Introduction

Exacerbation of COPD complicated by respiratory acidaemia is the commonest indication for noninvasive ventilation (NIV). The NIV outcomes (NIVO) score offers the best estimate of survival for those ventilated. Unfortunately, two-thirds of cases of COPD are unrecognised, and patients may present without COPD having been confirmed by spirometry.

Background

Quality of life is impaired in patients with sarcoidosis. The King's Sarcoidosis Questionnaire (KSQ) is a brief questionnaire assessing health-related quality of life in patients with sarcoidosis, comprising subdomains of General Health Status (GHS), Lung, Medication, Skin and Eyes. The aim of this study was to enhance the validation of the KSQ, incorporating longitudinal validation and known-groups validity in a cohort with mild sarcoidosis.

Background

Long COVID is a heterogeneous clinical syndrome characterised by a variety of reported symptoms and signs. Its clinical management is expected to differ significantly worldwide.

Extract

In 2021, the World Health Organization (WHO) issued recommendations for the use of artificial intelligence (AI), affirming the technology could be used instead of human readers for the interpretation of chest radiograph (CXR) images for the screening and triage of tuberculosis (TB), marking a historic precedent for a guideline on AI in health [1]. The forward-looking guidance highlights the utility of CXR in TB, despite past reluctance from WHO to use it in TB programmes [2]. Employing CXR in a diagnostic algorithm can identify people with subclinical TB who are asymptomatic but have lung pathology suggestive of TB, and refer them for testing and diagnosis [3].

Extract

There is an expanding literature on the association between obstructive sleep apnoea (OSA) and cancer risk [1, 2]. Evidence is growing from population- and clinic-based cohort studies that the severity of OSA and sleep-related hypoxaemia may adversely affect both overall cancer risk and incidence of certain cancers [3–7]. These clinical findings are supported by the identification of the intermediate mechanisms by which intermittent hypoxia and sleep fragmentation, the hallmark features of OSA, might promote oncogenesis, tumour growth and metastasis [8]. Although studies have shown a relationship between OSA and cancer, few have evaluated whether the risk of cancer development or progression in patients with OSA is modified by continuous positive airway pressure (CPAP) therapy (the primary treatment for OSA) [1, 2].

Background

The real-world consequences of a Philips Respironics recall for positive airway pressure (PAP) devices distributed between 2009 and 2021 are unknown.

The management of chylothorax remains challenging given the limited evidence and significant heterogeneity in practice. In addition, there are no practical guidelines on the optimal approach to manage this complex condition. We convened an international group of 27 experts from 20 institutions across five countries and four specialties (pulmonary, interventional radiology, thoracic surgery and nutrition) with experience and expertise in managing adult patients with chylothorax. We performed a literature and internet search for reports addressing seven clinically relevant PICO (Patient, Intervention, Comparison and Outcome) questions pertaining to the management of adult patients with chylothorax. This consensus statement, consisting of best practice statements based on expert consensus addressing these seven PICO questions, was formulated by a systematic and rigorous process involving the evaluation of published evidence, augmented with provider experience. Panel members participated in the development of the final best practice statements using the modified Delphi technique. Our consensus statement aims to offer guidance in clinical decision making when managing patients with chylothorax while also identifying gaps in knowledge and informing future research.

Non-invasive ventilation (NIV) is the mainstay to treat patients who need augmentation of ventilation for acute and chronic forms of respiratory failure. The last several decades have witnessed an extension of the indications for NIV to a variety of acute and chronic lung diseases. Evolving advancements in technology and personalised approaches to patient care make it feasible to prioritise patient-centred care models that deliver home-based management using telemonitoring and telemedicine systems support. These trends may improve patient outcomes, reduce healthcare costs and improve the quality of life for patients who suffer from chronic diseases that precipitate respiratory failure.

Background

Pseudomonas aeruginosa is a common pathogen that contributes to progressive lung disease in cystic fibrosis (CF). Genetic factors other than CF-causing CFTR (CF transmembrane conductance regulator) variations contribute ~85% of the variation in chronic P. aeruginosa infection age in CF according to twin studies, but the susceptibility loci remain unknown. Our objective is to advance understanding of the genetic basis of host susceptibility to P. aeruginosa infection.

Hepatocyte nuclear factor 4 alpha antisense 1 (HNF4A-AS1) is a long noncoding RNA (lncRNA) gene physically located next to the transcription factor HNF4A gene in the human genome. Its transcription products have been reported to inhibit the progression of hepatocellular carcinoma (HCC) and negatively regulate the expression of cytochrome P450s (CYPs), including CYP1A2, 2B6, 2C9, 2C19, 2E1, and 3A4. By altering CYP expression, lncRNA HNF4A-AS1 also contributes to the susceptibility of drug-induced liver injury. Thus, HNF4A-AS1 lncRNA is a promising target for controlling HCC and modulating drug metabolism. However, HNF4A-AS1 has four annotated alternative transcripts in the human genome browsers, and it is unclear which transcripts the small interfering RNAs or small hairpin RNAs used in the previous studies are silenced and which transcripts should be used as the target. In this study, four annotated and two newly identified transcripts were confirmed. These six transcripts showed different expression levels in different liver disease conditions, including metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, and obesity. The expression patterns of all HNF4A-AS1 transcripts were further investigated in liver cell growth from human embryonic stem cells to matured hepatocyte-like cells, HepaRG differentiation, and exposure to rifampicin treatment. Several HNF4A-AS1 transcripts highly displayed correlations with these situations. In addition, some of the HNF4A-AS1 transcripts also showed a strong correlation with CYP3A4 during HepaRG maturation and rifampicin exposure. Our findings provide valuable insights into the specific roles of HNF4A-AS1 transcripts, paving the way for more targeted therapeutic strategies for liver diseases and drug metabolism.

Over the past 20 years, quantitative proteomics has contributed a wealth of protein expression data, which are currently used for a variety of systems pharmacology applications, as a complement or a surrogate for activity of the corresponding proteins. A symposium at the 25th North American International Society for the Study of Xenobiotics meeting, in Boston, in September 2023, was held to explore current and emerging applications of quantitative proteomics in translational pharmacology and strategies for improved integration into model-informed drug development based on practical experience of each of the presenters. A summary of the talks and discussions is presented in this perspective alongside future outlook that was outlined for future meetings.

ATP-binding cassette transporter subfamily G member 2 (ABCG2) is a membrane-bound transporter responsible for the efflux of various xenobiotics and endobiotics, including protoporphyrin IX (PPIX), an intermediate in the heme biosynthesis pathway. Certain genetic mutations and chemicals impair the conversion of PPIX to heme and/or increase PPIX production, leading to PPIX accumulation and toxicity. In mice, deficiency of ABCG2 protects against PPIX-mediated phototoxicity and hepatotoxicity by modulating PPIX distribution. In addition, in vitro studies revealed that ABCG2 inhibition increases the efficacy of PPIX-based photodynamic therapy by retaining PPIX inside target cells. In this review, we discuss the roles of ABCG2 in modulating the tissue distribution of PPIX, PPIX-mediated toxicity, and PPIX-based photodynamic therapy.

The regulation of drug-metabolizing enzymes and transporters by cytokines has been extensively studied in vitro and in clinic. Cytokine-mediated suppression of cytochrome P450 (CYP) or drug transporters may increase or decrease the systemic clearance of drug substrates that are primarily cleared via these pathways; neutralization of cytokines by therapeutic proteins may thereby alter systemic exposures of such drug substrates. The Food and Drug Administration recommends evaluating such clinical drug interactions during clinical development and has provided labeling recommendations for therapeutic proteins. To determine the clinical relevance of these drug interactions to dose adjustments, trends in steady-state exposures of CYP-sensitive substrates coadministered with cytokine modulators as reported in the University of Washington Drug Interaction Database were extracted and examined for each of the CYPs. Coadministration of cytochrome P450 family 3 subfamily A (CYP3A) (midazolam/simvastatin), cytochrome P450 subfamily 2C19 (omeprazole), or cytochrome P450 subfamily 1A2 (caffeine/tizanidine) substrates with anti-interleukin-6 and with anti-interleukin-23 therapeutics led to changes in systemic exposures of CYP substrates ranging from ~ –58% to ~35%; no significant trends were observed for cytochrome P450 subfamily 2D6 (dextromethorphan) and cytochrome P450 subfamily 2C9 (warfarin) substrates. Although none of these changes in systemic exposures have been reported as clinically meaningful, dose adjustment of midazolam for optimal sedation in acute care settings has been reported. Simulated concentration-time profiles of midazolam under conditions of elevated cytokine levels when coadministered with tocilizumab, suggest a ~six- to sevenfold increase in midazolam clearance, suggesting potential implications of cytokine–CYP drug interactions on dose adjustments of sensitive CYP3A substrates in acute care settings. Additionally, this article also provides a brief overview of nonclinical and clinical assessments of cytokine–CYP drug interactions in drug discovery and development.

The precision medicine initiative has driven a substantial change in the way scientists and health care practitioners think about diagnosing and treating disease. While it has long been recognized that drug response is determined by the intersection of genetic, environmental, and disease factors, improvements in technology have afforded precision medicine guided dosing of drugs to improve efficacy and reduce toxicity. Pharmacometabolomics aims to evaluate small molecule metabolites in plasma and/or urine to help evaluate mechanisms that predict and/or reflect drug efficacy and toxicity. In this mini review, we provide an overview of pharmacometabolomic approaches and methodologies. Relevant examples where metabolomic techniques have been used to better understand drug efficacy and toxicity in major depressive disorder and cancer chemotherapy are discussed. In addition, the utility of metabolomics in drug development and understanding drug metabolism, transport, and pharmacokinetics is reviewed. Pharmacometabolomic approaches can help describe factors mediating drug disposition, efficacy, and toxicity. While important advancements in this area have been made, there remain several challenges that must be overcome before this approach can be fully implemented into clinical drug therapy.

A STING (stimulator of interferon genes) agonist GSK3996915 under investigation in early discovery for hepatitis B was orally dosed to a mouse model for understanding the parent drug distribution in liver, the target organ. Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) was used to quantify the distribution of GSK3996915 in liver collected from mice administered a single oral dose at 90 mg/kg. GSK3996915 was detected with a zonal distribution localized in the portal triad and highly concentrated in the main bile ducts, indicating clearance through biliary excretion. High spatial resolution imaging showed the distribution of the parent drug localized to the cellular populations in the sinusoids, including the Kupffer cells. Additionally, a series of drug-related metabolites were observed to be localized in the central zones of the liver. These results exemplify the potential of utilizing MALDI IMS for measuring not only quantitative drug distribution and target exposure but also drug metabolism and elimination in a single suite of experiments.

Drug–drug interaction (DDI) assessment of therapeutic peptides is an evolving area. The industry generally follows DDI guidelines for small molecules, but the translation of data generated with commonly used in vitro systems to in vivo is sparse. In the current study, we investigated the ability of advanced human hepatocyte in vitro systems, namely HepatoPac, spheroids, and Liver-on-a-chip, to assess potential changes in regulation of CYP1A2, CYP2B6, CYP3A4, SLCO1B1, and ABCC2 in the presence of selected therapeutic peptides, proteins, and small molecules. The peptide NN1177, a glucagon and GLP-1 receptor co-agonist, did not suppress mRNA expression or activity of CYP1A2, CYP2B6, and CYP3A4 in HepatoPac, spheroids, or Liver-on-a-chip; these findings were in contrast to the data obtained in sandwich cultured hepatocytes. No effect of NN1177 on SLCO1B1 and ABCC2 mRNA was observed in any of the complex systems. The induction magnitude differed across the systems (e.g., rifampicin induction of CYP3A4 mRNA ranged from 2.8-fold in spheroids to 81.2-fold in Liver-on-a-chip). Small molecules, obeticholic acid and abemaciclib, showed varying responses in HepatoPac, spheroids, and Liver-on-a-chip, indicating a need for EC₅₀ determinations to fully assess translatability data. HepatoPac, the most extensively investigated in this study (3 donors), showed high potential to investigate DDIs associated with CYP regulation by therapeutic peptides. Spheroids and Liver-on-a-chip were only assessed in one hepatocyte donor and further evaluations are required to confirm their potential. This study establishes an excellent foundation toward the establishment of more clinically-relevant in vitro tools for evaluation of potential DDIs with therapeutic peptides.

Pregnane X receptor (PXR) belongs to the nuclear receptor superfamily that plays a crucial role in hepatic physiologic and pathologic conditions. Phase separation is a process in which biomacromolecules aggregate and condense into a dense phase as liquid condensates and coexist with a dilute phase, contributing to various cellular and biologic functions. Until now, whether PXR could undergo phase separation remains unclear. This study aimed to investigate whether PXR undergoes phase separation. Analysis of the intrinsically disordered regions (IDRs) using algorithm tools indicated a low propensity of PXR to undergo phase separation. Experimental assays such as hyperosmotic stress, agonist treatment, and optoDroplets assay demonstrated the absence of phase separation for PXR. OptoDroplets assay revealed the inability of the fusion protein of Cry2 with PXR to form condensates upon blue light stimulation. Moreover, phase separation of PXR did not occur even though the mRNA and protein expression levels of PXR target, cytochrome P450 3A4, changed after sorbitol treatment. In conclusion, for the first time, these findings suggested that exogenous PXR does not undergo phase separation following activation or under hyperosmotic stress in nucleus of cells.

Protein abundance data of drug-metabolizing enzymes and transporters (DMETs) are useful for scaling in vitro and animal data to humans for accurate prediction and interpretation of drug clearance and toxicity. Targeted DMET proteomics that relies on synthetic stable isotope-labeled surrogate peptides as calibrators is routinely used for the quantification of selected proteins; however, the technique is limited to the quantification of a small number of proteins. Although the global proteomics-based total protein approach (TPA) is emerging as a better alternative for large-scale protein quantification, the conventional TPA does not consider differential sequence coverage by identifying unique peptides across proteins. Here, we optimized the TPA approach by correcting protein abundance data by the sequence coverage, which was applied to quantify 54 DMETs for characterization of 1) differential tissue DMET abundance in the human liver, kidney, and intestine, and 2) interindividual variability of DMET proteins in individual intestinal samples (n = 13). Uridine diphosphate-glucuronosyltransferase 2B7 (UGT2B7), microsomal glutathione S-transferases (MGST1, MGST2, and MGST3) carboxylesterase 2 (CES2), and multidrug resistance-associated protein 2 (MRP2) were expressed in all three tissues, whereas, as expected, four cytochrome P450s (CYP3A4, CYP3A5, CYP2C9, and CYP4F2), UGT1A1, UGT2B17, CES1, flavin-containing monooxygenase 5, MRP3, and P-glycoprotein were present in the liver and intestine. The top three DMET proteins in individual tissues were: CES1>CYP2E1>UGT2B7 (liver), CES2>UGT2B17>CYP3A4 (intestine), and MGST1>UGT1A6>MGST2 (kidney). CYP3A4, CYP3A5, UGT2B17, CES2, and MGST2 showed high interindividual variability in the intestine. These data are relevant for enhancing in vitro to in vivo extrapolation of drug absorption and disposition and can be used to enhance the accuracy of physiologically based pharmacokinetic prediction of systemic and tissue concentration of drugs.

Hydrolases represent an essential class of enzymes indispensable for the metabolism of various clinically essential medications. Individuals exhibit marked differences in the expression and activation of hydrolases, resulting in significant variability in the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs metabolized by these enzymes. The regulation of hydrolase expression and activity involves both genetic polymorphisms and nongenetic factors. This review examines the current understanding of genetic and nongenetic regulators of six clinically significant hydrolases, including carboxylesterase (CES)-1 CES2, arylacetamide deacetylase (AADAC), paraoxonase (PON)-1 PON3, and cathepsin A (CTSA). We explore genetic variants linked to the expression and activity of the hydrolases and their effects on the PK and PD of their substrate drugs. Regarding nongenetic regulators, we focus on the inhibitors and inducers of these enzymes. Additionally, we examine the developmental expression patterns and gender differences in the hydrolases when pertinent information was available. Many genetic and nongenetic regulators were found to be associated with the expression and activity of the hydrolases and PK and PD. However, hydrolases remain generally understudied compared with other drug-metabolizing enzymes, such as cytochrome P450s. The clinical significance of genetic and nongenetic regulators has not yet been firmly established for the majority of hydrolases. Comprehending the mechanisms that underpin the regulation of these enzymes holds the potential to refine therapeutic regimens, thereby enhancing the efficacy and safety of drugs metabolized by the hydrolases.

The orexigenic gut peptide ghrelin is an endogenous ligand for the growth hormone secretagogue receptor type 1a (GHSR1a). Systemic ghrelin administration has previously been shown to increase gastric motility and emptying. While these effects are known to be mediated by the vagus nerve, the cellular mechanism underlying these effects remains unclear. Therefore, the purpose of the present study was to investigate the signaling mechanism by which GHSR1a inhibits voltage-gated Ca²⁺ channels in isolated rat gastric vagal afferent neurons using whole-cell patch-clamp electrophysiology. The ghrelin pharmacological profile indicated that Ca²⁺ currents were inhibited with a log (Ic₅₀) = –2.10 ± 0.44 and a maximal inhibition of 42.8 ± 5.0%. Exposure to the GHSR1a receptor antagonist (D-Lys3)-GHRP-6 reduced ghrelin-mediated Ca²⁺ channel inhibition (29.4 ± 16.7% vs. 1.9 ± 2.5%, n = 6, P = 0.0064). Interestingly, we observed that activation of GHSR1a inhibited Ca²⁺ currents through both voltage-dependent and voltage-independent pathways. We also treated the gastric neurons with either pertussis toxin (PTX) or YM-254890 to examine whether the Ca²⁺ current inhibition was mediated by the Gα_i/o or Gα_q/11 family of subunits. Treatment with both PTX (Ca²⁺ current inhibition = 15.7 ± 10.6%, n = 8, P = 0.0327) and YM-254890 (15.2 ± 11.9%, n = 8, P = 0.0269) blocked ghrelin’s effects on Ca²⁺ currents, as compared with control neurons (34.3 ± 18.9%, n = 8). These results indicate GHSR1a can couple to both Gα_i/o and Gα_q/11 in gastric vagal afferent neurons. Overall, our findings suggest GHSR1a-mediated inhibition of Ca²⁺ currents occurs through two distinct pathways, offering necessary insights into the cellular mechanisms underlying ghrelin’s regulation of gastric vagal afferents.

The antitumor effect of cardiotonic steroids (CTS) has stimulated the search for new methods to evaluate both kinetic and thermodynamic aspects of their binding to Na⁺/K⁺-ATPase (IUBMB Enzyme Nomenclature). We propose a real-time assay based on a chromogenic substrate for phosphatase activity (pNPPase activity), using only two concentrations with an inhibitory progression curve, to obtain the association rate (k_on), dissociation rate (k_off), and equilibrium (K_i) constants of CTS for the structure-kinetics relationship in drug screening. We show that changing conditions (from ATPase to pNPPase activity) resulted in an increase of K_i of the cardenolides digitoxigenin, essentially due to a reduction of k_on. In contrast, the K_i of the structurally related bufadienolide bufalin increased much less due to the reduction of its k_off partially compensating the decrease of its k_on. When evaluating the kinetics of 15 natural and semisynthetic CTS, we observed that both k_on and k_off correlated with K_i (Spearman test), suggesting that differences in potency depend on variations of both k_on and k_off. A rhamnose in C3 of the steroidal nucleus enhanced the inhibitory potency by a reduction of k_off rather than an increase of k_on. Raising the temperature did not alter the k_off of digitoxin, generating a H (k_off) of –10.4 ± 4.3 kJ/mol, suggesting a complex dissociation mechanism. Based on a simple and inexpensive methodology, we determined the values of k_on, k_off, and K_i of the CTS and provided original kinetics and thermodynamics differences between CTS that could help the design of new compounds.

G protein–coupled receptors (GPCRs) couple to heterotrimeric G proteins, comprised of α and β subunits, to convert extracellular signals into activation of intracellular signaling pathways. Canonically, GPCR-mediated activation results in the exchange of GDP for GTP on G protein α subunits (Gα) and the dissociation of Gα-GTP and G protein β subunits (Gβ), both of which can regulate a variety of signaling pathways. Hydrolysis of bound GTP by Gα returns the protein to Gα-GDP and allows reassociation with Gβ to reform the inactive heterotrimer. Naturally occurring mutations in Gα have been found at conserved glutamine and arginine amino acids that disrupt the canonical G protein cycle by inhibiting GTP hydrolysis, rendering these mutants constitutively active. Interestingly, these dysregulated Gα mutants are found in many different cancers due to their ability to sustain aberrant signaling without a need for activation by GPCRs. This review will highlight an increased recognition of the prevalence of such constitutively activating Gα mutations in cancers and the signaling pathways activated. In addition, we will discuss new knowledge regarding how these constitutively active Gα are regulated, how different mutations are biochemically distinct, and how mutationally activated Gα are unique compared with GPCR-activated Gα. Lastly, we will discuss recent progress in developing inhibitors directly targeting constitutively active Gα mutants.

ABSTRACTWe document the effort over the last 30 years to respond to the call by women advocates at the International Conference on Population and Development for more woman-initiated single or dual-purpose contraceptive methods by developing the Caya contoured diaphragm, an innovative diaphragm designed to meet the needs of women and their partners and expand options for nonhormonal barrier contraception. We describe the complex and interrelated set of activities undertaken to develop the product using a human-centered design process and how we are working to create a corollary sustainable market. This review includes the evidence generated around improved acceptability among couples in low- and middle-income countries and depicts challenges and practical actions on how to dispel misconceptions about diaphragm use. Importantly, we share programmatic lessons learned on increasing universal access to this new sexual and reproductive health technology. Following our new model for increasing access to new and underutilized methods, Caya is now registered and being marketed in nearly 40 countries worldwide.

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ABSTRACTThe private health care sector is an important source of service delivery in low- and middle-income countries (LMICs). Yet, the private sector remains fragmented, making it difficult for health system actors to support and ensure the availability of quality health care services. In global health programs, social franchising is one model used to engage and organize the private health care sector. Two social franchise networks, ProFam in West Africa and Tunza in East and Central Africa, provide health care through branded networks of facilities. However, these social franchise networks include a limited number of private health care facilities, and in fragile contexts, like Burundi and Mali, they have faced challenges in integrating with national health systems. The MOMENTUM Private Healthcare Delivery (MPHD) project in Burundi and Mali sought to expand the number of health facilities it engaged beyond the existing ProFam and Tunza networks. The expansion aimed to help improve service quality in more private facilities while advancing localization and reducing fragmentation for improved stewardship by health system actors. MPHD achieved this expansion by removing barriers for private health facilities to join inclusive, nonbranded networks and engaging local partners to build and maintain these networks. We share lessons learned regarding the growing role of local organizations as actors within mixed health systems and provide insights on strengthening stewardship of the increasingly heterogeneous private health care delivery sector in LMICs, particularly in fragile settings.

ABSTRACTIntroduction:Emergency contraceptive pills (ECPs) are effective and can be used safely at any age repeatedly within the same cycle. They are often favored by youth yet are underutilized. Private facilities can increase ECP access but present barriers including cost. Identifying effective public-sector ECP distribution models can help ensure equitable access. The Malawi Ministry of Health developed a strategy to improve ECP access in 2020. We documented ECP provision through select public, youth-serving channels recommended by the strategy: general and youth-specific outreach, paid and unpaid community health workers (CHWs), and youth clubs.Methods:We conducted this mixed methods study from November 2022–March 2023 in 2 rural districts (Mchinji and Phalombe) implementing the strategy. We conducted qualitative interviews with 10 national stakeholders, 46 providers, and 24 clients aged 15–24 years about ECP service delivery. Additionally, 25 providers collected quantitative tally data about clients seeking ECPs. We analyzed qualitative data using grounded theory and quantitative data descriptively.Results:Stakeholders and providers reported ECP uptake increased in geographies where the strategy was implemented, especially among youth. Providers documented 3,988 client visits for ECPs over 3 months. Of these visits, 26% were from male clients, 36% were from clients aged younger than 20 years, and 64% received ECPs for the first time. Across channels, youth club leaders and unpaid CHWs reported the most client visits per provider and served the youngest clients. However, no ECPs were dispensed during 29% of visits due to stock-outs. While many providers were supportive of youth accessing ECPs, most held unfavorable attitudes toward repeat use.Conclusion:ECP access should be expanded through provision in the studied channels, especially youth clubs and CHWs. However, to meet demand, the supply chain must be strengthened. We recommend addressing providers’ attitudes about repeat use to ensure informed method choice.

ABSTRACTIntroduction:Health risks associated with short interpregnancy intervals, coupled with women’s desires to avoid pregnancy following childbirth, underscore the need for effective postpartum family planning programs. The antenatal period provides an opportunity to intervene; however, evidence is limited on the effectiveness of interventions aimed at reaching women in the antenatal period to increase voluntary postpartum family planning in low- and middle-income countries (LMICs). This systematic review aimed to identify and describe interventions in LMICs that attempted to increase postpartum contraceptive use via contacts with pregnant women in the antenatal period.Methods:Studies published from January 2012 to July 2022 were considered if they were conducted in LMICs, evaluated an intervention delivered during the antenatal period, were designed to affect postpartum contraceptive use, were experimental or quasi-experimental, and were published in French or English. The main outcome of interest was postpartum contraceptive use within 1 year after birth, defined as the use of any method of contraception at the time of data collection. We searched EMBASE, Global Health, and Medline and manually searched the reference lists from studies included in the full-text screening.Results:We double-screened 771 records and included 34 reports on 31 unique interventions in the review. Twenty-three studies were published from 2018 on, with 21 studies conducted in sub-Saharan Africa. Approximately half of the study designs (n=16) were randomized controlled trials, and half (n=15) were quasi-experimental. Interventions were heterogeneous. Among the 24 studies that reported on the main outcome of interest, 18 reported a positive intervention effect, with intervention recipients having greater contraceptive use in the first year postpartum.Conclusion:While the studies in this systematic review were heterogeneous, the findings suggest that interventions that included a multifaceted package of initiatives appeared to be most likely to have a positive effect.

ABSTRACTMore than half of births among Indigenous women in Guatemala are still being attended at home by providers with no formal training. We describe the incorporation of comadronas (traditional midwives) into casas maternas (birthing centers) in the rural highlands of western Guatemala. Although there was initial resistance to the casa, comadronas and clients have become increasingly enthusiastic about them. The casas provide the opportunity for comadronas to continue the cultural traditions of prayers, massages, and other practices that honor the vital spiritual dimension of childbirth close to home in a home-like environment with extended family support while at the same time providing a safer childbirth experience in which complications can be detected by trained personnel at the casa, managed locally, or promptly referred to a higher-level facility. Given the growing acceptance of this innovation in an environment in which geographical, financial, and cultural barriers to deliveries at higher-level facilities lead most women to deliver at home, casas maternas represent a feasible option for reducing the high level of maternal mortality in Guatemala.This article provides an update on the growing utilization of casas and provides new insights into the role of comadronas as birthing team members and enthusiastic promotors of casas maternas as a preferable alternative to home births. Through the end of 2023, these casas maternas had cared for 4,322 women giving birth. No maternal deaths occurred at a casa, but 4 died after referral.The Ministry of Health of Guatemala has recently adopted this approach and has begun to implement it in other rural areas where home births still predominate. This approach deserves consideration as a viable and feasible option for reducing maternal mortality throughout the world where home births are still common, while at the same time providing women with respectful and culturally appropriate care.

ABSTRACTWe describe the development, implementation, and evaluation of a novel twinning approach: the Twinning Partnership Network (TPN). Twinning is a well-known approach to peer learning that has been used in a variety of settings to build organizational capacity. Although twinning takes many forms, the heart of the approach is that institutions with shared characteristics collaborate via sharing information and experiences to achieve a specific goal. We adapted a twinning partnership strategy developed by the World Health Organization to create a network of like-minded health institutions. The key innovation of the TPN is the network, which ensures that an institution always has a high-performing peer with whom to partner on a specific topic area of interest. We identified 10 hospitals and 30 districts in Rwanda to participate in the TPN. These districts and hospitals participated in a kickoff workshop in which they identified capacity gaps, clarified goals, and selected twinning partners. After the workshop, districts and hospitals participated in exchange visits, coaching visits, and virtual and in-person learning events. We found that districts and hospitals that selected specific areas and worked on them throughout the duration of the TPN with their peers improved their performance significantly when compared with those that selected and worked on other areas. Accreditation scores improved by 5.6% more in hospitals selecting accreditation than those that did not. Districts that selected improving community-based health insurance coverage improved by 4.8% more than districts that did not select this topic area. We hypothesize that these results are due to senior management’s interest and motivation to improve in these specific areas, the motivation gained by learning from high-performing peers with similar resources, and context-specific knowledge sharing from peer hospitals and districts.

ABSTRACTPolitics is one of the critical factors that influence health policy agendas. However, scholarly efforts, especially in low- and middle-income countries, rarely focus on how politics influence health policy agenda-setting. We conducted a qualitative document review to examine the factors that led to developing the free primary health care policy for maternal health in Papua New Guinea. We also discuss mechanisms through which national politics, as an overriding factor, influenced the development of the policy. The review draws on Kingdon’s multiple-stream model for agenda-setting and incorporates theoretical insights from Fox and Reich’s framework for analyzing the politics of health reform for universal health coverage in low- and middle-income countries.

Although acute inflammation serves essential functions in maintaining tissue homeostasis, chronic inflammation is causally linked to many diseases. Macrophages are a major cell type that orchestrates inflammatory processes. During inflammation, macrophages undergo polarization and activation, thereby mobilizing pro-inflammatory and anti-inflammatory transcriptional programs that regulate ensuing macrophage functions. Fatty acid binding protein 5 (FABP5) is a lipid chaperone highly expressed in macrophages. FABP5 deletion is implicated in driving macrophages toward an anti-inflammatory phenotype, yet signaling pathways regulated by macrophage-FABP5 have not been systematically profiled. We leveraged proteomic and phosphoproteomic approaches to characterize pathways modulated by FABP5 in M1 and M2 polarized bone marrow-derived macrophages (BMDMs). Stable isotope labeling by amino acids-based analysis of M1 and M2 polarized wild-type and FABP5 knockout BMDMs revealed numerous differentially regulated proteins and phosphoproteins. FABP5 deletion impacted downstream pathways associated with inflammation, cytokine production, oxidative stress, and kinase activity. Toll-like receptor 2 (TLR2) emerged as a novel target of FABP5 and pharmacological FABP5 inhibition blunted TLR2-mediated activation of downstream pathways, ascribing a novel role for FABP5 in TLR2 signaling. This study represents a comprehensive characterization of the impact of FABP5 deletion on the proteomic and phosphoproteomic landscape of M1 and M2 polarized BMDMs. Loss of FABP5 altered pathways implicated in inflammatory responses, macrophage function, and TLR2 signaling. This work provides a foundation for future studies seeking to investigate the therapeutic potential of FABP5 inhibition in pathophysiological states resulting from dysregulated inflammatory signaling.

There is a growing interest in the use of medicinal plants to treat a variety of diseases, and one of the most commonly used medicinal plants globally is Cannabis sativa. The two most abundant cannabinoids (⁹-tetrahydrocannabinol and cannabidiol) have been governmentally approved to treat selected medical conditions; however, the plant produces over 100 cannabinoids, including cannabichromene (CBC). Although the cannabinoids share a common precursor molecule, cannabigerol, they are structurally and pharmacologically unique. These differences may engender differing therapeutic potentials. In this review, we will examine what is currently known about CBC with regards to pharmacodynamics, pharmacokinetics, and receptor profile. We will also discuss the therapeutic areas that have been examined for this cannabinoid, notably antinociceptive, antibacterial, and anti-seizure activities. Finally, we will discuss areas where new research is needed and potential novel medicinal applications for CBC.

Targeting the endocannabinoid (eCB) signaling system for pain relief is an important treatment option that is only now beginning to be mechanistically explored. In this review, we focus on two recently appreciated cannabinoid-based targeting strategies, treatments with cannabidiol (CBD) and α/β-hydrolase domain containing 6 (ABHD6) inhibitors, which have the exciting potential to produce pain relief through distinct mechanisms of action and without intoxication. We review evidence on plant-derived cannabinoids for pain, with an emphasis on CBD and its multiple molecular targets expressed in pain pathways. We also discuss the function of eCB signaling in regulating pain responses and the therapeutic promises of inhibitors targeting ABHD6, a 2-arachidonoylglycerol (2-AG)-hydrolyzing enzyme. Finally, we discuss how the novel cannabinoid biosensor GRAB_eCB2.0 may be leveraged to enable the discovery of targets modulated by cannabinoids at a circuit-specific level.

Low-efficacy mu opioid receptor (MOR) agonists may serve as novel candidate analgesics with improved safety relative to high-efficacy opioids. This study used a recently validated assay of pain-depressed behavior in mice to evaluate a novel series of MOR-selective C9-substituted phenylmorphan opioids with graded MOR efficacies. Intraperitoneal injection of dilute lactic acid (IP acid) served as a noxious stimulus to depress locomotor activity by mice in an activity chamber composed of two compartments connected by an obstructed door. Behavioral measures included (1) crosses between compartments (vertical activity over the obstruction) and (2) movement counts quantified as photobeam breaks summed across compartments (horizontal activity). Each drug was tested alone and as a pretreatment to IP acid. A charcoal-meal test and whole-body-plethysmography assessment of breathing in 5% CO₂ were also used to assess gastrointestinal (GI) inhibition and respiratory depression, respectively. IP acid produced a concentration-dependent depression in crosses and movement that was optimally alleviated by intermediate- to low-efficacy phenylmorphans with sufficient efficacy to produce analgesia with minimal locomotor disruption. Follow-up studies with two low-efficacy phenylmorphans (JL-2-39 and DC-1-76.1) indicated that both drugs produced naltrexone-reversible antinociception with a rapid onset and a duration of ~1 h. Potency of both drugs increased when behavior was depressed by a lower IP-acid concentration, and neither drug alleviated behavioral depression by a non-pain stimulus (IP lithium chloride). Both drugs produced weaker GI inhibition and respiratory depression than fentanyl and attenuated fentanyl-induced GI inhibition and respiratory depression. Results support further consideration of selective, low-efficacy MOR agonists as candidate analgesics.

The Registry of Fast Myocardial Perfusion Imaging with Next-Generation SPECT (REFINE SPECT) has been expanded to include more patients and CT attenuation correction imaging. We present the design and initial results from the updated registry. Methods: The updated REFINE SPECT is a multicenter, international registry with clinical data and image files. SPECT images were processed by quantitative software and CT images by deep learning software detecting coronary artery calcium (CAC). Patients were followed for major adverse cardiovascular events (MACEs) (death, myocardial infarction, unstable angina, late revascularization). Results: The registry included scans from 45,252 patients from 13 centers (55.9% male, 64.7 ± 11.8 y). Correlating invasive coronary angiography was available for 3,786 (8.4%) patients. CT attenuation correction imaging was available for 13,405 patients. MACEs occurred in 6,514 (14.4%) patients during a median follow-up of 3.6 y (interquartile range, 2.5–4.8 y). Patients with a stress total perfusion deficit of 5% to less than 10% (unadjusted hazard ratio [HR], 2.42; 95% CI, 2.23–2.62) and a stress total perfusion deficit of at least 10% (unadjusted HR, 3.85; 95% CI, 3.56–4.16) were more likely to experience MACEs. Patients with a deep learning CAC score of 101–400 (unadjusted HR, 3.09; 95% CI, 2.57–3.72) and a CAC of more than 400 (unadjusted HR, 5.17; 95% CI, 4.41–6.05) were at increased risk of MACEs. Conclusion: The REFINE SPECT registry contains a comprehensive set of imaging and clinical variables. It will aid in understanding the value of SPECT myocardial perfusion imaging, leverage hybrid imaging, and facilitate validation of new artificial intelligence tools for improving prediction of adverse outcomes incorporating multimodality imaging.

Recent studies have demonstrated promising results of fibroblast activation protein (FAP) inhibitor (FAPI) PET in prognosticating and monitoring interstitial lung diseases (ILDs). As a first step toward successful translation, our primary aim was to validate the FAPI PET uptake through immunohistochemistry in patients with advanced ILD who underwent lung transplantation after a FAPI PET scan. Methods: This is a preliminary analysis of a single-center, open-label, single-arm, prospective exploratory biodistribution study of ⁶⁸Ga-FAPI-46 PET imaging in patients with ILD (NCT05365802). Patients with ILD confirmed by high-resolution CT and scheduled for lung transplant were included. Tissue samples of explanted lungs were obtained from both the central and peripheral lung parenchyma of each lobe. Additional samples were obtained from areas of the lung corresponding to regions of FAPI PET activity. Immunohistochemical staining was performed with an anti-FAP antibody. Percentages of FAP immunohistochemistry-positive area were measured semiautomatically using QuPath software. SUVs in the areas of pathologic samples were measured on FAPI PET/CT by referencing the gross photomap of the explanted lung. A Spearman correlation coefficient test was used to assess the relationship between FAPI PET uptake and FAP immunohistochemical expression in each specimen. Results: Four patients with advanced ILD who underwent FAPI PET/CT before lung transplantation were included. The types of ILD were idiopathic pulmonary fibrosis (n = 2), rheumatoid arthritis–associated ILD (n = 1), and nonspecific interstitial pneumonia (n = 1). FAPI uptake was visualized mainly in the fibrotic area on CT. Twenty-nine surgical pathology samples from 3 patients were analyzed. FAP staining was predominantly positive in fibroblastic foci. FAPI PET SUV_max and SUV_mean showed a positive correlation with the immunohistochemical FAP expression score (SUV_max: r = 0.57, P = 0.001; SUV_mean: r = 0.54, P = 0.002). Conclusion: In this analysis conducted in patients who underwent lung transplantation after a FAPI PET scan, FAPI PET uptake was positively correlated with FAP immunohistochemistry. These findings provide a rationale for further investigation of FAPI PET as a potential imaging biomarker for ILD.

The diagnostic work-up of patients with fever of unknown origin (FUO) begins with a thorough history and physical examination, complete blood count with differential, chest x-ray, urinalysis and culture, electrolyte panel, liver enzymes, erythrocyte sedimentation rate, and C-reactive protein level. Additional imaging procedures, including nuclear medicine tests, are generally used as second-line procedures, with ¹⁸F-FDG PET and PET/CT assuming increasingly important roles in the diagnostic work-up. The Society of Nuclear Medicine and Molecular Imaging, the Infectious Diseases Society of America, and the American College of Nuclear Medicine convened an autonomous expert work group to comprehensively review the published literature for nuclear imaging in adults and children with FUO and establish appropriate use criteria (AUC). This process was performed in accordance with the Protecting Access to Medicare Act of 2014, which requires that all referring physicians consult AUC by using a clinical decision support mechanism before ordering advanced diagnostic imaging services. The complete findings and discussions of the work group were published on January 8, 2023, and are available at https://www.snmmi.org/ClinicalPractice/content.aspx?ItemNumber=15666. The AUC in the final document are intended to assist referring health care providers in appropriate use of nuclear medicine imaging procedures in patients with FUO. The work group noted limitations in the current literature on nuclear medicine imaging for FUO, with the need for well-designed prospective multicenter investigations. Consensus findings from published data and expert opinions were used to create recommendations in common clinical scenarios for adults and children. Included in the complete document is a discussion of inflammation of unknown origin (IUO), a recently described entity. In view of the fact that the criteria for FUO and IUO are similar (except for fever > 38.3°C [100.9°F]) and that the most common etiologies of these 2 entities are similar, it is the expert opinion of the work group that the recommendations for nuclear medicine imaging of FUO are also applicable to IUO. These recommendations are included in the full guidance document. This summary reviews rationale, methodology, and main findings and refers the reader to the complete AUC document.

Simplified methods of acquisition and quantification would facilitate the use of synaptic density imaging in multicenter and longitudinal studies of Alzheimer disease (AD). We validated a simplified tissue-to-reference ratio method using SUV ratios (SUVRs) for estimating synaptic density with [¹¹C]UCB-J PET. Methods: Participants included 31 older adults with AD and 16 with normal cognition. The distribution volume ratio (DVR) using simplified reference tissue model 2 was compared with SUVR at short scan windows using a whole-cerebellum reference region. Results: Synaptic density was reduced in AD participants using DVR or SUVR. SUVR using later scan windows (60–90 or 70–90 min) was minimally biased, with the strongest correlation with DVR. Effect sizes using SUVR at these late time windows were minimally reduced compared with effect sizes with DVR. Conclusion: A simplified tissue-to-reference method may be useful for multicenter and longitudinal studies seeking to measure synaptic density in AD.

The phase 3 VISION trial demonstrated that [¹⁷⁷Lu]Lu-PSMA-617 prolonged progression-free survival and overall survival (OS) in prostate-specific membrane antigen [PSMA]–positive metastatic castration-resistant prostate cancer (mCRPC) patients who progressed on taxane-based chemotherapy and androgen receptor–signaling inhibitors (ARSIs). The U.S. expanded-access program (EAP; NCT04825652) was opened to provide access to [¹⁷⁷Lu]Lu-PSMA-617 for eligible patients until regulatory approval was obtained. This study aimed to evaluate the efficacy and safety profile of [¹⁷⁷Lu]Lu-PSMA-617 within the EAP and compare the results with those from the VISION trial. Methods: Patients enrolled in the EAP at 4 institutions in the United States with available toxicity and outcome data were included. Outcome measures included OS, a prostate-specific antigen (PSA) response rate (RR) of at least 50%, and incidences of toxicity according to Common Terminology Criteria for Adverse Events version 5.0. Differences in baseline characteristics, outcome data, and toxicity between the EAP and VISION were evaluated using t testing of proportions and survival analyses. Results: In total, 117 patients with mCRPC who received [¹⁷⁷Lu]Lu-PSMA-617 within the EAP between May 2021 and March 2022 were eligible and included in this analysis. Patients enrolled in the EAP were more heavily pretreated with ARSI (≥2 ARSI regimens: 70% vs. 46%; P < 0.001) and had worse performance status at baseline (Eastern Cooperative Oncology Group score ≥ 2: 19% vs. 7%; P < 0.001) than VISION patients. EAP and VISION patients had similar levels of grade 3 or higher anemia (18% vs. 13%; P = 0.15), thrombocytopenia (13% vs. 8%; P = 0.13), and neutropenia (3% vs. 3%; P = 0.85) and similar PSA RRs (42% vs. 46%; P = 0.50) and OS (median: 15.1 vs. 15.3 mo; P > 0.05). Conclusion: Patients with PSMA-positive mCRPC who received [¹⁷⁷Lu]Lu-PSMA-617 within the EAP were later in their disease trajectory than VISION patients. Patients enrolled in the EAP achieved similar PSA RRs and OS and had a safety profile similar to that of the VISION trial patients.

In Canada and across the globe, access to PSMA PET/CT is limited and expensive. For patients with biochemical recurrence (BCR) after treatment for prostate cancer, novel strategies are needed to better stratify patients who may or may not benefit from a PSMA PET scan. The role of the free-to-total prostate-specific antigen (PSA) ratio (FPSAR) in posttreatment prostate cancer, specifically in the PSMA PET/CT era, remains unknown. Our aim in this study was to determine the association of FPSAR in patients referred for ¹⁸F-DCFPyL PSMA PET/CT in the BCR setting and assess the correlation between FPSAR and ¹⁸F-DCFPyL PSMA PET/CT positivity (local recurrence or distant metastases). Methods: This prospective study included 137 patients who were referred for ¹⁸F-DCFPyL PSMA PET/CT and had BCR with a total PSA of less than 1 ng/mL after radical prostatectomy (RP) (including adjuvant or salvage radiotherapy). Blood samples were collected on the day of ¹⁸F-DCFPyL PSMA PET/CT. FPSAR was categorized as less than 0.10 or as 0.10 or more. A positive ¹⁸F-DCFPyL PSMA PET/CT scan was defined by a PROMISE classification lesion score of 2 or 3, irrespective of the site of increased tracer uptake (e.g., prostate, pelvic nodes, bone, or viscera). Results: Overall, 137 blood samples of patients with BCR after RP were analyzed to calculate FPSAR. The median age at ¹⁸F-DCFPyL PSMA PET/CT was 68.6 y (interquartile range, 63.0–72.4 y), and the median PSA at ¹⁸F-DCFPyL PSMA PET/CT was 0.3 ng/mL (interquartile range, 0.3–0.6 ng/mL). Eighty-six patients (62.8%) had an FPSAR of less than 0.10, whereas 51 patients (37.2%) had an FPSAR of 0.10 or more. An FPSAR of 0.10 or more was identified as an independent predictor of a positive ¹⁸F-DCFPyL PSMA PET/CT scan, with an odds ratio of 6.99 (95% CI, 2.96–16.51; P < 0.001). Conclusion: An FPSAR of 0.10 or more after RP independently correlated with increased odds of a positive ¹⁸F-DCFPyL PSMA PET/CT scan among BCR post-RP patients. These findings may offer an inexpensive method by which to triage access to ¹⁸F-DCFPyL PSMA PET/CT in jurisdictions where availability is not replete.

[¹⁷⁷Lu]Lu-PSMA-617 was approved by the U.S. Food and Drug Administration for patients with prostate-specific membrane antigen (PSMA)–positive metastatic castration-resistant prostate cancer (mCRPC). Since the time of regulatory approval, however, real-world data have been lacking. This study investigated the efficacy, safety, and outcome predictors of [¹⁷⁷Lu]Lu-PSMA-617 at a major U.S. academic center. Methods: Patients with mCRPC who received [¹⁷⁷Lu]Lu-PSMA-617 at the Johns Hopkins Hospital outside clinical trials were screened for inclusion. Patients who underwent [¹⁷⁷Lu]Lu-PSMA-617 and had available outcome data were included in this study. Outcome data included prostate-specific antigen (PSA) response (≥50% decline), PSA progression-free survival (PFS), and overall survival (OS). Toxicity data were evaluated according to the Common Terminology Criteria for Adverse Events version 5.03. The study tested the association of baseline circulating tumor DNA mutational status in homologous recombination repair, PI3K alteration pathway, and aggressive-variant prostate cancer–associated genes with treatment outcome. Baseline PSMA PET/CT images were analyzed using SelectPSMA, an artificial intelligence algorithm, to predict treatment outcome. Associations with the observed treatment outcome were evaluated. Results: All 76 patients with PSMA-positive mCRPC who received [¹⁷⁷Lu]Lu-PSMA-617 met the inclusion criteria. A PSA response was achieved in 30 of 74 (41%) patients. The median PSA PFS was 4.1 mo (95% CI, 2.0–6.2 mo), and the median OS was 13.7 mo (95% CI, 11.3–16.1 mo). Anemia of grade 3 or greater, thrombocytopenia, and neutropenia were observed in 9 (12%), 3 (4%), and 1 (1%), respectively, of 76 patients. Transient xerostomia was observed in 23 (28%) patients. The presence of aggressive-variant prostate cancer–associated genes was associated with a shorter PSA PFS (median, 1.3 vs. 6.3 mo; P = 0.040). No other associations were observed between circulating tumor DNA mutational status and treatment outcomes. Eighteen of 71 (25%) patients classified by SelectPSMA as nonresponders had significantly lower rates of PSA response than patients classified as likely responders (6% vs. 51%; P < 0.001), a shorter PSA PFS (median, 1.3 vs. 6.3 mo; P < 0.001), and a shorter OS (median, 6.3 vs. 14.5 mo; P = 0.046). Conclusion: [¹⁷⁷Lu]Lu-PSMA-617 offered in a real-world setting after regulatory approval in the United States demonstrated antitumor activity and a favorable toxicity profile. Artificial-intelligence–based analysis of baseline PSMA PET/CT images may improve patient selection. Validation of these findings on larger cohorts is warranted.

gp130 functions as a shared signal-transducing subunit not only for interleukin (IL)-6 but also for eight other human cytokine receptor complexes. The IL-6 signaling pathway mediated through gp130 encompasses classical, trans, or cluster signaling, intricately regulated by a diverse array of modulators affecting IL-6, its receptor, and gp130. Currently, only a limited number of small molecule antagonists and agonists for gp130 are known. This review aims to comprehensively examine the current knowledge of these modulators and provide insights into their pharmacological properties, particularly in the context of cancer and other diseases. Notably, the prominent gp130 modulators SC144, bazedoxifene, and raloxifene are discussed in detail, with a specific focus on the discovery of SC144’s iron-chelating properties. This adds a new dimension to the understanding of its pharmacological effects and therapeutic potential in conditions where iron homeostasis is significant. Our bioinformatic analysis of gp130 and genes related to iron homeostasis reveals insightful correlations, implicating the role of iron in the gp130 signaling pathway. Overall, this review contributes to the evolving understanding of gp130 modulation and its potential therapeutic applications in various disease contexts.