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Although entirely preventable, rheumatic heart disease (RHD), a disease of poverty and social disadvantage resulting in high morbidity and mortality, remains an ever-present burden in low-income and middle-income countries (LMICs) and rural, remote, marginalised and disenfranchised populations within high-income countries. In late 2021, the National Heart, Lung, and Blood Institute convened a workshop to explore the current state of science, to identify basic science and clinical research priorities to support RHD eradication efforts worldwide. This was done through the inclusion of multidisciplinary global experts, including cardiovascular and non-cardiovascular specialists as well as health policy and health economics experts, many of whom also represented or closely worked with patient-family organisations and local governments. This report summarises findings from one of the four working groups, the Tertiary Prevention Working Group, that was charged with assessing the management of late complications of RHD, including surgical interventions for patients with RHD. Due to the high prevalence of RHD in LMICs, particular emphasis was made on gaining a better understanding of needs in the field from the perspectives of the patient, community, provider, health system and policy-maker. We outline priorities to support the development, and implementation of accessible, affordable and sustainable interventions in low-resource settings to manage RHD and related complications. These priorities and other interventions need to be adapted to and driven by local contexts and integrated into health systems to best meet the needs of local communities.

When people vest a position with moral conviction, that is, a sense that the position is grounded in fundamental right or wrong, good or bad, they tend to be particularly intolerant of those who disagree. Psychological states that mitigate or augment the effect of moral conviction on tolerance are lesser known. The present research investigated the immediate consequences of mindfulness and mindlessness (cognitive depletion) on the relationship between moral conviction and preferred social distance. Consistent with hypotheses, moral conviction did not predict preferred social distance in a mindfulness condition (mindfulness meditation), predicted greater preferred social distance in a mindlessness condition (cognitive depletion), and predicted marginally greater preferred social distance in a control condition (no manipulation). Findings suggest that adopting a mindful orientation toward people with different moral views may foster acceptance, while adopting a mindless orientation may foster greater intolerance.

Objectives Applying the biopsychosocial model of challenge and threat, the present research investigated the differential cognitive, affective, behavioral, and psychophysiological responses of experienced mindfulness meditation practitioners and non-meditators in response to an acute laboratory stressor. We also tested whether perceptions of closeness link mindfulness practice with experiencing challenge rather than threat in response to acute psychosocial stress. Method Experienced mindfulness practitioners ( n  = 40) and individuals interested in mindfulness but without a practice ( n  = 55) reported dispositional mindfulness and closeness before engaging with a validated psychosocial stressor (i.e., mental arithmetic). After receiving stressor instructions, participants reported appraisals and state affect. During the stressor, we assessed performance and cardiovascular reactivity. Results Findings revealed that mindfulness practitioners, relative to non-meditators, reported greater dispositional mindfulness ( η p 2  = 0.22) and closeness ( η p 2  = 0.13). For mindfulness practitioners, the stressor evoked more challenge-like responses, including greater positive affect ( η p 2  = 0.11) and better performance ( η p 2  = 0.07), compared to non-meditators. There were no significant group differences in appraisals or cardiovascular reactivity. Rather than a direct link, we found that mindfulness meditation practice was indirectly associated with greater challenge appraisals, fully mediated by increased perceptions of closeness ( CI [− 0.11, − 0.02]). Conclusions Findings suggest that a sustained mindfulness meditation practice confers some adaptive advantages in response to acute psychosocial stressors, such as increased positive affect and better performance. We also found that having a prolonged mindfulness meditation practice is linked to greater challenge appraisals in response to an acute stressor, but only due to having a sense of self that is characterized by greater interconnection and closeness with others. Preregistration This study is not pre-registered.

Objectives Breathing rate and pain are influenced by a spectrum of cognitive, affective, and physiological interactions. Yet, it is unknown if an individual’s resting breathing rate is associated with pain. Methods Continuous cerebral blood flow (CBF) and respiration rate were collected in 74 healthy participants during innocuous (35 °C) and noxious (49 °C) stimulation. Mindfulness and anxiety were assessed before acquiring perfusion fMRI data. Visual analog scale pain ratings were collected after pain testing. Results Slower resting respiration rate during noxious ( r  = 0.26, p  = 0.03) and innocuous ( r  = 0.28, p  = 0.02) heat was associated with lower pain sensitivity. Analyses of the whole-brain fMRI data revealed that higher CBF in the supramarginal gyrus, a central node of the ventral attention network, was associated with a slower breathing rate during noxious heat ( r  =  − 0.51, p  < 0.001) and lower reported pain levels ( r  =  − 0.24, p  = 0.04). Higher levels of dispositional mindfulness, but not anxiety ( p  > 0.20), were associated with slower breathing rate ( r  =  − 0.28, p  = 0.02) and lower pain ( r  =  − 0.25, p  = 0.03). Conclusions These findings demonstrate that individuals who naturally breathe slower report lower pain and engage unique mechanisms, suggesting the allocation of attention to physical bodily processes.

A study with a test-negative design analyzed 41,552 admissions to 187 hospitals and 21,522 visits to 221 EDs or urgent care clinics. The mRNA-based vaccines (≥14 days after the second dose) were highly effective against SARS-CoV-2 infection leading to hospitalization (89%), ICU admission (90%), or an urgent care visit (91%).

Immune checkpoint blockade is effective for some patients with cancer, but most are refractory to current immunotherapies and new approaches are needed to overcome resistance 1 , 2 . The protein tyrosine phosphatases PTPN2 and PTPN1 are central regulators of inflammation, and their genetic deletion in either tumour cells or immune cells promotes anti-tumour immunity 3 – 6 . However, phosphatases are challenging drug targets; in particular, the active site has been considered undruggable. Here we present the discovery and characterization of ABBV-CLS-484 (AC484), a first-in-class, orally bioavailable, potent PTPN2 and PTPN1 active-site inhibitor. AC484 treatment in vitro amplifies the response to interferon and promotes the activation and function of several immune cell subsets. In mouse models of cancer resistant to PD-1 blockade, AC484 monotherapy generates potent anti-tumour immunity. We show that AC484 inflames the tumour microenvironment and promotes natural killer cell and CD8 + T cell function by enhancing JAK–STAT signalling and reducing T cell dysfunction. Inhibitors of PTPN2 and PTPN1 offer a promising new strategy for cancer immunotherapy and are currently being evaluated in patients with advanced solid tumours (ClinicalTrials.gov identifier NCT04777994 ). More broadly, our study shows that small-molecule inhibitors of key intracellular immune regulators can achieve efficacy comparable to or exceeding that of antibody-based immune checkpoint blockade in preclinical models. Finally, to our knowledge, AC484 represents the first active-site phosphatase inhibitor to enter clinical evaluation for cancer immunotherapy and may pave the way for additional therapeutics that target this important class of enzymes. An orally bioavailable small-molecule active-site inhibitor of the phosphatases PTPN2 and PTPN1, ABBV-CLS-484, demonstrates immunotherapeutic efficacy in mouse models of cancer resistant to PD-1 blockade.

Background Globally, families play a critical role in providing care and support for persons living with schizophrenia. It is important to identify potentially modifiable factors that influence perceived caregiver burden in order to properly address the needs of caregivers. This is especially relevant in low-resource settings where psychiatric services are scarce and interventions could be most effective if targeted to both the individual living with schizophrenia and their caregiver. This study examines correlates of perceived burden among informal caregivers of individuals with schizophrenia in Tanzania, in particular, the association between burden and caregiver-reported family functioning. Methods This study used baseline data from an individually randomized controlled trial with 65 pairs of individuals with schizophrenia and their informal caregivers in Dar es Salaam and Mbeya, Tanzania. Caregiver burden was measured using the Burden Assessment Scale. Univariable and multivariable regression analyses were performed to determine the relationship between caregiver burden and family functioning and to explore other correlates of burden. Results Sixty-three percent of caregivers reported experiencing high burden as a result of caring for a relative with schizophrenia. Multivariable regression analyses revealed that poor family functioning and the caregiver being employed were associated with high caregiver burden, while higher levels of hopefulness in the caregiver was associated with low caregiver burden. Conclusion Caregivers who were employed, reported poor family functioning, and/or had low levels of hopefulness were more likely to perceive high caregiver burden. Future interventions aiming to reduce caregiver burden may benefit from improving family functioning and nurturing hope among caregivers of individuals living with schizophrenia. Policies and programs should be cognizant of the needs of caregivers that work in addition to providing care for a relative with schizophrenia in order to better support them.

This research advances understanding of interrelationships among three barriers to adherence to antiretroviral therapy (ART) among pregnant women living with HIV (WLWH) in Cameroon: probable common mental disorders (CMD), intimate partner violence (IPV), and hunger. The sample included 220 pregnant WLWH in Cameroon. Multivariable modified Poisson regression was conducted to assess the relationship between IPV, hunger, and CMD on ART adherence. Almost half (44%) of participants recently missed/mistimed an ART dose. Probable CMD was associated with greater risk of missed/mistimed ART dose (aRR 1.5 [95% CI 1.1, 1.9]). Hunger was associated with greater risk of missed/mistimed ART dose among those who reported IPV (aRR 1.9 [95% CI 1.2, 2.8]), but not among those who did not (aRR 0.8 [95% CI 0.2, 2.3]). Suboptimal ART adherence, CMD, and IPV were common among pregnant WLWH in Cameroon. Pregnant WLWH experiencing IPV and hunger may be especially vulnerable to suboptimal ART adherence.

Implementation failure is widely acknowledged as a major impediment to the success of water resource plans and policies, yet there are very few proactive approaches available for analysing potential implementation issues during the planning stage. The motivations and abilities (MOTA) framework was established to address this planning stage gap, by offering a multi-stakeholder, multilevel approach to evaluate the implementation feasibility of plans and policies. MOTA is a stepwise process focusing on the relationship between trigger, motivation and ability. Here we outline the base model of the MOTA framework and review existing MOTA applications in assorted water resource management contexts. From our review, we identify the strengths and limitations of the MOTA framework in various institutional implementation and social adoptability contexts. Our findings indicate that the existing MOTA base model framework has been successful in identifying the motivations and abilities of the stakeholders involved in a range of bottom-up water resource planning contexts and in subsequently providing insight into the types of capacity- or consent-building strategies needed for effective implementation. We propose several complementary add-in applications to complement the base model, which specific applications may benefit from. Specifically, the incorporation of formal context and stakeholder analyses during the problem definition stage (Step 1) could provide a more considered basis for designing the latter steps within the MOTA analyses. In addition, the resolution of the MOTA analyses could be enhanced by developing more nuanced scoring approaches or by adopting empirically proven ones from well-established published models. Through setting the base model application, additional add-in applications can easily be added to enhance different aspects of the analysis while still maintaining comparability with other MOTA applications. With a robust base model and a suite of add-in applications, there is great potential for the MOTA framework to become a staple tool for optimising implementation success in any water planning and policymaking context.

Background Hopefulness is a positive orientation or state of mind that can aid in the recovery and treatment of mental illness, as it can have significant impacts on clinical and psychosocial outcomes. As resource-constrained settings work to implement recovery-oriented care, there is a need to better understand hopefulness among people living with schizophrenia (PLWS) and caregivers in their extended family networks. This study seeks to examine the dyadic relationship of hopefulness and its associated correlates among PLWS attending outpatient psychiatric clinics and their caregivers in Tanzania. Methods This study utilized baseline and immediate post-intervention data collected as part of a randomized controlled trial testing a culturally tailored model of Family Psychoeducation, KUPAA, in Tanzania. The Herth Hope Index was used to measure hopefulness among PLWS ( n  = 33) and their caregivers ( n  = 33) at baseline and immediate post-intervention. Univariable and multivariable regression models were conducted to determine correlates of hopefulness at baseline, while the Actor-Partner Interdependence Model (APIM) was employed to examine the longitudinal, dyadic relationship of hopefulness among and between PLWS and their caregivers. Results Better family functioning was associated with higher levels of hopefulness in PLWS and their caregivers. Lower levels of stigma, lower symptom severity, and lower disability were associated with higher levels of hopefulness in PLWS. For PLWS and their caregivers, actor effects from the APIM model were less than one (PLWS, β = 0.261 ; caregivers, β = 0.318 ), indicating stability (within each person) in hopefulness over time. Regarding partner effects, a caregiver’s baseline hopefulness had a positive effect on the hopefulness of their PLWS at follow-up ( β = 0.100 ). This indicates that higher caregiver hope at time 0 is associated with higher levels of hope in PLWS at time 1. Baseline hopefulness levels for PLWS had a negative effect on caregivers’ hopefulness at follow-up ( β = - 0.106 ). This suggests that higher hopefulness among PLWS at baseline is associated with lower levels of hope in caregivers at follow-up. Conclusion Hopefulness is important to consider in family or caregiver-based treatments for PLWS because caregiver hopefulness may influence improvements in hopefulness among PLWS over time. Future studies should further explore the longitudinal dyadic relationship of hopefulness for these populations, as hope is a non-pharmacological and modifiable mechanism of change that is underutilized in care and treatment plans for PLWS globally. Trial registration Clinical Trials #NCT04013932, July 10, 2019.