How donors support civil society as government accountability advocates: a review of strategies and implications for transition of donor funding in global health.

BACKGROUND: Global health donors are increasingly transitioning funding responsibility to host governments as aid budgets plateau or decline and countries meet development and disease burden goals. Civil society organizations (CSOs) can play a critical role as accountability mechanisms over their governments, but transitions raise questions about how donor-supported CSOs will fare following transition, especially in environments of limited political commitment. Decreases in funding may force CSOs to scale back activities, seek other funding, or rely on their governments for funding. Vulnerable populations most in need of support may lose critical advocates, compromising their access to lifesaving care and threatening the reversal of global health achievements. This review investigates donor strategies used in the past to support CSOs as accountability advocates across the international development sector by exploring what activities are supported, how support is provided and who receives support. It provides considerations for global health donors to better equip civil society as advocates during and following transition. METHODS: A literature review of four databases of peer-reviewed literature, websites focused on civil society support and snowball searching identified 180 documents for review, after application of exclusion criteria, covering up to December 2019. Results were categorized and analyzed by who, what and how donors have supported civil society's accountability role. RESULTS: Donors support a variety of civil society actors, including individual organizations and networks, through capacity building, access to information, backing participation in policy dialogues, securing citizen engagement and targeting the broader policy context. Funding may be provided directly or through pooled, intermediary or bridge mechanisms. Key concerns identified include insufficient engagement of CSOs in defining support, limited donor flexibility, tensions in balancing organizational professionalization with community connections, and jeopardized CSO legitimacy and independence from relying on foreign funds. CONCLUSIONS: Given the urgency of global health donor transitions, the literature demonstrates that any donor support to CSO advocates should emphasize transition preparations from the start. Capacity building, institutionalizing mechanisms for civil society participation, planning for information needs, and flexible funding are priority mechanisms to ensure that vulnerable populations continue accessing lifesaving care and global health progress is not reversed.

Ventilatory and carotid body responses to acute hypoxia in rats exposed to chronic hypoxia during the first and second postnatal weeks.

Chronic hypoxia (CH) during postnatal development causes a blunted hypoxic ventilatory response (HVR) in neonatal mammals. The magnitude of the HVR generally increases with age, so CH could blunt the HVR by delaying this process. Accordingly, we predicted that CH would have different effects on the respiratory control of neonatal rats if initiated at birth versus initiated later in postnatal development (i.e., after the HVR has had time to mature). Rats had blunted ventilatory and carotid body responses to hypoxia whether CH (12 % O2) occurred for the first postnatal week (P0 to P7) or second postnatal week (P7 to P14). However, if initiated at P0, CH also caused the HVR to retain the "biphasic" shape characteristic of newborn mammals; CH during the second postnatal week did not result in a biphasic HVR. CH from birth delayed the transition from a biphasic HVR to a sustained HVR until at least P9-11, but the HVR attained a sustained (albeit blunted) phenotype by P13-15. Since delayed maturation of the HVR did not completely explain the blunted HVR, we tested the alternative hypothesis that the blunted HVR was caused by an inflammatory response to CH. Daily administration of the anti-inflammatory drug ibuprofen (4 mg kg-1, i.p.) did not alter the effects of CH on the HVR. Collectively, these data suggest that CH blunts the HVR in neonatal rats by impairing carotid body responses to hypoxia and by delaying (but not preventing) postnatal maturation of the biphasic HVR. The mechanisms underlying this plasticity require further investigation.

"When you have no water, it means you have no peace": A mixed-methods, whole-population study of water insecurity and depression in rural Uganda.

BACKGROUND: Lack of access to clean water has well known implications for communicable disease risks, but the broader construct of water insecurity is little studied, and its mental health impacts are even less well understood. METHODS AND FINDINGS: We conducted a mixed-methods, whole-population study in rural Uganda to estimate the association between water insecurity and depression symptom severity, and to identify the mechanisms underlying the observed association. The whole-population sample included 1776 adults (response rate, 91.5%). Depression symptom severity was measured using a modified 15-item Hopkins Symptom Checklist for Depression. Water insecurity was measured with a locally validated 8-item Household Water Insecurity Access Scale. We fitted multivariable linear and Poisson regression models to the data to estimate the association between water insecurity and depression symptom severity, adjusting for age, marital status, self-reported overall health, household asset wealth, and educational attainment. These models showed that water insecurity was associated with depression symptom severity (b = 0.009; 95% confidence interval [CI], 0.004-0.15) and that the estimated association was larger among men (b = 0.012; 95% CI, 0.008-0.015) than among women (b = 0.008; 95% CI, 0.004-0.012. We conducted qualitative interviews with a sub-group of 30 participants, focusing on women given their traditional role in household water procurement in the Ugandan context. Qualitative analysis, following an inductive approach, showed that water insecurity led to "choice-less-ness" and undesirable social outcomes, which in turn led to emotional distress. These pathways were amplified by gender-unequal norms. CONCLUSIONS: Among men and women in rural Uganda, the association between water insecurity and depression symptom severity is statistically significant, substantive in magnitude, and robust to potential confounding. Data from the qualitative interviews provide key narratives that reveal the mechanisms through which women's lived experiences with water insecurity may lead to emotional distress.

Prevalence and correlates of chronic obstructive pulmonary disease and chronic respiratory symptoms in rural southwestern Uganda: a cross-sectional, population-based study.

BACKGROUND: The global burden of chronic obstructive pulmonary disease (COPD) disproportionately affects resource-limited settings such as sub-Saharan Africa (SSA), but population-based prevalence estimates in SSA are rare. We aimed to estimate the population prevalence of COPD and chronic respiratory symptoms in rural southwestern Uganda. METHODS: Adults at least 18 years of age who participated in a population-wide census in rural southwestern Uganda completed respiratory questionnaires and lung function testing with bronchodilator challenge at health screening events in June 2015. We defined COPD as post-bronchodilator forced expiratory volume in one second to forced vital capacity ratio less than the lower limit of normal. We fit multivariable linear and log binomial regression models to estimate correlates of abnormal lung function and respiratory symptoms, respectively. We included inverse probability of sampling weights in models to facilitate population-level estimates. RESULTS: Forty-six percent of census participants (843/1814) completed respiratory questionnaires and spirometry, of which 565 (67%) met acceptability standards. COPD and respiratory symptom population prevalence were 2% (95% confidence interval (CI) = 1%-3%) and 30% (95% CI = 25%-36%), respectively. Respiratory symptoms were more prevalent and lung function was lower among women and ever-smokers (P < 0.05). HIV serostatus was associated with neither respiratory symptoms nor lung function. CONCLUSIONS: COPD population prevalence was low despite prevalent respiratory symptoms. This work adds to the growing body of literature depicting lower-than-expected COPD prevalence estimates in SSA and raises questions about whether the high respiratory symptom burden in rural southwestern Uganda represents underlying structural lung disease not identified by screening spirometry.

Combined effects of intermittent hyperoxia and intermittent hypercapnic hypoxia on respiratory control in neonatal rats.

Chronic exposure to intermittent hyperoxia causes abnormal carotid body development and attenuates the hypoxic ventilatory response (HVR) in neonatal rats. We hypothesized that concurrent exposure to intermittent hypercapnic hypoxia would influence this plasticity. Newborn rats were exposed to alternating bouts of hypercapnic hypoxia (10% O2/6% CO2) and hyperoxia (30-40% O2) (5 cycles h-1, 24 h d-1) through 13-14 days of age; the experiment was run twice, once in a background of 21% O2 and once in a background of 30% O2 (i.e., "relative hyperoxia"). Hyperoxia had only small effects on carotid body development when combined with intermittent hypercapnic hypoxia: the carotid chemoafferent response to hypoxia was reduced, but this did not affect the HVR. In contrast, sustained exposure to 30% O2 reduced carotid chemoafferent activity and carotid body size which resulted in a blunted HVR. When given alone, chronic intermittent hypercapnic hypoxia increased carotid body size and reduced the hypercapnic ventilatory response but did not affect the HVR. Overall, it appears that intermittent hypercapnic hypoxia counteracted the effects of hyperoxia on the carotid body and prevented developmental plasticity of the HVR.

Water insecurity and gendered risk for depression in rural Uganda: a hotspot analysis.

BACKGROUND: Water insecurity is linked to depression in low- and middle-income countries (LMICs), though it remains unclear how geospatial clustering of water insecurity in rural regions is associated with risk for depression. METHODS: We conducted a population-based survey of a rural parish in southwestern Uganda (N = 1603) to evaluate the joint geospatial clustering of water insecurity and risk for depression among men and women living in rural Uganda. RESULTS: Geospatial clustering of self-reported water insecurity and depressive symptoms was found to be present among both men and women. Depression hotspots were more often observed near water insecurity hotspots among women, relative to men. Multivariable regression revealed that residing in a water insecurity hotspot significantly increased risk for depressive symptoms among women, but not among men. CONCLUSIONS: Residing in a water insecurity hotspot is associated with greater risk for probable depression among women, but not among men, pointing to the need for focused depression screening among women residing in water insecure households.

Measuring personal beliefs and perceived norms about intimate partner violence: Population-based survey experiment in rural Uganda.

BACKGROUND: Demographic and Health Surveys (DHS) conducted throughout sub-Saharan Africa indicate there is widespread acceptance of intimate partner violence, contributing to an adverse health risk environment for women. While qualitative studies suggest important limitations in the accuracy of the DHS methods used to elicit attitudes toward intimate partner violence, to date there has been little experimental evidence from sub-Saharan Africa that can be brought to bear on this issue. METHODS AND FINDINGS: We embedded a randomized survey experiment in a population-based survey of 1,334 adult men and women living in Nyakabare Parish, Mbarara, Uganda. The primary outcomes were participants' personal beliefs about the acceptability of intimate partner violence and perceived norms about intimate partner violence in the community. To elicit participants' personal beliefs and perceived norms, we asked about the acceptability of intimate partner violence in five different vignettes. Study participants were randomly assigned to one of three survey instruments, each of which contained varying levels of detail about the extent to which the wife depicted in the vignette intentionally or unintentionally violated gendered standards of behavior. For the questions about personal beliefs, the mean (standard deviation) number of items where intimate partner violence was endorsed as acceptable was 1.26 (1.58) among participants assigned to the DHS-style survey variant (which contained little contextual detail about the wife's intentions), 2.74 (1.81) among participants assigned to the survey variant depicting the wife as intentionally violating gendered standards of behavior, and 0.77 (1.19) among participants assigned to the survey variant depicting the wife as unintentionally violating these standards. In a partial proportional odds regression model adjusting for sex and village of residence, with participants assigned to the DHS-style survey variant as the referent group, participants assigned the survey variant that depicted the wife as intentionally violating gendered standards of behavior were more likely to condone intimate partner violence in a greater number of vignettes (adjusted odds ratios [AORs] ranged from 3.87 to 5.74, with all p < 0.001), while participants assigned the survey variant that depicted the wife as unintentionally violating these standards were less likely to condone intimate partner violence (AORs ranged from 0.29 to 0.70, with p-values ranging from <0.001 to 0.07). The analysis of perceived norms displayed similar patterns, but the effects were slightly smaller in magnitude: participants assigned to the "intentional" survey variant were more likely to perceive intimate partner violence as normative (AORs ranged from 2.05 to 3.51, with all p < 0.001), while participants assigned to the "unintentional" survey variant were less likely to perceive intimate partner violence as normative (AORs ranged from 0.49 to 0.65, with p-values ranging from <0.001 to 0.14). The primary limitations of this study are that our assessments of personal beliefs and perceived norms could have been measured with error and that our findings may not generalize beyond rural Uganda. CONCLUSIONS: Contextual information about the circumstances under which women in hypothetical vignettes were perceived to violate gendered standards of behavior had a significant influence on the extent to which study participants endorsed the acceptability of intimate partner violence. Researchers aiming to assess personal beliefs or perceived norms about intimate partner violence should attempt to eliminate, as much as possible, ambiguities in vignettes and questions administered to study participants. TRIAL REGISTRATION: ClinicalTrials.gov NCT02202824.

Population-based study of intra-household gender differences in water insecurity: reliability and validity of a survey instrument for use in rural Uganda.

Hundreds of millions of people worldwide lack adequate access to water. Water insecurity, which is defined as having limited or uncertain availability of safe water or the ability to acquire safe water in socially acceptable ways, is typically overlooked by development organizations focusing on water availability. To address the urgent need in the literature for validated measures of water insecurity, we conducted a population-based study in rural Uganda with 327 reproductive-age women and 204 linked men from the same households. We used a novel method of photo identification so that we could accurately elicit study participants' primary household water sources, thereby enabling us to identify water sources for objective water quality testing and distance/elevation measurement. Our psychometric analyses provided strong evidence of the internal structure, reliability, and validity of a new eight-item Household Water Insecurity Access Scale (HWIAS). Important intra-household gender differences in perceptions of water insecurity were observed, with men generally perceiving household water insecurity as being less severe compared to women. In summary, the HWIAS represents a reliable and valid measure of water insecurity, particularly among women, and may be useful for informing and evaluating interventions to improve water access in resource-limited settings.

Chronic intermittent hyperoxia alters the development of the hypoxic ventilatory response in neonatal rats.

Chronic exposure to sustained hyperoxia alters the development of the respiratory control system, but the respiratory effects of chronic intermittent hyperoxia have rarely been investigated. We exposed newborn rats to short, repeated bouts of 30% O2 or 60% O2 (5 bouts h(-1)) for 4-15 days and then assessed their hypoxic ventilatory response (HVR; 10 min at 12% O2) by plethysmography. The HVR tended to be enhanced by intermittent hyperoxia at P4 (early phase of the HVR), but it was significantly reduced at P14-15 (primarily late phase of the HVR) compared to age-matched controls; the HVR recovered when individuals were returned to room air and re-studied as adults. To investigate the role of carotid body function in this plasticity, single-unit carotid chemoafferent activity was recorded in vitro. Intermittent hyperoxia tended to decrease spontaneous action potential frequency under normoxic conditions but, contrary to expectations, hypoxic responses were only reduced at P4 (not at P14) and only in rats exposed to higher O2 levels (i.e., intermittent 60% O2). Rats exposed to intermittent hyperoxia had smaller carotid bodies, and this morphological change may contribute to the blunted HVR. In contrast to rats exposed to intermittent hyperoxia beginning at birth, two weeks of intermittent 60% O2 had no effect on the HVR or carotid body size of rats exposed beginning at P28; therefore, intermittent hyperoxia-induced respiratory plasticity appears to be unique to development. Although both intermittent and sustained hyperoxia alter carotid body development and the HVR of rats, the specific effects and time course of this plasticity differs.

Role of TrkB during the postnatal development of the rat carotid body.

Brain-derived neurotrophic factor (BDNF) supports innervation of the carotid body by neurons projecting from the petrosal ganglion. Although carotid body glomus cells also express TrkB, BDNF's high affinity receptor, the role of BDNF in carotid body growth and O2 sensitivity has not been studied. Neonatal rats were treated with the TrkB antagonist K252a (100 µg kg(-1), i.p., b.i.d.) or vehicle on postnatal days P0-P6 and studied on P7. Carotid body volume was decreased by 35% after chronic K252a (P<0.001); a reduction in carotid body size was also elicited using the more selective TrkB antagonist ANA-12 (500 µg kg(-1), i.p., b.i.d.). In contrast, single-unit chemoafferent responses to 5% O2, measured in vitro, were unaffected by chronic K252a administration. Normoxic and hypoxic ventilation, measured by head-body plethysmography, were also normal after chronic K252a administration, but acute K252a administration produced a slower, deeper breathing pattern during the transition into hypoxia. These data suggest that BDNF regulates postnatal carotid body growth but does not influence the development of glomus cell O2 sensitivity.

Discovery of novel 2-((pyridin-3-yloxy)methyl)piperazines as α7 nicotinic acetylcholine receptor modulators for the treatment of inflammatory disorders.

Herein we report the design, synthesis, and structure-activity relationships for a new class of α7 nicotinic acetylcholine receptor (nAChR) modulators based on the 2-((pyridin-3-yloxy)methyl)piperazine scaffold. The oxazolo[4,5-b]pyridine, (R)-18, and 4-methoxyphenylurea, (R)-47, were identified as potent and selective modulators of the α7 nAChR with favorable in vitro safety profiles and good oral bioavailability in mouse. Both compounds were shown to significantly inhibit cellular infiltration in a murine model of allergic lung inflammation. Despite the structural and in vivo functional similarities in the compounds, only (R)-18 was shown to be an agonist. Compound (R)-47 demonstrated silent agonist activity. These data support the hypothesis that the anti-inflammatory activity of the α7 nAChR is mediated by a signal transduction pathway that is independent of ion current.

Efficacious inhaled PDE4 inhibitors with low emetic potential and long duration of action for the treatment of COPD.

Oral phosphodiesterase 4 (PDE4) inhibitors, such as cilomilast and roflumilast, have been shown to be efficacious against chronic obstructive pulmonary disease (COPD). However, these drugs have been hampered by mechanism-related side effects such as nausea and emesis at high doses. Compounds administered by inhalation are delivered directly to the site of action and may improve the therapeutic index required to overcome side effects. This paper describes systematic and rational lead optimization to deliver highly potent, long-acting, and efficacious preclinical inhaled PDE4 inhibitors with low emetic potential.