mSystems. 2024 May 10:e0103623. doi: 10.1128/msystems.01036-23. Online ahead of print.

ABSTRACT

Temperate bacteriophages (phages) are common features of bacterial genomes and can act as self-amplifying biological weapons, killing susceptible competitors and thus increasing the fitness of their bacterial hosts (lysogens). Despite their prevalence, however, the key characteristics of an effective temperate phage weapon remain unclear. Here, we use systematic mathematical analyses coupled with experimental tests to understand what makes an effective temperate phage weapon. We find that effectiveness is controlled by phage life history traits-in particular, the probability of lysis and induction rate-but that the optimal combination of traits varies with the initial frequency of a lysogen within a population. As a consequence, certain phage weapons can be detrimental when their hosts are rare yet beneficial when their hosts are common, while subtle changes in individual life history traits can completely reverse the impact of an individual phage weapon on lysogen fitness. We confirm key predictions of our model experimentally, using temperate phages isolated from the clinically relevant Liverpool epidemic strain of Pseudomonas aeruginosa. Through these experiments, we further demonstrate that nutrient availability can also play a critical role in driving frequency-dependent patterns in phage-mediated competition. Together, these findings highlight the complex and context-dependent nature of temperate phage weapons and the importance of both ecological and evolutionary processes in shaping microbial community dynamics more broadly.

IMPORTANCE: Temperate bacteriophages-viruses that integrate within bacterial DNA-are incredibly common within bacterial genomes and can act as powerful self-amplifying weapons. Bacterial hosts that carry temperate bacteriophages can thus gain a fitness advantage within a given niche by killing competitors. But what makes an effective phage weapon? Here, we first use a simple mathematical model to explore the factors determining bacteriophage weapon utility. Our models suggest that bacteriophage weapons are nuanced and context-dependent; an individual bacteriophage may be beneficial or costly depending upon tiny changes to how it behaves or the bacterial community it inhabits. We then confirm these mathematical predictions experimentally, using phages isolated from cystic fibrosis patients. But, in doing so, we also find that another factor-nutrient availability-plays a key role in shaping bacteriophage-mediated competition. Together, our results provide new insights into how temperate bacteriophages modulate bacterial communities.

PMID:38727217 | DOI:10.1128/msystems.01036-23

iScience. 2024 Apr 23;27(5):109801. doi: 10.1016/j.isci.2024.109801. eCollection 2024 May 17.

ABSTRACT

Combining an immune checkpoint inhibitor with batiraxcept (AVB-S6-500), an AXL inhibitor that acts via selective binding to growth arrest-specific protein 6 (GAS6), may improve anti-tumor immunity in platinum-resistant ovarian cancer (PROC). This phase 1b trial of durvalumab in combination with escalating doses of batiraxcept enrolled patients with recurrent PROC (NCT04019288). The primary objective was to determine the toxicity profile of the combination. Eleven patients were enrolled on the trial. No dose-limiting toxicities were observed, and no objective responses were noted. Median progression free survival (PFS) was 1.81 months (95% confidence interval (CI) 1.71-2.40), and median overall survival (OS) was 4.53 months (95% CI 2.10-24.74). Batiraxcept effectively reduced serum GAS6 levels at 1-h post-treatment, resulting in trough levels below the limit of detection in all cases but one. In conclusion, the combination of batiraxcept and durvalumab was safe and tolerable but did not demonstrate anti-tumor activity in a heterogenous population of patients with recurrent PROC.

PMID:38726365 | PMC:PMC11079458 | DOI:10.1016/j.isci.2024.109801

Eur Clin Respir J. 2024 May 8;11(1):2350206. doi: 10.1080/20018525.2024.2350206. eCollection 2024.

ABSTRACT

BACKGROUND: Respiration is an intricate interaction between visceral and musculoskeletal structures. In cystic fibrosis (CF), the airways and lungs are subject to progressive obstruction and destruction. However, knowledge about the musculoskeletal aspects of respiratory function and symptoms is still limited in this patient group.

METHODS: In a cross-sectional comparative study, 21 adults with CF enrolled at the Gothenburg CF Centre were matched with 42 healthy controls. The two groups were examined and compared in terms of thoracic mobility, respiratory muscle strength, lung function, and musculoskeletal pain in accordance with a predefined protocol.

RESULTS: Significant differences were observed between the groups in the number of tender points, thoracic excursion, forced vital capacity (FVC), and forced expiratory volume (FEV). The CF group also demonstrated a tendency toward reduced function in other measurements, although these were not statistically significant.

CONCLUSION: This cross-sectional study revealed that people with CF have reduced thoracic mobility and an increased prevalence of muscular tender points, alongside decreased lung function, compared to healthy controls. These findings stress the need for greater emphasis on the often-overlooked musculoskeletal aspects of CF care, especially as people with CF are living longer and may require more musculoskeletal health support.

PMID:38726022 | PMC:PMC11080665 | DOI:10.1080/20018525.2024.2350206

Front Pharmacol. 2024 Apr 25;15:1389586. doi: 10.3389/fphar.2024.1389586. eCollection 2024.

ABSTRACT

Cystic fibrosis (CF) is a monogenic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Premature termination codons (PTCs) represent ∼9% of CF mutations that typically cause severe expression defects of the CFTR anion channel. Despite the prevalence of PTCs as the underlying cause of genetic diseases, understanding the therapeutic susceptibilities of their molecular defects, both at the transcript and protein levels remains partially elucidated. Given that the molecular pathologies depend on the PTC positions in CF, multiple pharmacological interventions are required to suppress the accelerated nonsense-mediated mRNA decay (NMD), to correct the CFTR conformational defect caused by misincorporated amino acids, and to enhance the inefficient stop codon readthrough. The G418-induced readthrough outcome was previously investigated only in reporter models that mimic the impact of the local sequence context on PTC mutations in CFTR. To identify the misincorporated amino acids and their ratios for PTCs in the context of full-length CFTR readthrough, we developed an affinity purification (AP)-tandem mass spectrometry (AP-MS/MS) pipeline. We confirmed the incorporation of Cys, Arg, and Trp residues at the UGA stop codons of G542X, R1162X, and S1196X in CFTR. Notably, we observed that the Cys and Arg incorporation was favored over that of Trp into these CFTR PTCs, suggesting that the transcript sequence beyond the proximity of PTCs and/or other factors can impact the amino acid incorporation and full-length CFTR functional expression. Additionally, establishing the misincorporated amino acid ratios in the readthrough CFTR PTCs aided in maximizing the functional rescue efficiency of PTCs by optimizing CFTR modulator combinations. Collectively, our findings contribute to the understanding of molecular defects underlying various CFTR nonsense mutations and provide a foundation to refine mutation-dependent therapeutic strategies for various CF-causing nonsense mutations.

PMID:38725656 | PMC:PMC11079177 | DOI:10.3389/fphar.2024.1389586

MMWR Morb Mortal Wkly Rep. 2024 May 9;73(18):420-422. doi: 10.15585/mmwr.mm7318a3.

ABSTRACT

Mycobacterium abscessus is an intrinsically drug-resistant, rapidly growing, nontuberculous mycobacterium; extrapulmonary infections have been reported in association with medical tourism (1). During November-December 2022, two Colorado hospitals (hospitals A and B) treated patient A, a Colorado woman aged 30-39 years, for M. abscessus meningitis. In October 2022, she had received intrathecal donor embryonic stem cell injections in Baja California, Mexico to treat multiple sclerosis and subsequently experienced headaches and fevers, consistent with meningitis. Her cerebrospinal fluid revealed neutrophilic pleocytosis and grew M. abscessus in culture at hospital A. Hospital A's physicians consulted hospital B's infectious diseases (ID) physicians to co-manage this patient (2).

PMID:38722805 | DOI:10.15585/mmwr.mm7318a3

J Pediatr Nurs. 2024 May 8:S0882-5963(24)00175-1. doi: 10.1016/j.pedn.2024.04.049. Online ahead of print.

ABSTRACT

BACKGROUND: Self-care refers to the ability that an individual has or develops to regulate the functioning of the body. Health status and age are factors associated with dependency on, and the need for, someone else to take over self-care. In the present case, there was a self-care deficit. Cystic fibrosis is a chronic disease that occurs in one in 10,000 live births in Brazil, and the affected population in the country is predominantly pediatric (approximately 73%). Support from nursing teams is necessary to improve patients' skills until they can take full responsibility for their self-care.

PURPOSE: This study aimed to identify self-care deficits based on reports from schoolchildren with cystic fibrosis.

DESIGN AND METHOD: A qualitative study was conducted with eight Brazilian schoolchildren with cystic fibrosis, using an art-based technique during interviews. Minayo's thematic analysis was used for data analysis and interpretation.

RESULTS: These results emerged from Orem's theory of self-care deficits and needs. A main theme labeled as universal self-care requisites was identified, and three subthemes were derived-maintenance of an adequate air supply; maintenance of a balance between activity and rest; and avoiding risks to life, bodily functions, and well-being.

CONCLUSION: Schoolchildren living with cystic fibrosis have a negative attitude toward their disease, which makes it difficult for them to acquire the ability to care for themselves with greater autonomy. This leads to deficits in the self-care delivered by providers.

IMPLICATIONS TO PRACTICE: It is necessary to recognize the deficits in self-care and the extent to which children living with cystic fibrosis depend on self-care providers. Families must be aware of these self-care deficits to develop holistic self-care abilities.

PMID:38724312 | DOI:10.1016/j.pedn.2024.04.049

Eur Respir J. 2024 May 9;63(5):2400595. doi: 10.1183/13993003.00595-2024. Print 2024 May.

NO ABSTRACT

PMID:38724179 | DOI:10.1183/13993003.00595-2024

Arch Dis Child. 2024 May 9:archdischild-2024-326900. doi: 10.1136/archdischild-2024-326900. Online ahead of print.

NO ABSTRACT

PMID:38724066 | DOI:10.1136/archdischild-2024-326900

J Cell Biol. 2024 Jul 1;223(7):e202308003. doi: 10.1083/jcb.202308003. Epub 2024 May 9.

ABSTRACT

Aberrant proteins located in the endoplasmic reticulum (ER) undergo rapid ubiquitination by multiple ubiquitin (Ub) E3 ligases and are retrotranslocated to the cytosol as part of the ER-associated degradation (ERAD). Despite several ERAD branches involving different Ub E3 ligases, the molecular machinery responsible for these ERAD branches in mammalian cells remains not fully understood. Through a series of multiplex knockdown/knockout experiments with real-time kinetic measurements, we demonstrate that HERC3 operates independently of the ER-embedded ubiquitin ligases RNF5 and RNF185 (RNF5/185) to mediate the retrotranslocation and ERAD of misfolded CFTR. While RNF5/185 participates in the ERAD process of both misfolded ABCB1 and CFTR, HERC3 uniquely promotes CFTR ERAD. In vitro assay revealed that HERC3 directly interacts with the exposed membrane-spanning domains (MSDs) of CFTR but not with the MSDs embedded in liposomes. Therefore, HERC3 could play a role in the quality control of MSDs in the cytoplasm and might be crucial for the ERAD pathway of select membrane proteins.

PMID:38722278 | DOI:10.1083/jcb.202308003

Pediatr Pulmonol. 2024 May 9. doi: 10.1002/ppul.27030. Online ahead of print.

ABSTRACT

BACKGROUND: Despite the publication of the 2020 guidelines on how to manage Rett Syndrome (RS), some fundamental topics are still open, in particular respiratory problems.

OBJECTIVE: Identification and reinforcement of current recommendations concerning the management of respiratory issues in RS patients.

MATERIALS AND METHODS: Using a Delphi approach, the leading group reviewed the literature and formulated 14 statements. A multidisciplinary panel of 29 experts were invited to score, for each statement, their agreement on a 1-5 scale. The cut-off level for consensus was 75%, obtained through multiple rounds.

RESULTS: The panel agreed that in all RS types, respiratory issues should be faced at an early stage, regardless of epilepsy onset. It is recommended to perform periodically sleep studies in all Congenital Rett Syndrome, and in selected cases with other RS types. Noninvasive ventilation should be considered in all RS subjects with sleep respiratory disorders and in those with hypotonia associated with hypercapnia. Chest physiotherapy should be performed in all RS patients with difficult management of the accumulation of respiratory secretions, using airway clearance techniques and devices (PEP-mask, AMBU bag, or cough machine), more appropriate and tolerated by the patients. The panel recommended individualized programs for the management of scoliosis, and to consider performing gastrostomy in patients at increased risk of ab ingestis pneumonia.

CONCLUSIONS: This consensus could support everyday clinical practice on respiratory issues in RS patients, complementary to existing recommendations by regulatory agencies and guidelines.

PMID:38721909 | DOI:10.1002/ppul.27030

Pediatr Pulmonol. 2024 May 9. doi: 10.1002/ppul.27055. Online ahead of print.

NO ABSTRACT

PMID:38721868 | DOI:10.1002/ppul.27055

HGG Adv. 2024 May 7:100305. doi: 10.1016/j.xhgg.2024.100305. Online ahead of print.

ABSTRACT

Over the past decade, genomic data has contributed to several insights on global human population histories. These studies have been met both with interest and critically, particularly by populations with oral histories that are records of their past and often reference their origins. While several studies have reported concordance between oral and genetic histories, there is potential for tension that may stem from genetic histories being prioritized or used to confirm community-based knowledge and ethnography, especially if they differ. To investigate the interplay between oral and genetic histories, we focused on the southwestern region of India and analyzed whole-genome sequence data from 156 individuals identifying as Bunt, Kodava, Nair, and Kapla. We supplemented limited anthropological records on these populations with oral history accounts from community members and historical literature, focusing on references to non-local origins such as the ancient Scythians in the case of Bunt, Kodava, and Nair, members of Alexander the Great's army for the Kodava, and an African-related source for Kapla. We found these populations to be genetically most similar to other Indian populations, with the Kapla more similar to South Indian tribal populations that maximize a genetic ancestry related to Ancient Ancestral South Indians. We did not find evidence of additional genetic sources in the study populations than those known to have contributed to many other present-day South Asian populations. Our results demonstrate that oral and genetic histories may not always provide consistent accounts of population origins and motivate further community-engaged, multi-disciplinary investigations of non-local origin stories in these communities.

PMID:38720459 | DOI:10.1016/j.xhgg.2024.100305

J Cyst Fibros. 2024 May 7:S1569-1993(24)00065-1. doi: 10.1016/j.jcf.2024.05.001. Online ahead of print.

ABSTRACT

This manuscript addresses the development and operating procedures of the Cystic Fibrosis Foundation Data Safety Monitoring Board (CFF-DSMB) and its role in the development and approval of new therapies through complex clinical trials with an emphasis on ensuring patient safety and study integrity. The authors describe the processes that have been developed over the last 25 years including the development of educational curricula for DSMB members and patient representation on DSMBs. The experience and success of the CFF-DSMB can serve as a model for providing high quality oversight of clinical trials for other groups who are dedicated to developing treatments for rare and complex diseases.

PMID:38719765 | DOI:10.1016/j.jcf.2024.05.001

Life Sci Alliance. 2024 May 8;7(7):e202302441. doi: 10.26508/lsa.202302441. Print 2024 Jul.

ABSTRACT

Celiac disease (CD) is an autoimmune enteropathy resulting from an interaction between diet, genome, and immunity. Although many patients respond to a gluten-free diet, in a substantive number of individuals, the intestinal injury persists. Thus, other factors might amplify the ongoing inflammation. Candida albicans is a commensal fungus that is well adapted to the intestinal life. However, specific conditions increase Candida pathogenicity. The hypothesis that Candida may be a trigger in CD has been proposed after the observation of similarity between a fungal wall component and two CD-related gliadin T-cell epitopes. However, despite being implicated in intestinal disorders, Candida may also protect against immune pathologies highlighting a more intriguing role in the gut. Herein, we postulated that a state of chronic inflammation associated with microbial dysbiosis and leaky gut are favorable conditions that promote C. albicans pathogenicity eventually contributing to CD pathology via a mast cells (MC)-IL-9 axis. However, the restoration of immune and microbial homeostasis promotes a beneficial C. albicans-MC cross-talk favoring the attenuation of CD pathology to alleviate CD pathology and symptoms.

PMID:38719750 | DOI:10.26508/lsa.202302441

Thorax. 2024 May 6:thorax-2023-220559. doi: 10.1136/thorax-2023-220559. Online ahead of print.

ABSTRACT

BACKGROUND: Ivacaftor (IVA) improves lung function and other extrapulmonary outcomes in people with cystic fibrosis (CF). However, the effect of initiating IVA at earlier versus later ages has not been studied.

METHODS: We conducted an observational cohort study of people in the US CF Foundation Patient Registry aged ≥6 years with ≥1 CF transmembrane conductance regulator-gating mutation to compare the effects of initiating IVA at earlier ages on per cent predicted forced expiratory volume in 1 s (ppFEV1) and pulmonary exacerbation (PEx) outcomes. People with CF were grouped by age at IVA initiation (ages 6-10, 11-15, 16-20 and 21-25 years) to perform three analyses of younger versus older IVA initiation (6-10 vs 11-15, 11-15 vs 16-20 and 16-20 vs 21-25 years). For each analysis, baseline characteristics assessed over 1-year periods at the same age prior to IVA initiation were balanced by standardised mortality/morbidity ratio (SMR) weighting. For each analysis, outcomes were compared over a 5-year outcome assessment period when both groups were in the same age range and receiving IVA.

FINDINGS: Baseline characteristics were well balanced between younger and older IVA initiator groups after SMR weighting. In the outcome assessment period, younger IVA initiators had significantly higher mean ppFEV1 than older initiators across all comparisons, and those initiating IVA between ages 6-10 and 11-15 years had significantly lower PEx rates.

INTERPRETATION: Study findings showed the importance of early IVA initiation in people with CF.

PMID:38719441 | DOI:10.1136/thorax-2023-220559

CMAJ. 2024 May 5;196(17):E591-E595. doi: 10.1503/cmaj.231618.

NO ABSTRACT

PMID:38719222 | DOI:10.1503/cmaj.231618

Mol Cell Pediatr. 2024 May 8;11(1):4. doi: 10.1186/s40348-024-00178-6.

ABSTRACT

BACKGROUND: Highly-effective CFTR-modulator therapy with elexa-/teza-/ivacaftor (ETI) has led to improvements in pulmonary outcomes, sweat chloride, body mass index (BMI) and quality of life in people with cystic fibrosis (CF). Improved uptake of fat-soluble vitamins and micronutrients has been reported for CFTR-modulators but data regarding ETI therapy is lacking.

METHODS: This single-center retrospective study evaluated forced expiratory volume in one second (FEV-1), sweat chloride, BMI, transaminases (AST, ALT), bilirubin, vitamins A, D, E, zinc and selenium in children and adults eligible for ETI. Parameters were assessed before and up to one year after initiation of ETI.

RESULTS: 58 patients (median age m = 28 years, SD ± 11.6 years, 51.7% female14 < 18 years old) were included. FEV-1 and sweat chloride improved significantly after ETI. There were no changes in BMI or AST. ALT was increased significantly after 4 weeks of ETI but returned to normal levels in further course. Bilirubin levels remained elevated after ETI. Vitamin A was significantly higher 12 months after ETI. No changes were found for vitamins D, E, zinc and selenium.

CONCLUSIONS: This study adds to the evidence that improvements of some fat-soluble vitamin levels can be found after ETI. No changes regarding micronutrients were noted. Individualized follow-up and supplementation are recommended.

PMID:38717689 | DOI:10.1186/s40348-024-00178-6

JMIR Mhealth Uhealth. 2024 May 1;12:e49024. doi: 10.2196/49024.

ABSTRACT

BACKGROUND: Mobile health (mHealth) interventions have immense potential to support disease self-management for people with complex medical conditions following treatment regimens that involve taking medicine and other self-management activities. However, there is no consensus on what discrete behavior change techniques (BCTs) should be used in an effective adherence and self-management-promoting mHealth solution for any chronic illness. Reviewing the extant literature to identify effective, cross-cutting BCTs in mHealth interventions for adherence and self-management promotion could help accelerate the development, evaluation, and dissemination of behavior change interventions with potential generalizability across complex medical conditions.

OBJECTIVE: This study aimed to identify cross-cutting, mHealth-based BCTs to incorporate into effective mHealth adherence and self-management interventions for people with complex medical conditions, by systematically reviewing the literature across chronic medical conditions with similar adherence and self-management demands.

METHODS: A registered systematic review was conducted to identify published evaluations of mHealth adherence and self-management interventions for chronic medical conditions with complex adherence and self-management demands. The methodological characteristics and BCTs in each study were extracted using a standard data collection form.

RESULTS: A total of 122 studies were reviewed; the majority involved people with type 2 diabetes (28/122, 23%), asthma (27/122, 22%), and type 1 diabetes (19/122, 16%). mHealth interventions rated as having a positive outcome on adherence and self-management used more BCTs (mean 4.95, SD 2.56) than interventions with no impact on outcomes (mean 3.57, SD 1.95) or those that used >1 outcome measure or analytic approach (mean 3.90, SD 1.93; P=.02). The following BCTs were associated with positive outcomes: self-monitoring outcomes of behavior (39/59, 66%), feedback on outcomes of behavior (34/59, 58%), self-monitoring of behavior (34/59, 58%), feedback on behavior (29/59, 49%), credible source (24/59, 41%), and goal setting (behavior; 14/59, 24%). In adult-only samples, prompts and cues were associated with positive outcomes (34/45, 76%). In adolescent and young adult samples, information about health consequences (1/4, 25%), problem-solving (1/4, 25%), and material reward (behavior; 2/4, 50%) were associated with positive outcomes. In interventions explicitly targeting medicine taking, prompts and cues (25/33, 76%) and credible source (13/33, 39%) were associated with positive outcomes. In interventions focused on self-management and other adherence targets, instruction on how to perform the behavior (8/26, 31%), goal setting (behavior; 8/26, 31%), and action planning (5/26, 19%) were associated with positive outcomes.

CONCLUSIONS: To support adherence and self-management in people with complex medical conditions, mHealth tools should purposefully incorporate effective and developmentally appropriate BCTs. A cross-cutting approach to BCT selection could accelerate the development of much-needed mHealth interventions for target populations, although mHealth intervention developers should continue to consider the unique needs of the target population when designing these tools.

PMID:38717433 | DOI:10.2196/49024

Inn Med (Heidelb). 2024 May 7. doi: 10.1007/s00108-024-01717-z. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF, or mucoviscidosis) is one of the rare diseases with a fatal course and with the highest prevalence. Formerly known as a purely childhood disease, this multisystemic disease follows an autosomal recessive inheritance pattern and results in a malfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) channel, leading to the production of viscous secretions. The prognosis and outcome of CF are determined by the severity of the involvement of the lungs. Other typically affected organs include the pancreas, liver and intestines.

OBJECTIVE: This article reviews the clinical presentation and evolution of CF with a focus on the new era of the highly effective CFTR modulator treatment.

MATERIAL AND METHODS: An overview of the current state of knowledge on the care for CF patients is presented.

RESULTS AND DISCUSSION: The introduction of the CF newborn screening, the increased understanding of the disease and the development of novel treatment options have substantially increased the quality of life and life expectancy of people with CF. As a result, more than half of CF patients in Germany are now older than 18 years of age and the complications of a chronic disease as well as organ damage due to the intensive treatment are gaining in importance. The highly effective CFTR modulator treatment results in a significant improvement in CFTR function, lung function, body mass index and quality of life and is available to approximately 90% of patients in Germany, based on the genotype. Nevertheless, further research including the development of causal treatment, e.g., gene therapy, targeting the underlying defect in the remaining 10% of CF patients, is urgently needed. Even in adult patients, CF with a mild course or a CFTR-related disease should be considered, e.g., in cases of bronchiectasis and/or recurrent abdominal complaints.

PMID:38714556 | DOI:10.1007/s00108-024-01717-z

Arch Bronconeumol. 2024 Apr 24:S0300-2896(24)00115-7. doi: 10.1016/j.arbres.2024.04.007. Online ahead of print.

NO ABSTRACT

PMID:38714384 | DOI:10.1016/j.arbres.2024.04.007