The literature suggests that the ability to numerate cannot be fully understood without accounting for the social context in which mathematical activity is represented. Team-based learning (TBL) is an andragogical approach with theoretical links to sociocultural and community-of-practice learning. This study aimed to quantitatively explore the impact of TBL instruction on numeracy development in 2 cohorts of pharmacy students and identify the impact of TBL instruction on numeracy development from a social perspective for healthcare education.Two cohorts of students were administered the Health Science Reasoning Test-Numeracy (HSRT-N) before beginning pharmacy school. Two years after using TBL as the primary method of instruction, both comprehensive and domain data from the HSRT-N were analyzed.In total, 163 pharmacy student scores met the inclusion criteria. The students’ numeracy skills measured by HSRT-N improved after 2 years of TBL instruction.Numeracy was the most significantly improved HSRT-N domain in pharmacy students following two years of TBL instruction. Although a closer examination of numeracy development in TBL is warranted, initial data suggest that TBL instruction may be an adequate proxy for advancing numeracy in a cohort of pharmacy students. TBL may encourage a social practice of mathematics to improve pharmacy students’ ability to numerate critically. There are varying conceptualizations of numeracy in education. In general, numeracy is often described as being literate in mathematics. However, this description does not encompass the social practice of mathematics imbued in our sociality. The literature suggests that numeracy cannot be fully understood without critically accounting for the social context in which mathematical activity is represented. Thus, we borrow from Lerman  and PersTo better understand active-learning strategies that develop numeracy, the related idea of critical thinking as a core aspect of numeracy development should be considered. Numeracy involves the core skill of thinking critically, and Jain and Rogers  recentlyThis study aimed to determine whether enhanced numeracy skills are a potential consequence of improved critical thinking post-TBL instruction. Additionally, this study would characterize the context of TBL as a social condition that may play a part in improving numeracy in pharmacy students.This study was approved by the Institutional Review Board at the University of Texas at Tyler (SUM2015-103). Informed consent was obtained from the participants.https://www.strobe-statement.org/).This was a retrospective longitudinal quantitative study involving 2 cohorts of pharmacy students, with data collected from each cohort at 2 points in time. It is described according to the STROBE  statement . Then, each team took the same test as a group readiness assurance test (gRAT). This required each team to engage in intra-group feedback and come to a team consensus on the answers. Any discrepancy between the students’ iRAT and the gRAT was discussed openly through intra-group feedback to reinforce the content of the fundamental concepts. Any remaining unclear concepts were then clarified with inter-group feedback through class discussion. Following class discussion and a clear understanding of the concepts, teams spent the remaining time in class engaged in solving challenging real-world problems (application exercises) that further demonstrated the material being taught in an active learning context. Structurally, the application exercises followed the 4S framework  and often concluded with multiple-choice questions or gallery walk-style activities to reinforce the underlying concepts once again. Accordingly, the TBL method of instruction imbues a social dimension to the classroom that essentially functions to actively amplify a student's social and intellectual experience .The target participants were 190 students who were enrolled in a PharmD program at a regional university in East Texas, the University of Texas at Tyler Ben and Maytee Fisch College of Pharmacy. They were administered the Health Science Reasoning Test-Numeracy (HSRT-N) before the commencing year 1 of their pharmacy school fall semesters of 2015 and 2016 and were re-administered the HSRT-N after 2 years of TBL instruction in the fall semesters of 2017 and 2018, respectively. The inclusion criteria were all pharmacy students (n=190) who initially took the HSRT-N upon entry into the 2015 and 2016 cohorts. Exclusion criteria were incomplete HSRT-N data for the longitudinal analysis . Twenty-seven students were excluded due to incomplete HSRT-N data, leaving 163 qualified participants.The variables included 8 domains: analysis, inference, interpretation, evaluation, explanation, induction, deduction, and numeracy.The HSRT-N used in this study is from Insight Assessment (www.insightassessment.com). The HSRT-N is a 38-item multiple-choice test that measures reasoning and decision-making processes . ResponsConvenience sampling can produce a bias in which some members of the population are less likely to be included than others. The variables of gender, age, race, and degree level from the 2015 and 2016 cohorts were compared with variable data from a population of pharmacy students from the 2017 and 2018 cohorts (of the same institution) to account for sampling bias. A good variance of the mean determined homogeneity between the populations accounting for sampling bias concerns. However, the variables were not compared to pharmacy student cohorts from other pharmacy institutions.The study size was informed by a convenience sample (n=163) of student pharmacists . No studGraphical data and mean scores were determined using Microsoft Excel ver. 16.0 . Comparisons of HSRT-N scores before and after TBL instruction were performed using the paired Student t-test. A comparison of HSRT-N scores for students who did and did not improve their scores was performed using the Welch t-test. Data were analyzed using JASP ver. 0.10.2 .i=0.068) following 2 years of TBL instruction  increases in overall student HSRT-N scores and percentile rank scores were identified . Notablytruction . This fiWithin the health sciences, nurses, medical students, and physicians often demonstrate a lack of confidence in numeracy and struggle with basic conversions, probability analysis, and risk based on numerical data. Bullen et al.  found thMany sources have acknowledged active learning environments that incorporate communities of practice can be a potent solution for facilitating students’ understanding of complex problems. TBL instruction is an andragogical approach that engages pharmacy students to solve complex problems and prepares them to manage clinical situations with increased confidence. Importantly, TBL has also improved pharmacy students’ ability to think critically . This stBy refocusing critical thinking to include numeracy development through TBL, pharmacy students can experience mathematics through real-world sociocultural experience(s) that enable numeracy participation as ethical and active citizens of their group context. This retrospective review of HSRT-N numeracy data supports the conceptual association of critical thinking and numeracy. It also implores us to consider the social function context of TBL instruction as a potential facilitator of numeracy development. Specifically, numeracy concepts should include communities of practice that reflect how students numerate in the real world and how numeracy is shaped by ongoing sociocultural experiences. We suggest that TBL instruction may achieve this goal by providing students an opportunity to learn numeracy frameworks in a social practice format during the readiness assurance process and application exercises. The iRAT and gRAT provide consistent formative feedback, facilitated measurement of knowledge acquisition, and precise comprehension. Then, application exercises reinforce students critical thinking across a problem set to consider multiple solutions—forming a thinking habit of mind beneficial to all forms of decision-making, including numeracy. Finally, the shared discussions encouraged by TBL instruction permit students to consider peer perspectives and communal norms essential for social group learning . The socWe also must consider that engaging students socially to learn mathematics is critical for improving students’ numeracy knowledge . TBL is Extending this perspective to numeracy knowledge suggests that numeracy development may be shaped by TBL communities of practice that require socially engaged problem-solving in a real-world mathematical manner. Viewing numeracy as a social practice within pharmacy education exploits how students’ numeracy practices have sociocultural contingencies. O’Keeffe and Paige  add suppThis research was subject to a regional limitation because the data were obtained from 1 institution (the University of Texas at Tyler Ben and Maytee Fisch College of Pharmacy); thus, further studies at different institutions using TBL instruction would be beneficial. All instructors were trained in the implementation of TBL; however, not all instructors were certified in TBL.A TBL approach to numeracy may provide a rich classroom environment to help develop and apply mathematics in various healthcare education paradigms. The community-of-practice experience of pre-class preparation, readiness assurance, and application exercises can stimulate students to engage and render opportunities to think critically—the cognitive foundation of numeracy. The interpretation of many healthcare diagnostics and related medical decision-making has become more complicated and dependent on mathematically complex solutions. There is a growing need to enhance curricular design and incorporate andragogical approaches that prepare future healthcare professionals to be numerate successfully. Additionally, numeracy is consequential in understanding attitudes and behaviors associated with health-related recommendations. For example, the recent coronavirus disease 2019 (COVID-19) pandemic exposed sociocultural challenges to healthcare practices that could have benefited from greater use of social numeracy. An inability to effectively communicate healthcare recommendations can give rise to misinformation, medical hypervigilance, or reckless behavior.Numeracy is acutely linked to healthcare decision-making and outcomes. Yet, healthcare practitioners have shown inadequate skills in essential tasks like interpreting and communicating basic patient screening statistics. More of today’s healthcare practices, post-COVID-19 and beyond, demand problem-solving that orients social participation within healthcare solutions. Healthcare professionals must seek to increase numeracy skills and be competent conduits of medical information for the benefit of society, and TBL instruction may offer this opportunity. Our findings suggest that TBL instruction may offer meaningful implications to improve numeracy skills across multiple healthcare delivery paradigms. We encourage further research on this andragogical approach in various healthcare education settings.This study demonstrates enhanced numeracy skills of pharmacy students following two years of TBL instruction. The data showed that numeracy skills were the most significantly improved HSRT-N domain. By adopting critical thinking as a core element of numeracy, we aptly centered TBL instruction—including its sociocultural and communities of practice context—important for advancing pharmacy students’ numeracy skills. Although a closer examination of numeracy development in TBL is warranted, the initial data suggest that TBL may be an adequate proxy for advancing numeracy in pharmacy students.


Risk factors for child maltreatment are well-described, but clinicians may overlook these risk factors. The Safe Environment for Every Kid (SEEK) model is an evidence-based approach to identifying psychosocial risk factors for child maltreatment. This article describes a quality improvement initiative to implement the SEEK model in a unique pediatric setting, a Children’s Advocacy Center.The objectives were to (1) describe the identification of psychosocial risk factors for child maltreatment by implementing the SEEK screening tool with each new family, (2) achieve and sustain a SEEK completion rate of greater than 85%, and (3) achieve and sustain a SEEK follow-up compliance rate of greater than 75%. Structured quality improvement methods, including several plan-do-study-act cycles, were used to implement interventions.The percentage of caregivers who completed the SEEK questionnaire increased from a baseline of 76% to 86%, which was sustained for more than 2 years, resulting in a better understanding and support of families’ needs. Caregivers completed 3,606 SEEK Parent Questionnaire-R. Mental health concerns and food insecurity were among the most commonly endorsed items. Follow-up compliance increased from 47% to 90%, a level that has been maintained.While Children’s Advocacy Centers evaluate children with suspected abuse, identifying current stressors in the home and linking families with resources to address their immediate psychosocial concerns can improve short- and long-term outcomes. This initiative demonstrates the feasibility of incorporating consistent screening for psychosocial risk factors for child maltreatment in this busy environment. Abused and neglected children are at greater risk of injuries, psychological disorders, poor health, and other negative personal and social outcomes.13 Further, the SEEK model supports the concept that identifying social determinants of health, which are also risk factors for child maltreatment, in a pediatric healthcare setting provides a valuable opportunity to assist at-risk families in a supportive environment. Components of the model include healthcare professional training, a brief caregiver survey to identify psychosocial risk factors for child maltreatment, SEEK algorithms to prioritize and address targeted problems, referrals to behavioral health professionals, and written parent resources.15 Designed to support and strengthen families of children 0–5 years old, the SEEK program is an evidence-based, cost-effective approach associated with reductions in child maltreatment.17 Over the past decade, the SEEK model has been successfully implemented in various settings, including rural and urban primary care practices and child-care centers.18The Safe Environment for Every Kid (SEEK) model was developed with the perspective that pediatricians are uniquely positioned to help prevent child maltreatment through their routine interactions with families.19 While CACs evaluate children with suspected abuse, interventions administered in the CAC can aid in healing and prevent recurrent maltreatment. In addition, CACs can improve families’ short- and long-term outcomes by identifying current stressors and linking caregivers with resources. National Children’s Alliance, the national accreditation organization for CACs, has a mental health standard that CACs must provide “supportive services for caregivers” with “attention to mental health, substance abuse, domestic violence, and other trauma histories.”20 Our CAC did not have a consistent, systematic process to screen families for such concerns, and the SEEK model offered an approach to address this challenge.This quality improvement (QI) initiative expands upon existing SEEK research to implement the model in a unique pediatric setting—a Children’s Advocacy Center (CAC). CACs provide specialized services by evaluating children for suspected child maltreatment and serving families at risk for future abuse.This article describes a QI initiative implemented in the CAC at a large midwestern children’s hospital. The CAC employed a collaborative approach utilizing specially trained mental health advocates (MHAs) with advanced social work or counseling degrees in SEEK model administration. The objectives of this QI project were:(1) To describe the identification of psychosocial risk factors for child maltreatment by implementing the SEEK screening tool with each new family evaluated at the CAC;(2) To achieve and sustain a SEEK questionnaire completion rate of greater than 85%;(3) To achieve and sustain a SEEK follow-up compliance rate of greater than 75%.This study describes the use of the SEEK model in a novel clinic setting and expands its use to include caregivers of school-aged children and adolescents. The SEEK model creators have endorsed but not previously studied this population.Annually, the CAC evaluates > 1,300 patients referred for evaluation of suspected acute and nonacute child sexual abuse and/or physical abuse by several sources, including children services, law enforcement, emergency departments, primary care providers, and caregivers.The multidisciplinary team (MDT) CAC model is considered the best practice in child maltreatment investigations. At this CAC, the MDT includes a forensic interviewer, MHA, and medical provider. Patients undergo forensic interviews and medical examinations, while nonoffending caregivers receive education and support services from MHAs. The forensic interviewer performs nonleading interviews of children regarding child maltreatment for medical diagnosis and treatment. The MHA gathers psychosocial information from the family and provides mental health recommendations, making MHAs instrumental in SEEK implementation.The CAC launched the SEEK program as a QI initiative on July 15, 2017. As this QI project was not human subject research, it was exempt from review by the Institutional Review Board at the authors’ institution.14The CAC implemented the SEEK model in this high-risk population to improve the identification of modifiable psychosocial risk factors for future child maltreatment. The SEEK model includes 5 key components: (1) healthcare practitioner training on the SEEK model; (2) SEEK parent questionnaire; (3) use of the reflect, empathize, assess, and plan approach to discuss SEEK questionnaire findings; (4) inclusion of mental health professionals, when available, to aid in assessment and referrals; and (5) distribution of parent handouts.17 Pediatric health professionals who received SEEK training demonstrated significant improvements in addressing psychosocial risk factors for child maltreatment, including depression, substance use, intimate partner violence, and major parental stress compared with a control group.22The validated SEEK Parent Questionnaire-R (SEEK PQ-R) is the centerpiece of the model, allowing healthcare practitioners to screen efficiently for self-reported psychosocial risk factors for child maltreatment. Prior studies have demonstrated that SEEK implementation is a cost-effective way of reducing child maltreatment rates across multiple outcome measures, including fewer reports to children services, fewer instances of possible medical neglect, and less harsh punishment reported by parents.13 The SEEK PQ-R introduction explains the overall goal of the assessment is to help families and keep children safe. The questionnaire asks nonthreatening questions first  before asking more sensitive questions.13 SEEK PQ-R screens for food insecurity, harsh punishment, major parental stress, parental depression, intimate partner violence, and parental substance use. Caregivers may also write in other items for which they would like help.This QI project used the 2017 revised SEEK PQ-R, consisting of 16 questions to which caregivers can respond “yes” or “no.”13 If multiple children in a family presented, only 1 form was completed by the caregiver. The MHA met with the caregiver to discuss any endorsed responses and provide resources as appropriate. The MHA was also responsible for documenting SEEK PQ-R responses and any resources provided in each patient’s electronic health record (EHR).All caregivers of patients presenting to the CAC for initial evaluation of suspected child maltreatment received the SEEK PQ-R to complete. The SEEK PQ-R is voluntary and designed for caregivers to complete in 2–3 minutes.Early in implementation, we noted inconsistency in SEEK PQ-R completion; therefore, we assembled a multidisciplinary CAC QI team, including medical providers, a forensic interviewer, an MHA, intake/registration staff, and a QI data analyst. This group met regularly to identify steps for improving consistent administration. The aim was to increase the percentage of SEEK PQ-Rs completed and entered into the EHR for children evaluated at the CAC from 76% to > 85% by December 31, 2017 and sustain this increase for at least 12 months.At project onset, the team developed a process map to complete SEEK PQ-Rs Fig. , highligThe QI team identified multiple interventions to establish standardized processes for SEEK PQ-R administration and EHR entry. The team prioritized interventions using an Effort/Impact Analysis. Since MHAs were the one clinician type who followed patients through the entire visit, they were influential in creating a standardized workflow and ensuring SEEK PQ-R completion and EHR entry.The first Plan-Do-Study-Act (PDSA) cycle involved prioritizing paperwork for caregivers. Registration staff gave caregivers multiple forms to complete but did not provide specific guidance about the order of completion, highlighting an opportunity for improvement. By providing the SEEK PQ-R at registration and prioritizing its completion, caregivers had ample time to complete it in the waiting area or private mental health room while waiting to start the assessment. This intervention allowed MHAs to review responses and provide resources during assessments.During the second PDSA cycle, staff participated in additional education focusing on project goals, benefits, and team roles and responsibilities. Staff received regular feedback about completion rates, facilitating timely recognition of declining completion rates and exploration of causes. Competing duties impacted MHA completion rates and EHR entries; therefore, operation staff began tracking SEEK PQ-Rs and reminding staff to turn in the completed questionnaire or indicate why the questionnaire was incomplete.Despite interventions focused on process and education, SEEK PQ-Rs were still not consistently being completed and entered into the EHR. Therefore, the third PDSA involved redesigning the questionnaire format. The redesign used colored paper to differentiate it from other paperwork and included a checkbox to note the completed EHR entry. An additional note section allowed MHAs to indicate reasons for incomplete questionnaires. The redesign did not alter SEEK PQ-R questions. Pareto charts summarized the reasons for incomplete questionnaires and facilitated understanding . The team excluded the first 3 questions because they were not related to psychosocial risk factors for child maltreatment, and the MHAs had already provided resources during the assessment. The SEEK follow-up compliance rate monitored progress toward improving phone follow-up. Follow-up compliance was defined as a completed call with the caregiver or 2 documented attempts to contact the caregiver within 45 days of the CAC visit. Automated reports provided monthly compliance rates, which were recorded on a p-chart.P values were calculated using Fisher’s exact test and were determined to be significant at P = 0.05.For all p-charts, baseline data for an initial 6 months were tracked, and a centerline (average) and control limits  were calculated. Monthly data were entered into the p-chart while holding the baseline constant. We applied statistical process control rules to detect special cause variation versus common cause variation and determine when a centerline shift occurred. P < 0.001). This higher completion rate was sustained through mid-2020, with several months reaching completion rates of ≥ 90%. On average, 93 caregivers completed the SEEK PQ-R monthly.Figure The improved completion rate in January 2018 from 76% to 86% highlights the interventions’ impact. A change in workflow to engage MHAs in ensuring SEEK PQ-R completion and EHR entry was vital to this improvement. Automated reports highlighting missing data helped to sustain improvement. The QI team regularly shared these reports with the team, which informed subsequent interventions. In addition, CAC staff developed data entry reminders, allowing for their active involvement and promotion of a team approach.Table P < 0.001) with sustained improvement through mid-2020. Several months reached compliance rates of ≥ 95%. On average, 28 caregivers with SEEK PQ-R positive responses received follow-up each month. The increase in the compliance rate highlights the interventions’ impact. Assigning dedicated staff to complete follow-up calls alleviated MHA workload and a clearly defined 45-day completion period aided in achieving and sustaining follow-up compliance.Figure CACs are uniquely positioned to identify and address psychosocial factors associated with child maltreatment. However, our CAC was not consistently screening for these targeted psychosocial concerns before SEEK implementation. Therefore, the goal of this QI initiative was to create a consistent process change for the administration of the SEEK PQ-R to assess these risk factors and provide resources when applicable.The SEEK PQ-R was initially designed for a primary care setting, allowing for continuity with families and the ability to reassess ongoing needs periodically. Before implementation, the QI team consulted with the SEEK creators to inform implementation in a CAC setting, given the time-limited contact with families. This project demonstrated it was feasible to implement and sustain a process that administered SEEK PQ-Rs at greater than 85% compliance for more than 2 years in a high-volume CAC setting.One key factor in successful implementation was the demonstrated benefit to families. Before the consistent screening, the MHAs identified some needs during their sessions; however, the MHA role was largely supportive. SEEK model implementation enabled the identification of social and mental health needs in a structured, efficient manner, allowing MHAs to provide resources to families consistently. Although CAC involvement is time-limited, our MHA model supports short-term follow-up to facilitate linkage with services.During implementation, establishing process accountability was essential. Several interventions were necessary to improve this process, including regular completion rate feedback, periodic checks on process implementation, and staff education. A flowchart was created in the EHR to facilitate efficient documentation while allowing easy data extraction. Additionally, active participation by MDT members was integral to project success, including the identification of champion leads who provided direct patient care in the CAC. These champion leads identified interventions, provided periodic checks on process implementation, established reliable methods to maintain change, and provided bidirectional feedback and communication between their teams and the QI team. These champions also helped provide stability during periods of staff turnover.SEEK model implementation included challenges. The QI team recognizes the limitation that the SEEK model was developed for a primary care setting. However, we believe that there was a benefit to creating an efficient, standardized approach to identifying and addressing psychosocial concerns in families. Staff did not always recognize the importance of the project, and gaining support was difficult during the initial implementation phases. There were perceptions that the SEEK PQ-R would distract from acute child maltreatment concerns, limiting the MHA’s ability to support families and increasing staff workload if MHAs identified other psychosocial needs. To reframe concerns, the importance of helping families by addressing other critical issues, such as food insecurity or unstable housing, was emphasized regularly. To ease workloads, we developed a resource binder to aid staff in providing information on local housing programs, food pantries, and parenting classes. Despite providing resources, families not linked with services continue to be a concern. We plan to explore barriers further and implement strategies to promote linkage. This challenge highlights the importance of good referral processes and customized handouts.Another concern was the impact on clinic flow. During the beginning stages, staff perceived that adding the questionnaire to the other required forms inhibited the caregiver’s ability to complete the lengthier paperwork, potentially delaying the MHA’s contact with the caregiver. The QI team reviewed the brevity of the questionnaire with staff; however, initially, it was sometimes not completed due to a reported lack of time. This issue was mitigated by placing the SEEK questionnaire at the top of the registration paperwork.Ultimately, staff serving as project champions led to a more positive attitude regarding the project’s intent of helping to strengthen families. One champion took ownership of collecting every patient form and ensuring that MHAs identified reasons for incomplete forms. This change bolstered the expectation that caregivers should complete questionnaires unless extenuating circumstances existed. Additionally, an MHA champion embraced the project and modeled utilizing the questionnaire during assessments positively. When staff turnover occurred during the project, new MHAs seemed to accept the intention of the questionnaire and expectation to address psychosocial issues more easily as their onboarding introduced the SEEK program.The success of this QI effort has allowed for ongoing work to evaluate mediation of the risks for child maltreatment in this population. Our next goal is to evaluate families’ abilities to link with services and address barriers to service linkage.This initiative describes a systematic QI approach to implementing the SEEK model to assess psychosocial risk factors for child maltreatment. In addition, we demonstrated the feasibility of incorporating this screening process in a busy CAC setting. This finding may be beneficial to other CACs and facilitate compliance with CAC accreditation standards for mental health services to support the safety of children and reduce the risk of future abuse.The authors have no financial interest to declare in relation to the content of this article.Assistance with the study: The authors would like to thank the Nationwide Children’s Hospital QIS Department, the CAC Mental Health Advocates, and Gail Hornor for their commitment to the implementation of this project and to ensuring that the families receive needed assistance and support. The authors would also like to thank the SEEK Model developers for their assistance in the early implementation phases.


Behavioral and electrophysiological measures were examined in 30 older and 20 younger neurologically-healthy adults. Relationships between performance on the number comparison task, behavioral measures, and neural activity were used to determine correlates of listening deficits associated with aging. While older participants showed poorer performance overall on all behavioral measures, their scores on the number comparison task were largely predicted  by their sensitivity to temporal fine structure cues. Compared to younger participants, older participants required higher signal-to-noise ratios (SNRs) to achieve equivalent performance on the number comparison task. With increasing listening demands, age-related changes were observed in neural processing represented by the early-N1 and later-P3 time windows. Source localization analyses revealed age differences in source activity for the degraded listening condition that was located in the left prefrontal cortex. In addition, this source activity negatively correlated with task performance in the older group. Together, these results suggest that older adults exhibit reallocation of processing resources to complete a demanding listening task. However, this effect was evident only for poorer performing older adults who showed greater posterior to anterior shift in P3 response amplitudes than older adults who were good performers and younger adults. These findings might reflect less efficient recruitment of neural resources that is associated with aging during effortful listening performance.Factors affecting successful listening in older adults and the corresponding electrophysiological signatures are not well understood. The present study investigated age-related differences in attention and temporal processing, as well as differences in the neural activity related to signal degradation during a number comparison task. Participants listened to digits presented in background babble and were tested at two levels of signal clarity,  OA differences were evident across a range of latency windows. These results highlight the possibility of earlier processing deficits in OAs affecting subsequent higher-level functions of stimulus selection and response execution. Previous studies using a-priori selected electrode/s have shown increased N1 amplitudes with increasing task difficulty/speech degradation , and inon (e.g. ) or no con (e.g. ) in N1 aon  in adults with hearing loss (mild–moderate), compared to age-matched normal-hearing controls during passive listening , 96. RoqDifferences in neural processing in later time windows between OAs and YAs in the current study suggest that the effects of aging on early cognitive resource allocation subsequently had impacts on later time-windows of post-perceptual stimulus processing. Later time-windows beyond 400 ms include the P3b component that is often linked to processes involving cognitive processing and decision-making , 102. Ondegraded condition might be a strategy adopted by the OAs to match the level of cognitive control demanded by the task [degraded condition. There is complementary evidence for this from an fMRI study which also showed activation in this region when participants listened to sentences with increasing levels of acoustic degradation [The increased frontal distribution and enhanced frontal P3 amplitudes observed for the the task . The incradation . Recent radation . The metradation ; the difradation  shows soradation ).The current study demonstrated an association between left prefrontal cortex activation and poorer speech recognition abilities in OAs. This pattern is consistent with previous research that has shown age-related enhancement of frontal P3 ERPs associated with poorer performance on neuropsychological tests of frontal lobe function . Similarincreasing prefrontal (including left MFG) activation (baseline < follow-up) compared to those with stable performance on behavioral tasks [degraded) and in poorer performers who required higher SNRs to process degraded speech. In addition, we also showed supporting evidence for increasing posterior to anterior shift in poorer-performing OAs compared to high-performing OAs and YAs  compared to the good-performing OAs . Two previous studies that subdivided older participants based on their memory performance relative to IQ scores, showed similar evidence for more frontal activity (P3 time window) in poor performing OAs compared to high performers and younger adults [The results observed here are also consistent with recent longitudinal studies where only participants with declining cognitive functions showed al tasks , 113. Thr adults , 115. Her adults , 111. Dir adults ), compardegraded speech processing. The regression analyses suggested that task performance depended on supra-threshold auditory processing abilities (TFS1). Thus, hearing loss/audibility compensation via hearing aid amplification might not be the only determinant factor for successful speech recognition in noise by OAs with/without hearing loss [Overall, this study provides important insight into neural processing associated with age-related speech-in-noise difficulties. Our findings support evidence that age-related speech processing deficits are a consequence of early auditory processing deficits . Specifiing loss . Also, Oing loss ). Hence Despite the findings and methodological features of this study, the main limitation was the inclusion of participants with hearing loss in the OA group. The stimulus spectrum-audibility was adjusted across the OAs and stimuli were presented at similar intensity levels between groups. Although this minimized audibility effects, the contribution of peripheral hearing loss cannot be completely ruled out as OAs typically have some form of hearing loss or poorer hearing thresholds at frequencies beyond 8 kHz , 118. WeAlthough we used a within-subject design to control for individual differences, variables such as handedness, visual acuity, linguistic background, and neuropsychological profile are potential confounds (e.g ) that coWhile the number of electrodes used here gave us valuable insights about the differences in the underlying source activation, a more localized analysis of the brain activation would need a larger number of electrodes to avoid mislocalizations and blurring effects. A longitudinal study design with the addition of high-density EEG recordings to reduce source localization errors , may allS1 File(DOCX)Click here for additional data file.


Enzyme-responsive polymeric micelles hold great potentialas drugdelivery systems due to the overexpression of disease-associated enzymes.To achieve selective and efficient delivery of their therapeutic cargo,micelles need to be highly stable and yet disassemble when encounteringtheir activating enzyme at the target site. However, increased micellarstability is accompanied by a drastic decrease in enzymatic degradability.The need to balance between stability and enzymatic degradation hasseverely limited the therapeutic applicability of enzyme-responsivenanocarriers. Here, we report a general modular approach for designingstable enzyme-responsive micelles whose enzymatic degradation canbe enhanced on demand. The control over their response to the activatingenzyme is achieved by stimuli-induced splitting of triblock amphiphilesinto two identical diblock amphiphiles, which have the same hydrophilic–lipophilicbalance as the parent amphiphile. This architectural transition drasticallyaffects the micelle–unimer equilibrium and therefore increasesthe sensitivity of the micelles toward enzymatic degradation. As aproof of concept, we designed UV- and reduction-activated splittingmechanisms, demonstrating the ability to use architectural transitionas a tool for tuning amphiphile–protein interactions, providinga general solution toward overcoming the stability–degradabilitybarrier for enzyme-responsive nanocarriers. At the same time, micelles must also disassemble once theyreach their target site to release their therapeutic cargo.9 Furthermore, micellar degradation and disassembly are crucial fortraceless clearance of the DDSs from the body after delivering theirpayload.10 The high specificity and overexpressionof disease-associated enzymes in diseased tissues make enzymes highlypromising stimuli for triggering the selective release of drugs frommicellar nanocarriers.12 Unlike stimuli-responsive micellesthat respond to dimensionless stimuli such as light14 or temperature,15 enzymatically degradablemicelles show a reverse correlation between micellar stability andtheir responsiveness to the activating enzymes.16 Once micellar stability reaches a certain threshold, theybecome unreactive toward the activating enzyme. The challenge to balancebetween stability and degradability is one of the key limitationsof such nanocarriers. In previous reports, the authors and othersfound that decreasing the overall molecular weight of polymeric amphiphiles,while preserving their hydrophilic-to-lipophilic balance (HLB), significantlyreduces micellar stability toward enzymatic degradation.19 Based on these findings, herein, we set to develop a general strategyto overcome the stability–responsiveness barrier. Our approachis based on using stimuli-induced architectural transition of hydrophobic–hydrophilic–hydrophobic(B-A–B) triblock copolymer (TBC) amphiphiles to hydrophobic–hydrophilic(B-A′) diblock copolymer (DBC) amphiphiles as a tool for enhancingtheir enzymatic degradability.Polymeric micelles have great potentialto serve as smart drugdelivery systems (DDSs).22 Upon activationby external stimuli and cleavage of the responsive linker at the centerof the hydrophilic block, the TBCs will split into two identical DBCs.As these DBC amphiphiles have the same HLB as the original TBC, theyshould remain assembled as micelles, and only minor cargo releaseis expected. On the other hand, lowering the molecular weight by halfand changing the architecture from triblock to diblock copolymersshould significantly increase the unimer–micelle exchange rate.25 This change in unimer–micelle equilibrium is expected toaccelerate enzymatic degradation of the DBCs’ hydrophobic blocks,leading to complete disassembly of the hydrolyzed polymers  blocks (28 The dendrons contained hydrophobic ester end-groups (The reported triblock amphiphilesare designed to undergo on-demandsplitting exactly at the center of the hydrophilic (A) block, yieldingtwo identical amphiphilic diblock copolymers with the same HLB asthe parent TBC. In addition, the TBC amphiphiles contain two enzymaticallydegradable hydrophobic blocks on both sides of the central hydrophilicblock and hence are expected to self-assemble into nanosized flower-likemicelles, similar to other triblock amphiphiles.polymers 1. To dem) blocks 1.27,28 Td-groups 1, servintert-butyl acrylate (tBA) froma bifunctional initiator that contained the splittable linker at itscenter.31 To demonstrate the generality and modularity of ourapproach, two stimuli-responsive linkers were used: a redox-responsivelinker that bears a disulfide bond in its center, which can be cleavedby a reducing agent such as dithiothreitol (DTT), and a UV-responsivelinker that contains 4,5-dimethoxy-2-nitrobenzyl (DMNB) linked byan AB2 self-immolative spacer.32 After polymerization, the terminal bromides were substituted intoazides, which were conjugated by copper-catalyzed azide–alkynecycloaddition (CuAAC)33 with esterase-cleavablehydrophobic dendrons.34 The dendrons werefluorescently labeled with 7-diethylamino-3-carboxy coumarin (7-DEAC)due to its ability to form excimers when the micelles are assembled,as indicated by fluorescence emission maxima at 560 nm .35 This red-shifted emission of the fluorescently labeled amphiphilesin the assembled state can supply essential structural informationon the micellar mesophase37 during the transformation from the TBC to DBC amphiphiles.At the last step of the synthesis, the tert-butylprotecting groups were removed under acidic conditions, exposing highlyhydrophilic carboxylic acids of the poly (acrylic acid) (PAA) backbone. All TBCs were obtained in high purity and characterizedby NMR, HPLC, SEC, and UV-Vis and fluorescence spectroscopies (seethe Supporting Information).The synthesis of the TBCs 1A startebackbone1B. In adS32). Furthervalidation for the formation of micelles was obtained by transmittanceelectron microscopy (TEM), which showed spherical structures withsimilar diameters . Next, wecharacterized the architectural transition of self-assembled TBCsinto DBCs  by dynamic light scattering(DLS), which showed structures with diameters of 12 ± 4 nm forboth SS- and DMNB-TBC-based micelles (iameters S29. Nextiameters S29. NextS32) and after an additional8 h of incubation at 37 °C .SEC was then used to verify the splitting of theamphiphiles. Dueto the strong column interaction of the multiple carboxylic acidsof PAA, SEC was performed for the 25 we expected the changefrom TBC to DBC amphiphiles to lead to much faster exchange rates.As the enzymatic degradation process strongly depends on the abilityof the enzyme to reach its hydrophobic substrates, this change inarchitecture and the resulting increase in exchange rates should significantlyaccelerate the enzymatic degradation.18 The enzymatichydrolysis of the hydrophobic end-groups of the dendron by the activatingenzyme PLE should result in a significant decrease in the overallhydrophobicity of the amphiphiles, leading to the complete disassemblyof the micelles.Once the architectural transition from TBCto DBC was confirmed,we tested its effect on the enzymatic degradation of the amphiphiles.Based on the inspiring work of Lodge and Bates, which studied theeffects of molecular weight and architecture on unimer–micelleexchange rates,Figures S30 and S33). In addition, no hydrolysiswas observed for all three TBC and related DBC amphiphiles in theabsence of the activating enzyme . These control experiments demonstrate that the acceleration ofthe enzymatic degradation rates was solely due to the splitting ofthe TBC amphiphiles and not because of the background effects of theapplied stimuli.Micellar solutions of both TBCs and DBCs weretreated with PLEand incubated at 37 °C for 8 h. Using HPLC, we could directlyquantify the enzymatic degradation by monitoring the peak areas ofthe amphiphiles at 420 nm, which is the absorbance wavelength of thelabeling dye 7-DEAC. While SH-DBC amphiphiles were fully degradedwithin less than 4 h 3B. The pIn light of the potential application of thisarchitectural transitionas a release mechanism for controlled drug delivery systems, we wantedto test if the transition from TBC to DBC will affect the releaseof the encapsulated hydrophobic cargo. Nile red was selected as amodel cargo, as it is highly emissive in nonpolar hydrophobic microenvironmentssuch as a micelle and has a very weak emission in polar microenvironmentssuch as PBS. Nile red was encapsulated within the TBC micelles andas expected showed high fluorescence intensity. The TBC micelles werethen incubated with DTT or UV-irradiated to induce the splitting intoDBCs, followed by addition of PLE. While only minor changes in fluorescencewere observed for both types of TBC-based micelles in the presenceof the activating enzyme, significant decreases in fluorescence emissions,indicating the release of Nile red, were observed for the DBC-basedmicelles 3C,F.The40 was selected as a model protein, as it wasshown to interact with the hydrophobic domains of our amphiphiles.41 The self-reporting spectral mechanism of themicelles was utilized to evaluate the differences in the degree ofinteractions of micelles with BSA before and after splitting. Micellarsolutions of TBCs and DBCs were treated with either BSA , and fluorescence spectra were recordedevery 15 minutes for 2 h. To qualitatively analyze the degree of micellardestabilization, we calculated the ratio between fluorescence intensitiesat 480 and 560 nm, which correspond to 7-DEAC emissions, while theamphiphiles are in their unimer and micellar states, respectively.Interactions of BSA with the hydrophobic blocks of the amphiphilesshould tilt the unimer–micelle equilibrium toward the unimerstate and in addition cause a significant increase in the fluorescenceof the 7-DEAC dye due to a solvatochromic effect, causing an overallincrease in the unimer/micelle emission ratio.42 Based on the fluorescence spectra showing that the unimer/micellefluorescence ratio for the TBC-based micelles is roughly half of theratio for the DBC ones, it is clear that DBC micelles were more sensitivetoward BSA in comparison with TBC micelles. The comparable trendsof the increased degree of interactions for both PLE and BSA withDBC micelles indicate that these protein–amphiphile interactionsfollow a similar mechanism. As proteins cannot penetrate through thehydrophilic shell, unimers are required to escape the micelles tointeract with them.43 The observed dependence of polymer–proteininteractions on the polymeric architecture opens up the way for usingarchitectural change as a modular tool for controlling the proteinresponsiveness of the hydrophobic blocks.After confirming the abilityof the architectural transition fromTBC to DBC to affect the interaction of the hydrophobic blocks withPLE, we wished to examine the generality of this molecular strategyto tune the interactions with other proteins. Bovine serum albumin(BSA), a transport protein that is known to interact with hydrophobicmoieties,ther BSA 4 or PBS The need to balance between stability andenzymatic degradabilityof polymeric micelles has been a key obstacle toward their translationinto nanocarriers that can be activated by disease-associated enzymes.To address this challenge, we developed a modular approach based onstimuli-induced splitting of amphiphilic triblock copolymers intotwo equivalent diblock amphiphiles. This architectural transitionaffects the kinetic stability of the assemblies, as the faster unimer–micelleexchange rates of the smaller diblock amphiphiles make their hydrophobicblocks more accessible to proteins. As a proof of concept, we designedfluorescently labeled TBC amphiphiles with enzymatically degradabledendritic end-groups and a single cleavable linker, which was locatedexactly in the middle of the hydrophilic block. The high molecularprecision that emerges from using dendrons as the hydrophobic blocks,together with the self-reporting spectral mechanism, allowed us tocarefully study the transition from TBC- to DBC-based micelles inresponse to interactions with two proteins: an enzyme (PLE) and atransport protein (BSA). We show that this induced architectural changeis not affecting the HLB of the split amphiphiles, the size of themicelles, or their thermodynamic properties. However, the stimuli-inducedarchitectural transition from TBC to two DBC amphiphiles drasticallydecreases the kinetic stability of their micelles toward interactingwith enzymes. The ability to significantly affect the enzymatic responsivenessis demonstrated by the substantially faster enzymatic degradationand micellar disassembly of the DBC amphiphiles in comparison withthe TBC based micelles. To show the generality of our approach, wedesigned and studied TBC amphiphiles that can respond to two differenttypes of stimuli—reducing agent and UV light. Our results showthat this approach can potentially allow simple tailoring of TBC amphiphilesto different types of stimuli and enzymes by applying the appropriatesplittable linkers and end-groups. The triblock to diblock architecturaltransition opens up the way for the design of extremely stable andyet highly responsive polymeric assemblies for various applicationsranging from biomedicine to agriculture, where controlling the interactionbetween polymers and proteins is essential.


Inequities in health access and outcomes persist in low- and middle-income countries. While strengthening primary care is integral in improving patient outcomes, primary care networks remain undervalued, underfunded, and underdeveloped in many LMICs such as the Philippines. This paper underscores the value of strengthening primary care system interventions in LMICs by examining their impact on job satisfaction and intention to stay among healthcare workers in the Philippines.This study was conducted in urban, rural, and remote settings in the Philippines. A total of 36 urban, 54 rural, and 117 remote healthcare workers participated in the study. Respondents comprised all family physicians, nurses, midwives, community health workers, and staff involved in the delivery of primary care services from the sites. A questionnaire examining job satisfaction (motivators) and dissatisfaction (hygiene) factors was distributed to healthcare workers before and after system interventions were introduced across sites. Interventions included the introduction of performance-based incentives, the adoption of electronic health records, and the enhancement of diagnostic and pharmaceutical capabilities over a 1-year period. A Wilcoxon signed-rank test and a McNemar’s chi-square test were then conducted to compare pre- and post-intervention experiences for each setting.p = 0.001) and rural (p = 0.016) providers. The rural workforce also reported a significant improvement in medicine access (p = 0.012) post-intervention. Job motivation and turnover intention were sustained in urban and rural settings between periods. Despite the interventions introduced, a decline in perceptions towards supply accessibility, job security, and most items classified as job motivators was reported among remote providers. Paralleling this decline, remote primary care providers with the intent to stay dropped from 93% at baseline to 75% at endline (p < 0.001).Among the factors examined, results revealed a significant improvement in perceived compensation fairness among urban (The impact of strengthening primary care on health workforce satisfaction and turnover intention varied across urban, rural, and remote settings. While select interventions such as improving compensation were promising for better-supported settings, the immediate impact of these interventions was inadequate in offsetting the infrastructural and staffing gaps experienced in disadvantaged areas. Unless these problems are comprehensively addressed, satisfaction will remain low, workforce attrition will persist as a problem, and marginalized communities will be underserved.The online version contains supplementary material available at 10.1186/s12913-022-08799-1. The passage of the Universal Health Care Law in 2019 marked the Philippines’ commitment to achieve equitable health coverage for all, an endeavor shared by countries worldwide  and as aLargely driven by workforce maldistribution and system fragmentation, inequities in health have persisted in the absence of a well-supported primary care network . DispariLiterature examining emigration patterns forward the substantial impact of job satisfaction on turnover intention. Locke broadly defines job satisfaction as “a pleasurable or positive emotional state resulting from the appraisal of one’s job or job experiences” . A myriaAdopting Herzberg’s two-factor framework for analyzing job satisfaction, the objectives of this study are: 1) to evaluate the impact of strengthening urban, rural, and remote primary care system interventions on HCW satisfaction; and 2) to compare turnover intention among HCWs before and after the intervention period.A pretest-posttest design was used to assess HCW job satisfaction and turnover intention across urban, rural, and remote settings in the Philippines. This entailed data collection of satisfaction measures through a single pre-test, followed by an intervention, and then a collection of post-test data on the same measure. The present study was conducted as part of the Philippine Primary Care Studies (PPCS) program, a longitudinal and multi-sited research series aimed at strengthening primary care systems through patient-centered interventions. In 2016, PPCS piloted its urban program to model comprehensive primary care, which provided free access to outpatient services, laboratory and diagnostic procedures, and medicines to eligible patients. This model and its package of interventions were extended to the study’s rural and remote sites in 2019. In delivering these interventions, HCWs were supported through enhanced capacity-building, the development of electronic health records (EHR), and the introduction of performance-based financial incentives. The impact of these interventions was then assessed, with HCW job satisfaction being one of the eight health system outcome measures outlined in the PPCS primary care model .A pre-validated Stayers questionnaire  initiallSince the original instrument was used to measure physician satisfaction in a remote setting, several sections of the original questionnaire did not apply to the practice types and settings examined in this study. As such, only 18 of the original 77 items were maintained  an urban site—the University of the Philippines Health Service Diliman in Metro Manila; b) the rural municipality of Samal, Bataan; and c) the remote municipality of Bulusan, Sorsogon. A census of all HCWs from the urban, rural, and remote sites was obtained—totaling 36, 54, and 117 respondents respectively. Self-administered questionnaires were distributed to the respondents in September 2016 for the baseline period and again in December 2017 for the endline assessment at the urban site. Baseline surveys for rural and remote sites were distributed during the study preparation phase in April 2019 and assessed after the one-year implementation in June 2020 through the endline survey. Verbal and written consent from each respondent was obtained before survey distribution.P-values of < 0.05 were considered statistically significant for this study. Ethical approval for this study was obtained from the University of the Philippines Manila Research Ethics Board (UPMREB – 2015-489-01) and the Philippines’ Department of Health Single Joint Research Ethics Board (SJREB – 2029-55). Ethics approval was annually renewed for all study sites. Furthermore, verbal and written informed consent was obtained from all health workers who have participated in this study.Data gathered were encoded in Microsoft Excel and were analyzed using Stata version 12.0 and R version 3.5.0. Demographics were expressed through percentage comparisons for categorical variables, whereas mean scores were used to compare continuous data. Likert responses were scored as 1 = Strongly Disagree (SD); 2 = Disagree (D); 3 = Neutral (N); 4 = Agree (A); 5 = Strongly Agree (SA). Upon analysis, Likert-type responses were examined per item and as dichotomized responses  –31. Multbarangay health workers) who bridge the gap between health systems and localities [Majority of our respondents were female. Our participants were HCWs from the sites and included family physicians, nurses, midwives, community health workers, and staff. The urban site had the most number of physicians while the rural and remote sites being serviced by community health workers , far less perceived their work as enjoyable 63%) or felt positively towards their workplace morale (72%) at baseline. In contrast to urban data, the majority of rural and remote HCWs (> 85%) were generally more motivated despite experiencing moderate to low workplace hygiene at the start of the study period. Among hygiene factors, over half of the workforce across all sites felt undercompensated during the baseline period. The baseline percentage of HCWs satisfied with their job hygiene was lowest at the remote site, with less than 30% of remote HCWs expressing sufficient access to medical equipment  and rural HCWs (p = 0.016), and b) perceived sufficiency in medicine supply among rural HCWs (p = 0.012). Point estimates on the change in scores for both sites suggest that median satisfaction on perceived compensation fairness increased by a full rank  perceived compensation fairness among urban (nk Table . For thenk Table .Table 4Wp < 0.001). Remote HCWs also reported lower satisfaction scores towards hygiene factors like supply accessibility and job security post-intervention. In contrast to urban andrural responses, no statistically significant changes were noted in perceived compensation fairness at the remote site.When remote data were analyzed, significantly lower satisfaction scores were reported for both motivator and hygiene factors. Satisfaction towards motivating factors was significantly lower at the end of the study—with workplace morale exhibiting the steepest decline (p = 1.000). More HCWs in the rural site indicated intention to stay  while fewer HCWs practicing in the remote site intended to stay post-intervention   delayed incentivization ; 2) HCW Apart from administrative challenges, the demographic composition of remote-based staff likely had some impact on the reported dissatisfaction towards several hygiene factors. CHWs comprised the vast majority of the remote-based workforce surveyed in this study. CHWs are part-time volunteer workers, rendering them ineligible for receiving a regular wage, unlike other primary care providers. Non-urban CHWs typically receive a marginal monthly allowance of Php 1150 (estimated at $24.00 per month) alongside other benefits such as free groceries or medical care depending on the local government unit . While iThe sporadic distribution of HCWs, particularly physicians, in remote areas proves potentially hazardous for providers—threatening to overload both staff and infrastructure. Expanding primary care providers’ responsibilities to include public health service delivery may cause low job satisfaction due to inadequate work autonomy and high dissatisfaction due to income mismatch . HCWs arEnhanced retention necessitates providing basic resources required for the job—including improved infrastructure, a unified EHR, supply accessibility, and fair compensation. Furthermore, experiences from the remote site suggest that financial incentives prove more effective once other infrastructural hurdles have already been addressed. System interventions must indeed provide enabling environments to prevent dissatisfaction and reduce workforce attrition. However, as Herzberg’s theory posits, job satisfaction is primarily achieved with a motivated workforce. In the urban site, most HCWs were not dissatisfied with hygiene factors such as workload and overall job security. However, satisfaction with motivational factors was still lower compared to rural and remote scores. Despite being in a well-supported job environment that retained its workforce the longest compared to other sites, urban data shows that good job hygiene alone does not ascertain HCW satisfaction. Providing non-monetary incentives such as training opportunities, pathways for career advancement, and involvement in clinical decision-making proves foremost essential in improving job satisfaction.This study employed a diachronic approach in evaluating HCW satisfaction across three sites, with varying baseline and endline periods per site due to funding and infrastructural constraints. The endline responses from the rural and remote sites were obtained shortly after the onset of the COVID-19 pandemic. As such, the shifting social and economic climate may have affected responses at the time of the survey. Other factors such as survivor bias may have had some impact on the reported results. Only respondents with matched scores  were included for analysis. Other factors influencing satisfaction were not controlled. As such, the magnitude of each factor and its corresponding effect on satisfaction and intent to stay was outside the scope of the present study. Attempts to further contextualize satisfaction scores have been undertaken to grasp a holistic understanding of HCW experience. These were done through informal interviews with HCWs, and long-term participant observation of field teams deployed to each site. However, we were unable to measure the role of corruption in this study and we suggest that future studies collect data on this to better qualify and quantify its effect. With these limitations outlined, this research places greater focus on the possible impact of specific interventions undertaken in strengthening primary care networks in each area.This study presents the observed impact of strengthening urban, rural, and remote primary care system interventions on primary care providers. Using Herzberg’s two-factor classification, overall job satisfaction and turnover intention were examined through motivational and hygiene factors experienced in each site before and after the implementation of study interventions. Perceptions towards job hygiene factors improved post-intervention at urban and rural sites—likely because of performance-based financial incentives provided to all HCWs during the study. Alongside the provision of monetary incentives, the expansion of service delivery networks to include additional pharmacies in the rural site showed a positive impact among HCWs in their regard for medical supply.Despite attempts to strengthen the existing primary care system and potentially exacerbated by the effects of the COVID-19 pandemic, infrastructural deficits have contributed to lower motivation and higher dissatisfaction among remote HCWs during the endline period. Reducing dissatisfaction by addressing hygiene factors at the workplace proves vital in retaining HCWs in remote and disadvantaged areas. This may be done by providing adequate remuneration and ensuring work environments support the demands of person-centered integrated care. However, targeting system interventions aimed at improving motivational factors may render beneficial in retaining a satisfied workforce in the long term. Strengthening primary care systems must, therefore, consider interventions that address motivational and job hygiene needs to improve healthcare worker satisfaction and intention to stay. This includes addressing HCW needs, strengthening infrastructural support, and enhancing primary care training across all HCW cadres. In doing so, patient-centered primary care can ultimately be better sustained by the very workforce it is founded upon.Additional file 1.


Heuristic Attention Representation Learning (HARL). This self-supervised framework relies on the joint embedding architecture in which the two neural networks are trained to produce similar embedding for different augmented views of the same image. HARL framework adopts prior visual object-level attention by generating a heuristic mask proposal for each training image and maximizes the abstract object-level embedding on vector space instead of whole image representation from previous works. As a result, HARL extracts the quality semantic representation from each training sample and outperforms existing self-supervised baselines on several downstream tasks. In addition, we provide efficient techniques based on conventional computer vision and deep learning methods for generating heuristic mask proposals on natural image datasets. Our HARL achieves +1.3% advancement in the ImageNet semi-supervised learning benchmark and +0.9% improvement in AP50 of the COCO object detection task over the previous state-of-the-art method BYOL. Our code implementation is available for both TensorFlow and PyTorch frameworks. Recently, self-supervised learning methods have been shown to be very powerful and efficient for yielding robust representation learning by maximizing the similarity across different augmented views in embedding vector space. However, the main challenge is generating different views with random cropping; the semantic feature might exist differently across different views leading to inappropriately maximizing similarity objective. We tackle this problem by introducing  Visual representation learning has been an extended research area on supervised and unsupervised methods. Most supervised learning models learn visual representations by training with many labeled datasets, then transferring the knowledge to other tasks ,2,3,4,5.The new approaches are self-supervised representation learning to overcome the existing drawbacks of supervised learning ,13,14,15Most existing contrastive and non-contrastive objectives are optimized based on the whole image semantic features across different augmented views. However, under this assumption, several challenges exist. First, popular contrastive methods such as SimCLR  and MoCoHeuristic Attention Representation Learning (HARL) framework that comprises two main components. First, the early attention mechanism uses unsupervised techniques to generate the heuristic mask to extract object-level semantic features. Second, we construct a framework to abstract and maximize similarity object-level agreement (foreground and background) across different views beyond augmentations of the same image [Motivated by perceptual grouping, we proposed the me image ,18,23. TWe introduce a new self-supervised learning framework (HARL) that maximizes the similarity agreement of object-level latent embedding on vector space across different augmented views. The framework implementation is available in the We utilized two heuristic mask proposal techniques from conventional computer vision and unsupervised deep learning methods to generate a binary mask for the natural image dataset.We construct the two novel heuristic binary segmentation mask datasets for the ImageNet ILSVRC-2012  to facilFinally, we demonstrate that adopting early visual attention provides a diverse set of high-quality semantic features that increase more effective learning representation for self-supervised pretraining. We report promising results when transferring HARL’s learned representation on a wide range of downstream vision tasks.We can summarize our main findings and contributions as follows:The remainder of this paper is organized as follows. In Our method is mostly related to unsupervised visual representation learning methods, aiming to exploit input signals’ internal distributions and semantic information without human supervision. The early works focused on several design-solving pretext tasks, and image generation approaches. Pretext tasks focus on the aspects of image restoration such as denoising , predictSelf-supervised contrastive learning. The popular self-supervised contrastive learning frameworks [ameworks ,39,40 aiameworks ,18, whicSelf-supervised non-contrastive learning. Distillation learning-based framework [ramework ,18 inspiramework  is appliramework  or by shramework ,17,39.However, most contrastive or non-contrastive self-supervised techniques maximize similarity agreements of the whole-image context representation of different augmented views. While developing localization attention to separate the semantically features ,43 by thIn contrastive or non-contrastive learning-based frameworks, HARL object-level objectives are applicable. For example, our study implements a non-contrastive learning framework using an exponential moving average weight parameter of one encoder to another and an extra predictor inspired by BYOL . HARL’s The HARL framework consists of three essential steps. In step 1, we estimate the heuristic binary mask for the input image, which segments an image into foreground and background (see described detail in h = ƒ(x), where h ∈ In step 2, we implement standard ResNet-50  convolutHARL framework structure adapts from BYOL , in whicIn step 3, we compute the HARL’s loss function of the given foreground and background latent representations  requires roughly 10M FLOPS. In our implementation, the convolution network backbone and MLP network are similar compared to baselines BYOL. Since we forward to the foreground and background representation through the projection head two times instead of one, it results in an additional 10M FLOPS in our framework, less than 0.25% of the total. Finally, the cost of computing the heuristic mask images is negligible because they can be computed once and reused throughout training. Therefore, the complexity of each iteration between our method and the baseline BYOL is almost the same for “computational cost” and “training time”.We evaluate the learned representation from the self-supervised pretraining stage on various natural image datasets and tasks, including image classification, segmentation and object detection. First, we assess the obtained representation on the linear classification and semi-supervised learning on the ImageNet following the protocols of ,51. SecoThe evaluation for linear and semi-supervised learning follows the procedure in ,52,53. FWe evaluated the HARL’s quality of representation learning on linear classification and fine-tuned model following the evaluation setup protocol ,13,39,5550 and AP75 metrics in We further evaluated HARL’s generalization ability and robustness with different computer vision tasks, including object detection of VOC07 + 12  using FaWe study the HARL’s components to give the intuition of its behavior and impact on performance. We reproduce the HARL framework with multiple running experiments. For this reason, we hold the same set of hyperparameter configurations and change the configuration of the corresponding component, which we try to investigate. We perform our ablation experiments on the ResNet-50 and ResNet-18 architecture on the ImageNet training set without labels. We evaluate the learned representation on the ImageNet linear evaluation during the self-supervised pretraining stage. To do so, we attach the linear classifier on top of the base encoder with the block gradient flow on the linear classifier’s input, which stops influencing and updating the encoder with the label information (a similar approach to SimCLR ). We runIn our HARL framework, separating foreground and background features from the output spatial feature map is essential to maximize the similarity objective across different augmented views. To verify this hypothesis, we analyze several spatial outputs in various sizes and dimensions by modifying the ResNet kernel’s stride to generate the different feature map sizes with the same dimension. For illustration, the standard ResNet is the sequence of four convolution building blocks . For ResNet-50 architecture, the dimension of conv_5x block output feature map is 7 × 7 × 2048. After changing the kernel stride of the conv_4x block from two to one, its new dimension will be 14 × 14 × 2048. In this modified ResNet-50 architecture, the conv5_x block’s spatial feature map size is the same as the conv4_x block output.We conduct the experiment for three different sizes including a deep ResNet-50  and a shallow ResNet-18 . online network and target network. Each network is defined by a set of parameters HARL framework structure reuses elements of BYOL . We use Unlike previous approaches that minimize loss function only based on the whole image latent embedding vector between two augmented views, HARL minimized the similarity of object-level latent representation, which associated the same spatial regions abstracting from segmentation mask and thus same semantic meanings. As shown in The mask loss objective converges to minimizing the distance loss objective between foreground and background latent embedding on vector space The objective combines whole image representation embedding To study the impact of weighting coefficient We compare the obtained representation using mask loss and hybrid loss on self-supervised pretraining. To do so, we implement the HARL framework with both loss objectives on self-supervised pretraining. We use the cosine schedule function to control the weighting coefficient In our work, the HARL objective uses two different image segmentation techniques. Which ones lead to the best representation? We first consider the heuristics mask retrieving from the computer vision DRFI  approachTo fully evaluate the impact of representation learning on downstream performance, we inspect the obtained representational quality with the transfer learning performance on the object detection and segmentation shown in We introduce the HARL framework, a new self-supervised visual representation learning framework, by leveraging visual attention with the heuristic binary mask. As a result, HARL manages higher-quality semantical information that considerably improves representation learning of self-supervised pretraining compared to previous state-of-the-art methods ,13,17,18In our HARL framework, the heuristic binary mask is critical. However, the remaining challenge of estimating accurate masks is suitable for datasets with one primary object, such as the ImageNet dataset. The alternative is mining the object proposal of the image in the complex dataset which contains multiple things by producing heuristic semantic segmentation masks. Designing the new self-supervised framework to solve the remaining challenge of datasets which contain multiple objects is an essential next step and exciting research direction for our future work.


Immunotherapies are now emerging as an efficient anticancer therapeutic strategy. Cancer immunotherapy utilizes the host's immune system to fight against cancer cells and has gained increasing interest due to its durable efficacy and low toxicity compared to traditional antitumor treatments, such as chemotherapy and radiotherapy (RT). Although the combination of RT and immunotherapy has drawn extensive attention in the clinical setting, the overall response rates are still low. Therefore, strategies for further improvement are urgently needed. Nanotechnology has been used in cancer immunotherapy and RT to target not only cancer cells but also the tumor microenvironment (TME), thereby helping to generate a long-term immune response. Nanomaterials can be an effective delivery system and a strong autophagy inducer, with the ability to elevate autophagy to very high levels. Interestingly, autophagy could play a critical role in optimal immune function, mediating cell-extrinsic homeostatic effects through the regulation of danger signaling in neoplastic cells under immunogenic chemotherapy and/or RT. In this review, we summarize the preclinical and clinical development of the combination of immunotherapy and RT in cancer therapy and highlight the latest progress in nanotechnology for augmenting the anticancer effects of immunotherapy and RT. The underlying mechanisms of nanomaterial-triggered autophagy in tumor cells and the TME are discussed in depth. Finally, we suggest the implications of these three strategies combined together to achieve the goal of maximizing the therapeutic advantages of cancer therapy and show recent advances in biomarkers for tumor response in the evaluation of those therapies. Immune checkpoints play an important role in maintaining homeostasis of the immune system. Increasing research has indicated that in many types of cancers, immune checkpoints are overactivated, resulting in escape of immune surveillance on tumor cells RT has been used routinely in recent decades as one of the primary treatment strategies for more than 50% of cancer patients Currently, the use of nanotechnology in RT combined with immunotherapy has shown good potential to overcome these limitations + T cells, to further enhance antitumor responses + and CD8+ T cells, and cytotoxic natural killer T cells are recruited to the surrounding TME and result in immunogenic cancer cell death + T cells, and recruit regulatory T cells via CCR4-binding chemokines Figure .RT is classically known as a strong way to kill cancer cells directly by DNA damage and free radical generation. RT results in cancer cell apoptosis and increases the release of tumor-associated antigens (TAAs) and DAMPs. DAMPs elicit immunological reactions, such as the recruitment of antigen presenting cells (APCs) and subsequent tumor-specific CD8+ T cells) will begin to proliferate in lymph nodes and spread through blood and lymphatic vessels. Finally, the activated T cells migrate to the irradiated tumor and to distant tumor lesions to start their antitumor reaction The abscopal effect noted that RT could also trigger downsizing of metastatic tumors following ionizing radiation treatment of the primary site However, an overactivated immune response can cause damage to the human body. To avoid this situation, there are some molecules responsible for maintaining homeostasis in the body, called immune checkpoints. For example, CTLA-4 is expressed on regulatory T cells and is upregulated to inhibit T-cell activation, leading to downregulation of the immune response. In addition, immune-inhibitory receptor, PD-1, is expressed on NK and T cells and binds to PD-L1 and PD-L2 expressed on APCs. Accordingly, it interferes with T-cell-mediated signal transduction to limit the immune system's killing effect of cancer cells Figure . The development of new ICIs and their clinical trials are still ongoing.Recent studies have demonstrated that ICIs can inhibit tumor growth by regulating different TME cells Cytotoxic drugs have been the primary weapon against cancer for a long time for their capacity to kill tumor cells directly. In contrast, immunotherapy treats cancer by targeting the immune system, not the tumor itself + T-cell functions, significantly suppressed tumor growth, and improved the survival rate compared to the anti-PD-L1 or RT alone group + cytotoxic T cells in the tumor and augment the response of the tumor to SBRT Although RT can cause ICD, it also leads to subsequent immunosuppressive effects. A high percentage of PD-1/Tim-3 expression in CD8 T cells was reported in HCC patients after Y90-RE treatment, which shows the exhausted status of immune cells Nonetheless, the results are not always positive. Kwon et al. showed a disappointing result of ipilimumab and RT combined therapy for metastatic castration-resistant prostate cancer (mCRPC) patients in a phase III clinical trial. There was no difference in the median overall survival of the ipilimumab group compared with the placebo group Nanotechnology can improve therapeutic benefits by reducing systemic side effects and increasing drug accumulation inside tumors Table  Photoelectrons and Auger electrons generated from irradiated metal-based NPs could contribute to dose enhancement and subsequent radiobiological enhancement Figure A.Numerous studies have investigated the radiosensitizing and synergistic effects of nanoparticles (NPs) for RT in recent decades, and different types of NPs combined with RT are summarized in + T cells infiltrating the tumor site compared to codelivery of free antibodies Figure B.NPs can improve cargo delivery by targeting tumor cells, increasing drug stability and solubility, and extending circulation half-life Table  Erel-Akbaba et al. have shown that radiation followed by the administration of solid lipid NPs conjugated with immunotherapeutic small interfering RNAs (siRNAs) against epidermal growth factor receptor (EGFR) and PD-L1 leads to a significant decrease in glioblastoma growth and improved mouse survival Figure C. Li et al. also reported that high-Z quantum dots (PbS/CdS QDs) can promote immunogenic RT and abscopal effects against cancer metastasis Another approach to anticancer effects is to utilize NPs to improve the immune response post RT, and the studies are summarized in + T-cell infiltration Recent studies have indicated that RT-induced senescence-associated secretory phenotype (SASP) cells release TGF-β and attract immunosuppressive MDSCs, which results in RT resistance and decreased T-cell efficacy +/H2O2 to O2 and release Mn2+ that can relieve the hypoxic TME, sensitize immunogenic PDT/RT, and promote tumor ablation 100 Figure D. Glycopolymer NPs are also reported to improve the capacity to target cancer cells by promoting receptor-mediated endocytosis and endowing multivalent effects for activating immune signaling in immune cells More recently, zero valent iron (ZVI) NPs have also been revealed as potential immune modulators to augment anticancer immunity by switching protumor M2 macrophages into antitumor M1 macrophages, minimizing the population of regulatory T cells and attenuating PD-L1 expression in cancer cells Although the advantages of nanotechnology in drug delivery were discussed in a previous report 2O2 and GSH concentrations in the TME) can further weaken cancer cells to achieve radiosensitization processes and induce ICD to boost immunotherapy. Third, delivering antitumor drugs, radiosensitizers, oxygen, ICIs, and genetic regulatory RNAs or providing antigen capturing/presenting function can reverse immunosuppressive TME and enhance RT and immunotherapy by membrane camouflage or engineering-designed polymeric NPs. Finally, immunomodulation by TAM repolarization from a protumor to an antitumor phenotype induced antitumor immunity by iron-based materials and glycopolymer-composed NPs Figure .Indeed, nanotechnology can also greatly help improve RT and immunotherapy through other routes. First, a strong photoelectric absorption coefficient can generate photoelectrons and Auger electrons from irradiation to enhance RT-induced ICD and RT efficiency by high-Z materials. Second, the CDT-catalyzed reaction from transition metals in a high catalytic environment  play a vital role in possessing a strong photoelectric absorption coefficient and can generate photoelectrons and Auger electrons from irradiation to enhance RT-induced ICD and RT efficiency. The transition metals  showed enzyme-like reactions Despite the advantages of RT-based NPs, additional delivery of 0.1 Gy-induced drug release As published previously, anticancer therapies induce various types of cell death. Different types of cell death mechanisms may contribute to enhancing or inhibiting the immune reaction in the TME. In this review, we discuss the immune response that could be regulated by different cell death mechanisms and suggest that autophagy could be an important modulator of anticancer effects when using nanotechnology combined with immunotherapy and RT.Figure A. The different immune responses are activated in response to cell death types, thereafter affecting therapeutic effects. For instance, apoptosis and autophagy do not induce additional inflammatory responses 2+/histone deacetylase (HDAC)/signal transducer and activator of transcription 1 (STAT1)-induced transactivation pathway Anticancer therapy could induce different cell death types, including apoptosis, autophagy, necrosis, ferroptosis, pyroptosis, and necroptosis Figure A.Autophagy  plays an important role in many eukaryotes, and autophagy-related genes (Atgs) are highly conserved. The autophagy processes include phagophore assembly , autophagosome formation (maturation), and autolysosome degradation in vitroThe first pathway is mTOR/PI3K/Akt signaling, which is dysfunctional in many cancers and is related to cancer cell growth, cancer cell survival, cytoskeletal movement, and resistance to cancer therapy The third important mechanism is the MAPK signaling pathway, including the extracellular signal-regulated kinase (ERK), C-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), and p38 kinase signaling pathways Research in our laboratory and by other groups over the last 10 years has revealed nanomaterials to be strong autophagy inducers with the ability to elevate autophagy to very high levels. One of our previous works showed that autophagy activated by silver NPs failed to trigger the lysosomal degradation pathway, leading to defective autophagic flux or autophagy dysfunction + T cells and improve the curative effect in both irradiated primary tumors and nonirradiated abscopal tumors Knowing the relationship between autophagy and tumor immunological tolerance can be a crucial event for improving tumor immunotherapy. Induction of autophagy can decrease the inflammation-activated expression of IDO to inhibit tumor development in the cervical cancer cell lines HeLa and SiHa and promote the induction of phagocytosis in macrophages 2O3) nanocrystals induced autophagy by sensitizing NSCLC cells to irradiation The above studies strongly support the dual role of autophagy in immunotherapy. Therefore, if the induced autophagy is a pro-death pathway, it should be maximized. Otherwise, it should be inhibited to enhance the anticancer effects. Nanomaterials usually induce pro-death autophagy, which serves as a significant mechanism for enhancing cancer therapy effects Figure B. Several potential biomarkers are discussed in the following section.To date, there is a growing demand to develop predictive and prognostic biomarkers of RT and immunotherapy. Dynamic biomarkers are also used to investigate how treatments may influence key transitions and potentially identify responders and nonresponders in real time, sparing patients toxicities from ineffective treatments and potentially guiding therapy decisions to more effective approaches, especially combined with novel anticancer strategies such as nanotechnology in the future The level of PD-L1 within tumors has been suggested to be a promising prognostic biomarker in patients undergoing RT, but the role of PD-L1 as a predictive biomarker still needs further investigation CTLA-4 can be detected in normal human serum, and higher levels of soluble CTLA-4 in serum have been observed in many types of cancers Neoantigens are small peptide epitopes from tumor-specific mutations. Mutations in the protein-coding regions of DNA generate truncated proteins termed ''neoantigens.'' Neoantigens result in a higher degree of foreignness to cells, which helps immune cells readily target and eliminate tumor cells Other potential biomarkers include the total number of genetic mutations in cells, called the tumor mutation burden (TMB). TMB, defined as the total number of somatic mutations per coding area of a tumor genome, is an emerging clinical biomarker associated with the response to ICI therapy In recent years, noninvasive and clinically useful image-based techniques such as SPE-CT, PET-CT, and MRI have been developed to evaluate the immune response to RT and/or immunotherapy Exosomes are a subtype of extracellular vesicles (EVs) between 50 and 130 nm in diameter that are enriched in a set of molecular markers with an endosomal source Overall, there is still much work to be done to identify and develop novel biomarkers for RT and immunotherapy in clinical applications and combined with other anticancer therapies in the future. Although numerous predictive biomarkers for tumor response and ICI treatment have been identified, there are no single biomarkers that can predict tumor treatment response. Therefore, multiple biomarkers should be considered in determining the therapeutic effects of anticancer treatments.In the era of cancer therapy, incorporating NPs with RT or immunotherapy holds much promise for expanding therapeutic options for patients. Going forward, it would be important to verify the therapeutic benefits of mechanistic studies of cell death mechanisms and regulation of the TME. Activation of multiple cell death pathways highlights a close relationship between apoptosis, autophagy, necroptosis, and pyroptosis for immunotherapy in combination with NPs, RT, or immunotherapy