Fibril core regions in engineered α-synuclein dimer are crucial for blocking of fibril elongation.

Synucleinopathies like Parkinson's disease are neurodegenerative diseases which are associated with the deposition of fibrillar aggregates of the endogenous protein α-synuclein (α-syn). The inhibition of the elongation of α-syn fibrils is of great scientific interest and an option in the design of therapeutic strategies. Previously, we developed a disulfide-containing mutant of α-syn, called CC48, which inhibits fibril elongation by blocking of fibril ends. Surprisingly, wildtype (WT) α-syn molecules supported the blocked state, and a fusion of CC48 with WT α-syn, denoted WT-CC48, exhibited increased inhibitory potential. Here, we studied which regions of WT-CC48 are responsible for the strong inhibitory effect. To this end, we investigated a set of truncated versions of WT-CC48 by kinetic elongation assays, density gradient centrifugation, and atomic force microscopy. We show that in both the WT and the CC48 part of the fusion construct the hairpin region (residue 32-60) and NAC region (61-95), but not N- and C-terminal regions, are required for strong inhibition of fibril elongation. The required regions correspond to the segments forming the ß-sheet core of α-syn fibrils. As α-syn fibrils typically consist of two protofilaments, the dimeric construct WT-CC48 provides the critical regions sufficient to cover the full ß-sheetcore interface exposed at the fibril end, which can explain its high inhibitory efficiency. We suggest a mechanistic model of CC48-mediated inhibition of fibril elongation in which CC48 and WT α-syn cooperatively form an oligomer-like cap at the amyloid fibril end.

What Have We Learned? Implementation of a Shared Learning Agenda and Access Strategy for the Hormonal Intrauterine Device.

In 2015, a global learning agenda for the hormonal intrauterine device (IUD) was developed with priority research questions regarding use of the method in low- and middle-income countries. In addition, members of the Hormonal IUD Access Group aligned on a strategy to expand access in the context of volunteerism and contraceptive method choice. This article synthesizes evidence generated since then and describes steps taken to address demand- and supply-side barriers to access. Findings demonstrated high continuation rates and satisfaction among hormonal IUD users that are comparable to other long-acting reversible contraceptives (LARCs). Across studies, a sizable number of users reported they would have chosen a short-acting method or no method at all if the hormonal IUD were not an option, which suggests that women did not see the hormonal IUD as interchangeable with other LARC options and thus it may fill an important niche in the market. With several countries now poised to scale up the method, resource mobilization will be key. On the demand side, investments in implementation research will be critical to understanding how best to launch and scale the method, while ensuring the sustainability of multiple quality-assured suppliers with affordable public-sector pricing will be necessary on the supply side.

Integration of other services with human papillomavirus vaccination; lessons from earlier in the life course highlight the need for new policy and implementation evidence.

Integration of vaccination against human papillomavirus (HPV) with other essential health services for adolescents has been proposed in global strategies and tested in demonstration projects in low- and middle-income countries (LMIC). Published experiences, global guidance, and one key example, the implementation of "HPV Plus" in Tanzania, all demonstrate the need for greater operational evidence to guide future implementation and policy. Review of experiences earlier in the life course, integrating post-partum family planning with infant immunization, show lessons from 13 LMICs that can apply to provision of adolescent health information and services alongside HPV vaccination. Three distinct models of integration emerge from this review comprising: 1) multiple tasks and functions by health staff providing vaccination and other care, or 2) secondary tasks added to the main function of vaccination, or 3) co-location of matched services provided by different staff. These models, with strengths and weaknesses demonstrated in family planning and immunization experiences, apply in different ways to the three main platforms used for HPV vaccination: school, facility or community. For HPV vaccination policy and programming, an initial need is to combine the existing evidence on vaccine service delivery - including coverage, efficiency, cost, and cost-effectiveness information - with what is known on how integration works in practice; the operational detail and models employed. This synthesis may enable assessment which models best suit the different service delivery platforms. An additional need is to link this with more tailored local assessments of the adolescent burden of disease and other determinants of their well-being to develop new thinking on what can and cannot be done to integrate other services alongside HPV vaccination. New approaches placing adolescents at the center are needed to design services tailored to their preferences and needs. The potential synergies with cervical cancer screening and treatment for older generations of women, also require further exploration. Coordinated action aligning HPV vaccination with broader adolescent health and wellbeing will generate social, economic and demographic benefits, which in themselves are sufficient justification to devote more attention to integrated approaches.

Implementing a Novel Facility-Community Intervention for Strengthening Integration of Infant Nutrition and Family Planning in Mara and Kagera, Tanzania.

Tanzania has high fertility, low contraceptive prevalence and low exclusive breastfeeding (EBF). The Lake Zone, including Mara and Kagera regions, leads the country in total fertility; use of the lactational amenorrhea method (LAM) is negligible. This pre-/post-study explored the effects of a multi-level facility and community intervention (service delivery support, community engagement, media and LAM tracking) to integrate maternal and infant nutrition and postpartum family planning (FP) within existing health contacts. Mixed methods were used, including service statistics, exit interviews, patient-tracking tools for community health workers, client self-tracking tools, supervision data, focus group discussions and in-depth interviews. Results are presented using the reach, effectiveness, adoption, implementation and maintenance (RE-AIM) implementation science framework. The intervention reached primarily the second and fourth wealth quintiles, increased FP and EBF at six weeks postpartum. LAM was very acceptable, provided an entry point for FP conversations and for addressing misconceptions, and reinforced EBF practices. Partners felt encouraged to support spousal nutrition, breastfeeding and FP. Higher adoption in Kagera may be influenced by performance-based financing. The intervention was implemented with generally high fidelity. Maintenance data reflected stakeholder interest in continuing the intervention. A multi-level facility and community intervention was feasible to implement and likely contributed to improved EBF practices and FP uptake, including LAM use.

Expanding Contraceptive Method Choice With a Hormonal Intrauterine System: Results From Mixed Methods Studies in Kenya and Zambia.

INTRODUCTION: Few women in low- and middle-income countries have access to the hormonal intrauterine system (IUS). Past research from a small number of facilities and the private sector suggest the IUS could be an important addition to the contraceptive method mix because it is the only long-acting method some women will adopt and users report high satisfaction and continuation. We aimed to determine whether these promising results were applicable in public facilities in Kenya and Zambia. METHODS: We used a mixed-methods approach with program monitoring data, interviews with women who received an IUS, and qualitative focus group discussions with providers. Data were collected in 2017-2019. RESULTS: Facilities in Kenya and Zambia reported 1,985 and 428 IUS insertions, respectively. If the IUS had not been available, 30% of adopters would have chosen a short-acting method. Women and providers gave diverse reasons for adopting the IUS, with the desire for fewer side effects being frequently mentioned in focus group discussions. Many IUS adopters first heard of the method on the day it was inserted (70% in Kenya, 47% in Zambia), yet providers reported that many women were unwilling to try a method they were just hearing about for the first time. Satisfaction and continuation were high: 86% of adopters in Kenya were still using the method 3-6 months after insertion and 78% were in Zambia (average 10 months post insertion). Providers also reported that most IUS adopters were satisfied; they rarely returned with complaints that could not be addressed with additional counseling. CONCLUSION: Expanding IUS access through the public sector shows promise to increase contraception use and continuation in low- and middle-income countries. Efforts to strengthen availability should consider demand and engage directly with various communities, including youth, around availability of a new long-acting option.

Findings and Lessons Learned From Strengthening the Provision of Voluntary Long-Acting Reversible Contraceptives With Postabortion Care in Guinea.

Integrating voluntary family planning into postabortion care (PAC) presents a critical opportunity to reduce future unintended pregnancies. Although Guinea has low contraceptive prevalence overall, acceptance of long-acting reversible contraceptives (LARCs) among PAC clients is higher than among interval LARC users and higher than the national average. In 2014, we assessed the extent of LARC provision within PAC services and the factors influencing integration. Primary and secondary data collected from 143 interviews, 75 provider assessments, and facility inventories and service statistics from all 38 public facilities providing PAC in Guinea allowed exploration of voluntary family planning uptake in the context of PAC. Study findings showed that 38 of 456 (8.3%) public health facilities or 38 of 122 (31.1%) facilities with a mandate to manage obstetric complications provided PAC services. Service statistics from 4,544 PAC clients in 2013 indicate that 95.2% received counseling and 73.0% voluntarily left the facility with contraception, with 29.6% of acceptors choosing a LARC. Family planning within PAC was emphasized in advocacy, policy and guidelines, quality improvement, and supervision, and the range of contraceptive options for postabortion clients was expanded to enable them to avoid a second unintended pregnancy. Factors that influenced provision of family planning within PAC included (1) the ability of champions both within and outside the Ministry of Public Health to advocate for PAC and leverage donor resources, (2) the incorporation of PAC with postabortion family planning into national policies, standards, and guidelines, (3) training of large numbers of providers in PAC and LARCs, and (4) integration of LARCs within PAC into quality improvement and supervision tools and performance standards. Guinea has gradually scaled up provision of PAC services nationwide and its experience may offer learning opportunities for other countries; however, continued advocacy for further expansion to more rural areas of the country and among private health facilities is necessary.

Perspectives on maternal, infant, and young child nutrition and family planning: Considerations for rollout of integrated services in Mara and Kagera, Tanzania.

In Lake Zone, Tanzania, low contraceptive prevalence, closely spaced births, and child stunting are common. Synergies exist between postpartum family planning (PPFP) and maternal, infant, and young child nutrition (MIYCN), yet health services are often provided in silos. This qualitative formative research study aimed to identify barriers and facilitating factors for optimal nutrition and PPFP practices in Mara and Kagera, Tanzania. Results informed the program design of an integrated nutrition and family planning (FP) implementation approach. The study involved in-depth interviews with mothers of infants under 1 year (n = 24), grandmothers (n = 12), health providers (n = 6), and traditional birth attendants (n = 12), and 14 focus group discussions with community health workers, fathers, and community leaders. Findings reveal that breastfeeding initiation was often delayed, and prelacteal feeding was common. Respondents linked insufficient breast milk to inadequate maternal nutrition-in terms of the quality of the diet and small quantities of food consumed by mothers. Breast milk insufficiency was addressed through early introduction of foods and liquids. Mothers believed that breastfeeding prevents pregnancy, regardless of the frequency or duration of breastfeeding, yet were generally not aware of the lactational amenorrhea method (LAM) of FP. Joint decision-making on FP was viewed as important, and women often discussed it with their partner. Future programming should address misconceptions about return to fecundity knowledge gaps and concerns about FP methods including LAM; and perceptions regarding insufficient breast milk and early introduction of foods which are impediments to optimal MIYCN and FP practices.

The power of counseling: Changing maternal, infant, and young child nutrition and family planning practices in Dhamar, Yemen.

We conducted a study to determine current maternal, infant, and young child nutrition (MIYCN) and family planning (FP) practices and how practices can be improved with counseling. The study consisted of qualitative methods. Mothers and couples were able to attempt and adopt new practices after only one counseling visit, except consuming meat daily due to cost, and adopting contraception, which was challenging due to health system constraints. Most appreciated receiving information, reported positive experiences, and said they would continue practices. It is possible to improve these practices through counseling, although some systems factors should be addressed.

Characteristics of successful integrated family planning and maternal and child health services: Findings from a mixed-method, descriptive evaluation.

Background: Most postpartum women in low- and middle-income countries want to delay or avoid future pregnancies but are not using modern contraception. One promising strategy for increasing the use of postpartum family planning (PPFP) is integration with maternal, newborn and child health (MNCH) services. However, there is limited evidence on effective service integration strategies. We examine facilitators of and barriers to effective PPFP integration in MNCH services in Kenya and India.   Methods: We conducted a cross-sectional, mixed-method study in two counties in Kenya and two states in India. Data collection included surveying 215 MNCH clients and surveying or interviewing 82 health care providers and managers in 15 health facilities across the four sites. We analyzed data from each country separately. First, we analyzed quantitative data to assess the extent to which PPFP was integrated within MNCH services at each facility. Then we analyzed qualitative data and synthesized findings from both data sources to identify characteristics of well and poorly integrated facilities. Results: PPFP integration success varied by service delivery area, health facility, and country. Issues influencing the extent of integration included availability of physical space for PPFP services, health workforce composition and capacity, family planning commodities availability, duration and nature of support provided. Conclusions: Although integration level varied between health facilities, factors enabling and hindering PPFP integration were similar in India and Kenya. Better measures are needed to verify whether services are integrated as prescribed by national policies.

Contraceptive implant failures among women using antiretroviral therapy in western Kenya: a retrospective cohort study.

Background: Women living with HIV have the right to choose whether, when and how many children to have. Access to antiretroviral therapy (ART) and contraceptives, including implants, continues to increase due to a multitude of efforts. In Kenya, 4.8% of adults are living with HIV, and in 2017, 54% were receiving an efavirenz-based ART regimen. Meanwhile, 16.1% of all Kenyan married (and 10.4% of unmarried) women used implants. Studies have reported drug interactions leading to contraceptive failures among implant users on ART. This retrospective record review aimed to determine unintentional pregnancy rates among women 15-49 years of age, living with HIV and concurrently using implants and ART in western Kenya between 2011 and 2015. Methods: We reviewed charts of women with more than three months of concurrent implant and ART use. Implant failure was defined as implant removal due to pregnancy or birth after implant placement, but prior to scheduled removal date. The incidence of unintended pregnancy was calculated by woman-years at risk, assuming a constant rate. Results: Data from 1,152 charts were abstracted, resulting in 1,190 implant and ART combinations. We identified 115 pregnancies, yielding a pregnancy incidence rate of 6.32 (5.27-7.59), with 9.26 among ETG and 4.74 among LNG implant users, respectively. No pregnancies were recorded among women on non-NNRTI-based regimens, whereas pregnancy rates for efavirenz and nevirapine-containing regimens were similar, at 6.41 (4.70-8.73) and 6.44 (5.13-8.07), respectively. Conclusions: Our findings highlight the implications of drug interaction on women's choices for contraception.

Counseling at all contacts for postpartum contraceptive use: can paper-based tools help community health workers improve continuity of care? A qualitative study from Ethiopia.

Background: Globally, there has been a resurgence of interest in postpartum family planning (PPFP) to advance reproductive health outcomes. Few programs have systematically utilized all contacts a woman and her baby have with the health system, from pregnancy through the first year postpartum, to promote PPFP. Nested into a larger study covering two districts, this study assessed the use, acceptability, and feasibility of tools for tracking women's decision-making and use of PPFP in the community health system in Oromia region, Ethiopia. Community-level tracking tools included a modified Integrated Maternal and Child Health (IMCH) card with new PPFP content, and a newly developed tool for pregnant and postpartum women for use by Women Development Armies (WDAs). Proper completion of the tools was monitored during supervision visits. Methods: In-depth interviews and focus group discussions were conducted with health officials, health extension workers, and volunteers. A total of 34 audio-files were transcribed and translated into English, double-coded using MAXQDA, and analyzed using a thematic approach. Results: The results describe how HEWs used the modified IMCH card to track women's decision making through the continuum of care, to assess pregnancy risk and to strengthen client-provider interaction. Supervision data demonstrated how well HEWs completed the modified IMCH card. The WDA tool was intended to promote PPFP and encourage multiple contacts with facilities from pregnancy to extended postpartum period. HEWs have reservations about the engagement of WDAs and their use of the WDA tool. Conclusions: To conclude, the IMCH card improves counseling practices through the continuum of care and is acceptable and feasible to apply. Some elements have been incorporated into a revised national tool and can serve as example for other low-income countries with similar community health systems. Further study is warranted to determine how to engage WDAs in promoting PPFP.

Postpartum family planning integration with maternal, newborn and child health services: a cross-sectional analysis of client flow patterns in India and Kenya.

OBJECTIVES: Maternal, newborn and child health (MNCH) services represent opportunities to integrate postpartum family planning (PPFP). Objectives were to determine levels of MNCH-family planning (FP) integration and associations between integration, client characteristics and service delivery factors in facilities that received programmatic PPFP support. DESIGN AND SETTING: Cross-sectional client flow assessment conducted during May-July 2014, over 5 days at 10 purposively selected public sector facilities in India (4 hospitals) and Kenya (2 hospitals and 4 health centres). PARTICIPANTS: 2158 client visits tracked (1294 India; 864 Kenya). Women aged 18 or older accessing services while pregnant and/or with a child under 2 years. INTERVENTIONS: PPFP/postpartum intrauterine device-Bihar, India (2012-2013); Jharkhand, India (2009-2014); Embu, Kenya (2006-2010). Maternal, infant and young child nutrition/FP integration-Bondo, Kenya (2011-2014). PRIMARY OUTCOME MEASURES: Proportion of visits where clients received integrated MNCH-FP services, client characteristics as predictors of MNCH-FP integration and MNCH-FP integration as predictor of length of time spent at facility. RESULTS: Levels of MNCH-FP integration varied widely across facilities (5.3% to 63.0%), as did proportion of clients receiving MNCH-FP integrated services by service area. Clients travelling 30-59 min were half as likely to receive integrated services versus those travelling under 30 min (OR 0.5, 95% CI 0.4 to 0.7, P<0.001). Clients receiving MNCH-FP services (vs MNCH services only) spent an average of 10.5 min longer at the facility (95% CI -0.1 to 21.9, not statistically significant). CONCLUSIONS: Findings suggest importance of focused programmatic support for integration by MNCH service area. FP integration was highest in areas receiving specific support. Integration does not seem to impose an undue burden on clients in terms of time spent at the facility. Clients living furthest from facilities are least likely to receive integrated services.

Maximizing Opportunities: Family Planning and Maternal, Infant, and Young Child Nutrition Integration in Bondo Sub-County, Kenya.

Purpose This article shares learning from an innovative demonstration program integrating maternal, infant, and young child nutrition (MIYCN) and family planning (FP) services in western Kenya, providing recommendations for future work to expand MIYCN and FP integration. Description Six health facilities reorganized to integrate MIYCN and FP services and community health volunteers (CHVs) promoted MIYCN and FP in adjacent communities in Bondo Sub-County over a 1-year period. At the facility level, each provider was directed to provide both sets of services in a single room during FP, antenatal care, postnatal care, or child consultation visits (a "one stop shop" approach). At community level, CHVs were to conduct household visits equipped with new integrated materials and incorporate MIYCN and FP within community activities. Assessment Although the "one stop shop" approach, where one provider offers all integrated services in one room, was initially proposed for all facilities, this worked most effectively in the dispensary and health centers. The sub-county hospital adapted the approach such that integrated services were offered by more than one provider during a visit, with clients linked from one provider to another through same-day intra-facility referrals. CHVs were generally able to incorporate MIYCN and FP content within household visits and community activities; however some knowledge gaps were noted after initial training, necessitating additional refresher training. Conclusion This demonstration experience revealed that future replication efforts should enable sub-county team leadership, assess facility readiness, streamline data collection, build local buy-in, and prioritize dispensaries and health centers with high client loads.

A facility birth can be the time to start family planning: postpartum intrauterine device experiences from six countries.

Initiation of family planning at the time of birth is opportune, since few women in low-resource settings who give birth in a facility return for further care. Postpartum family planning (PPFP) and postpartum intrauterine device (PPIUD) services were integrated into maternal care in six low- and middle-income countries, applying an insertion technique developed in Paraguay. Facilities with high delivery volume were selected to integrate PPFP/PPIUD services into routine care. Effective PPFP/PPIUD integration requires training and mentoring those providers assisting women at the time of birth. Ongoing monitoring generated data for advocacy. The percentages of PPIUD acceptors ranged from 2.3% of women counseled in Pakistan to 5.8% in the Philippines. Rates of complications among women returning for follow-up were low. Expulsion rates were 3.7% in Pakistan, 3.6% in Ethiopia, and 1.7% in Guinea and the Philippines. Infection rates did not exceed 1.3%, and three countries recorded no cases. Offering PPFP/PPIUD at birth improves access to contraception.

Missed opportunities for family planning: an analysis of pregnancy risk and contraceptive method use among postpartum women in 21 low- and middle-income countries.

OBJECTIVES: To analyze data from recent Demographic and Health Surveys (DHS) conducted in 21 low- and middle-income countries (LMICs) to examine patterns of interpregnancy intervals, unmet need, pregnancy risk and family planning method use and method mix among women 0-23 months postpartum. STUDY DESIGN: Secondary analysis of postpartum women aged 15-49 years in 22 DHS surveys from 21 LMICs conducted between 2005 and 2012. We applied an adapted unmet need definition for postpartum women to look at prospective fertility preferences. We also constructed a new composite pregnancy risk indicator for postpartum women who have been sexually active since their last birth. RESULTS: In 9 of 22 surveys, 50% or more of nonfirst births occur at interpregnancy intervals that are too short. Overall prospective unmet need for family planning by postpartum women has not changed demonstrably since a 2001 analysis and is universally high: 61% of all postpartum women across the 21 countries have an unmet need for family planning. In 10 of 22 surveys, pregnancy risk rises steadily throughout the 2 years after birth. In the remaining 12 surveys, the risk of pregnancy peaks at 6-11 months after birth. Even when postpartum women are using family planning, they rely overwhelmingly on short-acting methods (51-96% in 21 of 22 surveys). CONCLUSION: Our approach of estimating pregnancy risk by postpartum timing confirms a high probability for pregnancies to be less than optimally spaced within 2 years of a prior birth and suggests that special consideration is needed to effectively reach this population with the right messages and services. IMPLICATIONS: Using recent, multicountry data for women within 2 years postpartum in LMICs, this paper updates existing estimates of high prospective unmet need for family planning and presents a new composite pregnancy risk analysis based on postpartum women's actual practices to demonstrate the magnitude of missed opportunities for programmatic intervention for the postpartum population.

Successful proof of concept of family planning and immunization integration in Liberia.

Globally, unmet need for postpartum family planning remains high, while immunization services are among the most wide-reaching and equitable interventions. Given overlapping time frames, integrating these services provides an opportunity to leverage existing health visits to offer women more comprehensive services. From March through November 2012, Liberia's government, with support from the Maternal and Child Health Integrated Program (MCHIP), piloted an integrated family planning and immunization model at 10 health facilities in Bong and Lofa counties. Vaccinators provided mothers bringing infants for routine immunization with targeted family planning and immunization messages and same-day referrals to co-located family planning services. In February 2013, we compared service statistics for family planning and immunization during the pilot against the previous year's statistics. We also conducted in-depth interviews with service providers and other personnel and focus group discussions with clients. Results showed that referral acceptance across the facilities varied from 10% to 45% per month, on average. Over 80% of referral acceptors completed the family planning visit that day, of whom over 90% accepted a contraceptive method that day. The total number of new contraceptive users at participating facilities increased by 73% in Bong and by 90% in Lofa. Women referred from immunization who accepted family planning that day accounted for 44% and 34% of total new contraceptive users in Bong and Lofa, respectively. In Lofa, pilot sites administered 35% more Penta 1 and 21% more Penta 3 doses during the pilot period compared with the same period of the previous year, while Penta 1 and Penta 3 administration decreased in non-pilot facilities. In Bong, there was little difference in the number of Penta 1 and Penta 3 doses administered between pilot and non-pilot facilities. In both counties, Penta 1 to Penta 3 dropout rates increased at pilot sites but not in non-pilot facilities, possibly due to higher than average background dropout rates at pilot sites prior to the intervention in Lofa and the disproportionate effect of data from 1 large facility in Bong. The project provided considerable basic support to assess this proof of concept. However, results suggest that introducing a simple model that is minimally disruptive to existing immunization service delivery can facilitate integration. The model is currently being scaled-up to other counties in Liberia, which could potentially contribute to increased postpartum contraceptive uptake, leading to longer birth intervals and improved health outcomes for children and mothers.

Findings from the use of a narrative story and leaflet to influence shifts along the behavior change continuum toward postpartum contraceptive uptake in Sylhet District, Bangladesh.

OBJECTIVES: Postpartum women face uncertainty about timing of return to fecundity. Many women wait to use contraception until menses return, resulting in unintended pregnancies. This study explored the use of behavior change communication to address perceptions of postpartum return to fecundity and contraceptive adoption. METHODS: This study, which took place in Sylhet District in Bangladesh, explored knowledge and perceptions about postpartum return to fecundity and used the Steps to Behavior Change framework to assess the reported influence of a leaflet and fictional story ("Asma's Story") incorporated within community health activities. The study relied on in- depth interviews and focus group discussions. RESULTS: The study revealed nearly universal exposure to Asma's Story. Reported shifts in perceived susceptibility to pregnancy, benefits of pregnancy spacing, and increased social support for postpartum family planning (PPFP) were noted. However, only approximately one third of women were using a modern contraceptive method. CONCLUSIONS: Using a fictional story offers a promising approach for motivating shifts along the continuum. PRACTICE IMPLICATIONS: It is recommended that Asma's Story be incorporated within future efforts to scale up PPFP in Bangladesh, and that similar approaches be tailored and tested in other countries.