Assessing Acceptability of Biodegradable Contraceptive Implants in Kenya and Senegal.

BACKGROUND: Contraceptive implants are popular in Africa, but barriers to removal exist. Biodegradable implants (BDIs) offer an alternative to the need for removal. This study explored potential user, provider, and other stakeholder perspectives on 2 BDI prototypes, revealing opportunities and challenges for introduction. METHODS: We conducted focus group discussions (FGDs) and in-depth interviews (IDIs) with women, men, family planning (FP) providers, community influencers, and FP policymakers and program staff in Kenya and Senegal. Characteristics of the 2 BDI prototypes were shared, and participants held and interacted with placebo prototypes. Structural coding was used to analyze the data focused on key product attributes, including biodegradation, removal potential, size, material, insertion site, and duration of effectiveness. RESULTS: We conducted 16 FGDs and 35 IDIs with 106 participants in Kenya and 15 FGDs and 43 IDIs with 102 participants in Senegal. Overall, respondents liked the idea of a BDI, noting the avoidance of pain and scarring and reduced transport and costs as benefits of no removal requirement. Kenyan respondents expressed greater understanding of the biodegradation process than those in Senegal, though potential users in both countries expressed concerns about possible side effects associated with the process. In Senegal, mention of cholesterol in a BDI caused concern, while Kenyan participants responded positively to the same BDI being composed of organic materials. The second BDI product was viewed as more similar to existing implants, which providers preferred. Participants suggested increasing the pregnancy protection duration beyond 18 months. No clear preference between products emerged, and participants liked and disliked some characteristics of both. CONCLUSIONS: Kenyan and Senegalese participants expressed interest in the BDI concept but expressed some reservations related to biodegradation, material, and side effects. BDIs offer the opportunity to expand contraceptive choice. However, messaging around product characteristics will be required for successful introduction and uptake.

"I could not find the strength to resist the pressure of the medical staff, to refuse to give commercial milk formula": a qualitative study on effects of the war on Ukrainian women's infant feeding.

Introduction: During emergencies, breastfeeding protects infants by providing essential nutrients, food security, comfort, and protection and is a priority lifesaving intervention. On February 24, 2022, the war in Ukraine escalated, creating a humanitarian catastrophe. The war has resulted in death, injuries, and mass internal displacement of over 5 million people. A further 8.2 million people have taken refuge in neighboring countries, including Poland. Among those impacted are infants and young children and their mothers. We conducted a study to explore the infant feeding challenges and needs of Ukrainian women affected by the war. Methods: We conducted a qualitative descriptive study involving in-depth interviews (IDIs) with 75 war-affected Ukrainian mothers who had at least one infant aged less than 12 months at the time of the interview. Eligible mothers were either (1) living as Ukrainian refugees in Poland, having crossed the border from Ukraine on or after February 24, 2022, when the war started (n = 30) or (2) living in Ukraine as internally displaced persons or as residents in the community (n = 45). All interviews were audio-recorded (either transcribed or had responses summarized as expanded notes) and analyzed using qualitative thematic analysis using a two-step rapid analysis process. Results: Participants in Ukraine who wanted to initiate breastfeeding right after birth faced opposition from healthcare workers at maternity hospitals. Ukrainian refugees who gave birth in Poland faced language barriers when seeking breastfeeding support. Half of the participants in Ukraine received commercial milk formula (CMF) donations even if they said they did not need them. Most respondents stated that breastfeeding information and support were urgently needed. Conclusion: Our data suggests that healthcare workers in Ukrainian maternity hospitals require additional training and motivation on delivering breastfeeding support. In addition, lactation consultants in maternity ward are needed in Ukraine, and interpretation support is needed for refugees to overcome language barriers. There is a need to control the indiscriminate donations of commercial milk formula and to ensure that complementary foods and commercial milk formula are available to those that need it. This study confirms the need for actions to ensure infant and young child feeding (IYCF) support is provided during emergencies.

Evaluation of a Novel Dermal Cooling System for the Treatment of Benign Pigmented Lesions in Asians.

OBJECTIVE: Our study aimed to evaluate the efficacy of this novel dermal cooling system (DCS) in reducing pigmentation in benign pigmented lesions in Asian patients and its potential side effects. METHODS: It was a prospective open-label single-center study. Asian patients, with the presence of benign pigmented lesions mainly including lentigines, melasma, nevus spilus, ephelides, café au lait, and seborrheic keratosis were recruited for a novel DCS. The DCS provided localized cooling of the epidermal layer below freezing but was less intense than cryotherapy. Each patient received DCS at Week 0 and repeated at 4-week intervals up to 10 sessions. Global aesthetic improvement scores (GAIS) by blinded physicians and subjects were recorded at 2, 6, and 12 months posttreatment follow-up. RESULTS: Eighty-one patients were recruited with a total of 305 sessions performed and 1716 lesion sites treated. At 2-month posttreatment, 76.5% and 58.6% treatment sites showed obvious to marked improvement respectively and the improvement sustained at 6 and 12 months. Only minor adverse events were reported. Erythema and edema were the most commonly anticipated effects immediately after treatment. The pain was minimal. Postinflammatory hyperpigmentation was only reported in 2.2% (38/1716) treated sites. CONCLUSION: To our knowledge, this study was the first study to demonstrate that this novel DCS was an effective, safe, and well-tolerated treatment for benign pigmented lesions in Asians.

Discovery of Potent and Selective Covalent Inhibitors of HER2WT and HER2YVMA.

HER2 overexpression and amplification have been identified as oncogenic drivers, and the development of therapies to treat tumors harboring these markers has received considerable attention. Activation of HER2 signaling and subsequent cell growth can also be induced by HER2 mutations, including the common YVMA insertion in exon 20 within the kinase domain. Enhertu is currently the only approved treatment for HER2 mutant tumors in NSCLC. TKIs tested in this space have suffered from off-target activity, primarily due to EGFRWT inhibition or attenuated activity against HER2 mutants. The goal of this work was to identify a TKI that would provide robust inhibition of oncogenic HER2WT and HER2 mutants while sparing EGFRWT activity. Herein, we describe the development of a potent, covalent inhibitor of HER2WT and the YVMA insertion mutant while providing oral bioavailability and avoiding the inhibition of EGFRWT.

The priming of stimulus-elicited involuntary mental imagery.

Percepts, urges, and even high-level cognitions often enter the conscious field involuntarily. The Reflexive Imagery Task (RIT) was designed to investigate experimentally the nature of such entry into consciousness. In the most basic version of the task, participants are instructed not to subvocalize the names of visual objects. Involuntary subvocalizations arise on the majority of the trials. Can these effects be influenced by priming? In our experiment, participants were exposed to an auditory prime 300 ms before being presented with the RIT stimuli. For example, participants heard the word "FOOD" before seeing two RIT stimuli (e.g., line drawings of BANANA and CAT, with the former being the target of the prime). The short span between prime and target allowed us to assess whether the RIT effect is strategic or automatic. Before each trial, participants were instructed to disregard what they hear, and not to think of the name of any of the objects. On an average of 83% of the trials, the participants thought (involuntarily) of the name of the object associated with the prime. This is the first study to use a priming technique within the context of the RIT. The theoretical implications of these involuntary effects are discussed.

A simple and sensitive differential digestion method to analyze adeno-associated virus residual host cell proteins by LC-MS.

Many methods using liquid chromatography-mass spectrometry (LC-MS) have been established for identifying residual host cell proteins (HCPs) to aid in the process development and quality control of therapeutic proteins. However, the use of MS-based techniques for adeno-associated virus (AAV) is still in its infancy, with few methods reported and minimal information available on potentially problematic HCPs. In this study, we developed a highly sensitive and effective differential digestion method to profile residual HCPs in AAV. Unlike direct digestion, which completely digests both AAV and HCPs, our differential digestion method takes advantage of AAV's unique characteristics to maintain the integrity of AAV while preferentially digesting HCPs under denaturing and reducing conditions. This differential digestion method requires only several micrograms of sample and significantly enhances the identification of HCPs. Furthermore, this method can be applied to all five different AAV serotypes for comprehensive HCP profiling. Our work fills a gap in AAV HCP analysis by providing a sensitive and robust strategy for detecting, monitoring, and measuring HCPs.

Creating allies: qualitative exploration of young women's preferences for PrEP methods and parents' role in PrEP uptake and user support in urban and rural Zambia.

BACKGROUND: Zambian adolescent girls and young women (AGYW) have high HIV incidence and face barriers to the use of pre-exposure prophylaxis (PrEP). Parental support improves PrEP use and adherence in some settings, but negative parental attitudes toward HIV prevention may inhibit engagement with AGYW. We explored perceptions of future PrEP methods among AGYW and parents and parent-youth engagement on HIV prevention and PrEP use. METHODS: We conducted a qualitative descriptive study among AGYW and parents of AGYW in five provinces in Zambia in September-October 2021. We conducted 10 focus group discussions (FGDs) and four in-depth interviews (IDIs) with AGYW participants (n = 87) and seven FGDs and four IDIs among parents of AGYW (n = 62). All FGDs and IDIs were audio-recorded, transcribed verbatim, and analyzed to identify qualitative themes. RESULTS: Most AGYW participants preferred the discreet nature and longer duration of injectable PrEP compared to the PrEP ring and oral PrEP. Many AGYWs reported inability to disclose PrEP use to their parents due to lack of parental support based on cultural taboos against premarital sex. Nevertheless, AGYW participants said they would like to talk to their parents about PrEP so their parents could support their use. Many parents also described difficulties discussing PrEP with their daughters because of cultural and religious beliefs about abstinence from sex before marriage. However, parents acknowledged that the threat of HIV is real and said they need PrEP knowledge and guidance on speaking with their children about HIV prevention and PrEP. CONCLUSIONS: Although many parents are currently not playing a role in daughters' decisions about PrEP use, both parents and AGYW are willing to engage with each other on HIV prevention issues. To foster parent-child engagement, HIV prevention programs should not only provide information about PrEP but also address social norms that impede discussion of HIV prevention and equip both parents and AGYW with skills and support for such conversations. Community sensitization is also needed as new PrEP products are introduced, to create an enabling environment for parent-child engagement by increasing awareness, countering misconceptions, and reducing stigma.

The use of fractional radiofrequency in Asian patients to improve skin texture.

BACKGROUND AND OBJECTIVES: Fractional radiofrequency devices have been demonstrated to improve skin texture, such as smoothness, rhytides, brightness, and atrophic acne scars, by increasing dermal thickness, dermal collagen content, and dermal fibrillin content. The objective of the study is to assess the efficacy and adverse effects of this device on Asian patients of skin type III and IV with skin textural changes. MATERIALS AND METHODS: The study was designed as a prospective, open-labeled single-arm study, which was conducted with 20 Chinese patients aged 21-60 years and having irregularities in their skin texture, rhytides, and acne scars. The patients received six treatments at intervals of 4 weeks. Treatment was initiated with the maximum energy tolerated, which was then adjusted during the course of treatment if the patients felt excessive discomfort. A total of two passes were delivered in each session. Physician assessment results and standardized photographs were collected at the baseline, after all treatment visits, and at 1, 2, and 6 months after the final treatment visit. RESULTS: A total of 17 patients completed the study according to the established protocol. At the 6-month follow-up, 71% of patients were satisfied and 24% of patients were very satisfied with the received treatments, and the treatment physician reported varying degrees of improvement based on the global assessment scale in 60% of the subjects. While the anticipated side effects, such as erythema, edema, pinpoint bleeding, scab formation, and flare of acne, were noted in the patients, no serious adverse effects occurred. CONCLUSION: The use of fractional radiofrequency improves skin texture and is safe for use in Asian patients of skin type III and IV. No long-term serious adverse effects were noted.

Can environmental information disclosure spur corporate green innovation?

How can the disclosure of environmental information (EID) stimulate corporate green innovation (CGI)? This research challenges the prevailing assumption that environmental regulations impact CGI by influencing corporate compliance costs. Instead, it offers a fresh theoretical framework to explain how EID affects CGI. This study combines signal theory and resource dependence theory to develop a moderated mediation model, illustrating how EID reduces information asymmetry and alleviates corporate financial constraints (CFC). To test these hypotheses, this study utilized data from A-share listed companies spanning the period 2004 to 2017. This study considered the year 2009 as a crucial point of analysis, marking the period before and after the implementation of China's first EID policy in 2008. This study employed a Difference-in-Differences (DID) model. The results reveal that EID has a positive impact on CGI by mitigating CFC, with non-state-owned enterprises (non-SOEs) exhibiting a more pronounced mediating effect. These findings remain robust even when the parallel trend assumption was tested to eliminate interference from other factors. This study unveils the mechanism through which voluntary environmental regulation, represented by EID, influences CGI by mitigating information asymmetry and alleviating CFC. These results deviate from the predictions of compliance cost theory and Porter's hypothesis regarding the impact of traditional environmental regulations on CGI, providing a fresh perspective on the role of voluntary environmental regulation in driving CGI.

Service Delivery Considerations for Introducing New Injectable Contraceptives Lasting 4 and 6 Months in Nigeria and Uganda: A Qualitative Study.

BACKGROUND: New family planning (FP) product introduction requires understanding the target market and support from stakeholders from across the health sector. We aimed to understand the perspectives of FP providers and other stakeholders on the potential introduction of new subcutaneous (SC) depot medroxyprogesterone acetate (DMPA) injectable contraceptives lasting 4 and 6 months in Nigeria and Uganda. METHODS: Between July 2021 and February 2022, we conducted 48 in-depth interviews (IDIs) and 11 focus group discussions (FGDs) with FP providers and other stakeholders involved with service delivery, program management, and policymaking in Lagos and Abuja in Nigeria and Kampala and Luwero in Uganda. IDIs and FGDs explored respondents' reactions to and preferences for the new injectables lasting 4 and 6 months. RESULTS: Most respondents liked the idea of longer-acting DMPA-SC products, noting the potential for reduced facility visits for clients and workloads for providers, cost savings for users and the health system, and potential for improved commodity logistics. Some nonproviders raised concerns about confusion among providers and clients with the availability of multiple injectable products; however, providers did not share this concern. The greatest interest among all groups was for the 6-month injectable, even without the option for self-injection. Several respondents reported that self-injection is not widespread in either context, and some noted that contact with a provider would be important for products with longer durations. Respondents' acceptability of the new injectables assumed that side effects would be no worse than the existing 3-month product. CONCLUSIONS: Family planning stakeholders in Nigeria and Uganda are supportive of expanding the method mix with new injectables, which they see as having the potential to meet the needs of more users. Concerted engagement of health providers, policymakers, and the community will be necessary for successful introduction once these new contraceptive products are available.

Discovery of 5-Azaquinoxaline Derivatives as Potent and Orally Bioavailable Allosteric SHP2 Inhibitors.

SHP2 has emerged as an important target for oncology small-molecule drug discovery. As a nonreceptor tyrosine phosphatase within the MAPK pathway, it has been shown to control cell growth, differentiation, and oncogenic transformation. We used structure-based design to find a novel class of potent and orally bioavailable SHP2 inhibitors. Our efforts led to the discovery of the 5-azaquinoxaline as a new core for developing this class of compounds. Optimization of the potency and properties of this scaffold generated compound 30, that exhibited potent in vitro SHP2 inhibition and showed excellent in vivo efficacy and pharmacokinetic profile.

Microglial Imaging in Alzheimer's Disease and Its Relationship to Brain Amyloid: A Human 18F-GE180 PET Study.

BACKGROUND: Emerging evidence suggests a potential causal role of neuroinflammation in Alzheimer's disease (AD). Using positron emission tomography (PET) to image overexpressed 18 kDA translocator protein (TSPO) by activated microglia has gained increasing interest. The uptake of 18F-GE180 TSPO PET was observed to co-localize with inflammatory markers and have a two-stage association with amyloid PET in mice. Very few studies evaluated the diagnostic power of 18F-GE180 PET in AD population and its interpretation in human remains controversial about whether it is a marker of microglial activation or merely reflects disrupted blood-brain barrier integrity in humans. OBJECTIVE: The goal of this study was to study human GE180 from the perspective of the previous animal observations. METHODS: With data from twenty-four participants having 18F-GE180 and 18F-AV45 PET scans, we evaluated the group differences of 18F-GE180 uptake between participants with and without cognitive impairment. An association analysis of 18F-GE180 and 18F-AV45 was then conducted to test if the relationship in humans is consistent with the two-stage association in AD mouse model. RESULTS: Elevated 18F-GE180 was observed in participants with cognitive impairment compared to those with normal cognition. No regions showed reduced 18F-GE180 uptake. Consistent with mouse model, a two-stage association between 18F-GE180 and 18F-AV45 was observed. CONCLUSIONS: 18F-GE180 PET imaging showed promising utility in detecting pathological alterations in a symptomatic AD population. Consistent two-stage association between 18F-GE180 and amyloid PET in human and mouse suggested that 18F-GE180 uptake in human might be considerably influenced by microglial activation.

Can China's carbon intensity constraint policies improve carbon emission performance? Evidence from regional carbon emissions.

Carbon Intensity Constraint Policies (CICPs) are vital for addressing climate change challenges and advancing sustainable development. Since 2010, China has rolled out three five-year CICPs. However, there is limited understanding of their impact on carbon emission performance (CEP). Addressing this, this study pioneers the exploration of the CICP's impact on China's CEP. Drawing from government intervention and green paradox theories, this study highlights a concerning scenario: local governments achieve emission targets via excessive intervention. For deeper insights, this study melds the overall technology frontier concept with a non-radial, non-angle directional distance function, introducing a novel efficiency model rooted in the Data Envelopment Analysis (DEA) method. This offers a CEP measure across 30 Chinese provincial regions from 2002 to 2019. Using the quasi-difference-in-differences (quasi-DID) and moderated mediation models, this study ascertains the presence of the green paradox, uncovers its reasons, and suggests mitigation strategies. The results indicate that high government intervention diminishes CEP. This negative effect intensifies under greater regional fiscal pressure. Alarmingly, local authorities' eagerness to meet targets shows a counterproductive, inverted N-shaped trend regarding CICPs' time-based influence on regional CEP. Moreover, the impact varies based on regional economic development levels and stages. This study has ensured the robustness of the findings via parallel trend tests, parallel exclusion policies, a strengthened quasi-DID framework, and diverse control variable configurations. This study underscores the need for more balanced government intervention. It offers valuable policy insights, guiding China's upcoming CICP phase to realize the ambition of peaking carbon by 2030 and achieving carbon neutrality by 2060.

Evaluation of Neighborhood-Level Disadvantage and Cognition in Mexican American and Non-Hispanic White Adults 50 Years and Older in the US.

Importance: Understanding how socioeconomic factors are associated with cognitive aging is important for addressing health disparities in Alzheimer disease. Objective: To examine the association of neighborhood disadvantage with cognition among a multiethnic cohort of older adults. Design, Setting, and Participants: In this cross-sectional study, data were collected between September 1, 2017, and May 31, 2022. Participants were from the Health and Aging Brain Study-Health Disparities, which is a community-based single-center study in the Dallas/Fort Worth area of Texas. A total of 1614 Mexican American and non-Hispanic White adults 50 years and older were included. Exposure: Neighborhood disadvantage for participants' current residence was measured by the validated Area Deprivation Index (ADI); ADI Texas state deciles were converted to quintiles, with quintile 1 representing the least disadvantaged area and quintile 5 the most disadvantaged area. Covariates included age, sex, and educational level. Main Outcomes and Measures: Performance on cognitive tests assessing memory, language, attention, processing speed, and executive functioning; measures included the Spanish-English Verbal Learning Test (SEVLT) Learning and Delayed Recall subscales; Wechsler Memory Scale, third edition (WMS-III) Digit Span Forward, Digit Span Backward, and Logical Memory 1 and 2 subscales; Trail Making Test (TMT) parts A and B; Digit Symbol Substitution Test (DSST); Letter Fluency; and Animal Naming. Raw scores were used for analyses. Associations between neighborhood disadvantage and neuropsychological performance were examined via demographically adjusted linear regression models stratified by ethnic group. Results: Among 1614 older adults (mean [SD] age, 66.3 [8.7] years; 980 women [60.7%]), 853 were Mexican American (mean [SD] age, 63.9 [7.9] years; 566 women [66.4%]), and 761 were non-Hispanic White (mean [SD] age, 69.1 [8.7] years; 414 women [54.4%]). Older Mexican American adults were more likely to reside in the most disadvantaged areas (ADI quintiles 3-5), with 280 individuals (32.8%) living in ADI quintile 5, whereas a large proportion of older non-Hispanic White adults resided in ADI quintile 1 (296 individuals [38.9%]). Mexican American individuals living in more disadvantaged areas had worse performance than those living in ADI quintile 1 on 7 of 11 cognitive tests, including SEVLT Learning (ADI quintile 5: ß = -2.50; 95% CI, -4.46 to -0.54), SEVLT Delayed Recall (eg, ADI quintile 3: ß = -1.11; 95% CI, -1.97 to -0.24), WMS-III Digit Span Forward (eg, ADI quintile 4: ß = -1.14; 95% CI, -1.60 to -0.67), TMT part A (ADI quintile 5: ß = 7.85; 95% CI, 1.28-14.42), TMT part B (eg, ADI quintile 5: ß = 31.5; 95% CI, 12.16-51.35), Letter Fluency (ADI quintile 4: ß = -2.91; 95% CI, -5.39 to -0.43), and DSST (eg, ADI quintile 5: ß = -4.45; 95% CI, -6.77 to -2.14). In contrast, only non-Hispanic White individuals living in ADI quintile 4 had worse performance than those living in ADI quintile 1 on 4 of 11 cognitive tests, including SEVLT Learning (ß = -2.35; 95% CI, -4.40 to -0.30), SEVLT Delayed Recall (ß = -0.95; 95% CI, -1.73 to -0.17), TMT part B (ß = 15.95; 95% CI, 2.47-29.44), and DSST (ß = -3.96; 95% CI, -6.49 to -1.43). Conclusions and Relevance: In this cross-sectional study, aging in a disadvantaged area was associated with worse cognitive functioning, particularly for older Mexican American adults. Future studies examining the implications of exposure to neighborhood disadvantage across the life span will be important for improving cognitive outcomes in diverse populations.

Leveraging Electronic Health Record Technology and Team Care to Address Medication Adherence: Protocol for a Cluster Randomized Controlled Trial.

BACKGROUND: Low medication adherence is a common cause of high blood pressure but is often unrecognized in clinical practice. Electronic data linkages between electronic health records (EHRs) and pharmacies offer the opportunity to identify low medication adherence, which can be used for interventions at the point of care. We developed a multicomponent intervention that uses linked EHR and pharmacy data to automatically identify patients with elevated blood pressure and low medication adherence. The intervention then combines team-based care with EHR-based workflows to address medication nonadherence. OBJECTIVE: This study aims to describe the design of the Leveraging EHR Technology and Team Care to Address Medication Adherence (TEAMLET) trial, which tests the effectiveness of a multicomponent intervention that leverages EHR-based data and team-based care on medication adherence among patients with hypertension. METHODS: TEAMLET is a pragmatic, cluster randomized controlled trial in which 10 primary care practices will be randomized 1:1 to the multicomponent intervention or usual care. We will include all patients with hypertension and low medication adherence who are seen at enrolled practices. The primary outcome is medication adherence, as measured by the proportion of days covered, and the secondary outcome is clinic systolic blood pressure. We will also assess intervention implementation, including adoption, acceptability, fidelity, cost, and sustainability. RESULTS: As of May 2023, we have randomized 10 primary care practices into the study, with 5 practices assigned to each arm of the trial. The enrollment for the study commenced on October 5, 2022, and the trial is currently ongoing. We anticipate patient recruitment to go through the fall of 2023 and the primary outcomes to be assessed in the fall of 2024. CONCLUSIONS: The TEAMLET trial will evaluate the effectiveness of a multicomponent intervention that leverages EHR-based data and team-based care on medication adherence. If successful, the intervention could offer a scalable approach to address inadequate blood pressure control among millions of patients with hypertension. TRIAL REGISTRATION: ClinicalTrials.gov NCT05349422; https://clinicaltrials.gov/ct2/show/NCT05349422. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/47930.

SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy.

Rationally targeted therapies have transformed cancer treatment, but many patients develop resistance through bypass signaling pathway activation. PF-07284892 (ARRY-558) is an allosteric SHP2 inhibitor designed to overcome bypass-signaling-mediated resistance when combined with inhibitors of various oncogenic drivers. Activity in this setting was confirmed in diverse tumor models. Patients with ALK fusion-positive lung cancer, BRAFV600E-mutant colorectal cancer, KRASG12D-mutant ovarian cancer, and ROS1 fusion-positive pancreatic cancer who previously developed targeted therapy resistance were treated with PF-07284892 on the first dose level of a first-in-human clinical trial. After progression on PF-07284892 monotherapy, a novel study design allowed the addition of oncogene-directed targeted therapy that had previously failed. Combination therapy led to rapid tumor and circulating tumor DNA (ctDNA) responses and extended the duration of overall clinical benefit. SIGNIFICANCE: PF-07284892-targeted therapy combinations overcame bypass-signaling-mediated resistance in a clinical setting in which neither component was active on its own. This provides proof of concept of the utility of SHP2 inhibitors in overcoming resistance to diverse targeted therapies and provides a paradigm for accelerated testing of novel drug combinations early in clinical development. See related commentary by Hernando-Calvo and Garralda, p. 1762. This article is highlighted in the In This Issue feature, p. 1749.

Global rural health disparities in Alzheimer's disease and related dementias: State of the science.

INTRODUCTION: Individuals living in rural communities are at heightened risk for Alzheimer's disease and related dementias (ADRD), which parallels other persistent place-based health disparities. Identifying multiple potentially modifiable risk factors specific to rural areas that contribute to ADRD is an essential first step in understanding the complex interplay between various barriers and facilitators. METHODS: An interdisciplinary, international group of ADRD researchers convened to address the overarching question of: "What can be done to begin minimizing the rural health disparities that contribute uniquely to ADRD?" In this state of the science appraisal, we explore what is known about the biological, behavioral, sociocultural, and environmental influences on ADRD disparities in rural settings. RESULTS: A range of individual, interpersonal, and community factors were identified, including strengths of rural residents in facilitating healthy aging lifestyle interventions. DISCUSSION: A location dynamics model and ADRD-focused future directions are offered for guiding rural practitioners, researchers, and policymakers in mitigating rural disparities. HIGHLIGHTS: Rural residents face heightened Alzheimer's disease and related dementia (ADRD) risks and burdens due to health disparities. Defining the unique rural barriers and facilitators to cognitive health yields insight. The strengths and resilience of rural residents can mitigate ADRD-related challenges. A novel "location dynamics" model guides assessment of rural-specific ADRD issues.

A systematic review and meta-analysis on the prevalence and clinical characteristics of dysphagia in patients with dermatomyositis.

BACKGROUND: Dermatomyositis (DM) is a rare autoimmune disease characterized by distinctive skin rash, muscle inflammation with symmetrical and progressive muscle weakness, and elevated serum levels of muscle-associated enzymes. DM may affect skeletal muscles involved in swallowing, leading to dysphagia, which can negatively impact individual's physical and psychosocial well-being. Despite this, dysphagia in patients with DM remains poorly understood. This systematic review and meta-analysis aimed to evaluate the prevalence and clinical features of dysphagia in patients with DM and juvenile DM (JDM). METHODS: Four electronic databases were systematically searched until September 2022. Studies with patients with DM or JDM and dysphagia were included. The pooled prevalence of all included studies was calculated, and the clinical characteristics of dysphagia were qualitatively analyzed. KEY RESULTS: Thirty-nine studies with 3335 patients were included. The overall pooled prevalence of dysphagia was 32.3% (95% CI: 0.270, 0.373) in patients with DM and 37.7% (95% CI: -0.031, 0.785) in patients with JDM. Subgroup analyses revealed that Sweden had the highest prevalence (66.7% [95% CI: 0.289, 1.044]), whereas Tunisia had the lowest prevalence (14.3% [95% CI: -0.040, 0.326]). Moreover, South America had the highest prevalence (47.0% [95% CI: 0.401, 0.538]), whereas Africa had the lowest prevalence (14.3% [95% CI: -0.040, 0.326]). Dysphagia in patients with DM and JDM was characterized by both oropharyngeal and esophageal dysfunctions, with predominant difficulties in motility. CONCLUSIONS & INFERENCES: Our findings showed that dysphagia affects one in three patients with DM or JDM. However, the documentation on the diagnosis and management of dysphagia in the literature is inadequate. Our results highlighted the need to use both clinical and instrumental assessments to evaluate swallowing function in this population.

Perspectives on sexual and reproductive health self-care among women, healthcare providers, and other key informants: a mixed-methods study in South Africa and Zambia.

BACKGROUND: "Self-care" for sexual and reproductive health (SRH) includes contraceptive methods and other supplies that people can use with or without the support of a healthcare provider. Self-administered tests, self-injection of injectable contraception, or self-removal of intrauterine devices (IUDs) can increase people's access to and autonomy over their own SRH. Objectives of this study were to assess women's current interest in and use of SRH self-care and explore key informants' (KI) opinions of self-care, especially during the COVID-19 pandemic. METHODS: Data for this study came from female participants in the longitudinal Contraceptive Use Beyond ECHO (CUBE) study, and KIs, including healthcare providers, in South Africa and Zambia between September 2020 and June 2021. For this analysis, we used data from a participant phone survey (n = 537), and from in-depth interviews (IDIs) completed with a sub-sample of women (n = 39) and KIs (n = 36). Survey data were analyzed with descriptive statistics, and IDI data were analyzed using applied thematic analysis. RESULTS: Female survey participants in South Africa were more interested in learning about emergency contraceptive pills, subcutaneous injectable contraception, and CycleBeads, while Zambian participants wanted more information and access to condoms. However, in IDIs in both countries, women described minimal experience with self-care beyond condom use. In the Zambian KI IDIs, COVID-19 led to increased self-care counseling on subcutaneous injectable contraception and HIV self-testing. KIs who do not counsel on self-care were concerned that women may harm themselves or blame the provider for difficulties. Two KIs thought that women could possibly self-remove IUDs, but most expressed concerns. Reported barriers to self-care included COVID movement restrictions, transport costs, lack of accessible pharmacies, women's low awareness, and possible stigma. CONCLUSIONS: Women surveyed reported interest in learning more about SRH self-care methods and resources, but in IDIs did not report extensive previous use besides condoms. KIs described some concerns about women's ability to use self-care methods. Counseling on and provision of self-care methods and supplies may have increased during the COVID-19 pandemic, but ensuring that self-care is more than just a temporary measure in health systems has the potential to increase access to SRH care and support women's autonomy and healthcare needs.

BACKGROUND: "Self-care" refers to healthcare that does not have to be given by a provider, but that people can use themselves. In sexual and reproductive health (SRH), this includes medicines or supplies like pills and injections that people can use to prevent or test for pregnancy or sexually transmitted infections. This study wanted to better understand women's interest in and use of SRH self-care and explore key informants' opinions of self-care, especially during the COVID-19 pandemic. METHODS: We surveyed 537 women in KwaZulu-Natal province, South Africa and Lusaka, Zambia in 2020­2021. We also conducted interviews with 39 women and 36 key informants, including healthcare providers, government officials, and community advocates. RESULTS: Women surveyed in South Africa were more interested than those in Zambia in learning more about self-care contraception, especially daily pills, emergency pills, and injections they could give themselves. In interviews, some key informants said that they do not tell women about self-care because they worried that women could hurt themselves or blame the provider if they experienced problems. COVID movement restrictions, transport costs, and inaccessible pharmacies were all barriers that key informants mentioned to accessing tests, tools, or contraceptive methods that women could give or use themselves. CONCLUSIONS: Women surveyed were interested in learning more about self-care and those interviewed reported minimal previous use of self-care methods besides condoms. Providers also have some concerns about women's ability to use self-care methods. Counseling on and providing self-care methods and supplies may have increased during COVID-19, but increasing access to self-care could help more women take care of their own sexual and reproductive healthcare.

Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease.

STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti-IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder.