aversive responses to nicotine that were observed in naïve animals vanished after chronic nicotine exposure, indicating the development of tolerance to nicotine's aversive taste. Additionally, nicotine abstinence after chronic exposure induced withdrawal. Following abstinence, animals reinstated nicotine use. Further, animals showed higher preference to nicotine after reinstatement, compared to preference values before nicotine withdrawal. Benzaldehyde did not alter nicotine's taste reactivity, withdrawal, and reinstatement experiments. Some sex differences were found in benzaldehyde's taste response and choice behavior experiments.

L-type calcium channel regulation of dopamine activity in the ventral tegmental area to nucleus accumbens pathway: Implications for substance use, mood disorders and co-morbidities.

L-type calcium channels (LTCCs), including the Cav1.2 and Cav1.3 LTCC subtypes, are important regulators of calcium entry into neurons, which mediates neurotransmitter release and synaptic plasticity. Cav1.2 and Cav1.3 are encoded by the CACNA1C and CACNA1D genes, respectively. These genes are implicated in substance use disorders and depression in humans, as demonstrated by genetic-wide association studies (GWAS). Pre-clinical models have also revealed a critical role of LTCCs on drug and mood related behavior, including the co-morbidity of substance use and mood disorders. Moreover, LTCCs have been shown to regulate the neuronal firing of dopamine (DA) neurons as well as drug and stress-induced plasticity within the ventral tegmental area (VTA) to nucleus accumbens (NAc) pathway. Thus, LTCCs are interesting targets for the treatment of neuropsychiatric diseases. In this review, we provide a brief introduction to voltage-gated calcium channels, specifically focusing on the LTCCs. We place particular emphasis on the ability of LTCCs to regulate DA neuronal activity and downstream signaling in the VTA to NAc pathway, and how such processes mediate substance use and mood disorder-related behavioral responses. We also discuss the bi-directional control of VTA LTCCs on drug and mood-related behaviors in pre-clinical models, with implications for co-morbid psychiatric diagnosis. We conclude with a section on the clinical implications of LTCC blockers, many which are already FDA approved as cardiac medications. Thus, pre-clinical and clinical work should examine the potential of LTCC blockers to be repurposed for neuropsychiatric illness. This article is part of the Special Issue on 'L-type calcium channel mechanisms in neuropsychiatric disorders'.

Cervical cancer prevention methods: awareness and use among urban Ghanaian women in Cape Coast, West Africa.

Background: Cervical cancer is the fourth most frequent malignancy and common cause of mortality in women worldwide, despite being one of the most preventable female cancers. Objectives: The aim of the study was to assess the awareness and knowledge of patients about cervical cancer prevention methods and the use of these methods by women in an urban setting. Method: A cross-sectional study design was employed. A census was conducted to include all women (n = 153) who met the inclusion criteria and attended the gynaecology clinic of the Cape Coast Teaching Hospital from May to July 2022 for various gynaecological reasons. Data were collected using a structured questionnaire adapted from the Cervical Cancer Knowledge Prevention-64. Results: The mean age was 40.0 years and ranges between 18 and 78 years. The majority of study participants had at least a secondary school level of education (78.8%), and almost all had at least a primary school education (95.4%). Most of the respondents (64.7%) were not aware of cervical cancer. Among those who had awareness, 64.8% of them knew about the existence of prevention methods; pap smear was the most common known method of prevention. There was a statistically significant association between the respondent's educational level and knowledge of the existence of cervical cancer prevention methods and the usage of pap smear. Only 16.3% of our study population has ever used a preventive method. Conclusion: More than half of the participants were not aware of cervical cancer and its preventive methods, and those who were aware had insufficient knowledge, which translated to very low usage of cervical cancer preventive methods. There is an urgent need to intensify public education on cervical cancer.

Animal Models to Investigate the Impact of Flavors on Nicotine Addiction and Dependence.

BACKGROUND: Tobacco use in humans is a long-standing public health concern. Flavors are common additives in tobacco and alternative tobacco products, added to mask nicotine's harsh orosensory effects and increase the appeal of these products. Animal models are integral for investigating nicotine use and addiction and are helpful for understanding the effects of flavor additives on the use of nicotine delivery products. OBJECTIVE: This review focuses on preclinical models to evaluate the contribution of flavor additives to nicotine addiction. MATERIALS AND METHODS: An electronic literature search was conducted by authors up to May 2022. Original articles were selected. RESULTS: The behavioral models of rodents described here capture multiple dimensions of human flavored nicotine use behaviors, including advantages and disadvantages. CONCLUSION: The consensus of the literature search was that human research on nicotine use behavior has not caught up with fast-changing product innovations, marketing practices, and federal regulations. Animal models are therefore needed to investigate mechanisms underlying nicotine use and addiction. This review provides a comprehensive overvie.

Cholinergic and dopaminergic-mediated motivated behavior in healthy states and in substance use and mood disorders.

Acetylcholine is an important neuromodulator of the mesolimbic dopamine (DA) system, which itself is a mediator of motivated behavior. Motivated behavior can be described by two primary components, termed directional and activational motivation, both of which can be examined and dissociated using effort-choice tasks. The directional component refers to motivated behavior directed towards reinforcing stimuli and away from aversive stimuli. Behaviors characterized by increased vigor, persistence, and work output are considered to reflect activational components of motivation. Disruption of DA signaling has been shown to decrease activational components of motivation, while leaving directional features intact. Facilitation of DA release promotes the activational aspects of motivated behavior. In this review, we discuss cholinergic and DA regulation of motivated behaviors. We place emphasis on effort-choice processes and the ability of effort-choice tasks to examine and dissociate changes of motivated behavior in the context of substance use and mood disorders. Furthermore, we consider how altered cholinergic transmission impacts motivated behavior across disease states, and the possible role of cholinergic dysregulation in the etiology of these illnesses. Finally, we suggest that treatments targeting cholinergic activity may be useful in ameliorating motivational disruptions associated with substance use and comorbid substance use and mood disorders.

Management of recurrent pheochromocytoma in pregnancy in a young Ghanaian.

The co-existence of pheochromocytoma and pregnancy is rare, with poor maternal and foetal outcomes. This is a case report of a young Ghanaian woman with a pre-existing diagnosis of recurrent pheochromocytoma who became pregnant and experienced elevated blood pressure in the third trimester with proteinuria and abnormal liver function. She was managed as an in-patient and delivered a live baby via caesarean section at 34 weeks after detecting intra-uterine growth restriction. Management of such cases by a multidisciplinary team is recommended for optimal outcomes.

Evaluation of Flavor Effects on Oral Nicotine Liking and/or Disliking Using the Taste Reactivity Test in Rats.

INTRODUCTION: Tobacco product flavors may change the sensory properties of nicotine, such as taste and olfactory cues, which may alter nicotine reward and aversion and nicotine taking behavior. The hedonic or aversive value of a taste stimulus can be evaluated by examining affective orofacial movements in rodents. AIMS AND METHODS: We characterized taste responses to various oral nicotine concentrations using the taste reactivity test in rats. We also evaluated the impact of menthol and benzaldehyde (cherry, almond) flavorants on both ingestive and aversive responses to oral nicotine. Adult Sprague-Dawley rats (n = 5-10 per sex per group) were implanted with intraoral catheters and received 20 infusions (200 µl/ea). Nicotine (1-100 µg/mL) was evaluated in taste reactivity test to determine taste responses to nicotine. Later, the effects of menthol (50 µg/mL) and benzaldehyde (100 µg/mL) on the taste responses to nicotine were determined. RESULTS: Nicotine at low concentrations (3 µg/mL in males, 1 µg/mL in females) elicited significantly greater ingestive responses compared with water, whereas higher nicotine concentrations (≥30 µg/mL in males, ≥10 µg/mL in females) elicited significant aversive reactions. Thus, intraoral nicotine induced both hedonic and aversive responses in a concentration- and sex-dependent manner. Females were more sensitive to nicotine's concentration. The addition of menthol or benzaldehyde significantly increased the hedonic responses to nicotine, and significantly decreased the aversive nicotine responses. CONCLUSIONS: Oral nicotine induces both hedonic and aversive taste responses, which may represent liking and disliking. Menthol and benzaldehyde can alter the orosensory experience of nicotine, which may influence nicotine's abuse liability. IMPLICATIONS: Our work represents a model to study impact of flavors on oral nicotine liking and disliking responses in rats. Moreover, our findings show that menthol and benzaldehyde alter the orosensory experience of nicotine, suggesting that both could influence nicotine's abuse liability.

An ongoing saga of nicotine complexity and dopamine heterogeneity: Nicotine activation and inhibition mediating reward and anxiety.

In this issue of Neuron, Nguyen and colleagues (Nguyen et al., 2021) investigate nicotine's effects on diverse midbrain dopamine neurons. Their findings provide new understanding of the functional role of ventral tegmental area (VTA) dopamine neurons and reveal topographically distinct, pathway-specific, and opposite dopaminergic responses to nicotine that likely mediate reward and anxiety, respectively.

A total facility approach to reducing HIV stigma in health facilities: implementation process and lessons learned.

OBJECTIVES: To describe development and implementation of a three-stage 'total facility' approach to reducing health facility HIV stigma in Ghana and Tanzania, to facilitate replication. DESIGN: HIV stigma in healthcare settings hinders the HIV response and can occur during any interaction between client and staff, between staff, and within institutional processes and structures. Therefore, the design focuses on multiple socioecological levels within a health facility and targets all levels of staff (clinical and nonclinical). METHODS: The approach is grounded in social cognitive theory principles and interpersonal or intergroup contact theory that works to combat stigma by creating space for interpersonal interactions, fostering empathy, and building efficacy for stigma reduction through awareness, skills, and knowledge building as well as through joint action planning for changes needed in the facility environment. The approach targets actionable drivers of stigma among health facility staff: fear of HIV transmission, awareness of stigma, attitudes, and health facility environment. RESULTS: The results are the three-stage process of formative research, capacity building, and integration into facility structures and processes. Key implementation lessons learned included the importance of formative data to catalyze action and shape intervention activities, using participatory training methodologies, involving facility management throughout, having staff, and clients living with HIV facilitate trainings, involving a substantial proportion of staff, mixing staff cadres and departments in training groups, and integrating stigma-reduction into existing structures and processes. CONCLUSION: Addressing stigma in health facilities is critical and this approach offers a feasible, well accepted method of doing so.

Combined Infusion and Stimulation with Fast-Scan Cyclic Voltammetry (CIS-FSCV) to Assess Ventral Tegmental Area Receptor Regulation of Phasic Dopamine.

Phasic dopamine (DA) release from the ventral tegmental area (VTA) to the nucleus accumbens plays a pivotal role in reward processing and reinforcement learning. Understanding how the diverse neuronal inputs into the VTA control phasic DA release can provide a better picture of the circuitry that controls reward processing and reinforcement learning. Here, we describe a method that combines intra-VTA cannula infusions of pharmacological agonists and antagonists with stimulation-evoked phasic DA release (combined infusion and stimulation, or CIS) as measured by in vivo fast-scan cyclic voltammetry (FSCV). Using CIS-FSCV in anesthetized rats, a phasic DA response can be evoked by electrically stimulating the VTA with a bipolar electrode fitted with a cannula while recording in the nucleus accumbens core. Pharmacological agonists or antagonists can be infused directly at the stimulation site to investigate specific VTA receptors' roles in driving phasic DA release. A major benefit of CIS-FSCV is that VTA receptor function can be studied in vivo, building on in vitro studies.

Results from a difference-in-differences evaluation of health facility HIV and key population stigma-reduction interventions in Ghana.

INTRODUCTION: Stigma undermines all aspects of a comprehensive HIV response, as reflected in recent global initiatives for stigma-reduction. Yet a commensurate response to systematically tackle stigma within country responses has not yet occurred, which may be due to the lack of sufficient evidence documenting evaluated stigma-reduction interventions. With stigma present in all life spheres, health facilities offer a logical starting point for developing and expanding stigma reduction interventions. This study evaluates the impact of a "total facility" stigma-reduction intervention on the drivers and manifestations of stigma and discrimination among health facility staff in Ghana. METHODS: We evaluated the impact of a total facility stigma-reduction intervention by comparing five intervention to five comparable non-intervention health facilities in Ghana. Interventions began in September 2017. Data collection was in June 2017 and April 2018. The primary outcomes were composite indicators for three stigma drivers, self-reported stigmatizing avoidance behaviour, and observed discrimination. The principal intervention variable was whether the respondent worked at an intervention or comparison facility. We estimated intervention effects as differences-in-differences in each outcome, further adjusted using inverse probability of treatment weighting (IPTW). RESULTS: We observed favourable intervention effects for all outcome domains except for stigmatizing attitudes. Preferring not to provide services to people living with HIV (PLHIV) or a key population member improved 11.1% more in intervention than comparison facility respondents (95% CI 3.2 to 19.0). Other significant improvements included knowledge of policies to protect against discrimination (difference-in-differences = 20.4%; 95% CI 12.7 to 28.0); belief that discrimination would be punished (11.2%; 95% CI 0.2 to 22.3); and knowledge of and belief in the adequacy of infection control policies (17.6%; 95% CI 8.3 to 26.9). Reported observation of stigma and discrimination incidents fell by 7.4 percentage points more among intervention than comparison facility respondents, though only marginally significant in the IPTW-adjusted model (p = 0.06). Respondents at intervention facilities were 19.0% (95% CI 12.2 to 25.8) more likely to report that staff behaviour towards PLHIV had improved over the last year than those at comparison facilities. CONCLUSIONS: These results provide a foundation for scaling up health facility stigma-reduction within national HIV responses, though they should be accompanied by rigorous implementation science to ensure ongoing learning and adaptation for maximum effectiveness and long-term impact.

Examining the role of muscarinic M5 receptors in VTA cholinergic modulation of depressive-like and anxiety-related behaviors in rats.

Acetylcholine is implicated in mood disorders including depression and anxiety. Increased cholinergic tone in humans and rodents produces pro-depressive and anxiogenic-like effects. Cholinergic receptors in the ventral tegmental area (VTA) are known to mediate these responses in male rats, as measured by the sucrose preference test (SPT), elevated plus maze (EPM), and the forced swim test (FST). However, these effects have not been examined in females, and the VTA muscarinic receptor subtype(s) mediating the pro-depressive and anxiogenic-like behavioral effects of increased cholinergic tone are unknown. We first examined the behavioral effects of increased VTA cholinergic tone in male and female rats, and then determined whether VTA muscarinic M5 receptors were mediating these effects. VTA infusion of the acetylcholinesterase inhibitor physostigmine (0.5 µg, 1 µg and 2 µg/side) in males and females produced anhedonic-like, anxiogenic, pro-depressive-like responses on the SPT, EPM, and FST. In females, VTA administration of the muscarinic M5 selective negative allosteric modulator VU6000181 (0.68 ng, 2.3 ng, 6.8 ng/side for a 3 µM, 10 µM, 30 µM/side infusion) did not alter SPT, EPM nor FST behavior. However, in males intra-VTA infusion of VU6000181 alone reduced time spent immobile on the FST. Furthermore, co-infusion of VU6000181 with physostigmine, in male and female rats, attenuated the pro-depressive and anxiogenic-like behavioral responses induced by VTA physostigmine alone, in the SPT, EPM, and FST. Together, these data reveal a critical role of VTA M5 receptors in mediating the anhedonic, anxiogenic, and depressive-like behavioral effects of increased cholinergic tone in the VTA.

Diversity and immune responses against Plasmodium falciparum gametocytes in non-febrile school children living in Southern Ghana.

BACKGROUND: Natural exposure to gametocytes can result in the development of immunity against the gametocyte by the host as well as genetic diversity in the gametocyte. This study evaluated the quantity and quality of natural immune responses against a gametocyte antigen, Pfs230 as well as the prevalence and diversity of gametocytes circulating in children living in two communities in southern Ghana. METHODS: Whole blood (2.5 ml) was collected from 137 non-febrile school children aged between 6 and 12 years old quarterly for a 6-month period. A drop of blood was used to prepare thick and thin blood films for parasite prevalence and density estimation. Subsequently, stored plasma samples were used in ELISAs assays to measure antibody responses and avidity against Pfs230. RNA was extraction from Trizol preserved packed cells and subsequently converted to complementary DNA (cDNA) which was used for reverse transcriptase PCR (RT-PCR) to determine gametocytes prevalence and diversity. RESULTS: Gametocyte carriage in the peak season (July) determined by Pfg377 RT-PCR was 49.2% in Obom and 22.2% in Abura, and was higher than that determined by microscopy. Gametocyte diversity was low and predominated by the same allele at both sites. The relative avidity index for antibodies measured in Abura was higher than that recorded in Obom at all time points although Pfs230 IgG concentrations were significantly high (P < 0.0001) in Obom than in Abura at all time points. The IgG responses in Obom were significantly higher than that in Abura during the peak season. CONCLUSION: Naturally induced antibody responses against Pfs230 in children living in both high perennial and low seasonal malaria transmission settings reduced significantly in moving from the peak to the off-peak season. The relative avidity of antibodies against Pfs230 in Abura was significantly higher than those measured in Obom, despite having lower IgG levels. Very limited diversity was identified in the gametocytes circulating in both Obom and Abura.