Cryogels Based on Poly(2-oxazoline)s through Development of Bi- and Trifunctional Cross-Linkers Incorporating End Groups with Adjustable Stability.

1,4-Bis(iodomethyl)benzene and 1,3,5-tris(iodomethyl)benzene were used as initiators for the cationic ring-opening polymerization (CROP) of 2-ethyl-2-oxazoline (EtOx) and its copolymerization with tert-butyl (3-(4,5-dihydrooxazol-2-yl)propyl)carbamate (BocOx) or methyl 3-(4,5-dihydrooxazol-2-yl)propanoate (MestOx). Kinetic studies confirmed the applicability of these initiators. Termination with suitable nucleophiles resulted in two- and three-armed cross-linkers featuring acrylate, methacrylate, piperazine-acrylamide, and piperazine-methacrylamide as polymerizable ω-end groups. Matrix-assisted laser desorption/ionization mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy confirmed the successful attachment of the respective ω-end groups at all initiation sites for every prepared cross-linkers. Except for acrylate, each ω-end group remained stable during deprotection of BocOx containing cross-linkers. The cryogels were prepared using EtOx-based cross-linkers, as confirmed by solid-state NMR spectroscopy, scanning electron microscopy, and thermogravimetric analysis. Stability tests revealed a complete dissolution of the acrylate-containing gels at pH = 14, whereas the piperazine-acrylamide-based cryogels featured excellent hydrolytic stability.

Determination of ω-end functionalities in tailored poly(2-alkyl-2-oxazoline)s by liquid chromatography and mass spectrometry.

The in-depth analytical characterization of polymers, in particular regarding intended biomedical applications, is becoming increasingly important to elucidate their structure-property relationships. Specifically, end group analysis of e.g. polymers featuring a 'stealth effect' towards the immune system is of particular importance because of their use in coupling reactions to bioactive compounds. Herein, we established a liquid chromatography (LC) protocol to analyse bicyclo[6.1.0]nonyne-functionalized poly(2-alkyl-2-oxazoline)s (POx)s as promising functional polymers that can be applied in strain-promoted click reactions. This work involved the synthesis of poly(2-methyl-2-oxazoline) (PMeOx) and poly(2-ethyl-2-oxazoline) (PEtOx) by living cationic ring-opening polymerization (CROP) with different molar masses ranging from 2 up to 17.5 kDa and, to our knowledge, the first liquid chromatographic analysis of PMeOx. The developed analytical protocol enables the quantitative determination of post-polymerization reaction sequences with respect to the conversion of the ω-end groups. All synthesized polymers were straightforwardly analysed on a C18-derivatized silica monolithic column under reversed-phase chromatographic conditions with a binary mobile phase gradient comprising a mixture of acetonitrile and water. Subsequent mass spectrometry of collected elution fractions enabled the confirmation of the desired ω-end group functionalities and the identification of synthetic by-products.

Comparative developmental genomics of sex-biased gene expression in early embryogenesis across mammals.

BACKGROUND: Mammalian gonadal sex is determined by the presence or absence of a Y chromosome and the subsequent production of sex hormones contributes to secondary sexual differentiation. However, sex chromosome-linked genes encoding dosage-sensitive transcription and epigenetic factors are expressed well before gonad formation and have the potential to establish sex-biased expression that persists beyond the appearance of gonadal hormones. Here, we apply a comparative bioinformatics analysis on a pair of published single-cell datasets from mouse and human during very early embryogenesis-from two-cell to pre-implantation stages-to characterize sex-specific signals and to assess the degree of conservation among early acting sex-specific genes and pathways. RESULTS: Clustering and regression analyses of gene expression across samples reveal that sex initially plays a significant role in overall gene expression patterns at the earliest stages of embryogenesis which potentially may be the byproduct of signals from male and female gametes during fertilization. Although these transcriptional sex effects rapidly diminish, sex-biased genes appear to form sex-specific protein-protein interaction networks across pre-implantation stages in both mammals providing evidence that sex-biased expression of epigenetic enzymes may establish sex-specific patterns that persist beyond pre-implantation. Non-negative matrix factorization (NMF) on male and female transcriptomes generated clusters of genes with similar expression patterns across sex and developmental stages, including post-fertilization, epigenetic, and pre-implantation ontologies conserved between mouse and human. While the fraction of sex-differentially expressed genes (sexDEGs) in early embryonic stages is similar and functional ontologies are conserved, the genes involved are generally different in mouse and human. CONCLUSIONS: This comparative study uncovers much earlier than expected sex-specific signals in mouse and human embryos that pre-date hormonal signaling from the gonads. These early signals are diverged with respect to orthologs yet conserved in terms of function with important implications in the use of genetic models for sex-specific disease.

Sex differences are traditionally assumed to arise after the reproductive systems are set up in male and female embryos, and especially after these organs begin producing sex hormones. However, very early in embryo development, the sex chromosomes distinguish males (XY) and females (XX) and genes on these chromosomes are expressed differentially. In this study, we have analyzed gene expression data from mouse and human early embryos to determine whether there is sex-biased expression before implantation. Our results confirm that there is abundant sex-biased expression from the earliest stages of development, soon after fertilization. The comparison between human and mouse embryos shows comparable function of the sex-biased genes, although the specific genes involved differ between the two species.

Perceptions of effective policy interventions and strategies to address antibiotic misuse within primary healthcare in India: A qualitative study.

Objectives: Antimicrobial resistance poses a major public health threat. Despite Indian retail sector antibiotic consumption per capita increasing by approximately 22% between 2008 and 2016, empirical studies that examine policy or behavioural interventions addressing antibiotic misuse in primary healthcare are scarce. Our study aimed to assess perceptions of interventions and gaps in policy and practice with respect to outpatient antibiotic misuse in India. Methods: We conducted 23 semi-structured, in-depth interviews with a variety of key informants with diverse backgrounds in academia, non-government organisations, policy, advocacy, pharmacy, medicine and others. Data were charted into a framework matrix and analysed using a hybrid, inductive and deductive thematic analysis. Themes were analysed and organised according to the socio-ecological model at various levels ranging from the individual to the enabling environment. Results: Key informants largely focused on the importance of adopting a structural perspective to addressing socio-ecological drivers of antibiotic misuse. There was a recognition that educational interventions targeting individual or interpersonal interactions were largely ineffective, and policy interventions should incorporate behavioural nudge interventions, improve the healthcare infrastructure and embrace task shifting to rectify staffing disparities in rural areas. Conclusions: Prescription behaviour is perceived to be governed by structural issues of access and limitations in public health infrastructure that create an enabling environment for antibiotic overuse. Interventions should move beyond a clinical and individual focus on behaviour change with respect to antimicrobial resistance and aim for structural alignment between existing disease specific programs and between the informal and formal sector of healthcare delivery in India.

"It's like asking for a necktie when you don't have underwear": Discourses on patient rights in southern Karnataka, India.

BACKGROUND: Ensuring patient rights is an extension of applying human rights principles to health care. A critical examination of how the notion of patient rights is perceived and enacted by various actors through critical discourse analysis (CDA) can help understand the impediments to its realization in practice. METHODS: We studied the discourses and discursive practices on patient rights in subnational policies and in ten health facilities in southern Karnataka, India. We conducted interviews (78), focus group discussions (3) with care-seeking individuals, care-providers, health care administrators and public health officials. We also conducted participant observation in selected health facilities and examined subnational policy documents of Karnataka pertaining to patient rights. We analyzed the qualitative data for major and minor themes. RESULTS: Patient rights discourses were not based upon human rights notions. In the context of neoliberalism, they were predominantly embedded within the logic of quality of care, economic, and consumerist perspectives. Relatively powerful actors such as care-providers and health facility administrators used a panoply of discursive strategies such as emphasizing alternate discourses and controlling discursive resources to suppress the promotion of patient rights among care-seeking individuals in health facilities. As a result, the capacity of care-seeking individuals to know and claim patient rights was restricted. With neoliberal health policies promoting austerity measures on public health care system and weak implementation of health care regulations, patient rights discourses remained subdued in health facilities in Karnataka, India. CONCLUSIONS: The empirical findings on the local expression of patient rights in the discourses allowed for theoretical insights on the translation of conceptual understandings of patient rights to practice in the everyday lives of health system actors and care-seeking individuals. The CDA approach was helpful to identify the problematic aspects of discourses and discursive practices on patient rights where health facility administrators and care-providers wielded power to oppress care-seeking individuals. From the practical point of view, the study demonstrated the limitations of care-seeking individuals in the discursive realms to assert their agency as practitioners of (patient) rights in health facilities.

Crying baby gets the milk? The governmentality of grievance redressal for patient rights violations in Karnataka, India.

BACKGROUND: Patient rights aim to protect the dignity of healthcare-seeking individuals. Realisation of these rights is predicated on effective grievance redressal for the victims of patient rights violations. METHODS: We used a critical case (that yields the most information) of patient rights violations reported in Karnataka state (South India) to explore the power dynamics involved in resolving grievances raised by healthcare-seeking individuals. Using interviews, media reports and other documents pertaining to the case, we explored the 'governmentality' of grievance redressal for patient rights violations, that is, the interaction of micropractices and techniques of power employed by actors to govern the processes and outcomes. We also examined whether existing governmentality ensured procedural and substantive justice to care-seeking individuals. RESULTS: Collective action was necessary by the aggrieved women in terms of protests, media engagement, petitions and follow-up to ensure that the State accepted a complaint against a medical professional. Each institution, and especially the medical professional council, exercised its power by problematising the grievance in its own way which was distinct from the problematisation of the grievance by the collective. The State bureaucracy enacted its power by creating a maze of organisational units and by fragmenting the grievance redressal across various bureaucratic units. CONCLUSION: There is a need for measures guaranteeing accountability, transparency, promptness, fairness, credibility and trustworthiness in the patient grievance redressal system. Governmentality as a framework enabled to study how subjects (care-seeking individuals) are rendered governable and resist dominant forces in the grievance redressal system for patient rights violations.

Rapid molecular tests for tuberculosis and tuberculosis drug resistance: a qualitative evidence synthesis of recipient and provider views.

BACKGROUND: Programmes that introduce rapid molecular tests for tuberculosis and tuberculosis drug resistance aim to bring tests closer to the community, and thereby cut delay in diagnosis, ensure early treatment, and improve health outcomes, as well as overcome problems with poor laboratory infrastructure and inadequately trained personnel. Yet, diagnostic technologies only have an impact if they are put to use in a correct and timely manner. Views of the intended beneficiaries are important in uptake of diagnostics, and their effective use also depends on those implementing testing programmes, including providers, laboratory professionals, and staff in health ministries. Otherwise, there is a risk these technologies will not fit their intended use and setting, cannot be made to work and scale up, and are not used by, or not accessible to, those in need. OBJECTIVES: To synthesize end-user and professional user perspectives and experiences with low-complexity nucleic acid amplification tests (NAATs) for detection of tuberculosis and tuberculosis drug resistance; and to identify implications for effective implementation and health equity. SEARCH METHODS: We searched MEDLINE, Embase, CINAHL, PsycInfo and Science Citation Index Expanded databases for eligible studies from 1 January 2007 up to 20 October 2021. We limited all searches to 2007 onward because the development of Xpert MTB/RIF, the first rapid molecular test in this review, was completed in 2009. SELECTION CRITERIA: We included studies that used qualitative methods for data collection and analysis, and were focused on perspectives and experiences of users and potential users of low-complexity NAATs to diagnose tuberculosis and drug-resistant tuberculosis. NAATs included Xpert MTB/RIF, Xpert MTB/RIF Ultra, Xpert MTB/XDR, and the Truenat assays. Users were people with presumptive or confirmed tuberculosis and drug-resistant tuberculosis (including multidrug-resistant (MDR-TB)) and their caregivers, healthcare providers, laboratory technicians and managers, and programme officers and staff; and were from any type of health facility and setting globally. MDR-TB is tuberculosis caused by resistance to at least rifampicin and isoniazid, the two most effective first-line drugs used to treat tuberculosis. DATA COLLECTION AND ANALYSIS: We used a thematic analysis approach for data extraction and synthesis, and assessed confidence in the findings using GRADE CERQual approach. We developed a conceptual framework to illustrate how the findings relate. MAIN RESULTS: We found 32 studies. All studies were conducted in low- and middle-income countries. Twenty-seven studies were conducted in high-tuberculosis burden countries and 21 studies in high-MDR-TB burden countries. Only one study was from an Eastern European country. While the studies covered a diverse use of low-complexity NAATs, in only a minority of studies was it used as the initial diagnostic test for all people with presumptive tuberculosis. We identified 18 review findings and grouped them into three overarching categories. Critical aspects users value People with tuberculosis valued reaching diagnostic closure with an accurate diagnosis, avoiding diagnostic delays, and keeping diagnostic-associated cost low. Similarly, healthcare providers valued aspects of accuracy and the resulting confidence in low-complexity NAAT results, rapid turnaround times, and keeping cost to people seeking a diagnosis low. In addition, providers valued diversity of sample types (for example, gastric aspirate specimens and stool in children) and drug resistance information. Laboratory professionals appreciated the improved ease of use, ergonomics, and biosafety of low-complexity NAATs compared to sputum microscopy, and increased staff satisfaction. Challenges reported to realizing those values People with tuberculosis and healthcare workers were reluctant to test for tuberculosis (including MDR-TB) due to fears, stigma, or cost concerns. Thus, low-complexity NAAT testing is not implemented with sufficient support or discretion to overcome barriers that are common to other approaches to testing for tuberculosis. Delays were reported at many steps of the diagnostic pathway owing to poor sample quality; difficulties with transporting specimens; lack of sufficient resources; maintenance of low-complexity NAATs; increased workload; inefficient work and patient flows; over-reliance on low-complexity NAAT results in lieu of clinical judgement; and lack of data-driven and inclusive implementation processes. These challenges were reported to lead to underutilization.  Concerns for access and equity The reported concerns included sustainable funding and maintenance and equitable use of resources to access low-complexity NAATs, as well as conflicts of interest between donors and people implementing the tests. Also, lengthy diagnostic delays, underutilization of low-complexity NAATs, lack of tuberculosis diagnostic facilities in the community, and too many eligibility restrictions hampered access to prompt and accurate testing and treatment. This was particularly the case for vulnerable groups, such as children, people with MDR-TB, or people with limited ability to pay. We had high confidence in most of our findings. AUTHORS' CONCLUSIONS: Low-complexity diagnostics have been presented as a solution to overcome deficiencies in laboratory infrastructure and lack of skilled professionals. This review indicates this is misleading. The lack of infrastructure and human resources undermine the added value new diagnostics of low complexity have for recipients and providers. We had high confidence in the evidence contributing to these review findings. Implementation of new diagnostic technologies, like those considered in this review, will need to tackle the challenges identified in this review including weak infrastructure and systems, and insufficient data on ground level realities prior and during implementation, as well as problems of conflicts of interest in order to ensure equitable use of resources.

Framing the detection of incipient tuberculosis infection: A qualitative study of political prioritisation.

OBJECTIVE: Incipient Tuberculosis (ITB) refers to Mycobacterium tuberculosis infection that is likely to progress to active disease in the absence of treatment, but without clinical signs, symptoms, radiographic or microbiological evidence of disease. Biomarker-based tests to diagnose incipient TB hold promise for better prediction and, through TB preventive therapy, prevention of disease. This study explored current and future framing and prioritisation of ITB. METHODS: Twenty-two interviews across eight countries were conducted. A modified Shiffman & Smith Framework, containing four categories-Ideas, Issue Characteristics, Actor Power, and Political Contexts-was used to analyse the current landscape and potential for prioritisation of diagnosis and treatment of ITB. RESULTS: Latent TB policy implementation has been slow due to technical, logistical and financial challenges, and because it has been framed in a manner non-conducive to gaining political priority. Framing ITB testing as 'early detection' rather than 'prediction', and its management as 'treatment' rather than 'preventive therapy', may help raise its importance in policies, and its acceptance among actors. CONCLUSION: Consensus surrounding the framing of ITB will be crucial for the successful adoption of ITB diagnostics and treatment. When designing ITB tools and policies, it will be important to address challenges that pertain to latent TB policies.

User perspectives and preferences on a novel TB LAM diagnostic (Fujifilm SILVAMP TB LAM)-a qualitative study in Malawi and Zambia.

Widely available tuberculosis (TB) diagnostics use sputum samples. However, many patients, particularly children and patients living with HIV (PLHIV), struggle to provide sputum. Urine diagnostics are a promising approach to circumvent this challenge while delivering reliable and timely diagnosis. This qualitative study in two high TB/HIV burden countries assesses values and preferences of end-users, along with potential barriers for the implementation of the novel Fujifilm SILVAMP TB-LAM (FujiLAM, Fujifilm, Japan) urine test. Between September 2020 and March 2021, we conducted 42 semi-structured interviews with patients, health care providers (HCPs) and decision makers (DMs) (e.g., in national TB programs) in Malawi and Zambia. Interviews were transcribed verbatim and analyzed using a framework approach supported by NVIVO. Findings aligned with the pre-existing Health Equity Implementation Framework, which guided the presentation of results. The ease and convenience of urine-based testing was described as empowering among patients and HCPs who lamented the difficulty of sputum collection, however HCPs expressed concerns that a shift in agency to the patient may affect clinic workflows (e.g., due to less control over collection). Implementation facilitators, such as shorter turnaround times, were welcomed by operators and patients alike. The decentralization of diagnostics was considered possible with FujiLAM by HCPs and DMs due to low infrastructure requirements. Finally, our findings support efforts for eliminating the CD4 count as an eligibility criterion for LAM testing, to facilitate implementation and benefit a wider range of patients. Our study identified barriers and facilitators relevant to scale-up of urine LAM tests in Malawi and Zambia. FujiLAM could positively impact health equity, as it would particularly benefit patient groups currently underserved by existing TB diagnostics. Participants view the approach as a viable, acceptable, and likely sustainable option in low- and middle-income countries, though adaptations may be required to current health care processes for deployment. Trial registration: German Clinical Trials Register, DRKS00021003. URL: https://www.drks.de/drks_web/setLocale_EN.do.

Constructing confidence: User perspectives on AlereLAM testing for tuberculosis.

BACKGROUND: Diagnosing tuberculosis (TB) in people living with HIV (PLHIV) is challenging due to atypical clinical and radiological presentation and higher rates of sputum-negative or extrapulmonary disease. Urine LAM is a promising diagnostic biomarker to address these challenges. Yet, AlereLAM, a World Health Organization-recommended point-of-care (POC) test of this kind, remains underutilized. This study aimed to understand perspectives and experiences of those using AlereLAM. METHODS: Fifteen semi-structured interviews were conducted with clinicians, nurses, program officers, laboratory staff, and patient advocates in Uganda, Kenya, and South Africa. Discussed topics included the approach to diagnosing TB, and experiences, perspectives, and country policy of AlereLAM testing. RESULTS: The POC-friendly characteristics of AlereLAM require more work to be realized. Although limited by relatively low sensitivity and specificity, AlereLAM has important value for identifying TB in people with advanced HIV disease, especially when the environment enables constructing confidence in the test. The initial communication about the low performance by global agencies, restrictive eligibility criteria, reliance on CD4+ testing, and lack of advocacy and awareness were noted as reasons for its slow uptake. CONCLUSION: The work of operationalizing diagnostics, including constructing confidence, is important to consider for policymakers, implementers, and funders when assessing acceptability, feasibility, and scale-up of a diagnostic.

Impact of a personalised, digital, HIV self-testing app-based program on linkages and new infections in the township populations of South Africa.

INTRODUCTION: Implementation data for digital unsupervised HIV self-testing (HIVST) are sparse. We evaluated the impact of an app-based, personalised, oral HIVST program offered by healthcare workers in Western Cape, South Africa. METHODS: In a quasirandomised study (n=3095), we recruited consenting adults with undiagnosed HIV infection from township clinics. To the HIVST arm participants (n=1535), we offered a choice of an offsite (home, office or kiosk based), unsupervised digital HIVST program (n=962), or an onsite, clinic-based, supervised digital HIVST program (n=573) with 24/7 linkages services.With propensity score analyses, we compared outcomes (ie, linkages, new HIV infections and test referrals) with conventional HIV testing (ConvHT) arm participants (n=1560), recruited randomly from geographically separated clinics. RESULTS: In both arms, participants were young (HIVST vs ConvHT) (mean age: 28.2 years vs 29.2 years), female (65.0% vs 76.0%) and had monthly income <3000 rand (80.8% vs 75%).Participants chose unsupervised HIVST (62.7%) versus supervised HIVST and reported multiple sex partners (10.88% vs 8.7%), exposure to sex workers (1.4% vs 0.2%) and fewer comorbidities (0.9% vs 1.9%). Almost all HIVST participants were linked (unsupervised HIVST (99.7%), supervised HIVST (99.8%) vs ConvHT (98.5%)) (adj RR 1.012; 95% CI 1.005 to 1.018) with new HIV infections: overall HIVST (9%); supervised HIVST (10.9%) and unsupervised HIVST (7.6%) versus ConvHT (6.79%) (adj RR 1.305; 95% CI 1.023 to 1.665); test referrals: 16.7% HIVST versus 3.1% ConvHT (adj RR 5.435; 95% CI 4.024 to 7.340). CONCLUSIONS: Our flexible, personalised, app-based HIVST program, offered by healthcare workers, successfully linked almost all HIV self-testers, detected new infections and increased referrals to self-test. Data are relevant for digital HIVST initiatives worldwide.

HIV self-testing with digital supports as the new paradigm: A systematic review of global evidence (2010-2021).

BACKGROUND: HIV self-testing (HIVST) is recommended by the WHO as an innovative strategy to reach UNAIDS targets to end HIV by 2030. HIVST with digital supports is defined as the use of digital interventions (e.g., website-based, social media, mobile HIVST applications (apps), text messaging (SMS), digital vending machines (digital VMs)) to improve the efficiency and impact of HIVST. HIVST deployment and integration in health services is an emerging priority. We conducted a systematic review aiming to close the gap in evidence that summarizes the impact of digitally supported HIVST and to inform policy recommendations. METHODS: We searched PubMed and Embase for articles and abstracts on HIVST with digital supports published during the period February 1st, 2010 to June 15th, 2021, following Cochrane guidelines and PRISMA methodology. We assessed feasibility, acceptability, preference, and impact outcomes across all populations and study designs. Metrics reported were willingness to use HIVST, preferences for HIVST delivery, proportion of first-time testers, HIVST uptake, HIVST kit return rate, and linkage to care. Heterogeneity of the interventions and reported metrics precluded us from conducting a meta-analysis. FINDINGS: 46 studies were narratively synthesized, of which 72% were observational and 28% were RCTs. Half of all studies (54%, 25/46) assessed web-based innovations (e.g., study websites, videos, chatbots), followed by social media (26%, 12/46), HIVST-specific apps (7%, 3/46), SMS (9%, 4/46), and digital VMs (4%, 2/46). Web-based innovations were found to be acceptable (77-97%), preferred over in-person and hybrid options by more first-time testers (47-48%), highly feasible (93-95%), and were overall effective in supporting linkage to care (53-100%). Social media and app-based innovations also had high acceptability (87-95%) and linkage to care proportions (80-100%). SMS innovations increased kit return rates (54-94%) and HIVST uptake among hard-to-reach groups. Finally, digital VMs were highly acceptable (54-93%), and HIVST uptake was six times greater when using digital VMs compared to distribution by community workers. INTERPRETATION: HIVST with digital supports was deemed feasible, acceptable, preferable, and was shown to increase uptake, engage first-time testers and hard-to-reach populations, and successfully link participants to treatment. Findings pave the way for greater use of HIVST interventions with digital supports globally.

Sexual Dimorphism of the Heart: Genetics, Epigenetics, and Development.

The democratization of genomic technologies has revealed profound sex biases in expression patterns in every adult tissue, even in organs with no conspicuous differences, such as the heart. With the increasing awareness of the disparities in cardiac pathophysiology between males and females, there are exciting opportunities to explore how sex differences in the heart are established developmentally. Although sexual dimorphism is traditionally attributed to hormonal influence, expression and epigenetic sex biases observed in early cardiac development can only be accounted for by the difference in sex chromosome composition, i.e., XX in females and XY in males. In fact, genes linked to the X and Y chromosomes, many of which encode regulatory factors, are expressed in cardiac progenitor cells and at every subsequent developmental stage. The effect of the sex chromosome composition may explain why many congenital heart defects originating before gonad formation exhibit sex biases in presentation, mortality, and morbidity. Some transcriptional and epigenetic sex biases established soon after fertilization persist in cardiac lineages, suggesting that early epigenetic events are perpetuated beyond early embryogenesis. Importantly, when sex hormones begin to circulate, they encounter a cardiac genome that is already functionally distinct between the sexes. Although there is a wealth of knowledge on the effects of sex hormones on cardiac function, we propose that sex chromosome-linked genes and their downstream targets also contribute to the differences between male and female hearts. Moreover, identifying how hormones influence sex chromosome effects, whether antagonistically or synergistically, will enhance our understanding of how sex disparities are established. We also explore the possibility that sexual dimorphism of the developing heart predicts sex-specific responses to environmental signals and foreshadows sex-biased health-related outcomes after birth.

Multilevel governance framework on grievance redressal for patient rights violations in India.

The notion of patient rights encompasses the obligations of the state and healthcare providers to respect the dignity, autonomy and equality of care-seeking individuals in healthcare processes. Functional patient grievance redressal systems are key to ensuring that the rights of individuals seeking healthcare are protected. We critically examined the published literature from high-income and upper-middle-income countries to establish an analytical framework on grievance redressal for patient rights violations in health facilities. We then used lawsuits on patient rights violations from the Supreme Court of India to analyse the relevance of the developed framework to the Indian context. With market perspectives pervading the health sector, there is an increasing trend of adopting a consumerist approach to protecting patient rights. In this line, avenues for grievance redressal for patient rights violations are gaining traction. Some of the methods and instruments for patient rights implementation include charters, ombudsmen, tribunals, health professional councils, separating rules for redressal and professional liability in patient rights violations, blame-free reporting systems, direct community monitoring and the court system. The grievance redressal mechanisms for patient rights violations in health facilities showcase multilevel governance arrangements with overlapping decision-making units at the national and subnational levels. The privileged position of medical professionals in multilevel governance arrangements for grievance redressal puts care-seeking individuals at a disadvantaged position during dispute resolution processes. Inclusion of external structures in health services and the healthcare profession and laypersons in the grievance redressal processes is heavily contested. Normatively speaking, a patient grievance redressal system should be accessible, impartial and independent in its function, possess the required competence, have adequate authority, seek continuous quality improvement, offer feedback to the health system and be comprehensive and integrated within the larger healthcare regulatory architecture.

The role of CTCF in the organization of the centromeric 11p15 imprinted domain interactome.

DNA methylation, chromatin-binding proteins, and DNA looping are common components regulating genomic imprinting which leads to parent-specific monoallelic gene expression. Loss of methylation (LOM) at the human imprinting center 2 (IC2) on chromosome 11p15 is the most common cause of the imprinting overgrowth disorder Beckwith-Wiedemann Syndrome (BWS). Here, we report a familial transmission of a 7.6 kB deletion that ablates the core promoter of KCNQ1. This structural alteration leads to IC2 LOM and causes recurrent BWS. We find that occupancy of the chromatin organizer CTCF is disrupted proximal to the deletion, which causes chromatin architecture changes both in cis and in trans. We also profile the chromatin architecture of IC2 in patients with sporadic BWS caused by isolated LOM to identify conserved features of IC2 regulatory disruption. A strong interaction between CTCF sites around KCNQ1 and CDKN1C likely drive their expression on the maternal allele, while a weaker interaction involving the imprinting control region element may impede this connection and mediate gene silencing on the paternal allele. We present an imprinting model in which KCNQ1 transcription is necessary for appropriate CTCF binding and a novel chromatin conformation to drive allele-specific gene expression.

Implementing radical cure diagnostics for malaria: user perspectives on G6PD testing in Bangladesh.

BACKGROUND: The radical cure of Plasmodium vivax requires treatment with an 8-aminoquinoline drug, such as primaquine and tafenoquine, to eradicate liver hypnozoite stages, which can reactivate to cause relapsing infections. Safe treatment regimens require prior screening of patients for glucose-6-phosphate dehydrogenase (G6PD) deficiency to avoid potential life-threatening drug induced haemolysis. Testing is rarely available in malaria endemic countries, but will be needed to support routine use of radical cure. This study investigates end-user perspectives in Bangladesh on the introduction of a quantitative G6PD test (SD Biosensor STANDARD™ G6PD analyser) to support malaria elimination. METHODS: The perspectives of users on the SD Biosensor test were analysed using semi-structured interviews and focus group discussions with health care providers and malaria programme officers in Bangladesh. Key emerging themes regarding the feasibility of introducing this test into routine practice, including perceived barriers, were analysed. RESULTS: In total 63 participants were interviewed. Participants emphasized the life-saving potential of the biosensor, but raised concerns including the impact of limited staff time, high workload and some technical aspects of the device. Participants highlighted that there are both too few and too many P. vivax patients to implement G6PD testing owing to challenges of funding, workload and complex testing infrastructure. Implementing the biosensor would require flexibility and improvisation to deal with remote sites, overcoming a low index of suspicion and mutual interplay of declining patient numbers and reluctance to test. This approach would generate new forms of evidence to justify introduction in policy and carefully consider questions of deployment given declining patient numbers. CONCLUSIONS: The results of the study show that, in an elimination context, the importance of malaria needs to be maintained for both policy makers and the affected communities, in this case by ensuring P. vivax, PQ treatment, and G6PD deficiency remain visible. Availability of new technologies, such as the biosensor, will fuel ongoing debates about priorities for allocating resources that must be adapted to a constantly evolving target. Technical and logistical concerns regarding the biosensor should be addressed by future product designs, adequate training, strengthened supply chains, and careful planning of communication, advocacy and staff interactions at all health system levels.

'You're only there on the phone'? A qualitative exploration of community, affect and agential capacity in HIV self-testing using a smartphone app.

Mobile health (mHealth) technologies for HIV care are developed to provide diagnostic support, health education, risk assessment and self-monitoring. They aim to either improve or replace part of the therapeutic relationship. Part of the therapeutic relationship is affective, with the emergence of feelings and emotion, yet little research on mHealth for HIV care focuses on affect and HIV testing practices. Furthermore, most of the literature exploring affect and care relations with the introduction of mHealth is limited to the European and Australian context. This article explores affective dimensions of HIV self-testing using a smartphone app strategy in Cape Town, South Africa and Montréal, Canada. This study is based on observation notes, 41 interviews and 1 focus group discussion with study participants and trained HIV healthcare providers from two quantitative studies evaluating the app-based self-test strategy. Our paper reveals how fear, apathy, judgement, frustration and comfort arise in testing encounters using the app and in previous testing experiences, as well as how this relates to care providers and test materials. Attending to affective aspects of this app-based self-testing practice makes visible certain affordances and limitations of the app within the therapeutic encounter and illustrates how mHealth can contribute to HIV care.

Improving primary care for diabetes and hypertension: findings from implementation research in rural South India.

BACKGROUND: Chronic conditions are a leading cause of death and disability worldwide. Low-income and middle-income countries such as India bear a significant proportion of this global burden. Redesigning primary care from an acute-care model to a model that facilitates chronic care is a challenge and requires interventions at multiple levels. OBJECTIVES: In this intervention study, we aimed to strengthen primary care for diabetes and hypertension at publicly funded primary healthcare centres (PHCs) in rural South India. DESIGN AND METHODS: The complexities of transforming the delivery of primary care motivated us to use a 'theory of change' approach to design, implement and evaluate the interventions. We used both quantitative and qualitative data collection methods. Data from patient records regarding processes of care, glycaemic and blood pressure control, interviews with patients, observations and field notes were used to analyse what changes occurred and why. INTERVENTIONS: We implemented the interventions for 9 months at three PHCs: (1) rationalise workflow to include essential tasks like counselling and measurement of blood pressure/blood glucose at each visit; (2) distribute clinical tasks among staff; (3) retain clinical records at the health facility and (4) capacity building of staff. RESULTS: We found that interventions were implemented at all three PHCs for the first 4 months but did not continue at two of the PHCs. This fadeout was most likely the result of staff transfers and a doctor's reluctance to share tasks. The availability of an additional staff member in the role of a coordinator most likely influenced the relative success of implementation at one PHC. CONCLUSION: These findings draw attention to the need for building teams in primary care for managing chronic conditions. The role of a coordinator emerged as an important consideration, as did the need for a stable core of staff to provide continuity of care.