Characterizing the "HIV Care Adherence Journey" for Persons With HIV in the Philippines: Conceptual Foundation for Person-Centered Intervention.

ABSTRACT: Promoting adherence to HIV care among persons with HIV (PWH) is a key component to addressing the rising HIV epidemic in the Philippines. HIV care adherence is a complex process that may change throughout an individual's life course or "journey" living with HIV. This qualitative study aimed to explore the HIV care adherence journey of PWH. Maximum variation sampling was used to select 12 PWH and 3 health care providers for in-depth online interviews, which were analyzed using thematic analysis. The four themes that emerged to describe the HIV care adherence journey are integration, relation, navigation, and manifestation. Each theme corresponds to a unique set of activities and goals related to PWH's lived experiences as they initiate, practice, and maintain care adherence. This study provides a preliminary framework to characterize the HIV care adherence journey as a dynamic, complex, and multifaceted phenomenon, which can help to inform holistic interventions to support PWH.

Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127.

Increasing use of covalent and noncovalent inhibitors of Bruton's tyrosine kinase (BTK) has elucidated a series of acquired drug-resistant BTK mutations in patients with B cell malignancies. Here we identify inhibitor resistance mutations in BTK with distinct enzymatic activities, including some that impair BTK enzymatic activity while imparting novel protein-protein interactions that sustain B cell receptor (BCR) signaling. Furthermore, we describe a clinical-stage BTK and IKZF1/3 degrader, NX-2127, that can bind and proteasomally degrade each mutant BTK proteoform, resulting in potent blockade of BCR signaling. Treatment of chronic lymphocytic leukemia with NX-2127 achieves >80% degradation of BTK in patients and demonstrates proof-of-concept therapeutic benefit. These data reveal an oncogenic scaffold function of mutant BTK that confers resistance across clinically approved BTK inhibitors but is overcome by BTK degradation in patients.

Exploring the status and critical issues in mixed methods research in doctoral nursing education in the Philippines.

BACKGROUND: Mixed methods research (MMR) can be a pathway for doctoral nursing students to create innovative and noble contributions for the advancement of nursing theory, practice, and education. Several issues and challenges must be identified to successfully train, mentor, and support doctoral nursing students in conducting MMR. AIM: The study aimed to explore the status and critical issues in conducting, mentoring, and training MMR in doctoral nursing programs in the Philippines. METHODS: A descriptive qualitative study was conducted by performing semi-structured online interviews with 10 purposively selected participants who were faculty and educators with doctoral degrees, involved in teaching and mentoring MMR among doctoral nursing students in the last 10 years. Data were analyzed using Braun and Clarke's thematic analysis. FINDINGS: Four key themes emerged, namely, (1) perceptions on the use of MMR, (2) facilitators to use MMR, (3) barriers to the use of MMR, and (4) recommendations to promote the use of MMR focused on the student, faculty, and educational institution levels. CONCLUSION: Providing educational, institutional, and research support for doctoral nursing students and faculty could flourish the use of MMR in doctoral nursing programs with deeper meaning and reasoning.

The resting state of the human T-cell receptor-CD3 complex.

The T-cell receptor (TCR) is central to the ligand-dependent activation of T lymphocytes and as such orchestrates both adaptive and pathologic immune processes 1 . However, major questions remain regarding the structure and function of the human TCR 2-4 . Here, we present cryogenic electron microscopy structures for the unliganded human TCR-CD3 complex in a native-like lipid bilayer, revealing two related conformations that are distinct from its structure in detergent. These new "closed and compacted" conformations afford insights into the interactions between the TCR-CD3 and the membrane, including conserved surface patches that make extensive outer leaflet contact, and suggest novel conformational regulation by glycans. We show that the closed/compacted conformations, not the extended one previously reported in detergent 5-8 , represent the unliganded resting state for the TCR-CD3 in vivo , underscoring the importance of structural interrogation of membrane proteins in native-like environments. We use conformation-locking disulfide mutants to show that ectodomain opening is necessary for maximal ligand-dependent TCR-CD3 activation, demonstrating that TCR-intrinsic conformational change is necessary for full TCR-CD3 activation and opening numerous avenues for immunoreceptor engineering.

Psychometric Testing of the Filipino Version of the Clients' Perceptions of Providers' Cultural Competency (CPOPCC) Instrument Among LGBTQ+ Population in the Philippines.

Background and Purpose: Cultural competence is significant in addressing the health needs of vulnerable populations. This study conducted psychometric testing of a cultural competency instrument in the Philippines. Methods: Brislin's translation and a cross-sectional online design were used. Exploratory factor analysis (EFA) with varimax rotation examined construct validity of the 23-item scale among 157 adult LGBTQ+ residents. The scale revealed overall reliability (α = .85) including two subscales (α = .87, α = .81, and α = .61). The EFA yielded three theoretical factorial solutions. Conclusion: The Filipino version of the instrument demonstrated reliability and validity. Measuring clients' perceptions of provider and organizational cultural competency can improve the utilization of healthcare in Filipino LGBTQ+ communities. Future research will examine the dimensional structures of the instrument among expanded LGBTQ+ communities.

Neoantigen-specific stem cell memory-like CD4+ T cells mediate CD8+ T cell-dependent immunotherapy of MHC class II-negative solid tumors.

CD4+ T cells play key roles in a range of immune responses, either as direct effectors or through accessory cells, including CD8+ T lymphocytes. In cancer, neoantigen (NeoAg)-specific CD8+ T cells capable of direct tumor recognition have been extensively studied, whereas the role of NeoAg-specific CD4+ T cells is less well understood. We have characterized the murine CD4+ T cell response against a validated NeoAg (CLTCH129>Q) expressed by the MHC-II-deficient squamous cell carcinoma tumor model (SCC VII) at the level of single T cell receptor (TCR) clonotypes and in the setting of adoptive immunotherapy. We find that the natural CLTCH129>Q-specific repertoire is diverse and contains TCRs with distinct avidities as measured by tetramer-binding assays and CD4 dependence. Despite these differences, CD4+ T cells expressing high or moderate avidity TCRs undergo comparable in vivo proliferation to cross-presented antigen from growing tumors and drive similar levels of therapeutic immunity that is dependent on CD8+ T cells and CD40L signaling. Adoptive cellular therapy (ACT) with NeoAg-specific CD4+ T cells is most effective when TCR-engineered cells are differentiated ex vivo with IL-7 and IL-15 rather than IL-2 and this was associated with both increased expansion as well as the acquisition and stable maintenance of a T stem cell memory (TSCM)-like phenotype in tumor-draining lymph nodes (tdLNs). ACT with TSCM-like CD4+ T cells results in lower PD-1 expression by CD8+ T cells in the tumor microenvironment and an increased frequency of PD-1+CD8+ T cells in tdLNs. These findings illuminate the role of NeoAg-specific CD4+ T cells in mediating antitumor immunity via providing help to CD8+ T cells and highlight their therapeutic potential in ACT.

Integrated programmable strongly coupled three-ring resonator photonic molecule with ultralow-power piezoelectric control.

Photonic molecules can realize complex optical energy modes that simulate states of matter and have application to quantum, linear, and nonlinear optical systems. To achieve their full potential, it is critical to scale the photonic molecule energy state complexity and provide flexible, controllable, stable, high-resolution energy state engineering with low power tuning mechanisms. In this work, we demonstrate a controllable, silicon nitride integrated photonic molecule, with three high-quality factor ring resonators strongly coupled to each other and individually actuated using ultralow-power thin-film lead zirconate titanate (PZT) tuning. The resulting six tunable supermodes can be fully controlled, including their degeneracy, location, and degree of splitting, and the PZT actuator design yields narrow PM energy state linewidths below 58 MHz without degradation as the resonance shifts, with over an order of magnitude improvement in resonance splitting-to-width ratio of 58, and power consumption of 90 nW per actuator, with a 1-dB photonic molecule loss. The strongly coupled PZT-controlled resonator design provides a high-degree of resolution and controllability in accessing the supermodes. Given the low loss of the silicon nitride platform from the visible to infrared and the three individual bus, six-port design, these results open the door to novel device designs and a wide range of applications including tunable lasers, high-order suppression ultranarrow-linewidth lasers, dispersion engineering, optical parametric oscillators, physics simulations, and atomic and quantum photonics.

Silicon nitride stress-optic microresonator modulator for optical control applications.

Modulation-based control and locking of lasers, filters and other photonic components is a ubiquitous function across many applications that span the visible to infrared (IR), including atomic, molecular and optical (AMO), quantum sciences, fiber communications, metrology, and microwave photonics. Today, modulators used to realize these control functions consist of high-power bulk-optic components for tuning, sideband modulation, and phase and frequency shifting, while providing low optical insertion loss and operation from DC to 10s of MHz. In order to reduce the size, weight and cost of these applications and improve their scalability and reliability, modulation control functions need to be implemented in a low loss, wafer-scale CMOS-compatible photonic integration platform. The silicon nitride integration platform has been successful at realizing extremely low waveguide losses across the visible to infrared and components including high performance lasers, filters, resonators, stabilization cavities, and optical frequency combs. Yet, progress towards implementing low loss, low power modulators in the silicon nitride platform, while maintaining wafer-scale process compatibility has been limited. Here we report a significant advance in integration of a piezo-electric (PZT, lead zirconate titanate) actuated micro-ring modulation in a fully-planar, wafer-scale silicon nitride platform, that maintains low optical loss (0.03 dB/cm in a 625 µm resonator) at 1550 nm, with an order of magnitude increase in bandwidth (DC - 15 MHz 3-dB and DC - 25 MHz 6-dB) and order of magnitude lower power consumption of 20 nW improvement over prior PZT modulators. The modulator provides a >14 dB extinction ratio (ER) and 7.1 million quality-factor (Q) over the entire 4 GHz tuning range, a tuning efficiency of 162 MHz/V, and delivers the linearity required for control applications with 65.1 dB·Hz2/3 and 73.8 dB·Hz2/3 third-order intermodulation distortion (IMD3) spurious free dynamic range (SFDR) at 1 MHz and 10 MHz respectively. We demonstrate two control applications, laser stabilization in a Pound-Drever Hall (PDH) lock loop, reducing laser frequency noise by 40 dB, and as a laser carrier tracking filter. This PZT modulator design can be extended to the visible in the ultra-low loss silicon nitride platform with minor waveguide design changes. This integration of PZT modulation in the ultra-low loss silicon nitride waveguide platform enables modulator control functions in a wide range of visible to IR applications such as atomic and molecular transition locking for cooling, trapping and probing, controllable optical frequency combs, low-power external cavity tunable lasers, quantum computers, sensors and communications, atomic clocks, and tunable ultra-low linewidth lasers and ultra-low phase noise microwave synthesizers.

Native-like environments afford novel mechanistic insights into membrane proteins.

Advances in cryogenic electron microscopy (cryo-EM) enabled routine near-atomic structure determination of membrane proteins, while nanodisc technology has provided a way to provide membrane proteins with a native or native-like lipid environment. After giving a brief history of membrane mimetics, we present example structures of membrane proteins in nanodiscs that revealed information not provided by structures obtained in detergent. We describe how the lipid environment surrounding the membrane protein can be custom designed during nanodisc assembly and how it can be modified after assembly to test functional hypotheses. Because nanodiscs most closely replicate the physiologic environment of membrane proteins and often afford novel mechanistic insights, we propose that nanodiscs ought to become the standard for structural studies on membrane proteins.

Mechanisms of Resistance to Noncovalent Bruton's Tyrosine Kinase Inhibitors.

BACKGROUND: Covalent (irreversible) Bruton's tyrosine kinase (BTK) inhibitors have transformed the treatment of multiple B-cell cancers, especially chronic lymphocytic leukemia (CLL). However, resistance can arise through multiple mechanisms, including acquired mutations in BTK at residue C481, the binding site of covalent BTK inhibitors. Noncovalent (reversible) BTK inhibitors overcome this mechanism and other sources of resistance, but the mechanisms of resistance to these therapies are currently not well understood. METHODS: We performed genomic analyses of pretreatment specimens as well as specimens obtained at the time of disease progression from patients with CLL who had been treated with the noncovalent BTK inhibitor pirtobrutinib. Structural modeling, BTK-binding assays, and cell-based assays were conducted to study mutations that confer resistance to noncovalent BTK inhibitors. RESULTS: Among 55 treated patients, we identified 9 patients with relapsed or refractory CLL and acquired mechanisms of genetic resistance to pirtobrutinib. We found mutations (V416L, A428D, M437R, T474I, and L528W) that were clustered in the kinase domain of BTK and that conferred resistance to both noncovalent BTK inhibitors and certain covalent BTK inhibitors. Mutations in BTK or phospholipase C gamma 2 (PLCγ2), a signaling molecule and downstream substrate of BTK, were found in all 9 patients. Transcriptional activation reflecting B-cell-receptor signaling persisted despite continued therapy with noncovalent BTK inhibitors. CONCLUSIONS: Resistance to noncovalent BTK inhibitors arose through on-target BTK mutations and downstream PLCγ2 mutations that allowed escape from BTK inhibition. A proportion of these mutations also conferred resistance across clinically approved covalent BTK inhibitors. These data suggested new mechanisms of genomic escape from established covalent and novel noncovalent BTK inhibitors. (Funded by the American Society of Hematology and others.).

Determinants of anticipated turnover of nurses in selected hospitals in Metro Manila

Background@#Nurses comprise the largest group of health professionals in the Philippines, and turnover remains a challenge to the workforce and healthcare system. Understanding the extent of the problem and multiple factors related to turnover rates is crucial in retaining nurses in the organization and profession. @*Objectives@#The study aimed to (1) describe and compare nurses' turnover intention, (2) identify factors for nurses' turnover intention, and (3) determine factors to promote nurses' retention in their current organization. @*Methodology@#This descriptive, cross-sectional, and correlational study was conducted through a survey that sought the participants' sociodemographic and work-related characteristics and their perceived practice environment, job satisfaction, organizational commitment, job stress, and alternative job opportunities. Additional questions were added to identify the participants' reasons for their intention to leave their current job and stay in their current organizations. @*Results@#The final sample comprised 297 nurses. Significant differences in the nurses' turnover intention scores were found across multiple demographic, personal, and work-related factors. The final multiple logistic regression model revealed that 'influence of peers to leave,' 'desire to try new things,' practice environment, and organizational commitment were significant factors in the nurses' turnover intention. Staff nurses perceived practice environment (n=246) as the primary reason to stay in their current organization while it was compensation and benefits (n=25) for nurse managers. @*Conclusion@#A collaborative approach among the sectors of a healthcare organization is needed to develop a policy framework that advocates and promotes positive practice environment, job satisfaction, career progression, and personal well-being among nurses and other healthcare workers.

Neisseria Gonorrhoeae Spontaneous Bacterial Peritonitis.

We describe a case of gonococcal spontaneous bacterial peritonitis (SBP) in a 48-year-old sexually active female with alcoholic cirrhosis and chronic hepatitis B. She was admitted with fever, abdominal pain and distension without dysuria, dyspareunia, or vaginal discharge. On exam, she was icteric with features of sepsis and tense ascites. She underwent paracentesis. The ascitic fluid analysis revealed a neutrophil count of 1,050/µL, and culture grew Neisseria gonorrhoeae. Pelvic examination findings were negative for pelvic inflammatory disease; however, an endocervical swab was positive for N. gonorrhoeae by PCR. She was diagnosed with spontaneous bacterial peritonitis secondary to N. gonorrhoeae and was successfully treated with a seven-day course of IV ceftriaxone. N. gonorrhoeae spontaneous bacterial peritonitis is an extremely rare entity reported only twice despite the high prevalence of gonorrhoeae in the general population. We hypothesize that gonococcal SBP may be frequently undiagnosed since it responds to empiric antibiotics used to treat SBP. It is important for the clinician to be aware of gonococcus as a rare but potential pathogen in SBP. Future studies are needed to determine if routine gonococcal screening in SBP cases would be of clinical utility.

Synthesis of 3-aryl-1-phosphinoimidazo[1,5-a]pyridine ligands for use in Suzuki-Miyaura cross-coupling reactions.

3-Aryl-1-phosphinoimidazo[1,5-a]pyridine ligands were synthesized from 2-aminomethylpyridine as the initial substrate via two complementary routes. The first synthetic pathway underwent the coupling of 2-aminomethylpyridine with substituted benzoyl chlorides, followed by cyclization, iodination and palladium-catalyzed cross-coupling phosphination reactions sequence to give our phosphorus ligands. In the second route, 2-aminomethylpyridine was cyclized with aryl aldehydes, followed by the iodination and palladium-catalyzed cross-coupling phosphination reactions to yield our phosphorus ligands. The 3-aryl-1-phosphinoimidazo[1,5-a]pyridine ligands were evaluated in palladium-catalyzed sterically-hindered biaryl and heterobiaryl Suzuki-Miyaura cross-coupling reactions.

Significance of Home Visiting in Providing Care to Filipino Mothers and Their Infants During the Postpartum Period.

INTRODUCTION: Home visiting is recommended for mothers and young infants during the first week of life to provide needed support. This study describes the significance of home visiting in providing care to Filipino mothers and their infants during the postpartum period. METHODOLOGY: Using a descriptive qualitative design, individual interviews were conducted with 10 mothers, four registered nurses, and five barangay health workers involved in home visits. Data analysis was guided by the four phases of Leininger's ethnonursing method. RESULTS: Three themes emerged: (1) home visiting provides accessible, affordable, and meaningful interventions; (2) home visiting allows for contextual understanding of mothers' behaviors and realistic planning of care; and (3) barangay health workers promote mothers' engagement in care. CONCLUSION: Home visits enable negotiation of differences between generic and professional care practices, thus enhancing professional collaboration with families and community workers, potentiating culturally congruent participation and empowerment of clients in their care.

An integrative review of home visiting programs for mothers and infants from birth to 12 months in developed and underdeveloped countries

OBJECTIVES@#To investigate home visiting for mothers and young infants, age birth-to-12 months, program goals, interventions used, home visitor characteristics and qualifications, and the program content and outcomes.@*METHODS@#Electronic databases PubMed, CINAHL, ScienceDirect, and Sagepub were used. Eleven studies investi- gating home visiting from 2011-to-2016 were included. Studies were included if they: 1) were a primary study; 2) commenced during the antepartum or early postpartum period for mothers and finished before or when the infant was 12 months old; 3) and provided a description of home visiting program in terms of goal, type of home visitor, content, length, and outcomes. Data extraction included goals, activities, home visitor characteristics and qualifications, and outcomes. A descriptive approach was used to synthesize data.@*RESULTS@#Home visiting impacted birth preparedness, newborn care practices, breastfeeding practices, and home environment necessary for maternal wellness and child health and development.@*CONCLUSION@#Home visits in developed and underdeveloped countries create positive outcomes for mothers and infants. It is important to understand the process in order to make it more effective.

Development and effect of the online HIV Prevention and Care Training (HPCT) program for student nurses

@#Student nurses must be competently prepared to address the rising human immunodeficiency virus (HIV) epidemic in the Philippines. This article presents the development and effect of the online HIV Prevention and Care Training (HPCT) program for student nurses. The Iowa Model-Revised guided the development of the program. Literature review, student and faculty engagements, advocate participation, resources and protocol assessment, and pre-HPCT survey analysis were systematically performed to determine the contents and delivery of the program. The participants were 2nd and 3rd year level student nurses who were asked to answer the pre- and post-HPCT online surveys containing sociodemographic, HIV knowledge, attitudes, and perceived practices, and program evaluation questionnaires. Descriptive and inferential statistics were performed using SPSS version 23. Student nurses in the post-HPCTsurvey obtained significantly higher HIV knowledge scale mean scores (mean=18.22, SD=4.138) than those in the pre-HPCT survey (mean=15.01, SD=4.069) (p=.000). Pre- to post-HPCT survey revealed significant decreases in the proportions of student nurses who agreed on the following: HIV-positive patients should not be put in rooms with other patients when admitted to hospital (44.3%, 31.6%; p=.004); the need to worry about putting family and friends at risk of contracting the disease when caring for a person with HIV/AIDS (39.7%, 26.4%; p=.002); and healthcare workers are worried of getting HIV/AIDS from caring for a person with HIV/AIDS in their work environment (47.2%, 37.5%; p=.011). Significantly, more student nurses in the post-HPCT survey agreed in all the items of the HIV practice scale than those in the pre-HPCT survey. The online HPCTprogram was acceptable with beneficial effects on student nurses' HIV knowledge, attitudes, and perceived practices. There is a need to highlight basic HIV concepts and integrate HIV developments in the education of student nurses.

Facilitators and barriers to condom use among Filipinos: A systematic review of literature.

Background: Between 2010 and 2018, the Philippines had a 203% increase in new human immunodeficiency virus (HIV) infections. The use of condoms is an effective and practical means to prevent HIV transmission. The purpose of this study was to identify facilitators and barriers to condom use among Filipinos guided by the Ecological Model of Health Promotion. Methods: A systematic review of literature using electronic databases was performed using the following keywords: "condom," "Filipinos," and "Philippines." To be included in this review, papers should be (1) research studies, (2) studies that examined condom use, and (3) studies that sampled Filipinos residing in the Philippines. The final sample comprised of 27 articles. Results: Multiple and interrelated factors at the individual and social environment levels influence condom use among different groups of Filipinos. Majority of these factors originated at the intrapersonal level. Some of the facilitators to condom use were knowledge on HIV, higher perceived HIV risk, peer support, positive manager attitude, health provider engagement, and city ordinances. In contrast, some of the barriers to condom use were discomfort and displeasure on condom use, low parental communication, lack of sex education, social stigma, and the high price of condoms. Conclusion: A collaborative, culturally-sensitive, and population-specific approach is essential to develop and implement acceptable, sustainable, and successful condom use interventions.

Processing-Structure-Property Relations for Radiation Tolerance of Relaxor-Ferroelectric Thin Films.

This work investigates the role of microstructure on the radiation tolerance of relaxor-ferroelectric, lead magnesium niobate-lead titanate, thin films for piezoelectric microelectromechanical system (MEMS) applications. Thin films comprised of 0.7Pb[Mg1/3Nb2/3]O3-0.3PbTiO3 were fabricated via chemical solution deposition on platinized silicon wafers. Processing parameters, i.e., pyrolysis and annealing temperatures and durations, were varied to change the microstructure of the films. The functional response of the films was characterized before and after exposure to gamma radiation [up to 10 Mrad(Si)]. Within the total ionization dose studied, all films showed a <5% change in dielectric response and polarization and <15% change in piezoelectric response, after irradiation. While all films showed substantial radiation tolerance, those with large columnar grains showed the highest dielectric and piezoelectric response and, therefore, might offer the best approach for enabling piezoelectric MEMS devices for applications in radiative environments.

TLR9 Sensing of Self-DNA Controls Cell-Mediated Immunity to Listeria Infection via Rapid Conversion of Conventional CD4+ T Cells to Treg.

CD4+ T lymphocytes are crucial for controlling a range of innate and adaptive immune effectors. For CD8+ cytotoxic T lymphocyte (CTL) responses, CD4+ T cells can function as helpers (TH) to amplify magnitude and functionality or as regulatory cells (Treg) capable of profound inhibition. It is unclear what determines differentiation to these phenotypes and whether pathogens provoke alternate programs. We find that, depending on the size of initial dose, Listeria infection drives CD4+ T cells to act as TH or induces rapid polyclonal conversion to immunosuppressive Treg. Conversion to Treg depends on the TLR9 and IL-12 pathways elicited by CD8α+ dendritic cell (DC) sensing of danger-associated neutrophil self-DNA. These findings resolve long-standing questions regarding the conditional requirement for TH amongst pathogens and reveal a remarkable degree of plasticity in the function of CD4+ T cells, which can be quickly converted to Tregin vivo by infection-mediated immune modulation.