Background: Studies examining how the capacity of health facilities affect implementation of free healthcare policies in low and middle-income countries are limited.Objective: This study describes how the context and institutional capacity of health facilities influenced implementation of the free maternal and child health programme (FMCHP) in Enugu state, South-east Nigeria.Methods: We conducted a qualitative case study at the state level and in two health districts (Isi-Uzo and Enugu Metropolis) in Enugu State. Data were collected through document review and semi-structured, in-depth interviews with policymakers (n = 16), healthcare providers (n = 16) and health facility committee leaders (n = 12) guided by an existing capacity framework and analysed using a thematic framework approach.Results: The findings reveal that active health facility committees, changes in provider payment process, supportive supervision, drug revolving fund, availability of medical equipment, electronic data transmission and staff sanction system enhanced the capacity of health facilities to offer free healthcare. However, ineffective decentralisation, irregular supervision and weak citizen participation limited this capacity. Uncertain provider payment, evidence of tax payment policy and a co-existing fee-exempt scheme constrained health facilities in following the FMCHP guidelines. Poor recording and reporting skills and lack of support from district officials constrained providers’ adherence to claims’ submission timeline. Poor funding, weak drug supply system, inadequate infrastructure and lack of participatory decision-making constrained delivery of free healthcare. Insufficient trained workforce, mission-inconsistent postings and transfers, and weak staff disciplinary system limited the human resource capacity.Conclusions: Effectiveness of FMCHP at the health facility level depends on the extent of decentralisation, citizen participation, concurrent and conflictive policies, timely payment of providers, organisation of service delivery and human resources practices. Attention to these contextual and institutional factors will enhance responsiveness of health facilities, sustainability of free healthcare policies and progress towards universal health coverage. Many low and middle-income countries (LMICs) have adopted free healthcare policies to mitigate the negative impact of user fees on the poor, improve access to health services and accelerate progress towards universal health coverage and the sustainable development goals (SDGs) –3. That Growing evidence suggests that factors affecting the capacity of health facilities to implement free healthcare policies are context-sensitive. Use of service charters to curb informal payments to service providers , active Enugu State adopted the free maternal and child healthcare programme (FMCHP) in 2007, which removed user fees at the point of service delivery for pregnant women and under-five children based on a minimum services package . The FMCThe FMCHP is administered through a decentralized health system in which the State Ministry of Health (MOH) is organized into a Policy Development and Planning Directorate (PDPD) and State Health Board (SHB); and the state delineated into seven District Health Boards (DHBs) and 68 Local Health Authorities (LHAs) . The PDPEvidence indicates that the initial improvement on service utilization has not been sustainable, out-of-pocket payments are common, and the FMCHP does not seem pro-poor nor does it improve use of the public health system –42. The The purpose of this study was to examine how context and institutional capacity of health facilities affect implementation of FMCHP in Enugu, South-east Nigeria. Such evidence will help decision makers in Nigeria and similar settings to develop a governance model for strengthening the capacity of health facilities to offer free healthcare that contributes towards universal health coverage and the SDGs.The study was guided by the Hilderbrand and Grindle  CapacityThis study, which is part of a doctoral thesis that assessed the governance of FMCHP in Enugu State, Nigeria , took plThis study adopted a qualitative, case study design because experiences with implementation of the FMCHP are embedded in the context that formed the focus of inquiry ,48. The We categorised the seven health districts into two groups of three well-performing and four less-well-performing districts using provider payment data over five years (2009–2014), which ranged from 2% to 26% with a median of 14% serving as the cut-off point ,49. We uA semi-structured, in-depth interview guide, developed based on conceptual framework of this study, validated by two experts and adapted following analysis of pilot interviews, was used to conduct interviews. In total, 44 people were interviewed between February and September 2015  using thAdditional data were collected through document review. Thirteen documents, relevant to the research questions, were identified in consultation with key government officials (Appendix 2). The documents reviewed included policy documents, programme reports and memoranda on FMCHP.Data were analysed using a framework approach which involved coding the data, mapping and organising data under common themes, and interpretation . NVivo 1The Health Research Ethics Committee of the University of Nigeria Teaching Hospital Enugu, Nigeria, approved this study. All participants provided written informed consent.Five themes emerged from the study, namely action environment (three sub-themes), institutional context of public providers (three sub-themes), task network (two sub-themes), organisation (four sub-themes) and human resources (three sub-themes). Each sub-theme is further divided into two categories (enabling factor and constraints) as shown in Decentralisation, supervision and accountability emerged as key themes in the action environment.Despite the existence of district health system (DHS) policy, most policymakers and providers identified dysfunctional District Health Boards (DHBs) and District FMCHP Committees as constraints to providers’ capacity to offer free health care. Meetings of DHBs were rarely held. Quarterly review meetings that provided opportunities for review of FMCHP implementation were no longer held since 2012 due to irregular funding . A few policymakers and providers observed that Local Government monitoring and evaluation officers by-pass the district information office in data transmission from health facilities to the MOH. Most HFC leaders do not know about the DHBs’ activities, nor the existence of the District FMCHP Committee.Most policymakers and providers mentioned that supervision is supportive and offers opportunity for on-the-job capacity building, but it is irregular. In Isi-Uzo, all HFC leaders revealed that supervision by government officials is poor. ‘One hardly sees supervisors from the local government. The occasional supervisors we see are those of SURE-P and PATHS2 (development partners)’ (HFC leader 4). Some HFC leaders in Enugu Metropolis mentioned that providers receive routine quarterly supervision. Conversely, some HFC leaders in Enugu Metropolis stated that ‘they (supervisors) do not even visit most of the health centres that are within accessible areas’ (HFC leader 11). Though vehicles were provided to districts to enhance supervision, the districts lack operating funds to conduct regular supervision (DR10).All categories of participants identified HFCs as the only functioning social accountability initiative in health facilities. HFCs effectively oversee the Drug Revolving Fund (DRF) and staff attendance. ‘We have been monitoring health workers. Their salaries were not paid until we endorsed their time book’ (HFC leader 6). HFCs are not involved in identifying eligible users of free care and managing free care refunds (DR9). HFCs lack the legislative framework for effective and efficient discharge of their functions (DR2). Some policymakers and HFC leaders noted that HFC Alliances exist but are ineffective. Most policymakers, providers and HFC leaders corroborated the findings that health facilities lacked service charters and complaint boxes . A few policymakers and providers observed that complaint boxes and service charters may not be useful because ‘people know their right…they are ready to bare their mind any time anywhere, even if it hurts you’ (Provider 8).Reimbursement standard, concurrent policies and poor remuneration emerged as key themes related to the institutional context of providers.“Ooh! There was a time the fund ceased for almost a year or two years…. the officers-in-charge lost hope, almost all of them lost hope. I do not even think that most providers are submitting their invoices now from this district” (Policymaker 14).Reimbursement was often delayed, health facilities were sometimes paid fractions of their claims, and health workers did not seem to understand the reimbursement procedure . Most policymakers and providers indicated that reimbursement of health facilities was poorly enforced in both districts. Many health facilities were not paid for over a year resulting in stoppage of free maternal and child health services in Isi-Uzo. In Enugu Metropolis, delayed reimbursement was compounded by under-payment of providers which resulted in interrupted free maternal and child health services. Delayed provider payment resulted in stock-outs and resumption of user fees . In both districts, most HFC leaders were not aware of the reimbursement process but a few HFC leaders corroborated policymakers’ and providers’ views that many providers no longer submitted claims for reimbursement.Evidence of tax payment was introduced as a proof of residence in the state but resulted in under-utilisation of free services . Most district-level policymakers and providers incorrectly interpreted evidence of tax payment as tax clearance or a salary slip of a ‘civil servant’ husband, payment of some money in lieu of tax clearance or Gen 35 (evidence of appointment) for civil servants. The evidence of tax payment policy was never implemented in Isi-Uzo but partially implemented in Enugu Metropolis. Most HFC leaders in both districts were not aware that evidence of tax payment was implemented in their facilities. Few HFC leaders observed that, other than civil servants, clients pay some money in lieu of tax in Enugu Metropolis.Most providers and HFC leaders in Isi-Uzo stated that Subsidy Reinvestment Programme (SURE-P), a federal government scheme, provided an alternative to the failing state-owned FMCHP. ‘Many patients now prefer going to SURE-P centre for treatment and delivery, where they did not have to pay out-of-pocket. Since then we rarely had patients here’ (Provider 8). The SURE-P supported health facilities with free drugs, delivery kits, equipment, health workers and infrastructure. However, few HFC leaders noted that the health workers ‘came only when we had the SURE-P intervention’ (HFC leader 4).“Though doctors were paid with approved salary scale, other health workers were not. It is not possible that other health workers will wholeheartedly run the free maternal and child healthcare programme per guidelines” (Provider 11).Participants of all categories indicated that non-implementation of nationally approved health salary scales, discriminatory compensation for different cadres of health workers and unpaid salaries undermine staff motivation to implement FMCHP:Submission of claims and communication of service entitlements and obligations emerged as two main tasks of providers . Most poMost HFC leaders in both districts said that they were not involved in claims preparation and submission. Only one HFC leader in Enugu Metropolis was aware of the reimbursement procedure. The HFC leader noted that providers were unable to correctly fill claims forms, and sometimes inflated their claims. Moreover, most policymakers, providers and HFC leaders agreed that providers do not sufficiently communicate service entitlements and obligations to users, which resulted in low awareness of the requirement for evidence of tax payment among users.Facility funding, health management information system, drugs, equipment, infrastructure and communication shaped provider capacity.The FMCHP policy stipulates that 70% of health facilities’ claim for free services should be paid to the health facilities as operating cost (DR1). However, health facilities had poor access to the funds paid through the LHAs prior to 2010 when payment policy changed to direct facility funding . Most policymakers stated that the operating costs are paid directly to health facilities due to leakages at the LHAs. In Isi-Uzo, most district policymakers and providers observed that ‘health facilities no longer receive overhead from FMCHP due to cessation of reimbursement’ (Policymaker 14) and providers relied on funds from non-free services retained. One provider observed that ‘there was a time, health facilities received overhead, which was not regular, though. Within the preceding two years, I don’t think that there is anything like overhead for us’ (Provider 3). In Enugu Metropolis, most policymakers and providers indicated health facilities received insufficient reimbursements. The majority of HFC leaders in both districts indicated that they were signatories to health facilities’ account, but providers were unwilling to involve them in financial management.The capacity of providers to record and report data is low (DR3). However, most policymakers and providers in both districts indicated that use of mobile phones facilitated data transmission to the State HMIS office. Few policymakers and providers in both districts observed that data collection and transmission are poorly funded. ‘It was agreed that M&E officer should be given N10,000 every month, but it has not been implemented’ (Policymaker 13). Most providers in both districts also stated that inadequate staffing and absence of data review meetings constrained providers’ capacity to report and use data for planning. Most HFC leaders stated that HFCs are not involved in data collection and reporting. Few HFC leaders noted that charts of maternal and child healthcare attendance are discussed in their HFC meetings.Existence of the drug revolving fund (DRF) scheme and procurement of drugs from the central medical stores enabled health facilities to offer free MCH services (DR2). Nonetheless, delayed payment of health facilities resulted in stock-outs . Most policymakers, providers and HFC leaders observed that providers’ DRF stocks were depleted due to delayed – or non-reimbursement of – FMCHP drug expenditure. Most policymakers and providers noted that many providers were supplied drugs beyond their level of care and drugs close to expiry. In both districts, most policymakers and few HFC leaders revealed that health workers dispensed private drugs in public health institutions. ‘The woman (provider) has resorted to buying drugs with her own money and selling them to those who come to the facility’ (HFC leader 4).Most policymakers, providers and HFC leaders in both districts also stated that providers have equipment but lacked buildings to house equipment and support service delivery. Equipment were not always tailored to the scope of health facilities and staff received no training on how to operate and maintain them . Furthermore, in Isi-Uzo, few providers and HFC leaders highlighted the absence of a functional ambulance to support referral services. Even though ambulances were allocated to the district hospitals or the apex hospital in each local government (DR1), ambulances are usually used for other purposes and out of reach of the health facilities . In Enugu Metropolis, providers indicated that an insecure working environment led to incidence of thefts and sexual harassment of health workers on night shift. Many health facilities have dilapidated buildings, no perimeter fencing, poor electricity supply and poor water supply .Despite policy stipulation that users be educated on service entitlements and obligations in FMCHP (DR1), users’ lack of confidence in public health facilities limit use of free services (DR13). Whereas some policymakers and providers claimed that providers ‘delivered services in a professional manner’ (Policymaker 15), other policymakers and providers said that users complain about poor attitudes of healthcare providers. ‘Last time, I met a woman who said that she would never go for free MCH services because if one went to the health centre, providers would be insulting one’ (Provider 10). Most HFC leaders in Isi-Uzo stated that providers were not courteous and responsive to clients’ expectations; and are not available for afternoon and night shifts. Conversely, most HFC leaders in Enugu Metropolis said that providers were approachable and treated clients with respect.Availability, posting and transfer, and weak disciplinary mechanisms emerged as sub-themes in human resources.Health facilities lack the appropriate number and mix of human resources . Most policymakers and providers indicated that lack of qualified health workers hampered delivery of free maternal and healthcare services. ‘We cried out bitterly that trained health workers in the system were too small to carry out this laudable programme.’ (Policymaker 16). Some providers and few HFC leaders observed that SURE-P improved availability of staff in Isi-Uzo.Participants of all categories supported the findings from document review that distribution of health workers was skewed in favour of urban districts . A few providers in Isi-Uzo observed that health workers were posted to health posts leaving busier health centres. In Enugu Metropolis, few providers stated that ‘some doctors were posted to less busy hospitals avoiding busier hospitals’ (Provider 12).Most policymakers stated that district officials do not sanction primary health staff and heads of facilities are reluctant to implement staff disciplinary procedures because ‘higher authorities’ (Policymaker 11) do not act on their recommendations. Also, whereas the Local Government Service Commission (LGSC) is responsible for managing health workers, the district officials have only technical oversight of primary healthcare service delivery. In both districts, most providers and HFC leaders explained that heads of health facilities do not comply with staff disciplinary procedures because ‘heads of facilities do not want to be marked as the ones responsible for the ordeal of their co-workers’ (Provider 7) and due to political interference. ‘Most staff, who are truant, are people that you are unable to discipline. When you query them, a higher authority will query you’ (Provider 15). Most HFC leaders stated that ‘no head of facility has actually queried or reported staff for insubordination’ .This study has explored how the context and institutional capacity of health facilities affect implementation of the FMCHP. Evidence from this in-depth analysis could inform design of an improved governance model for strengthening the capacity of health facilities offering free maternal and child healthcare.The study findings reveal that while decentralisation policy promoted integrated supportive supervision and monitoring of FMCHP in principle, ineffectual district FMCHP leadership resulted in poor provider performance monitoring, lack of support to frontline health workers and weak disciplinary mechanisms. These findings are consistent with results from previous studies ,16–20. DThe study’s findings show that though citizen participation in management of health facilities implementing FMCHP enabled oversight of the drug revolving fund and staff attendance at work, HFCs did not play strong roles in FMCHP. Our findings are consistent with low citizen participation found in other studies ,22–24. IThe study findings highlight the importance of providers’ use of discretion in modifying free healthcare policy and make services unresponsive . First, Poor remuneration in the state public health sector created a weak incentive environment for providers of free care. This finding is consistent with findings in Nigeria ,35, but The findings further suggest that any provider performance monitoring system that excludes district and local health authority officials is structured to fail. Even though tools for FMCHP claims were available, the preparation of claim documents was problematic at the health facility level as is the case in Burkina Faso and Burundi ,25. In tThe study findings highlight a requirement for resource allocation to providers to be need-based. The policy of remitting 70% of FMCHP service refunds directly to health facilities while potentially effective in principle, was unpredictable in practice. Also, equipment donated by development partners enabled health facilities to offer free services. However, buildings are dilapidated, health facilities lack public utilities and functional ambulances to support referrals, equipment is stacked and not tailored to the scope of services provided by facilities, which are consistent with findings of several studies ,24,36. EFurthermore, the study findings indicate the need to fill gaps in staffing to meet service entitlements through recruitment and retention of appropriate cadres and mission-consistent postings and transfers especially in rural health facilities. Similarly, shortage of appropriate qualified health workers, worse in remote areas, constrained provision of maternal, neonatal and child health services in the Lao People’s Democratic Republic and three African countries, where health workers had preference for urban posts ,36. ThouDespite the existence of sanction procedures and HFCs’ monitoring of staff attendance, which could reduce rate of absenteeism among health workers, heads of health facilities are reluctant to invoke staff disciplinary measures because state-level officials do not act on recommendations of district officials, for fear of political interference in staff disciplinary processes and for sense of comradeship, similar to weak mechanisms of answerability and enforceability found in Zambia . ContrasThe use of case study design in this study enhanced identification of how provider factors can mediate implementation of the FMCHP. However, while sampling participants was informed by anticipated richness and relevance of information in relation to the study questions , the vieThis study contributes to the scholarship and policy debate on implementation of user fee policies through its detailed analysis of Nigeria’s implementation experiences. Key lessons that should strengthen the capacity of health facilities to implement free healthcare policies include: ensure effective devolution of functions, powers and resources to district-level organisations; strengthen facility-based social accountability initiatives; harmonize concurrent and conflictive policies; ensure adequate and fair compensation of health workers, and timely reimbursement of providers; fill service delivery gaps in health facilities; and attract and retain appropriate mix of human resources. Overall, decision makers must pay attention to institutional designs and organisational practices shaping implementation of user fee removal policy at the facility level.


State legislation in many U.S. states, including California, mandates informing women if they have dense breasts on screening mammography, meaning over half of their breast tissue is comprised of non-adipose tissue. Breast density is important to interpret screening sensitivity and is an established breast cancer risk factor. Environmental chemical exposures may play an important role in this, especially during key windows of susceptibility for breast development: in utero, during puberty, pregnancy, lactation, and the peri-menopause. There is a paucity of research, however, examining whether environmental chemical exposures are associated with mammographic breast density, and even less is known about environmental exposures during windows of susceptibility. Now, with clinical breast density scoring being reported routinely for mammograms, it is possible to find out, especially in California, where there are large study populations that can link environmental exposures during windows of susceptibility to breast density. Density scores are now available throughout the state through electronic medical records. We can link these with environmental chemical exposures via state-wide monitoring. Studying the effects of environmental exposure on breast density may provide valuable monitoring and etiologic data to inform strategies to reduce breast cancer risk. Mammographic breast density (MBD) is a measure of the amount of fibroglandular breast tissue compared to overall breast tissue and is an established risk factor for breast cancer, and this association is not just from masking . Both thTwin studies have long supported the importance of genetics and early life environment on MBD, with concordance in monozygotic twins as high as 60% and concordance in dizygotic twins and siblings as high as 30% ,8. Even MBD, in addition to its great potential to play a key role as a biosensor, particularly for hormonal treatments, may also hold the key to understanding the complex role of body mass index (BMI) and breast cancer risk. Specifically, the positive association between higher BMI and postmenopausal breast cancer, coupled with the negative association between higher BMI in adolescence and early adulthood and premenopausal breast cancer, is incredibly consistent across many diverse populations and remains poorly understood . The conWe hypothesize the MBD may also hold the key to understanding the role of environmental exposures and breast cancer risk, particularly as it can be used as a biosensor at the breast tissue level for changes over time, as it has been for HRT and other exogenous hormones. However, even though the literature on environmental chemical and breast cancer risk has generally not been specific to measuring exposures during key windows of susceptibility (WOS) when the breast changes in form and function , the litMBD can be measured continuously, like we did in our studies ,20, usinMost states report results if a woman has a BI-RADS 3 or 4, and approximately half of all adult women of screening mammography age do have a BI-RADS score in this range . Thus, nGeographic Information Systems (GIS) studies to map high MBD hotspots and associated geographic distribution of exposures;Prospective epidemiological studies that link MBD to environmental factors during WOS;Multiple ‘omics investigations to discover individual pathways to risk;Developmental toxicology studies to confirm causation and investigate mechanism.Identify geographic areas with high MBD, defined as heterogeneously dense (BI-RADS 3), and extremely dense (BI-RADS 4), and link these patterns to modifiable environmental exposures via trans-disciplinary designs that include:Engage communities of concern in discovery and create advocacy to reduce deleterious exposures via public policy.Implement an ongoing biomonitoring project that integrates state-wide environmental data with MBD data.Methods: It is now feasible to conduct large-scale studies of MBD and environmental exposures across the state of California using mapping and other GIS methods. GIS methods can inform prospective human studies that can be rapidly completed in existing long-term California cohorts that include risk factors during WOS. Human cohorts can now be linked to resources for density scoring, making large-scale research feasible and affordable. Based on human findings, metabolomics and experimental animal studies can identify mechanisms and investigate causality. Trans-disciplinary collaboration with metabolomics and developmental toxicology can be pursued and is now feasible, as we have shown .Critical features for successful GIS studies of MBD are in place in California. There has been mandatory reporting of MBD in the state since April of 2013 . MammogrCalifornia has an extensive database that describes the geographic and historic distribution of the use of pesticides beginning in 1991  and has GIS studies offer the further opportunity to integrate social with environmental risk factors. Many diseases, including breast cancer, differ by social factors either in incidence, age at incidence, mortality or aggression, or severity at the time of diagnosis . Few stuKey hypotheses related to environmental exposures and MBD can be tested by using GIS mapping to large-scale MBD registry data. Specific hypotheses related to WOS and MBD will require appropriate assumptions about lagging effects of environmental exposures based on age at mammogram, and average ages at menopause, pregnancy, and menarche. Ecological associations could be then followed up on with individual cohort data, with individual data available for each WOS.A special feature of California, in addition to its size and diversity of population and place, is the presence of long-term cohorts that can be accessed for breast cancer research. Some of these are listed in Once descriptive GIS and prospective epidemiological studies identify environmental chemical exposures that correlate with MBD for a given geographic area, an important next step is to identify individual biomarkers and susceptibility to complement the ecological data. This requires relevant biospecimens, either archived or contemporary. A range of ‘omics  may be relevant and a significant advantage is offered by the metabolome . Large cIntegrating experimental toxicology with human environmental studies of MBD through supported, close collaboration will accelerate the discovery of causation and mechanism. This level of evidence strengthens advocacy and policy development for risk reduction and improved mammography screening efficiency. This step should not be left to chance. To accelerate discovery, close collaboration of human population scientists and experimental toxicologists is essential and requires incentives and monetary support. A recent example of how human and animal data can be interrogated together is found in metabolomic signatures of DDT in human specimens that were shown to be consistent with metabolomic signatures following controlled experimental DDT exposure in mice . The insChange can be accelerated and is more likely to succeed when scientists partner with the communities they study and serve ,37,38. BCommunity partners working with the state and population scientists can also develop scalable and sustainable biomonitoring projects. A strong existing biomonitoring program in California  will facThe problem of mixture exposures, including the overlap of environmental exposures, social and economic disparities and related psychosocial stress, can be addressed by querying multiple data bases to discover links. In a series of recent papers, Krieger and colleagues argue eloquently for using geospatial measures of “social polarization”, termed Indexes of Concentration at the Extremes (ICEs) ,27,31. TGeographic cluster investigations of breast cancer cases present known methodologic problems due to low frequency of breast cancer in small cluster areas and high statistical uncertainty . ImportaAs noted above, we expect exposures during WOS  to have the strongest impacts on MBD. Discovery of the relation of environmental exposures during WOS to future MBD is made possible by combining birth cohort MBD with historical exposure data via NATA monitoring and pesticide monitoring in California. However, given that MBD responds quickly to changes in hormone medication , we cannProspective epidemiological studies with available biospecimens or GIS data linked to environmental exposures and place of residence during WOS periods are an additional, complementary source of information on the etiology of MBD. Understanding the etiology of high MBD offers the opportunity for breast cancer prevention.Until we query the geographic distribution of MBD, it is difficult to predict trends over place or time. Observing these patterns will determine the role of monitoring MBD and associated exposures as a tool for finding high-risk geographic areas and designing intervention policies and programs that can reduce risk of breast cancer. Initially, MBD monitoring is, appropriately, the subject of sound scientific research to establish feasibility and potential as a biomonitoring tool directed towards breast cancer prevention. If MBD monitoring is effective and if MBD is significantly tied to environmental factors, there are a number of state and federal agencies or community partnerships that may add MBD as a health indicator by place and time. Examples include The California Healthy Places Index , CaliforWe propose an approach to accelerate etiological studies, as well as future biomonitoring of environmental exposure effects at the population level. Specifically, by using the opportunities available through clinical reporting as well as state-wide environmental data, we can efficiently examine whether environmental exposures are linked to MBD and inform strategies to reduce these exposures. These population-based strategies have advantages over any one single epidemiological study, which may have its own issues of selection bias. Thus, pairing registry data with individual cohort data will be a robust way to test hypotheses regarding environmental exposures and changes at the breast tissue level. It is highly likely that MBD and breast cancer share common determinants because of the strength of MBD associations with breast cancer. Environmental pressures on breast structure during WOS have been least studied and are a “black box”. We can look into this box using study designs that link exposures during WOS to MBD patterns over space and time using existing resources now in California. These designs fall in two categories: 1) Prospective studies of diverse cohorts with relevant biospecimens and/or residency history during susceptible periods in the life course, that can be linked to geographic data bases documenting environmental chemical exposure; 2) Ecologic studies linking residence patterns to MBD in communities. Follow-up studies can use the new and promising methods of high-throughput sensitive metabolomics that measure both toxics and individual responses in biospecimens that represent the result of gene by environmental interaction. Affiliated experimental toxicology studies with doses relevant to humans can increase certainty about causation and find mechanisms. These etiological studies are important when learning how to prevent breast cancer. Moreover, describing the geographic distribution of MBD can find communities at highest risk and environmental correlates of high risk. This information is critical to find vulnerable communities and create public policy to prevent breast cancer specific to place, as well as other known socioeconomic disparities in breast cancer risk that are strongly linked to place. For example, the recent national study conducted by White and colleagues provides evidence that supports clean air initiatives for breast cancer prevention . SimilarCreating an initial model for MBD monitoring in relation to environmental exposures will open opportunities for breast cancer prevention that have not existed previously. Significantly, this approach uses existing data, making this approach feasible in the short-term and cost-effective. Mandated reporting of BI-RADS scores, in combination with existing cohort and environmental monitoring data by place and time, are available in California. MBD monitoring, in concert with environmental monitoring, is potentially scalable to other states with mandatory MBD reporting, available environmental data by place, and existing long-term cohorts with residence history and/or biospecimens during critical WOS.


Caruana and colleagues found that stimulation of the aMCC was highly likely to evoke movement. There was, however, little evidence of any nociceptive effects in this subregion. This raises questions for theories that it is part of the ‘pain matrix’ and crucial for processing information about pain. Beyond this it certainly provides rather robust evidence that this subregion is not ‘selective for pain’ as some have argued : The most anterior zone of the cingulate cortex extending into the frontal cortex. It includes a subgenual (sACC) subregion lying below the corpus callosum, a pregenual section, which lies superior to (above) the sACC and a perigenual subregion lying dorsal and posterior to (above and behind) that. Pregenual stimulation elicited laughter, perigenual elicited interoceptive sensations.Midcingulate cortex (MCC): The zone of the cingulate cortex lying posterior to the ACC. It contains at least four subregions, two of which are anterior to the others but lie posterior to the ACC, one being more dorsal (aMCCd) to the other (aMCCv), with two further subregions directly posterior to those (pMCCd and pMCCv). These regions are often referred to as dorsal anterior cingulate cortex (dACC). Goal-directed behaviours were elicited by stimulation of aMCC.Posterior cingulate cortex (PCC): The zone of the cingulate cortex lying caudal to the other zones. Stimulation elicited vestibular sensations.Stereo-electroencephalography electrode localization: To precisely determine the location of electrodes, patients underwent magnetic resonance scans after electrode implantation. The electrode locations are warped onto a template brain allowing for comparison of stimulation sites within a unified space across patients. This allows greater precision for localization of electrodes, and for them to be compared to previous anatomical parcellations of the cingulate cortex.


Today, several pharmaceutic and non-pharmaceutic approaches exist to treat psychiatric and neurological diseases. Because of the lack of treatment procedures that are medication free and without severe side effects, transcranial direct current stimulation (tDCS) and aerobic exercise (AE) have been tested to explore the potential for initiating and modulating neuroplasticity in the human brain. Both tDCS and AE could support cognition and behavior in the clinical and non-clinical context to improve the recovery process within neurological or psychiatric conditions or to increase performance. As these techniques still lack meaningful effects, although they provide multiple beneficial opportunities within disease and health applications, there is emerging interest to find improved tDCS and AE protocols. Since multimodal approaches could provoke synergetic effects, a few recent studies have begun to combine tDCS and AE within different settings such as in cognitive training in health or for treatment purposes within clinical settings, all of which show superior effects compared to single technique applications. The beneficial outcomes of both techniques depend on several parameters and the understanding of neural mechanisms that are not yet fully understood. Recent studies have begun to directly combine tDCS and AE within one session, although their interactions on the behavioral, neurophysiological and neurochemical levels are entirely unclear. Therefore, this review: (a) provides an overview of acute behavioral, neurophysiological, and neurochemical effects that both techniques provoke within only one single application in isolation; (b) gives an overview regarding the mechanistic pathways; and (c) discusses potential interactions and synergies between tDCS and AE that might be provoked when directly combining both techniques. From this literature review focusing primarily on the cognitive domain in term of specific executive functions , it is concluded that a direct combination of tDCS and AE provides multiple beneficial opportunities for synergistic effects. A combination could be useful within non-clinical settings in health and for treating several psychiatric and neurologic conditions. However, there is a lack of research and there are several possibly interacting moderating parameters that must be considered and more importantly must be systematically investigated in the future. One of the most striking characteristics of the human brain is its ability to respond to changing internal and external states by reorganizing and restructuring neural circuitry on different timescales ranging from milliseconds to many years. This ability, called neuroplasticity, is extremely important throughout a person’s entire life, whether it is in skill or knowledge acquisition or within recovery processes after brain injury   may initiate synergistic or additive effects and increase effectiveness  the exact mechanistic pathways of tDCS and AE in exerting their impact on the brain are still not fully understood; (b) there is a large number of moderating parameters and variabilities known for each technique alone; and (c) there is a complete lack of knowledge about how those moderating parameters interact specifically and how both techniques interact generally when applied together. This work describes the mechanistic pathways of tDCS and AE and asserts that understanding the possible interactions of these pathways is critical when designing combination interventions aimed at improving cognition in healthy individuals or patients suffering neuropsychiatric or neurological diseases.Based on chronic exercise effects , Moreau et al.  provide Our literature search in central databases  for this narrative review primarily included studies that investigated the effects of AE  or tDCS  on tests that measure EFs or cognition in a single session intervention. Based on this search we also checked the reference list of selected articles. The intention of such a broad search strategy was to find as many studies as possible, simultaneously reducing the risk of missing any studies that combined tDCS and AE in one single session intervention on the cognitive system. We used the logical operators “OR” and “AND” between exercise-related terms  and brain stimulation terms  and the cognition search modifier cogniti* . We did not restrict the time interval of the search but concentrated our study description on tasks that are thought to measure EFs . We also excluded studies that investigated effects in more than one session  and in other domains  as this would require additional reviews. Based on this review and the performed comparison of tDCS and AE effects on EFs, possible interacting pathways and mechanisms are discussed while additionally consulting insights from studies focusing on other functions . As there are several forms of exercise paradigms, we use the term AE when cardiovascular exercise had been performed within highly automated movements such as in cycling, walking or running. AE includes physiological changes on the metabolic, respiratory and cardiovascular system of the body, while anaerobic exercise includes higher intensity activities which can be maintained only during a short time frame. Other exercise paradigms are resistance exercise  which affects also metabolic systems but also intra- and inter-muscular coordination, or coordinative exercise which often involve less physiological demand on the human body , Wisconsin Card Sorting Test] tap into multiple EFs or have been used in one study to test one specific EF and in another to test a different EF. For example, the well-known Stroop test has been used in AE studies to measure inhibition ability in one study  by a short period of physical whole-body exercise , and ratings of perceived exertion scales . Absolute intensity metrics include parameters such as the metabolic equivalent (MET). One current categorization   in Go/No-Go and Stop-Task paradigms  studies investigating tasks that evoke EEG responses during, immediately after, or with a time delay after AE. They are mostly quantified using event-related potentials (ERPs) P300, contingent negative variation (CNV), error-related negativity (ERN) and error positivity (EP). P300 is a prominent marker that can be seen as a positive deflection in the EEG amplitude about 300 ms after a stimulus and P300 is an index of attentional resources devoted to task completion Polich, . TherebyBy using additional markers such as the ERN and EP , those ERPs clearly demonstrate that the exercise-cognition relationship is reflected in task-evoked brain activity  activity recorded during and after exercise indicated increases in the alpha band ; however, this was not different from the increase measured for other frequency bands  Ca2+  and long-term depression (LTD)  approaches reported local functional synchronization due to tDCS  using a combined tDCS-EEG approach observed that an anodal bilateral tDCS  of the right inferior frontal cortex (IRF) modulated the P300 ERP component, while no clear effects were observed on a behavioral level  and ERPs. Consequently, tDCS of the PFC initiates comparable synaptic-plasticity and associated neuroplastic markers known from motor cortex studies . This mechanism was tested by Carvalho et al.  using twA further aspect to consider may be that meta-analyses provide evidence that moderate exercise intensity is most beneficial for cognitive functions, but affects only the speed of processing and not accuracy  on a molecular and system level has not yet been investigated. However, the outcome of both techniques is modulated by many parameters, and all of which may be of relevance when both techniques are directly combined , timing , sequence , and polarity  of tDCS are critical factors to be considered. Regardless of metaplasticity, depending on the study objective or clinical objectives, whether downregulation of a given brain area (such as in depressive patients) or upregulation  is intended, should be carefully considered.Especially with respect to the reticular activation hypofrontality theory , it might also be worth systematically modulating prefrontal cortical activity with tDCS or transcranial alternating stimulation (tACS) to actively upregulate or downregulate PFC activity during exercise. Using tDCS or tACS  as a versatile tool and possibility for making causal inferences may help to confirm or reject the idea of rising hypofrontality with increasing exercise intensity  can be provoked by exercise and tDCS and tACS , gender or specific neurological and psychiatric states, all of which might be differently affected by the two techniques and specifically by the moderating parameters reviewed here. Lastly, even if there are any potential synergistic combined tDCS-AE effects from one application, it must also be examined whether this has an impact on any longer lasting  interventional approaches, where additional factors must also be considered.AE and tDCS can have remarkably similar effects on EFs and other cognitive domains and support rapid initiating of neuroplasticity in the human brain within a short timescale. This similarity offers multiple beneficial opportunities within clinical research, such as treatment of psychiatric diseases or neuro-rehabilitation and also in non-clinical settings, such as sport. Compared to other multimodal approaches, such as combined AE-TMS studies or treatments combined with pharmaceutics, tDCS-AE has the advantages of its easy-to-apply and time and cost-effective applications without any yet known severe side effects. The acute effects of both techniques on the neurophysiological, neurochemical, and behavioral level, such as the enhancement of cognitive skills, modifications of neural activity, and catecholamine, have striking similarities and provide synergistic mechanistic pathways that might improve brain functions and neuroplasticity in health and disease when both techniques are applied in direct combination. While AE might provoke more large-scale changes across the entire brain, serving as a brain primer to provoke a given desired brain state, tDCS may then: (a) be used to more focally and specifically modulate brain activity and behavior; and (b) lead to more robust and higher effects possibly due to lower intersubjective variability and potential metaplastic effects.Due to various interacting and dynamically changing parameters, caution must be given to those moderating parameters that could significantly impact the interaction between both techniques, possibly leading to the abolishment of any effect (see Singh et al., The acute interactions of one session of exercise and tDCS on cognition have not been empirically addressed so far and should be systematically and experimentally investigated in the future. Special emphasis should determine whether there is a dose-response relationship in terms of exercise and tDCS intensity and duration, stimulation area and polarity, and whether the time course between exercise and stimulation could interact on several levels of the healthy and the impaired human brain. If synergistic or additive effects from acute combined effects can be experimentally observed in the cognitive or in the motor domain, future interventions may benefit from synergies between both techniques.All authors provided substantial contributions to the work. FS drafted the manuscript. FF and NP revised it critically.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


A balanced sleep-wake cycle is essential for maintaining an optimum circadian rhythm, as this feature of mammalian systems largely determines our overall alertness, cognition, and general well-being. When our circadian rhythm is disrupted by prolonged periods of wakefulness or hypersomnolence, our brain's “master clock”—the suprachiasmatic nucleus (SCN)—triggers spontaneous neuronal firing patterns  within brain networks. These LRTC's seek to explicate the scale-invariant or It has been a long-held view that critical brain states generally underpins scale-free cortical activity, i.e., small or large fluctuating timescales of activity that are highly ordered despite their seemingly random occurrences  and rapid eye movement (REM) sleep are at play , has been associated with increases in sleep spindles ranging between delta and alpha frequencies in EEG , within the purview of critical brain states, is an immediate area in which human behavior and pathological brain activity is primed for further study. Whole-brain functional connectivity studies have offered a view into putative correlations that exists within and between brain regions in the sleep-wake cycle. However, these approaches have proven limitation in their lack of specificity of more complex sleep phenomena, such as sleep disorders  and the effects of consciousness and awareness  and focused cognitive attention (Fagerholm et al., This is a sole author paper by KKI who is responsible for the synthesis of prior work to discuss concepts and techniques related to the subject matter.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Universal thyroid screening in pregnancy is a key debate in thyroidology and obstetrics. It is well-established that thyroid hormones are essential for maintaining pregnancy and optimal fetal development. Thyroid dysfunction is common in women of child-bearing age and also results in substantial adverse obstetric and child neurodevelopmental outcomes. Furthermore, thyroid dysfunction is readily diagnosed with reliable blood tests and easily corrected with inexpensive and available treatments. Screening only high-risk patients appears to miss the majority of cases and economic models show that compared to high-risk screening, universal screening is cost effective even if only overt hypothyroidism was assumed to have adverse obstetric effects. As a result, several countries now implement universal screening. Opponents of universal thyroid screening argue that asymptomatic borderline thyroid abnormalities such as subclinical hypothyroidism and isolated hypothyroxinemia form the bulk of cases of thyroid dysfunction seen in pregnancy and that there is a lack of high quality evidence to support their screening and correction. This review critically appraises the literature, examines the pros and cons of universal thyroid screening using criteria laid down by Wilson and Jungner. It also highlights the growing evidence for universal thyroid screening and indicates the key challenges and practicalities of implementation. Thyroid hormones are essential for maintaining pregnancy and optimal fetal development , 2. It iBecause thyroid disorders are particularly common in women of reproductive age, thyroid dysfunction is frequently encountered during pregnancy, sometimes as a new diagnosis , 8. The These competing considerations have fuelled continued debate on the merits of gestational thyroid screening . While uBox 1Is the condition an important health problem?Is there an accepted treatment?Are facilities for diagnosis and treatment readily available?Is there a recognizable latent or early symptomatic stage?Is there a suitable test or examination?Is the test acceptable to the population?Is the natural history of the condition, adequately understood?Is there an agreed policy on whom to treat?Is the cost of case-finding economically viable?Case-finding should be a continuing process and not a “once and for all” project.Adapted from Wilson and Jungner .It is well-established that overt thyroid dysfunction is an important health condition in pregnancy. Overt hypothyroidism occurs in ~0.2–0.6% of pregnant women  while ovIn addition, observational studies show that offspring of women with hypothyroidism  or isolaWomen with thyroid dysfunction also suffer an increased risk of adverse pregnancy outcomes an association which is well-established for overt thyroid dysfunction but is also seen with subclinical hypothyroidism . One metThe health impact of overt thyroid dysfunction is not in doubt but the bulk of cases of thyroid dysfunction that will be detected by systematic screening in pregnancy will be asymptomatic subclinical or borderline biochemical abnormalities. For example, subclinical hyperthyroidism, in which TSH is low in the presence of normal FT4, is usually due to the transient thyroid stimulatory effects of human chorionic gonadotrophin (hCG) and does not require treatment . Also, tLevothyroxine is a safe and well-tolerated treatment for hypothyroidism . There iAlthough Levothyroxine is the accepted treatment for overt hypothyroidism its benefits in gestational subclinical thyroid dysfunction remains uncertain. More so, the use of Levothyroxine is not without the risk of over-treatment especially in women with borderline abnormalities. Studies have shown a high proportion of over-treatment in levothyroxine users ranging from 20 to 40% in the general population , and 10%The diagnosis of thyroid dysfunction is established by measurement of the thyroid hormones FT4, FT3, and TSH . In addiThe assessment of thyroid function in pregnancy is by no means straightforward and is subject to misinterpretation due to the range of physiological adaptations that maintain fetal thyroid hormone delivery in the face of increased thyroid hormone requirements . These cSubclinical hypothyroidism and thyroid autoimmunity may represent early-disease states in the evolution of hypothyroidism. Subclinical hypothyroidism is present in 4–10% of the general population  and progIt can be difficult, without the appropriate expertise, to reliably distinguish pathological thyroid disease from non-significant fluctuations in thyroid hormones. Although subclinical disease may precede overt disease, not all patients with subclinical disease develop overt disease. More importantly, the wealth of observational data showing an increased risk of adverse pregnancy outcomes in women with subclinical thyroid dysfunction are not reconciled with data from randomized controlled trials. Thus, targeting subclinical thyroid disease in pregnancy will inadvertently promote overdiagnosis and fuel unwarranted clinician and patient anxiety.All society guidelines endorse the treatment of overt thyroid disease and in addition, most recommend treating antibody-positive women with subclinical hypothyroidism , 48, 49.Navigating the various diagnostic gray areas could be challenging for general clinicians and patients alike. An individualized approach is reasonable but will be difficult to administer outside of special-interest units. Ultimately, frontline clinicians may be overwhelmed by demands for treatment from an increasingly health-seeking population.Current international guidelines recommend screening for thyroid dysfunction in women at high risk of thyroid dysfunction, i.e., case-finding. However, various antenatal clinic studies have consistently shown that case-finding fails to diagnose 30–80% of women with hypothyroidism –54. An eThe analysis by Dosiou et al. was based on two RCTs conducted in Southern Italy, an area of mild iodine deficiency. There is no guarantee that the benefit reported in these studies will be applicable to countries with different iodine nutrition or resource settings. Furthermore, the overall costs of establishing a universal screening programme will need to be carefully considered and will need to incorporate the costs of personnel training, public education, establishment of healthcare infrastructure, and the burden of over-diagnosis and over-treatment.In this appraisal, we have examined the pros and cons of universal thyroid screening in early pregnancy using the template set by Wilson and Jungner. Our analysis presents a number of compelling arguments in support of universal screening but also raises areas of uncertainties and practical caveats. Universal thyroid screening in pregnancy fulfills most of the criteria for screening Table . ThyroidOf all ten criteria, only criteria 8, “there should be an agreed policy on whom to treat as patients,” is not satisfied. This is understandable given that thyroid dysfunction, like some other conditions with screening programmes such as hypertension or dyslipidaemia, is a continuum in which the thresholds for intervention are uncertain. Whilst all societal guidelines endorse treatment of overt thyroid disease, the uncertainty lies in the management of subclinical hypothyroidism, isolated hypothyroxinemia, and euthyroid autoimmunity. Here, the current ATA guidance  to definA number of practical considerations will need to be addressed before a universal thyroid screening can be safely implemented. First, the use of pregnancy specific reference ranges derived from a local population of thyroid disease-free pregnant women should be considered a priority, even a prerequisite for thyroid disease management in pregnancy. This will go some way in distinguishing true pathology from pregnancy induced physiological adaptation and will help curtail the dilemma of over-diagnosis. Second is the need to establish consensus criteria and unified nomenclature for the diagnosis of thyroid conditions in pregnancy, using definitions that are adaptable across populations and laboratories. The acquisition of skills in interpreting abnormal thyroid function tests in pregnancy by endocrinologists and obstetricians and the availability of resource, referral pathways, and well-defined inter-disciplinary responsibilities is essential.The ultimate aim of maternal thyroid disease screening in pregnancy is to optimize feto-maternal outcomes. Thus, therapeutic intervention when indicated should be implemented as early as possible in the course of fetal development. Accordingly, universal screening should ideally be performed once pregnancy is suspected or pre-conception if pregnancy is planned. A pragmatic algorithm is to measure TSH and then reflex FT4 and TPOAb if TSH is outside of the relevant reference range. This will be challenging to achieve but with thoughtful planning can be integrated into routine community health services. An example of good practice in this regard is China's national free preconception health examination project which offers access to preconception health examinations including thyroid hormone measurement in rural parts of China . A recenMost national societies recommend targeted case-finding, although with an expanding definition of high-risk . In pracEnsuring preconception iodine sufficiency through targeted public health campaigns and sufficient prenatal iodine supplementation should be integrated with thyroid screening programmes. Iodine deficiency is common during pregnancy, particularly in Europe  and corrUniversal thyroid screening in pregnancy fulfills most criteria for a beneficial and cost-effective screening programme and holds promise for improving fetal and maternal outcomes. However, areas of uncertainty remain especially with regards to the significance of borderline biochemical abnormalities and whether correction of such abnormalities can improve outcomes. A consensus is unlikely to be reached without further controlled trials and such trials should aspire to recruit women pre-conception or as early as possible in pregnancy. In the interim regular audit of existing screening programmes will be crucial in gaining insights into the practicalities of universal thyroid screening in pregnancy. For centers undertaking universal or high-risk screening integrating thyroid auto-immunity into decision making is essential.PT, SZ, TM, and KN drafted the manuscript with supervision and guidance from JL and OO. OO substantially edited the manuscript. All authors approved the final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer EP declared a past co-authorship with one of the authors JL to the handling editor.


A strong eye health workforce is essential if we are to achieve the goal of universal eye health for all. Strategic investment is needed to meet the growing demand for eye health services worldwideA shift in thinking is needed: spending money to train, recruit and keep eye health workers in post (retain them) is an investment not a costDesigning competency-based curriculums that allow trainees to develop essential skillsOffering life-long learning opportunities/ continuing professional developmentTraining allied opthalmic personnel in order to strengthen eye teamsCreating and funding posts for skilled eye care workers, where they are neededEstablishing well-functioning health facilities and offering appropriate incentives to help retain staff members in remote and rural areasJoined-up education and eye health workforce planning will help to ensure that there are enough trained people, with the right skills, to provide services where they are neededInvestigate, research, and/or forecast local eye needs by volume and type of service needed. This will guide the training and placement of eye health workers


Art therapies are a broad suite of treatments including drawing, painting and music that can facilitate non-verbal communication through artistic expression. They have been used as adjunctive therapies for a range of mental health conditions. Significant numbers of returning military personnel experience post-traumatic stress disorder (PTSD), and discontinuation of care is a concern. Using drawing-based art therapy as an adjuvant to classical therapies may provide a benefit for such military patients. Dear Editors:Art therapies are a broad suite of treatments including drawing, painting, dance, and music Fig.  that facPTSD rates vary from 13.5%  to as hiDrawing and painting to facilitate verbalization because such activities allow expression through a fundamentally different route from speaking ;Music for depression due to the emotive nature of music and its ability to decrease anxiety in patients ;Body-oriented and movement psychotherapies for avoidance behaviours because of the group interaction, working towards a common goal, and working through traumatic memories in a kinaesthetic way ;Clay and sculpture for permissive expression of anger and cathartic release on an inanimate object and ultimately creating with the hands rather than harming .Initial studies of various art therapies suggest efficacy of these nonverbal communication tools in relieving anxiety and depression, improving ability to focus, and breaking down avoidance strategies . PotentiThe remarkable interplay between PTSD symptoms and the purported effects of drawing-based art therapy suggest that this complementary therapy may be valuable as part of a holistic treatment plan. This intriguing synergy seems appealing, as art therapy serves as an alternative means of expressing thoughts, memories and feelings for those challenged by verbal-focused therapies. While limited to case studies and small controlled trials, data involving drawing-based art therapy as a supplemental treatment for PTSD are encouraging . These eThe calling to serve in the military is answered by dedicated individuals who undergo specialized rigorous training to allow them to perform acts that some may consider unconscionable, however necessary. Similarly, the techniques for treating these battle-hardened military personnel potentially should not be identically transferred from the civilian sector, as these individuals are not civilians. This assertion is supported by the fact that military service personnel often experience repeated and extended trauma and feel exposure to traumatic losses. These experiences can be morally compromising.If drawing-based art therapy is effective, it cannot be without risk. Specifically, there are case reports of art therapy potentially triggering treatment dropout . DrawingFor art therapy to be more broadly implemented in the treatment of military personnel with PTSD, further research needs to be conducted. Specifically, such investigation would include comparing the current treatment practice to that with a standardized adjuvant application of art therapy.Art therapies consist of many modalities that may be particularly suited as adjuvant therapies for specific disorders. Drawing-based art therapy holds promise for the treatment of PTSD. While rigorous controlled trials are necessary, there is little reason not to consider drawing-based art therapies in combination with classic treatment approaches. Finally, some military personnel with PTSD may feel the same as the American painter and printmaker Edward Hopper: “If I could say it in words, there would be no reason to paint”.


There is a need to develop an evaluation framework to identify intervention priorities to reduce antimicrobial use (AMU) across clinical, agricultural and environmental settings. Antimicrobial resistance (AMR) can be conceptualised and therefore potentially managed in the same way as an environmental pollution problem. That is, over-use of antimicrobial medicines as inputs to human and animal health leads to unintended leakage of resistance genes that further combine with natural or intrinsic resistance in the environment. The diffuse nature of this leakage means that the private use decision is typically neither cognisant, nor made responsible for the wider social cost, which is the depletion of wider antibiotic effectiveness, a common pool resource or public good. To address this so-called market failure, some authors have suggested a potential to learn from similar management challenges encountered in the sphere of global climate change, specifically, capping use of medically important drugs analogous to limits set on greenhouse gas emissions. Drawing on experience of the economics of greenhouse gas mitigation, this paper explores a potential framework to develop AMU budgets based on a systematic comparative appraisal of the technical, economic, behavioural and policy feasibility of AMU reduction interventions across the One Health domains. The suggested framework responds to a call for global efforts to develop multi-dimensional metrics and a transparent focus to motivate research and policy, and ultimately to inform national and global AMR governance. There are many interventions to reduce antimicrobial use (AMU), but there is no common framework for their prioritisation on the basis of cost-effectivenessConceptualised as an environmental pollution problem, AMU can be managed using analogous approaches used to reduce global greenhouse gas emissions.An abatement cost curve framework offers a systematic approach for data collection across the One Health settings, with a view to setting rational AMU targetsPolicy interventions need to identify and prioritise the most cost-competitive interventions to modify AMU across all settings.Global governance of AMR will benefit from a transparent approach to guide data collection for global and national action planning.The biological bounty of antibiotic discovery is measurable in terms of the avoided human and animal health burden over more than six decades. As noted in countless reports and papers, and indeed as originally foreseen, this period is potentially ending with the prospect of increased multi-drug resistant infections born of poor stewardship and over use of an existing suite of drugs, and supply side barriers inhibiting innovation of replacements.A nexus of human, animal and environmental origin, antimicrobial resistance (AMR), and its driver antimicrobial use (AMU), is a quintessential One Health challenge. The biologically complex properties of AMR are well documented and have been likened to similar wicked diffuse environmental pollution problems, and the challenge of reducing global greenhouse gas (GHG) emissions in particular.As a regulatory response, global AMR action plans offer only the broadest parameters around the notion of good antimicrobial stewardship.et al,Links between AMU and AMR are complex, but there is growing consensus that AMU is a driver of resistance pressure, and that the common property and market failures need to be a focus of attention alongside drug innovation. As noted by Hoffman The climate change experience can be instructive and there is value in exploring how the analogy of a GHG emissions cap may translate into the context of managing AMU. Drawing on experience in developing UK GHG budgets,The alarm around rising drug resistant infection and scrutiny of governance structures has highlighted overlapping roles and gaps in existing multi-lateral structures and national strategies, and the need to seek consensus on both the magnitude of the problem and national responses.Different metrics and frameworks have been advanced to communicate and help regulate complex AMU/AMR links within and across One Health settings. These include systems mapping and models,This situation is reminiscent of the climate change experience. A decade ago, there was much unstructured discussion and data uncertainty around different GHG mitigation measures, but a limited sense of the lowest cost ways to avoid carbon dioxide equivalent emissions across different sectors. In seeking to identify their contribution to global emissions reduction targets, some governments took the initiative to develop a more rational approach to sectoral carbon budgeting. These ranked cost competitive mitigation interventions cheapest to most expensive (per unit reduction in emissions), in each sector, thereby facilitating comparison of abatement costs across sectors. A comparison of these costs, across all emitting sectors reveals where the next  abatement intervention should notionally be implemented. If some upper marginal abatement cost limit is defined, then this process illustrates the overall extent of emissions mitigation that is economically feasible for each sector and in aggregate. With this information, it is possible to identify the relative contribution of different sectors and implicitly the remaining emissions envelope within each, a carbon budget, which would be excessively expensive to reduce. Cost in this context means the private cost of compliance associated with the intervention, but can also include wider assessment of life cycle and social  costs and benefits that can be incurred when inserting a technology into a production system.The abatement cost logic derives from basic economic theory of pollution control, which for point source pollution models suggests that an allocation of emissions among polluters is efficient if it minimises the costs of achieving an ambient environmental target.Conceptualised as diffuse pollutants, AMR and GHGs share similar properties that can be explored using marginal abatement cost theory of optimal pollution abatement. Given the complex nature of AMR in the environment, we are more pragmatically applying this to AMU as a precursor or potential interventions that reduce the pressure of environmental pollution. We apparently know little about the relative cost-effectiveness of mitigating AMU or reducing environmental exposures across One Health settings; that is, in clinical, agricultural, and environmental spheres. Learning from climate change, this is arguably the most conspicuous gap for economists to help bridge the disciplinary divides and reframe the challenge in a way that provides a clear way forward for policy and governance.If society wants to prioritise lowest cost AMU reductions, for each sector there is a theoretical schedule that traces out the increasing marginal cost of units of pollution reduction . At the Translating this theory into practice requires a bottom up variant of the MACC approach that recognises that the schedule is not comprised of infinitely divisible homogeneous interventions implied by the curve in Estimating this information within a sector implies a series of analytical steps, approximately summarised to:identify all known technical mitigation interventions or measures that could apply in a setting;understand how each works and their current  use or research potential;the extent to which each measure can be applied alone or combined, and with what approximate forecast outcome in terms or reduced AMU or reduction in emissions to the environment relative baseline trajectory;calculate financial implementation costs plus wider economic and ancillary costs and benefits derived from implementation;identify which measures are relatively cost-effective including those that are win-win; that is, implying negative or cost savings;identify which available policy instruments apply to which measures;identify measures that need further research, are relatively uncertain, currently out of scope due to unproven technical effectiveness, excessive cost or policy/regulatory feasibility;identify measures with behavioural barriers that can reduce technical, economic and policy feasibility.MACCs are typically derived at scales meaningful in terms of governance and policy jurisdiction, and some of the more galvanising messages come from analysis at the global scale.Stages (i)–(viii) frame and summarise an interdisciplinary science-policy research agenda that can provide different potential abatement estimates as policy targets. A full technical potential is the mitigation opportunity available in a sector where all technically feasible measures are fully applied over a given time horizon. This potential is a largely theoretical benchmark due to applicability constraints on some technologies, which may rule them out on technical, economic or ethical grounds. In practice, the focus is on the economic potential, which comprises the total abatement of the lowest cost or most cost-effective measures. As noted, there is no analogous pollution price  benchmark to set a cut-off point for excessive cost,The economic potential is in turn limited by the fact that there may be insufficient policy levers to implement (incentivise or mandate) application of some measures. Again, the framework serves to focus attention on policy design. This remaining ‘policy-feasible’ potential is finally limited by potential behavioural barriers that mean that measures are not adopted as anticipated.These potentials can be increased by measure-specific research spanning the science-policy continuum. As noted previously, in relation to potential cost-saving interventions, there are demonstrable behavioural anomalies that impede the adoption of even cost saving measures. In this case, insights can be derived from both psychology and behavioural economics.Applying a MACC framework implies a consistent multi-disciplinary research agenda to define cost-effective interventions across the One Health space. In the climate change context, MACCs have focused debate around a common problem framing and methodology that has galvanised science to identify gaps and refine assumptions relevant to each measure, and to understand immediate versus less proximate priorities for accelerating cost-effective abatement potential. This includes research on integrated modelling, behavioural barriers and a focus on the relative effectiveness of measure-specific policies. Note that there is no suggestion of a definitive MACC; rather that the exercise provides an estimate that is continually improved as new data emerge and are captured. The UK agricultural GHG MACC is in its sixth iteration since 2008 and is in some senses an exemplar of multi-disciplinary science-policy collaboration.AMR is biologically complex and there will be significant heterogeneity in the cost-effectiveness of measures implemented indifferent contexts. Focusing on AMU and interventions that reduce environmental pollution side steps uncertainties in managing AMR,More immediately, they respond to several recommendations set out by IACG.Current AMR governance spans organisations sharing no obvious analytical frameworks to cumulate data systematically over the different One Health settings to understand AMU reduction opportunities and targets. Although advocated,


Due to advances over the last several decades, many fields of medicine are moving toward a precision medicine approach where treatments are tailored to nuanced patient factors. While in some disciplines these innovations are commonplace leading to unique biomarker-guided experimental medicine trials, there are no such analogs in psychiatry. In this brief review, we will overview two unique biomarker-guided trial designs for future use in psychiatry: basket and umbrella trials. We will illustrate how such trials could be useful in psychiatry using schizophrenia as a candidate illness, the EEG measure mismatch negativity as the candidate biomarker, and cognitive impairment as the target disease dimension. In stark contrast to our growing understanding of mental illnesses, diagnoses and treatments heavily rely on the clinical interview rather than direct, reliable assays of brain function. The results are hardly surprising: we have not meaningfully improved clinically relevant endpoints for many serious mental illnesses in the last several decades . Recent Biomarker-informed clinical trial approaches are becoming common in other fields of medicine [; for revWhile psychiatry currently has no candidate biomarkers which have graduated from academic laboratories to guide treatments in real-world settings, the stage is being set for a future which successfully leverages a precision psychiatry approach. In this brief review, we provide an overview of what a precision psychiatry approach could look like using a well-validated translational electroencephalography (EEG) measure called mismatch negativity (MMN) as a candidate biomarker, and neurocognitive impairment in schizophrenia as a target disease dimension.Schizophrenia (SZ) is characterized by positive  and negative  symptoms which contribute to functional impairment. Beyond these defining symptoms of SZ, hundreds of studies have suggested that neurocognitive impairments are both core features of the illness and robust determinants of psychosocial disability –12. NeurIndeed, recent analyses of over 1,400 patients with chronic psychoses recruited for the multi-site Consortium on the Genetics of Schizophrenia (COGS) provided strong empirical support for a hierarchical model linking cognition with functional outcome in SZ . In thisNeurophysiological indicators have indexed abnormalities in EAIP in SZ for several decades, and differences in EAIP in patients are prominently featured as endophenotypes in genomic studies. The above analyses confirmed that the neurocognitive impairments in SZ appear to be a core disease component, reliably able to be measured and directly-linked to the symptoms and functional outcomes. Despite this advance, decades of clinical trials testing the effectiveness of currently approved antipsychotic medications and other novel therapeutics as putative pro-cognitive agents have failed to improve cognitive symptoms in SZ in any durable, meaningful way , 18. TheThe usefulness of EEG measures in guiding new treatments depends on their ability to serve as biomarkers. Useful biomarkers must be accessible and measurable in preclinical models of disease; should be sufficiently well-characterized such that those biomarkers are linked to relevant underlying neural circuits and known mechanisms of dysfunction in psychiatric disease; and are able to be assessed in both healthy subjects and affected individuals. For usefulness in human trials biomarkers must be insensitive to practice or order effects, reliable, and responsive to interventions. To succeed in real-world settings, biomarker acquisition should also be scalable, low-cost, and suitable for use in multi-center studies.All of the above criteria have been identified for biomarker development for neurocognitive impairment in SZ by a variety of expert consensus panels –23. The At the time of CNTRICS, mismatch negativity (MMN) was already considered a mature neurophysiologic biomarker based on meeting the above criteria, and generally believed to be ready for widespread implementation in clinical trial studies , 23. In MMN is an event-related potential and a neurophysiological measure of EAIP that is evoked when a train of “standard” auditory stimuli is interrupted by an oddball or “deviant” stimulus that differs from standards as shown in Figure Reduction of auditory MMN amplitude was reported over two decades ago in SZ and has been replicated numerous times . MMN defMechanistically, auditory MMN is thought to be an index of N-methyl-D-aspartate receptor (NMDA) functioning , 68. NMDArguably, the most important metric of biomarker applicability in psychiatric illnesses is the ability to track functional outcome. In patients with SZ, several studies have detailed that MMN deficits are able to account for a large degree of variance in cognitive and psychosocial functioning, as well as the ability to achieve or maintain independent living , 82–86.Given the cognitive deficits observed in SZ, many studies have attempted to use pro-cognitive drugs to help attenuate this dimension of illness . In partMemantine is a non-competitive moderate affinity NMDAR antagonist , 91. It In clinical trials with Alzheimer's disease patients, memantine has been found to have a modest pro-cognitive impact , 98. Howmax of memantine, on both testing days. We found that memantine enhanced MMN in patients with SZ; since improved MMN is associated with less cognitive impairment and greater psychosocial success, this type of signal suggests that MMN could be a biomarker of treatment engagement in pro-cognitive interventions. While only a single dose of memantine would not be expected to durably improve cognition, the ability of memantine to alter MMN in a patient could signify that such an individual has the neural plasticity to benefit from pro-cognitive interventions  for enhancing cognition in patients with chronic psychoses , 107. TCWith what is currently known about MMN and neurocognitive impairment in SZ, we can consider how EEG biomarkers can be used in the service of a precision medicine approach to clinical trials in psychiatry.While pro-cognitive interventions for psychotic illnesses tend to focus on single diseases like SZ, cognitive impairment has been noted in related illnesses, including schizoaffective disorder and bipolar disorder with psychotic features. This parallels genetic evidence which supports a link between SZ, schizoaffective disorder and bipolar disorder. Despite this link, in traditional drug development pro-cognitive interventions are generally assessed in one population first , and then subsequent trials assess if such an intervention is useful in other related conditions. However, a basket-style precision medicine approach using EEG biomarkers could offer a more streamlined way to discover drugs targeted at transdiagnostically-related illness domains like cognitive impairment. For example, as shown in Figure Similarly, using EEG-guided umbrella designs in psychiatry would better improve pragmatic trials matching interventions to patient strengths. For example, in a SZ trial comparing different pro-cognitive interventions, positive response to particular EEG biomarkers would help stratify different treatment strategies (see Figure These new trial designs are not without limitations. First, due to their relative novelty such designs have not yet been attempted in psychiatry, and thus there is little precedent for how these trials would be staged. Such trials require greater logistical burdens, require larger cohorts of patients, and are costlier to run. Furthermore, such trials may face barriers in recruiting enough patients with specific biomarker profiles, and experience challenges in balancing treatment arms. Both basket and umbrella trials would require new collaborative frameworks, and require nuanced statistical and administrative support.Despite these potential limitations, using biomarkers to inform clinical trials in psychiatry holds the potential to improve our current understanding of psychiatric illness, and creates an additional way to determine the effectiveness of novel therapeutic strategies. Just as how various cancers are currently molecularly phenotyped, neurophysiologically-guided basket and umbrella trials could help “EEG-phenotype” cognitive impairment in illnesses like SZ. This precision-medicine approach would enhance the development of not only novel drugs, but also other comprehensive rehabilitation strategies in SZ like TCT.While this mini-review has focused on neurophysiological biomarkers in SZ, the rationale described could broadly apply to other psychiatric illnesses and other types of biomarkers, including genetic and imaging biomarkers. We anticipate that as the tools of neuroscience allow us to understand complex diseases in a more nuanced way, further development of biomarker-informed precision medicine approaches to clinical trials will help further optimize matching the right treatment to the right patient.Both authors have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer CA and handling editor declared their shared affiliation at the time of the review.