GBM) are at increased risk of hepatitis C/HIV co‐infection. In Australia, the availability of subsidized direct‐acting antiviral treatment for hepatitis C has rendered eliminating co‐infection possible. High reinfection rates in subgroups with continued exposure may compromise elimination efforts. To inform the development of hepatitis C risk reduction support in GBM, we explored reinfection risk perceptions and attitudes among GBM living with HIV recently cured from hepatitis C.Gay and bisexual men (HIV primary care services in Melbourne following successful hepatitis C treatment. In‐depth interviews were conducted exploring understandings of hepatitis C risks, experiences of co‐infection and attitudes towards reinfection. Constructivist grounded theory guided data aggregation.Between April and August 2017, 15 GBM living with diagnosed HIV were recruited from high caseload HIV disease dichotomies:Hepatitis C and  Hepatitis C diagnosis was a shock to most participants and contrasted with feelings of inevitability associated with HIV seroconversion. While HIV was normalized, hepatitis C was experienced as highly stigmatizing. Despite injecting drug use, interviewees did not identify with populations typically at risk of hepatitis C. Risk environments and avoiding reinfection: Interviewees identified their social and sexual networks as risk‐perpetuating environments where drug use was ubiquitous and higher risk sex was common. Avoiding these risk environments to avoid reinfection resulted in community disengagement, leaving many feeling socially isolated. Hepatitis C care as a catalyst for change: Engagement in hepatitis C care contributed to a better understanding of hepatitis C risks. Interviewees were committed to applying their improved competencies around transmission risk reduction to avoid reinfection. Interviewees also considered hepatitis C care as a catalyst to reduce their drug use.Participants’ understandings of their hepatitis C infection and reinfection trajectories were captured in three categories. HIV co‐infection among GBM cannot be understood in isolation from co‐occurring drug use and sex, nor as separate from their HIV infection. Hepatitis C prevention must address subcultural heterogeneity and the intersectionality between multiple stigmatized social identities. Hepatitis C care presents an opportunity to provide support beyond cure. Peer support networks could mitigate social capital loss following a commitment to behaviour change and reduce hepatitis C reinfection risks.Hepatitis C/ This methodology assumes the social construction of reality and aims to maintain participants’ voice in producing a conceptual interpretation of the social processes under study 2.2We adopted a consecutive sampling strategy of all eligible participants who attended post‐HCV treatment visits (SVR12 or SVR24) between April and August 2017 at three high caseload HIV clinics in Melbourne. Eligibility criteria included male gender, self‐identifying as gay or bisexual, living with diagnosed HIV and having recently completed DAA treatment and achieved HCV cure . Interested participants were telephoned by the first author to arrange face‐to‐face interviews in mutually convenient locations. Of the 22 eligible men who presented to the clinic over the recruitment period, 17 agreed to be interviewed but two were later unavailable, resulting in a total of 15 interviews.2.3We developed a semi‐structured interview schedule by reviewing literature, drawing on the expertise of HCV and HIV researchers and consulting GBM researchers. The schedule was pilot tested with two GBM community members living with HIV. Questions focused on HCV awareness and experiences of HCV care, living with HCV/HIV co‐infection and participants’ understanding of and attitudes towards HCV reinfection risk. Prior to being interviewed, a written informed consent was obtained from all participants. Interviews took a median of 63 minutes (range 30 to 80 minutes), were digitally recorded and complemented by interviewer field notes. In accordance with standard research practice, participants were reimbursed AUD40 for their time and expertise.2.4The first author transcribed each interview verbatim and preliminary inductive analyses informed subsequent interviews. Identifying information was removed and pseudonyms assigned. Transcripts were uploaded into a qualitative software program (NVivo 11) for analysis. Following constructivist grounded theory methods The study was approved by the Alfred Hospital Ethics Committee.33.1Fifteen participants, aged 26 to 60 years median 46 years), were interviewed. With the exception of one participant who identified as bisexual, all participants identified as gay. Participants had been living with diagnosed HIV for a median time of 15 years (range 2 to 29 years). Diagnostic HCV testing was prompted primarily by irregularities in liver function which was assessed as part of HIV management. The median time since HCV diagnosis was seven years (range one to twenty‐three years). Twelve participants had used illicit drugs in their lifetime and 10 reported ever injecting drugs; these characteristics broadly reflect the characteristics of the co‐EC cohort  years, w3.2I'd already come to terms with [HIV] before I was diagnosed. I was like cool, the way that I'm living my life at the moment it's going to happen… I've always known that it wasn't so much a death sentence as a treatable disease.Interviewees commonly used HIV as a point of comparison when describing their experiences with HCV. Despite lingering stigma, participants perceived HIV as normalized within the gay community and a manageable illness. Several interviewees discussed that an HIV diagnosis “means nothing these days”  and those more recently diagnosed had accepted HIV infection as an inevitable consequence of their lifestyles:In the gay community there's a lot of hype about HIV and protecting yourself but there wasn't really much about hep C so I was a bit ignorant of it.It was suggested that prevention messages among gay men are generally focused on HIV at the expense of other threats to wellbeing, including HCV. As Michael (48) pointed out: a taboo thing  resulting from HCV‐related stigma and a lack of information about sexual transmission risks:I knew that [hepatitis] C existed and was one that injecting drug users tended to have, but I thought that was more associated with heroin users who were desperate and sharing needles.Since being diagnosed with HIV most had limited their sexual networks to other PLHIV and HIV disclosure formed a natural – albeit uncomfortable – part of sexual negotiations. In contrast, HCV was experienced as It was bad enough when I found out I was HIV positive but when I found out that I had hep C… I felt disgusted, like I was a disease, and judged, and felt dirty and gross… and where did I catch it from?The HCV diagnosis came as a shock to almost everyone and evoked feelings of shame, which interviewees associated with contracting a virus they perceived as more stigmatizing than HIV. The contrasting responses between HCV diagnosis and HIV infection illustrated community stigma around injecting drug use and PWID which extended to internalized stigma and label avoidance:I perceived it as not really a risk worth being concerned about or mentioning unless you're doing the activities that you believe are at risk [for HCV transmission], which is sharing drugs or needles.Despite injecting drug use being prevalent – six participants reported currently injecting – a preference for using stimulants in sexual and/or party settings was used by participants to distinguish themselves from more stereotypical injecting drug users outside of the gay community whom they perceived as being at risk of HCV infection. As a result of risk perceptions centred largely on the sharing of needles by people who inject drugs, HCV did not feature in the interviewees’ general risk analyses:I was very confused [when diagnosed with HCV]. The closest running theory I've got is that it was somehow transmitted sexually. Because I didn't start injecting until I was already diagnosed.To make sense of their diagnosis, some blamed a lack of awareness of risk reduction strategies related to sharing other drug paraphernalia, but most pointed to sexual HCV exposure as their likely mode of transmission:3.3My idea of the gay community got replaced by this, the whole public that use drugs. Which is probably half the reason I'm fearful for kind of getting back into that because I'm still not sure how to be sober within that.Multiple interviewees attributed their HCV acquisition primarily to associating with peers in high‐risk environments rather than their personal engagement in risk behaviours. Gay community venues and the sexual and social networks of interviewees were portrayed as risk‐perpetuating environments, where higher risk sexual practices were common and drug use was perceived as ubiquitous:It kind of becomes this thing where you no longer know whether you're looking for sex for the sex or whether you're looking for sex for the drug. Interviewees commonly described being introduced to methamphetamine or invited to inject the drug by a sexual partner. Some participants described seeking out people with similar drug habits, in part to avoid judgement and negative self‐appraisal resulting from the social unacceptability of methamphetamine use, and spoke about selecting sexual partners to facilitate drug use: I was pretty lonely…But I had to stay in (at home) and I knew it . Those who maintained relationships within drug‐using networks were mindful of the challenges these environments presented:I've been clean since [the beginning of HCV treatment]. So it's been pretty good but hard, only because now I gotta change my circle of friends again because… it's difficult, they'll be still using when I'm with them.Interviewees who used methamphetamines spoke about being rejected by friends who disapproved of these practices. Lifestyle changes catalysed by HCV treatment therefore resulted in periods of loneliness and isolation as interviewees disengaged from drug‐using social networks: 3.4one less thing to deal with . While the availability of effective HCV treatment made some participants less concerned about the implications (of reinfection) , everyone expressed commitment to staying HCV‐free. This was partially motivated by the fear of being labelled an injecting drug user and having to disclose HCV:In a way I'm glad the stigma does stick with me in the sense that I don't want to have the stigma of having it. I don't want to have the stigma if that [my partner] and I were no longer going out with each other it would mean I'd have to get back on that merry‐go‐round (of disclosure). And I don't want to get reinfected. Participation in the co‐EC trial was described as an opportunity to cure a life‐threatening illness and reducing anticipated stigma, accompanied by the relief of having people that have had hep C and finished the treatment…are more open about it once they don't have it anymore , but discussing HCV with sexual partners was described as challenging:Now I've been asking people [about hep C] and some people get a bit offended. … I go, “I wasn't making it sound like you were a user, it was just in case.” We're still gonna use a condom anyway, it's just one of those precautions.Engagement in HCV care contributed to improved competencies around HCV transmission risk reduction. Interviewees said they intended to ask prospective sexual partners about their HCV serostatus and avoid condomless, mucosally abrasive sex with partners whose HCV serostatus was unknown and who were known to be injecting drugs. It was observed that set me up with supports that I could use to change my life…if I wanted to change my life, now would be a good time to do it because I'm gonna have a lot of knowledgeable people in it who will support me through things.[The treatment] That's why I wanted to stop using [drugs]. I'm too scared, in case I get reinfected. Because to me that would be a waste of time.Beyond motivating an enhanced awareness and practice of harm minimization, several interviewees described their engagement in HCV care as a catalyst for more significant changes that resulted in reducing their use of methamphetamines and engagement in sexualized drug use:Because I've stopped using besides the occasional relapse it's clear that I don't want ice (methamphetamine) in my life. So that makes it much easier [to avoid reinfection], because I'll be much less in any circle, close to circles at higher risk.For some, HCV reinfection was framed in terms of a failure to maintain abstinence. They perceived risk as rooted in drug‐using social environments and prevention strategies therefore centred on avoiding certain social networks to circumvent drug exposure and temptation to use:I like to communicate all this stuff with people that also do the same drug. That way we make things safer for ourselves. Interviewees who continued to use methamphetamines expressed confidence about practising better drug‐related risk reduction. Some regarded themselves as advocates for peer education within drug‐using networks: 4We explored the experiences, attitudes and beliefs of GBM living with diagnosed HIV who had recently been treated and cured of HCV. Participants typically described a lack of acknowledgement of HCV and associated risk which was fuelled by an “othering” of HCV as a disease belonging to heroin injectors and related specifically to injecting risk. Their lack of awareness of sexual transmission of HCV, which is how most believed they acquired the virus, resulted in participants blaming their infection on a combination of lack of awareness, high‐risk environments and sexual networks, rather than their personal engagement in risk behaviours. The explicit connection made by participants between HCV exposure in sexual environments and ‘sexualized’ drug use resulted in participants framing their desire to avoid reinfection in the context of maintaining abstinence from drugs and disengaging from drug‐using social networks. In this way, GBM shared commonalities with PWID in terms of acknowledging the need to modify drug‐using behaviours to avoid HCV reinfection. However, the desire of GBM to avoid drug use – beyond some participants being at a stage of maturing out of drug use – was related to its association with sexual risk as opposed to injecting‐related risk. These insights suggest that strategies aimed at reducing post‐treatment HCV reinfections among GBM must address a range of factors that characterize HCV risk environments for GBM, including the use of drugs as both direct and indirect drivers of transmission.The lack of HCV knowledge and awareness – in particular among drug‐injecting GBM – may seem surprising, as GBM in Australia are generally described as risk aware in the context of HIV Interviewees reported seeking out people similar to them in terms of HIV serostatus and drug use which may reflect a form of psychological risk management to avoid anticipated stigma and negative self‐perception When discussing HCV risk reduction practices with GBM living with diagnosed HIV, healthcare providers should consider several social factors. The potential conflict between a wish to maintain a lifestyle that reduces health risks and fear of social isolation as a result of risk management may present a considerable challenge to reinfection avoidance. While the literature reports good community support for GBM living with diagnosed HIV 5There are some limitations to this study. The potential for social acceptability bias must be acknowledged, with some participants possibly describing their commitment to HCV reinfection avoidance more positively. Similarly, interviewer bias may have led participants to be less open about their experiences in front of a young, heterosexual woman; however, being interviewed by an outsider may have allowed others to speak more freely. Furthermore, our sample was comprised only of GBM engaged in HIV care who had already undergone HCV treatment, possibly excluding members of the population at higher risk of ongoing HCV transmission whose attitudes might differ. Finally, the limited time available to conduct this study did not allow the theoretical sampling period typically included in grounded theory studies 6This study illustrates that HCV infection among GBM is experienced as both a behavioural and social outcome. Our findings suggest that adoption and reduction in risk behaviours emerges from the complex interplay between individuals and the  environments they find themselves in, as well as personal motivations and individual ability to identify and act upon specific risks. HCV prevention campaigns tailored towards GBM living with diagnosed HIV need to take account of the multiplicity of transmission risks in the context of sexualized drug use and the intersectionality of multiple stigmatized social identities. Engagement in HCV care presents an important opportunity to provide support beyond curing HCV and could be pivotal in facilitating the behaviour change necessary to achieve elimination targets. GBM choosing to disengage from their communities as a form of risk management may be stifled by a loss of social capital which could present a long‐term barrier to avoiding HCV reinfection. Healthcare practitioners providing treatment support should be mindful of this potential conflict between a desire to remain HCV uninfected and in control of drug use and a wish for belonging and social integration. Establishing supportive peer networks among GBM with a shared experience of HCV infection could alleviate social capital loss and mitigate HCV reinfection risks.The co‐EC study was funded by an investigator initiated research grant from Bristol Myers Squibb. JD and MH's institution receives investigator initiated research funding from Abbvie, Merck, Gilead Sciences and Bristol Myers Squibb. JD and his institution have received consultancy fee/honoraria from AbbVie, Merck, Gilead Sciences and Bristol Myers Squibb. PH receives investigator initiated research funding from Gilead Sciences and Abbvie for research not related to this study. The authors declare no other potential conflicts of interest.All authors have read and approved the final manuscript. S.S., P.H., M.S. and J.D. performed the research. M.S., J.D., M.H. and S.S. designed the research study. P.H., G.B. and A.P. contributed to the development of the interview schedule. R.W. coordinated and facilitated the recruitment. S.S., M.S. and P.H. analysed the data. S.S. and M.S. were primary writers of the paper.


Mother's Milk Substitutes  Act in order to regulate the sale, distribution and promotion of substitutes for breastmilk within Nepal, in an effort to protect and promote breastfeeding. Helen Keller International, in collaboration with Nepal's Ministry of Health and Population's Child Health Division, implemented a study to assess mothers' exposure to promotions for and utilization of breastmilk substitutes in Kathmandu Valley, Nepal. A health facility‐based, cross‐sectional survey was conducted among 304 mothers being discharged after delivery. Prelacteal feeding of breastmilk substitutes is prevalent . Reported recommendations during antenatal checks and after delivery from health professionals to use breastmilk substitutes were prevalent, occurring among 47.4% (n = 144) of mothers; rates of these recommendations were significantly higher for mothers that delivered in private health facilities, as compared with public . Mothers that received a recommendation to use a breastmilk substitute from a health worker were 16.7 times more likely to provide a prelacteal feed of a breastmilk substitute, as compared with mothers that did not receive a recommendation (P < 0.001). Few mothers reported observation of commercial advertisements for breastmilk substitutes inside a health facility (reported by 3.6% of mothers). No mothers reported receiving a sample of a breastmilk substitute, bottle or teat from a health professional. More information is needed to determine why there is such a high rate of health worker recommendations for breastmilk substitute use in the first few days after delivery.In 1992, Nepal passed the While utilization of breastmilk substitutes is low among mothers of young children in Nepal, prelacteal feeding of breastmilk substitutes is highly prevalent in Kathmandu Valley.Reported recommendations from health professionals to use breastmilk substitutes are common (over 40%) and are associated with prelacteal feeding among Nepal mothers included in this study.Provision of lactation management training to health workers and monitoring their practices regularly could strengthen breastfeeding counselling, aid in reducing high rates of prelacteal feeding and contribute to improved infant feeding practices. The initiation of breastfeeding within the first hour after delivery is associated with the reduced risk of neonatal morbidity and mortality  Act. The Act was passed to regulate the sale, distribution and promotion of substitutes for breastmilk within Nepal, including breastmilk substitutes and ‘any other such food or beverage marketed or otherwise distributed as is suitable for feeding to the infant’  products . Informed consent was obtained from all participants prior to the conducting of any interview.Approval for this study was obtained from the Nepal Health Research Council prior to data collection.The questionnaire collected data on mothers' and newborns' characteristics, including mother's age, marital status, caste, educational attainment, household assets and drinking water source, details regarding antenatal care and delivery of the newborn, and the newborn's date of birth, gender and birth order. Data on breastfeeding initiation, prelacteal feeding and current breastfeeding practices for the newborn were also collected. Data to assess these infant and young child feeding practices were gathered in accordance with the World Health Organization guidelines on IYCF practices WHO . Mothersvia tablets, using the Android application Open Data Kit (ODK) Collect, and data were then submitted online to a web‐based database (Formhub.org 2013). The questionnaires were translated from English into Nepali, back translated into English to ensure accuracy, and uploaded into Formhub in Nepali. Interviews were conducted in Nepali using the Samsung Galaxy tab 2.07 model tablet. Submitted questionnaires were reviewed weekly to ensure data quality.Data were collected using a mobile technology system in order to allow for immediate data entry, reduction in data errors, and prompt analyses. The questionnaires were designed in Microsoft Word and then entered in Formhub, an open‐source online platform that allowed data to be collected spss version 21  and stata version 11 . Proportions and mean ± standard deviation were used to describe the sample. Differences in age categories and associations were assessed through bivariate comparison, using two‐sided Pearson's chi‐square test for proportions and through multivariate analysis, using logistic regression.Data were cleaned and analyzed using This study defined breastmilk substitutes to include infant/starter formula (to be used from birth up to 6 months of age), follow‐up formula (to be used from 6 months to 12 months), infant/follow‐up formula for special dietary or medical purposes, growing‐up milk (to be used from 12 months to 36 months) and other milk or milk‐like products (in liquid or powdered form) marketed or otherwise represented as suitable for feeding children younger than 6 years of age. Mothers were also asked to report brands of breastmilk substitutes mentioned in order to verify that these products fit this definition.Commercial promotions were defined as any type of marketing technique intended to increase sales, including media or print advertising, provision of free samples or any other activity to encourage or induce the purchase of a product  P = 0.494.Multivariate logistic regression was conducted to assess the impact of variables shown to influence prelacteal feeding of breastmilk substitutes among mothers during bivariate analysis. Covariates included in the model were mother's age in years, attainment of secondary or higher level of education, vaginal vs. caesarean delivery and receipt of a recommendation from a health worker to use breastmilk substitutes. The model was also adjusted for cluster sampling. Goodness‐of‐fit for this model was determined through the Hosmer–Lemeshow test, with a significance of n = 189) of mothers reported their newborn to be their only child. Among those that were currently married, 14.5% (n = 44) of mothers reported that their husband currently worked outside of Kathmandu. Ninety per cent of mothers had attended any level of formal education and 19.1% (n = 58) of mothers reported attending university or higher graduate studies. Only 15.1% (n = 46) of mothers reported currently working outside the home.Demographic and socioeconomic characteristics for mothers of newborns discharged after delivery are shown in Table n = 171) of the newborns included in this survey were male. The mean age of newborns referred to in interviews with mothers discharged after delivery was 2.2 days. Almost all mothers had received some antenatal care (ANC) during pregnancy with their newborn; 93.7% of women living in urban Nepal had received ANC according to the most recent Nepal Demographic and Health Survey (NDHS)  MOHP . ApproxiHS) MOHP .A comparison of these characteristics to the 2011 NDHS indicates that the mothers included in this study are of a slightly higher socioeconomic status than general women in urban Nepal. Seventy per cent of mothers in this study had achieved an educational level of secondary school or higher, as compared with 63.7% of urban Nepal women, and only 7.6% of mother included in the survey had never attended school, as compared with 22.0% of women living in urban Nepal MOHP . Househovia C‐section, as compared with 24.0% of mothers from public maternity wards (P = 0.004).Several differences in demographic and socioeconomic characteristics were found when comparing mothers attending public vs. private health facilities in Kathmandu Valley. Ownership of refrigerators, motorbikes and cars was higher among mothers attending private health facilities, as compared with those attending public facilities (data not shown). Mothers attending private facilities reported higher rates of C‐section deliveries as compared with mothers attending public facilities; 40.6% of mothers from private maternity wards delivered Information was gathered from participants in order to assess mothers' experience of advice and counselling within health facilities that would support and encourage optimal breastfeeding and complementary feeding practices. Mothers discharged after delivery in a maternity ward were asked about their exposure to breastfeeding counselling and messages throughout their pregnancy and during delivery (results are shown in Table n = 35) reported receiving breastfeeding information during an ANC visit. The most commonly reported breastfeeding messages received among these mothers were related to promotion of exclusive breastfeeding and early initiation of breastfeeding. Messages regarding the risks of feeding infant formula, the risks of feeding other foods/liquids before 6 months, and increasing breastfeeding during and after illness were the least commonly reported information received by mothers. Approximately two‐thirds  of mothers reported receiving assistance in positioning and/or attachment for breastfeeding from a health worker after delivery of their newborn. Rates of assistance with positioning/attachment were significantly higher in private health facilities as compared with public .Among mothers discharged after delivery who received ANC during this pregnancy, 11.6%  received a recommendation from a health professional, either during pregnancy or just after delivery, to feed their newborn breastmilk substitutes. The majority of these mothers reported recommendations by health professionals to use a breastmilk substitute in the first 3 days after delivery of their youngest child; health professional recommendations to use infant formula for prelacteal feeding were reported by 40.8% (n = 124) of mothers. Nurses made the majority of recommendations  for breastmilk substitutes to mothers, with doctors accounting for the remaining recommendations. Rates of breastmilk substitute recommendations from health professionals were significantly higher for mothers that delivered in private health facilities, as compared with public . Among those that received a health professional recommendation to feed their newborn breastmilk substitute, around one‐third  of mothers were recommended to feed a specific brand of breastmilk substitute. The majority of these brand recommendations were for Nestle Lactogen, accounting for 91.2% (n = 31) of brand recommendations.Recommendations for breastmilk substitute use by health professionals were commonly reported by mothers that had been discharged after delivery. Nearly half  of mothers discharged after delivery reported seeing, hearing or reading such an advertisement within a health facility during pregnancy or since delivery of their newborn. Slightly more mothers attending public health facilities  reported observation of a breastmilk substitute advertisement within a health facility, as compared with those attending private facilities ; however, this difference was not significant (P = 0.165). Nine of the 10 health facility advertisements reported were for Nestle Lactogen brand. Mothers reporting observations of breastmilk substitute or commercially produced complementary food branding or logos on health facility equipment or materials were also rare, reported by 15 (4.9%) of the 304 mothers. Almost all cases of observed branding were reported to have occurred on posters displayed in a health facility.Observation of commercial advertisements for breastmilk substitutes within the health system was not common among mothers interviewed; only 3.6%  and 26 (8.6%) mothers reported receiving a gift of diapers or baby clothes, respectively, from a health professional. However, none of the mothers reported any commercial product branding present on these gifts.n = 124) initiated breastfeeding early, defined as within one hour after delivery (WHO n = 109), as compared with private . Immediate initiation of skin‐to‐skin contact with the newborn was low, occurring among less than 9% (n = 26) of mothers who had just delivered. Prelacteal feeding, referring to the provision of liquids other than breastmilk in the first 3 days after delivery, was prevalent, with over half of mothers discharged after delivery reporting prelacteal feeding for their newborn. Rates of prelacteal feeding among mothers discharged after delivery in public facilities  were found to be significantly lower, as compared with private facilities . Additionally, more mothers who delivered by C‐section reported provided a prelacteal feed, as compared with mothers who delivered vaginally .Breastfeeding initiation and practices by mothers soon after delivery were documented among mothers (findings are shown in Table very WHO . Early in = 170) of mothers discharged after delivery who practiced prelacteal feeding fed their newborn a breastmilk substitute. Plain water (not bottled) was the second most common liquid used for prelacteal feeding; however, this was only reported among 4.1% (n = 7) of discharged mothers. Approximately three‐quarters  of mothers who gave a breastmilk substitute as a prelacteal feed reported using Nestle Lactogen brand, while approximately one‐quarter  fed their newborn Wockhardt Farex brand. Almost all  mothers that fed a breastmilk substitute in the first 3 days after delivery obtained the breastmilk substitute by purchase, vs. receiving it for free or from another mother in the delivery ward. As detailed previously, health professionals, specifically doctors and nurses, were reported as recommending breastmilk substitutes by the majority of mothers who practiced prelacteal feeding.Among mothers who gave their newborn something to drink other than breastmilk in the first 3 days after delivery, breastmilk substitute was the most commonly used liquid for prelacteal feeding. Ninety‐nine per cent (n = 101) of mothers who provided breastmilk substitutes as a prelacteal feed reported having not wanted breastmilk substitutes fed to their newborn. The most common reasons mothers reported were related to their own breastmilk supply. Over half of mothers that gave a prelacteal feed  reported using a breastmilk substitute because their own breastmilk supply was low and around one‐third  reported prelacteal feeding a breastmilk substitute because their breastmilk had not yet come in. There was no statistical association between particular reasons mothers reported using a breastmilk substitute as a prelacteal feed and their receipt of a health worker's recommendation to use breastmilk substitute (data not shown). Mothers who reported that they thought their own breastmilk supply was low were asked why they believe this was so; the majority of these mothers reported their own breastmilk supply as low because of their poor health or nutrition. Several  also reported that lactation is generally poor on the first day after delivery, and some  reported their milk supply to be low because it was their first child.Although prelacteal feeding of breastmilk substitutes was high among mothers interviewed, many mothers reported that this was not actually what they wanted for their newborn. Nearly two‐thirds  of discharged mothers who received a recommendation to use a breastmilk substitute from a health professional reported feeding a prelacteal, as compared with 26.9% (n = 43) of discharged mothers who did not receive a health professional's recommendation (P < 0.001).In bivariate analyses, 88.2% . Mothers that reported receiving a health professional's recommendation to use a breastmilk substitute were 16.7 times more likely to provide this product as a prelacteal feed to their newborns as compared with mothers that did not receive a recommendation (P < 0.001).Results of multivariate analysis are shown in Table Study findings suggest that almost half of women residing in Kathmandu Valley who give birth in one of eight large health facilities in Kathmandu Valley receive a recommendation from a health professional to use a breastmilk substitute during their pregnancy or since delivery. Those receiving such a recommendation and/or who give birth by C‐section are 8.8 to 16.7 times more likely to feed their newborn a breastmilk substitute as a prelacteal. Mothers' exposure to commercial advertisements promoting breastmilk substitutes within the health system was low.Mother's Milk Substitutes Act states that ‘health workers shall not allow any act inhibiting the commencement and expansion of breastfeeding, whether directly or indirectly’ and Clause 9.5 prohibits promotion by manufacturers within any health facilities  reported receiving a recommendation from a health professional during pregnancy or since delivery to feed their newborn a breastmilk substitute.Clause 8.3 of Nepal's n = 170) of mothers at discharge after delivery reported feeding their youngest child a breastmilk substitute in the first 3 days after delivery. Despite increasing rates of early initiation of breastfeeding, the practise of prelacteal feeding is prevalent among mothers in Nepal and has been increasing over the last decade , and mothers who delivered their newborn by C‐section reported higher rates of prelacteal feeding, as compared with mothers who delivered vaginally . Among mothers interviewed, rates of C‐section delivery were high, reaching almost 30%, which may be one contributing factor to the high rates of prelacteal feeding. Following this survey, additional qualitative interviews were conducted among clinical staff in nine Kathmandu Valley hospitals, during which many doctors and nurses reported difficulties with initiating breastfeeding soon after caesarean deliveries, including separation of mother and infant after surgery because such mothers recuperate in general wards and infants are not permitted there because risk of infection . Research has also found that early post‐partum skin‐to‐skin contact between mothers and newborns has a powerful influence over the duration of exclusive breastfeeding  of mothers discharged after delivery reported receiving such advice during their ANC visits. Increasing mothers' exposure to breastfeeding advice during antenatal care could ensure that messages regarding exclusive breastfeeding are heard before a child is born. Additionally, addressing mothers' fears about insufficient milk supply and health workers' misconceptions about milk production in the first few days after delivery, as well as emphasizing that colostrum is all a newborn needs in the first days of life, may help to reduce the early introduction of other foods or liquids.Findings from this survey also indicate that mothers' exposure to breastfeeding advice before delivery may be low in Kathmandu Valley; only 11.6% (et al. Lack of breastfeeding support skills and knowledge among health workers may result in mothers thinking their breastfeeding problems are because of a lack of milk and lead to health workers recommending infant formula. The provision of lactation management training, particularly around encouragement of early initiation of breastfeeding, early skin‐to‐skin contact, the importance of colostrum and introduction of complementary foods at 6 months, may bolster health workers' practical knowledge and skills and could reduce the high rates of prelacteal feeding and increase the duration of exclusive breastfeeding among mothers living in Kathmandu Valley. Additionally, given the high rate of caesarean section deliveries found in these Kathmandu Valley hospitals, specific breastfeeding counselling for mothers who have delivered by caesarean section would be beneficial. The reinforcement and expansion of the Baby Friendly Hospital Initiative may also improve breastfeeding counselling by increasing the number of trained hospital staff in Kathmandu Valley. Four hospitals in Kathmandu Valley were designated as BFHI in 1997–1998; however, a 2012 assessment showed that none were still fully compliant with the all BFHI criteria (Shrestha The main limitations of this study relate to the nature of conducting a facility‐based survey. The main objective of the study was to assess promotions within Kathmandu Valley's health system; therefore, interviews were conducted within health facilities in order to ensure access to a study population that was currently utilizing healthcare within this system. However, for assessment of early breastfeeding practices and utilization of breastmilk substitutes among the general population of Kathmandu Valley, this presented a limitation. These practices remain unknown among mothers who deliver at home; in 2011, 27.9% of women in urban Nepal reported delivering their last child at home MOHP . FinallyThis research was funded by the Bill & Melinda Gates Foundation.The authors have no conflicts of interest to declare.AP analyzed the data and prepared the manuscript. SH and EZ conceptualized and designed the study, with input from SU. MC oversaw questionnaire development and technology for data collection. IA and SD managed data collection. All authors reviewed and provided input on the final article.


PKNP) in Cambodia and to assess how these dynamics vary between community‐protected forests and a wider study area. Medium‐resolution Landsat, ALOS PALSAR data, and high‐resolution LiDAR data were used to study the spatial distribution of forest degradation patterns and their impacts on above‐ground biomass (AGB) changes. Analysis of the remotely sensing data acquired at different spatial resolutions revealed that between 2012 and 2015, the community forests had higher forest cover persistence and lower rates of forest cover loss compared to the entire study area. Furthermore, they faced lower encroachment from cashew plantations compared to the wider landscape. Four of the six community forests showed a recovery in canopy gap fractions and subsequently, an increase in the AGB stock. The levels of degradation decreased in forests that had an increase in AGB values. However, all community forests experienced an increase in understory damage as a result of selective tree removal, and the community forests with the sharpest increase in understory damage experienced AGB losses. This is the first time multitemporal high‐resolution LiDAR data have been used to analyze the impact of human‐induced forest degradation on forest structure and AGB. The findings of this work indicate that while community‐protected forests can improve conservation outcomes to some extent, more interventions are needed to curb the illegal selective logging of valuable timber trees.Community forests are known to play an important role in preserving forests in Cambodia, a country that has seen rapid deforestation in recent decades. The detailed evaluation of the ability of community‐protected forests to retain forest cover and prevent degradation in Cambodia will help to guide future conservation management. In this study, a combination of remotely sensing data was used to compare the temporal variation in forest structure for six different community forests located in the Phnom Kulen National Park ( Optical data such as those derived from Landsat have been extensively used for mapping temporal changes in forest cover and land use types in the tropics  and structure of six different community forests located in a National Park in Cambodia and assess how these dynamics vary between this community‐protected forests and the wider study area.to quantify the variation in Landsat‐derived forested areas in the study area and across the different community‐protected forests;to use a combination of LiDAR and Landsat data to map and monitor the changes in forest cover, cashew plantation, and bare soil from 2012 to 2015;to quantify the variation in LiDAR‐derived forest structure parameters (such as AGB) from 2012 to 2015; andto quantify the variation in the vegetation greenness and forest degradation for both the study area and the different community forests.The specific aims of this study are as follows:In addition to these, the impact of selective logging from 2012 to 2015 will be estimated by identifying tree height classes that have faced losses .It is expected that the findings of our research will help us to quantify the efficacy of community‐protected forests in preventing deforestation and facilitating regeneration (compared to the wider landscape) and their ability to curb the selective illegal logging of individual tree species. The countries of Greater Mekong region have high rates of deforestation resulting from factors ranging from plantation agriculture to selective logging, with the latter being more difficult to detect  is located 48km from Siem Reap in northwestern Cambodia Figure . It is aOver recent decades, Cambodia has experienced some of the highest rates of deforestation globally  and Khlah Khmum (CPA‐KK: 3.06 km2). Aside from the two CPAs, Archaeological‐Protected Areas (APAs) have also been created within PKNP to protect vulnerable archaeological sites and forests from destructive agricultural practices and to build awareness in the local population about the natural environment and historical heritage , Khlah Khmum (APA‐KK: 0.94 km2), Rong Chen (APA‐RC: 3.98 km2), and Thma Dap (APA‐TD: 1.48 km2). While the establishment of the CPAs and APAs was driven by slightly different motives, the management plans of both the community forest types seek to prevent forest loss within their bounds and reduce human encroachment.Community‐protected areas (CPAs) were established in different parts of PKNP 2001 onwards with assistance from the Food and Agriculture Organization (FAO). The purpose of these CPAs was to promote the participation of local communities in forest conservation and allow the recovery of forest resources. The study area under consideration is a 32 km2.2Field survey was conducted in March 2016 and during this the geo‐locations of the different land cover types, including, forests, cashew plantations and bare earth were collected. The standard FAO definitions of forests  was used; “land of at least 0.5 ha covered by trees higher than 5 m and with a canopy cover of more than 10%, or by trees able to reach these thresholds, and predominantly under forest land use”  for March 2011–2015 were downloaded from Earth Explorer. The month of Landsat data acquisition was selected to match the season of LiDAR data acquisition. Raw Landsat data were converted to surface reflectance by applying both radiometric and atmospheric correction to these data through the freely available software CLASlite  , which is a commonly used indicator of vegetation greenness and health. More degraded ecosystems have lower values of NDVI  while vegetation returns were used to generate a Canopy Height Model (CHM) giving the upper boundary of the canopy  were computed from the LiDAR data of 2012 and 2015. This metric helps to map the impact of logging roads, skid trails, and landings. It is a raster layer indicating the percentage of LiDAR returns within a user‐specified above‐ground height category  have been provided in Table In addition to tree heights and crown areas, there was a statistically significant difference in the percentage gap fraction from 2012 to 2015 for all the community forests except APA‐TD. The gap fractions show signs of recovery in all the APAs except the CPAs and have increased slightly in the CPAs. Some of the AGB values decline in community forests while others increase .In addition to the analysis of the variation in LiDAR‐derived forest canopy structure, ALOS PALSAR and Landsat data were also used to derive measures of forest degradation (RFDI) and green vegetation concentration (NDVI) across the community forests in the two time periods Table .NDVI was significantly different for all the community‐protected areas between 2012 and 2015, and it increased by 29.6%, 17%, 18.2%, 20.3%, 22.6%, and 24.1% for APA‐KK, APA‐NT, APA‐RC, APA‐TD, CPA‐KK, and CPA‐AT, respectively, indicating an increase in greenness of all community forests. RFDI was significantly different between 2012 and 2015 for APA‐NT, APA‐RC, CPA‐AT, and CPA‐KK. For both CPA‐AT and CPA‐KK, the RFDI increased by 4.17% and 3.7%, respectively, indicating a slight increase in forest degradation. RFDI of APA‐NT decreased by 3.2%, indicating a decline in forest degradation.3.3Visual inspection of the LiDAR‐derived CHM shows that individual canopy trees that were present in 2012 are no longer present in 2015 in the differently selected community forests Figure :Loss of individual trees in different community forests took place across the different tree height classes. CPA‐AT lost 3.46% trees with heights less than 10m. APA‐KK lost 4.5% trees in the height category 20–30 m and 3.15% trees in the height category 30–40 m. APA‐TD lost 5.12% and 5.7% of trees in categories 20–30 m and 30–40 m, respectively. The RDM values declined for all the community forests from 2012 to 2015 .44.1Analysis of the Landsat‐based binary forest–nonforest map revealed that all the community forests have much higher level persistence of forest cover persistence (72%–99%) compared to the wider landscape, where more than 20% of forest cover was lost in these three years. However, binary forest cover maps are unable to distinguish between different forest types, including plantation monocultures .While the AGB of the APAs has increased considerably from 2012 to 2015, it has undergone a slight decline in the CPAs . Previous research has established that regenerating forests can accumulate a large amount of carbon  to help distinguish between the different forest classes  also revealed that all community forests had faced an increase in understory damage caused by skidding and haulage, which are the hallmarks of selective logging for specific tree species  to conduct a detailed analysis of forest cover retention and biodiversity conservation benefits provided by different protection and management schemes, including community forests and strict nature reserves.A meta‐scale study of the community forests in South and South‐East Asia revealed that community forests have had a positive impact on improving tree species biodiversity and forest biomass production , the problem of selective logging of luxury hardwoods still persists within them. The removal of large trees can have an adverse impact on the AGB stocks and trees with DBH>70cm have a considerable impact on the AGB stocks of the different tropical forests across the globe . The levels of degradation decreased in forests that saw an increase in AGB values. While community forests have been shown to facilitate prevent cashew plantation expansion, forest cover persistence and recovery from degradation, illegal selective logging of individual tree species were not entirely curtailed within their boundaries. Analysis of LiDAR data indicates that all community forests experienced an increase in understory damage as a result of increased skidding and haulage . Community forests with the sharpest increase in understory damage underwent AGB losses. An examination of individual trees identified by LiDAR data for 2012 and 2015 indicated a slight decline in the number of trees for the different classes. On the basis of these findings, it may be recommended that community‐protected forests can produce robust conservation outcomes in terms of forest cover persistence but more interventions are needed to curb the illegal selective logging of valuable timber trees.The authors declare no conflict of interest.Minerva Singh: Analyzed the data and wrote the manuscript. Damian Evans: Preprocessed the LiDAR data and helped to edit the manuscript. JB Chevance: Helped with fieldwork, provide study area details and edited the manuscript. Helped with study design. Mr. Nick Wiggins : Collection of field data and study design. Ms. Leaksmy Kong: Collection of field data and study design. Mr. Sakhoeun Sakada : GIS assistance and field data help. Dr. Boun Suy Tan : Facilitated the field study and study area historyhttps://doi.org/10.5061/dryad.nt7kg5g).Data availability statement: Raw aerial data were generated through the Cambodian Archaeological LiDAR Initiative. Derived data supporting the findings of this study are present in the manuscript itself. The corresponding author [M.S.] will provide additional clarifications on request. Relevant data available via Dryad ( Click here for additional data file.


Results were replicated in an independent dataset (49 SVD with confluent WMH cases and 108 SVD controls) with SVD patients having a similar SVD phenotype to that of the discovery cases. Rich club organisation was examined in structural networks derived from DTI followed by deterministic tractography. Structural networks in SVD patients were less dense with lower network strength and efficiency. Reduced connectivity was found in SVD, which was preferentially located in the connectivity between the rich club nodes rather than in the feeder and peripheral connections, a finding confirmed in both datasets. In discovery dataset, lower rich club connectivity was associated with lower scores on psychomotor speed  and executive functions . These results suggest that SVD is characterized by abnormal connectivity between rich club hubs in SVD and provide evidence that abnormal rich club organisation might contribute to the development of cognitive impairment in SVD. Hum Brain Mapp 38:1751–1766, 2017. © 2017 Wiley Periodicals, Inc.Cerebral small vessel disease (SVD) is an important cause of vascular cognitive impairment. Recent studies have demonstrated that structural connectivity of brain networks in SVD is disrupted. However, little is known about the extent and location of the reduced connectivity in SVD. Here they investigate the rich club organisation—a set of highly connected and interconnected regions—and investigate whether there is preferential rich club disruption in SVD. Diffusion tensor imaging (DTI) and cognitive assessment were performed in a discovery sample of SVD patients ( Cerebral small vessel disease (SVD) is an important cause of vascular cognitive impairment and vascular dementia [Roman et al., Brain networks are comprised of a few selective central regions with a high number of connections  that also show evidence of ‘rich club’ properties. This refers to the presence of a clique of highly connected nodes  that furthermore strongly connect to each other, often over physically long distances [Van den Heuvel et al., In this article we analyse rich clubs in patients with SVD to increase our understanding of the SVD‐related pathophysiology. Building on the previous work showing reduced network efficiency in SVD which correlates with cognitive impairment [Lawrence et al., n = 115) enrolled in the St George's Cognition and Neuroimaging in Stroke (SCANS) study [Lawrence et al., n = 50) recruited to the St. George's Neuropsychology and Imaging in Elderly (GENIE) study [Charlton et al., n = 49) with a phenotype identical to those patients in SCANS were recruited, that is, inclusion criteria were a clinical lacunar stroke syndrome as well as confluent white matter hyperintensities  [Fazekas et al., n = 108).Two datasets were included in this study. The discovery dataset comprised all baseline data from SVD patients (n = 165) and the replication dataset (n = 157) are shown in Table The characteristics of the discovery dataset n = 65 and thz‐scores across groups of related tasks were produced. Premorbid IQ was estimated using the National Adult Reading Test—Revised (NART‐R). NART‐R error scores were converted to estimated full‐scale IQ scores (NART‐IQ). Executive function and processing speed was calculated as previously described [Lawrence et al., The results of the cognitive data is only reported for SVD patients because cognitive assessments used in the GENIE study from which the control group was obtained were not comparable. Testing was performed at least 3 months post‐stroke to minimise acute effects of stroke on performance. Tests comprised previously published, widely‐used tasks chosen to characterise reported cognitive impairment in SVD [Charlton et al., Psychomotor speed was calculated as the mean of the z‐scores of the 1‐letter subtask of the Paper‐Pencil Memory Scanning Task, the reading subtask of the Stroop test and the Symbol‐Digit Substitution Task [Tuladhar et al., 3), 4 unweighted scans and 25 non‐collinear diffusion gradient directions at b = 1,000 s/mm2 in positive and negative diffusion gradient directions.MR images were acquired at St George's University of London using a 1.5T Signa HDxt MRI system , which included an axial fluid‐attenuated inversion recovery (FLAIR), coronal spoiled gradient recalled echo 3‐dimensional T1‐weighted, axial single shot diffusion‐weighted spin echo planar imaging with isotropic voxels .MR images were acquired on a 1.5 Tesla Siemens Magneton Sonata scanner  and included T1‐weighted 3D magnetization‐prepared rapid gradient‐echo (MPRAGE) imaging, a FLAIR sequence and a DTI sequence . WMH were manually segmented and lacunes were counted by a trained rater [Lawrence et al., Similarly, WMH were manually delineated and lacunes were counted by a trained rater. Brain volume was calculated as a sum of grey and white matter volume using automated segmentation procedure in SPM5 on a T1‐weighted image and normalized to the total intracranial volume to adjust for the head size [Tuladhar et al., 3) using in‐house software [Lawrence et al., DW‐MRIs were corrected for eddy current distortions using FSL toolbox and DTI were calculated. Whole‐brain deterministic tractography was performed at super‐resolution (0.5 mmhttp://www.trackvis.org). The tracking algorithm started at the centre of the voxels with fractional anisotropy greater than 0.15 and ended when the fibre tracks left the brain mask, encountered voxels with fractional anisotropy less than 0.15 or when the turning angle exceeded 60°. These turning angles and FA thresholds were used in the replication dataset in order to achieve similar number of constructed streamlines between the dataset due to the tractography at super‐resolution in the discovery dataset.DW‐MRI was corrected for cardiac and head motion artefacts as well as eddy currents using ‘PATCH’ Zwiers, . Whole‐bFor both datasets, brain regions were parcellated in each subject using the Automatic Anatomical Label (AAL) template [Tzourio‐Mazoyer et al., Two regions were considered connected if the endpoints of a tractography streamline were located within the pair of brain regions. Connection strengths were estimated based on a modified method of Hagmann and colleagues [Hagmann et al., n = 100) with the same size and degree distribution using Brain Connectivity Toolbox.Graph theoretical measures were calculated from the structural network using the Brain Connectivity Toolbox [Rubinov and Sporns, The rich club coefficient is measured as the ratio between the sum of the weights of the edges connecting a subset of nodes (exceeding a certain degree‐threshold) and the sum of the weights of the strongest connections of the total network. The rich club coefficients were then normalised by dividing by the averaged rich club coefficients of a set of random networks (with the same size and degree distribution). A network with a normalized rich club coefficient exceeding 1 is considered as a network with a rich club organisation. Rich club coefficients were estimated using weighted network connections [Van den Heuvel and Sporns, For analysis of the rich club in SVD we selected the top 8 highest degree nodes (top 9% of the nodes) averaged across both groups. The node degree was calculated by taking the mean observed average degree for each node across subjects from both groups. Other selection procedures of rich club nodes were also evaluated to test whether results were independent of the methods used: (1) defining the rich club nodes based on a group‐averaged network, comprising edges present in at least 30% of the group and 2) the selection of top 8 highest ranking degree nodes calculated per‐subject . The selection of top 8 highest ranking nodes was based on previous reports [Collin et al.,  the selet‐tests because of the unequal sample sizes. Since the control group was age‐ and sex‐matched, we did not additionally correct for age and sex. Permutation testing  was used to create a null distribution of the largest cluster size, which then used to calculate the family‐wise error p‐corrected value. Finally, multiple regression analyses were performed to examine the relation between rich club connectivity and cognitive functions, while adjusted for the effects of confounding factors . To establish mediation, we performed Sobel tests, in which the z‐score represents a test of statistical significance for the indirect (mediated) relationship between the outcome and the potentially mediated variable given a potential mediator. Variance inflation factors were calculated to examine whether multicollinearity was present in the models. Multicollinearity was considered if the variance inflation factor was above five.WMH volumes and the number of lacunes were log‐transformed to obtain a normal distribution. Differences in network measures between the control and SVD group were examined for statistical significance using Welch's independent P < 0.001, df = 106.5), total network strength , global efficiency  and local efficiency  compared with the networks of control group  and executive function , adjusted for age, sex and NART‐IQ.Both SVD and control networks showed a right skewed degree distribution Fig. A, which oup Fig. C. GlobalP < 0.001, df = 78.2), total network strength , global efficiency  and local efficiency , compared with the control group. Global efficiency was associated with psychomotor speed , adjusted for age, sex and education.Similar results were found for the replication dataset Fig. . Both SVP = 0.022; 10,000 permutations). SVD patients showed 37.0% reduction in the connectivity strength of the rich club connections , 20.7% reduction in feeder and peripheral connections  relative to the control groups , whereas the reductions for the feeder and peripheral connection strengths were not significant. Also, these differences remained significant after controlling for brain volume (to account for brain atrophy).The 8 nodes (≈9%) with the highest degree averaged across both groups were selected as the rich club nodes. The top 8 most connected brain regions of the discovery dataset were bilateral precuneus, bilateral putamen, left medial superior occipital gyrus, left medial superior frontal gyrus, right thalamus and right dorsal superior frontal gyrus Fig. A. The peP < 0.001, df = 84.5) and rich club/peripheral connection .Given the differential reduction in rich club connection strength, we tested for group differences in the ratio of rich‐club to feeder and of rich club to peripheral connection strengths [Van den Heuvel et al., P < 0.001, df = 73), 30.6% reduction in feeder  and 25% reduction in peripheral connections . Compared with the control group, SVD patients showed significantly lower ratios for rich club/feeder (P < 0.001) and rich club/peripheral connection (P < 0.001).The results were comparable when using the streamline count normalized for the ROI volume as the weighting procedure for edges. SVD patients showed 41.4% reduction in the connectivity strength of the rich club connections (P < 0.001), 22.9% reduction in feeder connections (P < 0.001) and 20.6% reduction in peripheral connections relative to the group (P < 0.001). In addition, selecting the rich club nodes on basis of individual networks, set at the threshold of top ≈9% of the highest degree nodes  showed similar results: 26.9% reductions in rich club connections (P < 0.001), 20.5% in feeder connections (P < 0.001) and 21.3% in peripheral connections (P < 0.001).Additional analyses were performed using different selection methods of rich club nodes to examine the robustness of the results independent of the methods used. Similar results were found when the rich club nodes were selected on basis of the group‐average network: 27.5% reduction in rich club connections . The SVD group showed 25.4% reduction in rich club connections relative to the control group , 12.0% reduction in feeder connections  and 10.8% reduction in peripheral connections  .The top 8 most connected brain regions of the replication dataset were bilateral precuneus, bilateral putamen, bilateral dorsal superior frontal gyrus, right medial superior occipital gyrus and left thalamus left Fig. C, comparP < 0.001), and marginally significant for peripheral connections (P = 0.077). These results suggest that the vulnerability of the rich club to SVD effects is independent of the longer fibre length found in the rich club.Rich club connections are on average physically longer than feeder or peripheral connections [Van den Heuvel et al., β = 0.28, P < 0.001). Further adjusting for WMH or lacunes reduced the variance explained, but coefficients remained significant . Higher WMH and higher lacunes were associated with lower scores on processing speed adjusted for age, sex, NART‐IQ . A significant indirect effect indicated that rich club connection strength mediated the association between WMH and processing speed , while a marginally significant indirect effect was seen for the association between lacunes and processing speed mediated by rich club connection strength . Higher rich club connection strength was associated with better scores on executive function , which was also significant after adjusting for WMH . Higher WMH was not associated with lower scores on executive function , while higher lacune count was associated with lower scores on executive function . However, the explained variance of rich club connection strength on executive function was reduced after controlling for lacune count and was not significant  and likewise no mediation effect was observed for the association between lacune count and executive function.In the SVD group, higher connection strength of the rich club connections was associated with better scores on processing speed adjusted for age, sex, NART‐IQ ; perhaps reflecting the smaller sample size (n = 45 due to missing data for psychomotor speed).In the SVD cases the direction of effect and coefficient value of the association between rich club connection strength and psychomotor speed were comparable to that seen in the discovery dataset, although this did not reach significance . An important question for future research is the time course of network disruption in SVD. It might be that impairment of the rich club connections occurs preferentially with secondary mild impairments of feeder/peripheral connections. Another possibility is that impaired feeder or peripheral connections might be present in the early stages of the disease without evident clinical symptoms, until the rich club connections are affected due to the progression of the disease which then produces clinical overt symptoms [Crossley et al., The association between the rich club connection strength and cognitive impairment provides evidence for a possible link between the rich club (dis)organisation and the occurrence of cognitive impairment in symptomatic SVD. This is further corroborated by a recent study showing that central network connections, which were based on edge betweenness centrality, were related to cognitive impairment in SVD [Reijmer et al., Several studies have shown that rich club network is also altered in other brain disorders including neuropsychiatric disorders, such as schizophrenia [Collin et al., P < 0.001) and that the number of lacunes was marginally significant with the rich club connection strength (P = 0.064), while WMH or lacunes was not associated with non‐rich club connections , which reduced statistical power for testing within group associations with cognitive performance.Another limitation is the differences in preprocessing methodology between the two datasets, which reduce the control over experimental factors and exclude a systematic investigation of different processing methods. Such differences might be expected to reduce similarities between findings from the two datasets; however we found very similar patterns of rich club disorganisation in the two cohorts of SVD cases. Another consideration is the selection of the rich club nodes: we base our main findings on a rich club defined from the 8 nodes with the highest average degree (across both patient and control participants). Other methods can be used and were evaluated in this study: identification of rich club nodes based on a group‐averaged network [De Reus and Van den Heuvel, SVD represents a broad phenotype ranging from asymptomatic WMH in community populations to symptomatic patients with severe radiological disease and symptomatic lacunar stroke and/or vascular cognitive impairment. We chose a group with a well‐defined phenotype, namely radiologically confirmed lacunar stroke and confluent WMH. It is likely similar findings will apply to other phenotypes of SVD but this needs confirming in further studies.In conclusion, this study provides a novel perspective on how SVD disrupts brain network organisation. Rich club connections are a fundamental motif in brain networks and are thought to be key for the integration of information among distributed network modules. In SVD the connections of the rich club were disproportionally impaired and associated with cognitive impairment. Further longitudinal research is needed to examine how and whether the changes of white matter connectivity, including the investigation of the rich club properties, are related to clinical deterioration in SVD patients.


We conducted a virtual randomized phase III trial stratified by age to compare the effectiveness of lobectomy and SABR for medically operable patients with stage IA (AJCC eighth) NSCLC using the Markov model analysis.Although the choice between stereotactic ablative radiotherapy A Markov model was developed to simulate a cohort of patients aged 45–85 years with stage IA NSCLC who had undergone either lobectomy or SABR and were followed up for their remaining lifetime. Each virtual patient was randomly assigned to undergo lobectomy or SABR, and 10 000 patients were allocated to each group. All estimates of the variables were obtained by a systematic review of published articles.P = 0.0689).The lobectomy group showed a better life expectancy than the SABR group, in patients under 75 years of age. However, no statistically significant difference was seen in patients 75 years or older. The predicted life expectancy was 9.43 and 8.70 years in 75‐year‐old patients in the lobectomy and SABR groups, respectively. However, the 95%CI for the difference in life expectancy between the two groups was ‐ 0.06–1.50 years (The Markov model showed no statistically significant difference in the expected overall survival in stage IA NSCLC patients who were older than 75 years and had undergone SABR or lobectomy. P = 0.037).Lobectomy with sampling or dissection of mediastinal lymph nodes is the standard of care for early‐stage non‐small cell lung cancer (NSCLC). In the past decade, stereotactic ablative radiotherapy (SABR) has emerged as the preferred treatment for medically inoperable and operable early‐stage NSCLC.A Markov cohort model was developed to simulate a cohort of patients aged 45–85 years with stage IA NSCLC who had undergone either lobectomy or SABR and were followed‐up over a time period of their remaining life expectancy Fig . InclusiFor this Markov model, 22 states of health were defined, nine for patients undergoing lobectomy and 13 for those treated with SABR. From the initial state, patients were randomized to undergo lobectomy or SABR  while keeping the other parameters constant. A two‐way sensitivity analysis was performed to evaluate the effect of the simultaneous change in two variables. To evaluate the uncertainty associated with parameter estimation, we performed a second‐order Monte Carlo probabilistic sensitivity analysis.We selected all articles published as abstracts or full papers in English from 2000 to September 2018 in peer‐reviewed journals that assessed a survival benefit or tumor response after lobectomy or SABR for the primary treatment for NSCLC less than 3 cm in size without lymph node or distant metastasis. Studies were identified by searching MEDLINE on PubMed using ‘lung cancer’ as the key text word in combination with ‘SABR’, ‘SBRT’, ‘stereotactic radiotherapy’, ‘surgery’ or ‘lobectomy’. The technique of lobectomy includes both video‐assisted thoracic surgery (VATS) and open lobectomy. The literature on SABR with low BEDs of less than 100 Gy or tumors located centrally were excluded. All estimates of the variables used in this model were obtained by a systematic review of published articles .The procedure‐related mortality rate for lobectomy was 90 days. The post‐treatment mortality after surgery and parameters by age group were extracted from the Stokes’ study.During follow‐up, some patients with locoregional recurrence were considered as candidates for salvage treatment. Although various treatment modalities could be applied for locoregional control, it was assumed that lobectomy would be performed for local recurrence after SABR, while radiotherapy would be performed for regional recurrence after lobectomy or SABR to simplify the Markov model. Solitary distant metastasis or secondary primary lung cancer also could be re‐treated with SABR or surgery. However, our tumor board determined that the likelihood of either of these procedures affecting the outcome would be low because the probability of occurrence is unknown, could fall within a very wide range and be similar in both groups.In the literature, 21–49% of patients with locoregional recurrence who had been treated with lobectomy or SABR for the primary NSCLC were treated with salvage treatment.Each outcome in the average was weighed by the number of patients in the articles to calculate an overall representative value for each component.We evaluated the validity of our Markov model by comparing the overall survival we obtained with those from previously reported studies that investigated NSCLC patients with tumors smaller than 3 cm. Predicted survival curves were created from our Markov model, and the survival outcomes of real studies were marked as points on the survival curves.For a systematic review of parameter estimation, validation of the Markov model and to discuss the overall scenario, we organized a small tumor board composed of a radiation oncologist, thoracic surgeon, and a pulmonologist.The predicted life expectancies by five year age windows at diagnosis are shown in Table P = 0.0689).The mean differences and 95% confidence intervals (CIs) for the difference in the estimated life expectancies between the lobectomy and SABR groups are shown in Table A sensitivity analysis was performed for the group of 75‐year‐old patients. The tornado diagrams in Figure A two‐way sensitivity analysis demonstrated that the patients with a 1% probability of disease progression after lobectomy or SABR, had the same life expectancy when other variable values remained constant at preset values Fig c. If theFigure et al. used a population‐based registry to conduct a matched‐pair analysis of overall survival after surgery versus SABR for elderly patients (age > 75 years). Similar overall survival outcomes were achieved with surgery or SABR for stage I NSCLC in elderly patients. The three year overall survival has been reported to be 75% and 60% after surgery, and 87% and 42% after SBRT, respectively (log‐rank P = 0.22).et al. also reported similar outcomes in the older age group. The Surveillance, Epidemiology, and End Results database linked to Medicare was used to determine the baseline characteristics and outcomes of 9093 patients with early‐stage, node‐negative NSCLC who underwent lobectomy or SABR. Propensity score‐matching analysis of well‐matched SABR and lobectomy cohorts demonstrated similar overall survival in both groups . The median age in this study was 75 years.et al. analyzed two clinical trials and seven cohort studies matched by propensity scores to compare the efficacy of SABR and lobectomy in stage I NSCLC. This meta‐analysis revealed significant benefits of lobectomy for three year overall survival . It is noteworthy that most studies except one had included patients with a mean age of under 75 years.et al. reported the superiority of lobectomy by analysis of a large cohort (4069 patients) database from the Veteran's Affairs system. The multivariable analysis considering long‐term survival found higher cancer‐specific mortality associated with SABR compared with lobectomy . The mean age of this cohort was also under 75 years.Lobectomy is undoubtedly the standard of care for operable early‐stage NSCLC in the current situation where there are no randomized trials comparing SABR with lobectomy. However, most of the previously reported studies on lobectomy included young patients with an average age of 65 years,et al. T2 lesions were associated with significantly increased local, regional, and distant recurrences compared to T1 lesions at three years (P = 0.02).Unlike current studies involving only T1 tumors, previously terminated randomized trials  and the presently recruiting randomized trials  included both T1 and T2 (AJCC eighth) tumors to compare the outcomes of surgical resection and SABR. When SABR is delivered with the planning target volume receiving BED more than 100 Gy, good local control is achieved in not only T1 but also T2 tumors. It results in local control in more than 90% of the tumors with very little acute or severe chronic toxicity.36894) an61) inclu and the 629458 thIn the present study, both VATS and open lobectomy were allowed. Clinicians who are of the opinion that the VATS and open lobectomy have similar outcomes might find this scenario disadvantageous for the lobectomy group because VATS may be associated with lower mortality than open lobectomy. Several meta‐analyses have shown no significant difference in the overall survival between VATS and open lobectomy for early NSCLC.There are several limitations to this study. First, we simplified the scenario for the convenience of handling the Markov model. In a real clinical situation, solitary distant metastasis or secondary primary lung cancer can also be retreated with SABR or surgery, but the scenario of our model did not reflect them. We limited the number of salvage treatments to just one since we could not find any reports of repetitive salvage treatments, though several salvage treatments are possible in the clinic. Although simplification of the model may result in a discrepancy between the estimated values and reality, since the probability of these factors is identical for both groups, they would have little impact on clarifying the difference of survival in the two groups. Second, it was difficult to extract some parameters because of a lack of studies reporting their outcomes. There are only a few studies reporting the probability of disease progression after radical salvage treatment for regional recurrence in stage IA NSCLC patients treated with SABR or lobectomy. Therefore, we extracted those parameters from studies of stage I to IIIA NSCLC treated with SABR or lobectomy Table . There iIn conclusion, for medically operable patients with stage IA NSCLC, our Markov model has verified that lobectomy is a preferred strategy for patients younger than 75 years, while for those older than 75 years there is no significant difference in the expected overall survival between SABR and lobectomy. Until the results of the randomized study are available in the future, we hope that the results of the present study can serve as the background and rationale for clinicians to plan treatment modalities in elderly patients with stage IA NSCLC. In addition, we recommend that age should be considered when designing future randomized studies.There was no funding support.We declare no competing interests. All authors are in agreement with the content of the manuscript.Young‐Seok Seo and Hak Jae Kim contributed to the conception and design of the study. Young‐Seok Seo, Hak Jae Kim, Sun Mi Choi, and Samina Park were responsible for data acquisition. Young‐Seok Seo and Hak Jae Kim analyzed the data. Young‐Seok Seo, Hak Jae Kim, Hong Gyun Wu, Sun Mi Choi, and Samina Park interpreted the data. Young‐Seok Seo and Hak Jae Kim prepared the first draft of the manuscript.Figure S1 One‐way sensitivity analysis of variables affecting survival following lobectomy versus SABR in 75‐year‐old patients. The tornado diagram shows that the probability of disease progression after lobectomy or SABR is an important factor that affects survival outcomes. SABR could be a preferred strategy if the probability of these two variables were changed beyond the threshold. Other variables did not change the preferred treatment option from lobectomy. SABR, stereotactic ablative radiotherapy; LR, local recurrence; RR, regional recurrence.Click here for additional data file.Table S1 Estimated values of the variables used for the Markov model extracted from the literature.Click here for additional data file.


These encouraging data show overall declines in both AIDS‐related deaths and new HIV infections worldwide Despite this progress, the optimism is tempered by concern that reducing HIV incidence rates must be further accelerated to guarantee epidemic control UNAIDS estimates that 44% of all new HIV infections among adults worldwide occur among key populations and their partners 2Evidence of the disproportionate epidemiological burden that members of key populations shoulder has been met with important policy developments and funding commitments. In 2014, the Global Fund to Fight AIDS, Tuberculosis and Malaria launched the Key Populations Action Plan, reflecting its commitment to help meet their HIV prevention, care and treatment needs and rights The President's Emergency Plan for AIDS Relief (PEPFAR) has also launched specific initiatives to expand key populations’ access to and retention in HIV services. Through programmes such as the Key Populations Challenge Fund, the Key Populations Implementation Science Initiative and the Local Capacity Initiative, PEPFAR supported work to understand and better serve key populations, as well as to strengthen capacity of key population‐led organizations to address the epidemic in their communities Finally, the UNAIDS HIV Prevention 2020 Roadmap deems combination prevention programmes for key populations necessary to accelerate declines in new HIV infections at country level. The Roadmap calls for combination prevention programmes that are evidence‐informed, community‐owned, and human rights‐based; implemented at scale; and tailored to the specific needs of key populations 3These commitments are critical to advancing a more effective response. However, progress translating commitments into improved outcomes for key populations has been hindered by persistent barriers, such as stigma (including self‐stigma), discrimination, and punitive legal and policy environments. In addition, the field faces ever‐present data challenges with key populations, who often do not self‐disclose their current or former status as key population members. Consequently, they may be included as members of the “general population” and their contribution to HIV transmission underreported and unrecognized. Alternatively, they may be connected to key population community services in one place but receive testing or treatment services anonymously in another, making it difficult for programmes to track and support clients across multiple service points.The limited population‐based data that are available show that testing and treatment coverage among key populations remains disproportionately low with no key population group close to achieving 90‐90‐90 targets The HIV prevention, care and treatment cascade has been globally adopted as a useful framework for guiding key population programming Figure  8. It caAchieving epidemic control will not be possible without more robust and rapid progress in delivering evidence‐based interventions that improve key populations’ access to and uptake of HIV services across the cascade. Fundamental to that progress is the generation and use of key population‐specific cascade data. The recently relaunched Key Populations Atlas from UNAIDS represents an important step in that direction 4Recognition of these needs has led to advances in monitoring key populations’ uptake of services across the cascade to identify “leaks” in the system, as well as more sophisticated analysis and use of data to identify solutions and strengthen programming As programming is scaled up globally, it is critical that we maximize public health impact by sharing the latest evidence of what works to engage key populations in targeted prevention, treatment, and retention programmes. The contents of this supplement represent high‐quality articles from a range of multidisciplinary efforts to advance key population science and practice across the cascade. They offer new evidence and data‐driven strategies for improving programming with MSM, sex workers, transgender people and PWID across diverse geographies. The supplement does not contain articles addressing prisoners as they require significantly different approaches from key populations in communities outside incarcerated settings.5Five of the papers in this supplement describe methods and analyses specific to key populations that can be used to refine and focus interventions. The data generated from these approaches are important to guide strategic planning, resource allocation and programme quality improvement initiatives.et al. in which the authors make the case for why we need better key population cascade data and how we can get it The supplement opens with a commentary by Hakim et al. presents a new methodology to estimate the contribution of onward HIV transmission among key populations to the overall HIV dynamic in Dakar, Senegal An article by Mukandavire et al. describe a partnership between PEPFAR and The Global Fund to conduct key populations cascade assessments To better refine key population programming at country level, Lillie et al. describe determinants of HIV service uptake among a global sample of MSM Using data collected from an online survey implemented through the gay social networking application, Hornet, Ayala et al. contribute the first estimates on the costs and cost‐effectiveness of providing oral PrEP for MSM in Thailand Finally, Suraratcheda 6et al. report data from two bio‐behavioural surveys in Malawi and Angola that illustrate the value of providing venue‐based outreach and testing services in “hotspots,” where people including MSM, FSWs and transgender people meet and seek sex partners The supplement features two articles that broaden our understanding of strategies for improving the reach of prevention services and uptake of HIV testing among previously unreached key population members. Herce et al. from Tajikistan compares the effectiveness of three network‐based approaches to recruitment and case finding among PWID A study by Kan 7et al. present the results of a pilot intervention to distribute oral HIV self‐testing kits to MSM through key opinion leaders in Lagos, Nigeria Recognizing that innovations in HIV testing options are needed to improve coverage, three articles in the supplement examine feasibility, acceptability, and effectiveness of new HIV testing modalities. Tun et al. explore HIV testing interventions through MSM lay providers and HIV self‐testing, promoted through online channels and face‐to‐face interactions In a study from Vietnam, Green et al. explore preferences among three different modalities of HIV testing including: (1) offline HIV counselling and testing; (2) online pre‐test counselling and offline HIV testing; and (3) online counselling and online, supervised, HIV self‐testing. The study demonstrated that online counselling coupled with online, supervised, HIV self‐testing is feasible and acceptable. In addition, the online strategy produced the highest proportion of first time testers (47.3%) and had the highest HIV prevalence (15.9%). Being a transgender woman and spending more than four hours per day on social media increased a participant's likelihood to self‐select for online counselling and HIV testing.A study from Thailand also demonstrates the promise of leveraging technology and self‐testing to improve reach and testing uptake among MSM and transgender women 8et al. report results from an evaluation of ‘Sisters with a Voice’, Zimbabwe's nationally scaled comprehensive programme for FSWs, following intensified community mobilization activities Two papers in the supplement report outcomes from large‐scale, key population‐led efforts to improve outcomes across the cascade. Ndori‐Mharadze et al. report on the expansion and tailoring of the Internet‐based self‐testing platform to increase HIV testing coverage among MSM in São Paulo, Brazil's largest metropolitan area with the highest number of new HIV infections.Results of an innovative HIV self‐testing component within a broader, community‐wide implementation science project in Curitiba, Brazil demonstrated feasibility and improved HIV diagnosis among young MSM who had not previously tested for HIV 9Due to the criminalized and stigmatized nature of key populations globally, sex workers, MSM, PWID and transgender people are often afraid to visit healthcare services and, when they do go, are reluctant to disclose their sexual histories for fear of rejection, derision or other negative reactions from providers et al. describe successful efforts to integrate violence prevention and response services into the national key population programme in Kenya Two papers in this supplement address structural barriers to better HIV‐related outcomes. Bhattacharjee et al. reflects on the evolution of the PLHIV Stigma Index, which at the end of 2017 had interviewed more than 100,000 PLHIV in 90 countries and key population‐related stigma, within the context of modern global testing and treatment guidelines. The updated tool was pilot‐tested through a community‐led process in Cameroon, Senegal and Uganda, and provides essential evidence and opportunities for communities in other countries to more effectively document stigma and advocate for and implement stigma mitigation interventions as part of human rights‐affirming HIV responses.A commentary by Friedland 10These papers provide much‐needed contributions to the evidence base for key population programming across the HIV prevention, care and treatment cascade. Our hope is that this supplement will compel funders, policymakers, implementers and other stakeholders to do more now to champion data‐driven programming. One common theme that emerges from this supplement is that we should establish and scale‐up innovative, community‐led services, while expanding the integration and options for key populations within the health system. In addition, we will not make sustainable improvements in outcomes if we do not better address the stigma, discrimination and violence that key populations experience at the hands of family, community members, health care providers and the state.As more evidence on key population programmes emerges, it is critical that the international community catalyse these advances with supportive policies that promote widespread uptake of effective approaches. Important studies are ongoing through the PEPFAR Key Populations Implementation Science and amfAR Implementation Science Grants initiatives, from which we anticipate more rich data designed to fill further gaps in our understanding of how to implement better services for key populations.After more than three decades in the fight against HIV, plans to end the HIV epidemic through goals such as UNAIDS 90‐90‐90 have been adopted by governments, major donors, and stakeholders globally. Investments to address the epidemic among key populations should be central to these efforts. With ever‐present threats of stigma, discrimination, violence, and other human rights abuses, the gains that have been made among key populations are precarious. The urgency of continuing to maintain focus on these groups cannot be understated. To leave no one behind, the substantial progress that has been made to date against the epidemic will need to be bolstered with rigorous, key population‐specific data collection and use, with partnerships focused on vigilance, courage, tolerance and commitment.The authors have no other funding or conflicts of interest to disclose.RCW, TB, GM and RW all contributed to the preparation of the first draft. All authors approved the final manuscript.This manuscript was supported by multiple agencies including the United States Agency for International Development (USAID) and the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) through the Linkages across the Continuum of HIV Services for Key Populations Affected by HIV project ; PEPFAR through the Centers for Disease Control and Prevention (CDC); and amfAR, the Foundation for AIDS Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of any of the funding agencies.