Association between state minimum wage and firearm suicides in the USA, 2000-2020.

BACKGROUND: Firearm suicides constitute a major public health issue. Policies that enhance economic security and decrease community-level poverty may be effective strategies for reducing risk of firearm suicide. This study examined the association between state minimum wage and firearm suicide. METHODS: State minimum wage, obtained from Temple's Law Atlas and augmented by legal research, was conceptualised using the modified Kaitz Index and a continuous variable centred on the federal minimum wage. State-level suicide counts were obtained from 2000 to 2020 multiple-cause-of-death mortality data from the National Vital Statistics System. Log-linear regressions were conducted to model the associations between state minimum wage and firearm suicides, stratifying by demographic groups. Analyses were conducted in 2023. RESULTS: A one percentage point increase in a state's modified Kaitz Index was associated with a 0.3% (95% CI -0.6% to -0.0%) decrease in firearm suicides within a state. A US$1.00 increase in a state's minimum wage above the federal minimum wage was associated with a 1.4% (95% CI -2.1% to -0.6%) decrease in firearm suicides. When stratified by quartile of firearm ownership, the modified Kaitz Index was associated with decreases in firearm suicides most consistently in the two lowest quartiles. CONCLUSION: Increasing a state's minimum wage may be a policy option to consider as part of a comprehensive approach to reducing firearm suicides. These findings expand the evidence base for how economic policies may be leveraged to reduce firearm suicides.

Drug resistance and genomic variations among Mycobacterium tuberculosis isolates from The Nile Delta, Egypt.

Tuberculosis is a global public health concern. Earlier reports suggested the emergence of high rates of drug resistant tuberculosis in Egypt. This study included 102 isolates of Mycobacterium tuberculosis collected from two reference laboratories in Cairo and Alexandria. All clinical isolates were sub-cultured on Löwenstein-Jensen medium and analyzed using both BD BACTEC MGIT 960 SIRE Kit and standard diffusion disk assays to identify the antibiotic sensitivity profile. Extracted genomic DNA was subjected to whole genome sequencing (WGS) using Illumina platform. Isolates that belong to lineage 4 represented > 80%, while lineage 3 represented only 11% of the isolates. The percentage of drug resistance for the streptomycin, isoniazid, rifampicin and ethambutol were 31.0, 17.2, 19.5 and 20.7, respectively. Nearly 47.1% of the isolates were sensitive to the four anti-tuberculous drugs, while only one isolate was resistant to all four drugs. In addition, several new and known mutations were identified by WGS. High rates of drug resistance and new mutations were identified in our isolates. Tuberculosis control measures should focus on the spread of mono (S, I, R, E)- and double (S, E)-drug resistant strains present at higher rates throughout the whole Nile Delta, Egypt.

A rare presentation of inguinal mass in postmenopausal women: leiomyoma of round ligament mimicking an irreducible inguinal hernia.

Tumors of the round ligament rarely happen; leiomyomas are considered the most common. Round ligament leiomyomas are benign tumors mimicking inguinal hernia, lymph nodes, or other inguinal masses. They are usually asymptomatic and take place in premenopausal female patients. This paper will present a case of a postmenopausal female patient who presented to our outpatient surgical clinic complaining of a right groin mass for 3 months. She was clinically diagnosed as a case of an irreducible inguinal hernia. After investigations, it turned out to be a round ligament leiomyoma, confirmed by the histopathological examination. There are broad differential diagnoses of inguinal masses. Although imaging exams could help diagnose leiomyomas, surgical excision followed by histopathological assessment is the best to confirm the diagnoses.

Distribution and Antimicrobial Resistance of Complicated Intraabdominal Infection Pathogens in Two Tertiary Hospitals in Egypt.

Background: Management of complicated intraabdominal infections (cIAIs) requires containment of the source and appropriate initial antimicrobial therapy. Identifying the local data is important to guide the empirical selection of antimicrobial therapy. In this study, we aimed to describe the pathogen distribution and antimicrobial resistance of cIAI. Methods: In two major tertiary care hospitals in Egypt, we enrolled patients who met the case definition of cIAI from October 2022 to September 2023. Blood cultures were performed using the BACTAlert system (BioMerieux, Marcy l'Etoile, France). A culture of aspirated fluid, resected material, or debridement of the infection site was performed. Identification of pathogens and antimicrobial susceptibility testing were conducted by the VITEK-2 system (BioMerieux, Marcy l'Etoile, France). Gram-negative resistance genes were identified by PCR and confirmed by whole bacterial genome sequencing using the Nextera XT DNA Library Preparation Kit and sequencing with the MiSeq Reagent Kit 600 v3 (Illumina, USA) on the Illumina MiSeq. Results: We enrolled 423 patients, 275 (65.01%) males. The median age was 61.35 (range 25-72 years). We studied 452 recovered bacterial isolates. Gram-negative bacteria were the vast majority, dominated by E. coli, followed by Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, and Proteus mirabilis (33.6%, 30.5%, 13.7%, 13%, and 5.4%, respectively). High rates of resistance were detected to third- and fourth-generation cephalosporins and fluoroquinolones. No resistance was detected to colistin. Resistance to amikacin and tigecycline was low among all isolates. Resistance to meropenem and ceftazidime/avibactam was moderate. ESBL genes were common in E. coli and K. pneumoniae. CTX-M15 gene was the most frequent. Among Enterobacterales, blaOXA-48 and blaNDM were the most prevalent carbapenemase genes. Pseudomonas aeruginosa isolates harbored a wide variety of carbapenemase genes (OXA, NDM, VIM, SIM, GIM, SPM, IMP, AIM), dominated by metallo-beta-lactamases. In 20.6% of isolates, we identified two or more resistance genes. Conclusion: High resistance rates were detected to third- and fourth-generation cephalosporins and fluoroquinolones. Amikacin and tigecyclines were the most active antimicrobials. Our data call for urgent implementation of antimicrobial stewardship programs and reinforcement of infection control.

Establishing an early warning surveillance system in jails in Calabarzon, the Philippines, 2021.

The Philippines' Republic Act 11332 (2020) mandates prisons, jails and detention centres to participate in disease surveillance, but currently no surveillance system exists in these facilities. This report aims to describe the piloting of an early warning disease surveillance system in 21 selected jails in Calabarzon from July to September 2021. Sites were selected based on congestion, proximity to health facilities and logistical capacity. Data sources, collection mechanisms and reporting tools were determined and health personnel were trained in the operation of the system. During the implementation period, the system detected 10 health events, with influenza-like illness and foodborne illness being the most common. Nine of these events were reported within 24 hours. The local health unit provided medications for clinical management and instructed jail nurses on infection prevention and control measures, including active case finding, the isolation of cases and the inspection of food handling. Twelve sites reported over 8 of the 10 weeks, with all sites reporting zero cases promptly. The challenges identified included insufficient workforce, slow internet speed and multitasking. It was concluded that the jail-based early warning surveillance system is feasible and functional, but the perceived benefits of jail management are crucial to the acceptability and ownership of the system. It is recommended to replicate the surveillance system in other penitentiaries nationwide.

Understanding forms of childhood adversities and associations with adult health outcomes: A regression tree analysis.

BACKGROUND: Empirical studies have demonstrated associations between ten original adverse childhood experiences (ACEs) and multiple health outcomes. Identifying expanded ACEs can capture the burden of other childhood adversities that may have important health implications. OBJECTIVE: We sought to identify childhood adversities that warrant consideration as expanded ACEs. We hypothesized that experiencing expanded and original ACEs would be associated with poorer adult health outcomes compared to experiencing original ACEs alone. PARTICIPANTS: The 11,545 respondents of the National Longitudinal Surveys (NLS) and Child and Young Adult Survey were 48.9 % female, 22.7 % Black, 15.8 % Hispanic, 36.1 % White, 1.7 % Asian/Native Hawaiian/Pacific Islander/Native American/Native Alaskan, and 7.5 % Other. METHODS: This study used regression trees and generalized linear models to identify if/which expanded ACEs interacted with original ACEs in association with six health outcomes. RESULTS: Four expanded ACEs-basic needs instability, lack of parental love and affection, community stressors, and mother's experience with physical abuse during childhood -significantly interacted with general health, depressive symptom severity, anxiety symptom severity, and violent crime victimization in adulthood (all p-values <0.005). Basic needs instability and/or lack of parental love and affection emerged as correlates across multiple outcomes. Experiencing lack of parental love and affection and original ACEs was associated with greater anxiety symptoms (p = 0.022). CONCLUSIONS: This is the first study to use supervised machine learning to investigate interaction effects among original ACEs and expanded ACEs. Two expanded ACEs emerged as predictors for three adult health outcomes and warrant further consideration in ACEs assessments.

Multimodal decoding of human liver regeneration.

The liver has a unique ability to regenerate1,2; however, in the setting of acute liver failure (ALF), this regenerative capacity is often overwhelmed, leaving emergency liver transplantation as the only curative option3-5. Here, to advance understanding of human liver regeneration, we use paired single-nucleus RNA sequencing combined with spatial profiling of healthy and ALF explant human livers to generate a single-cell, pan-lineage atlas of human liver regeneration. We uncover a novel ANXA2+ migratory hepatocyte subpopulation, which emerges during human liver regeneration, and a corollary subpopulation in a mouse model of acetaminophen (APAP)-induced liver regeneration. Interrogation of necrotic wound closure and hepatocyte proliferation across multiple timepoints following APAP-induced liver injury in mice demonstrates that wound closure precedes hepatocyte proliferation. Four-dimensional intravital imaging of APAP-induced mouse liver injury identifies motile hepatocytes at the edge of the necrotic area, enabling collective migration of the hepatocyte sheet to effect wound closure. Depletion of hepatocyte ANXA2 reduces hepatocyte growth factor-induced human and mouse hepatocyte migration in vitro, and abrogates necrotic wound closure following APAP-induced mouse liver injury. Together, our work dissects unanticipated aspects of liver regeneration, demonstrating an uncoupling of wound closure and hepatocyte proliferation and uncovering a novel migratory hepatocyte subpopulation that mediates wound closure following liver injury. Therapies designed to promote rapid reconstitution of normal hepatic microarchitecture and reparation of the gut-liver barrier may advance new areas of therapeutic discovery in regenerative medicine.

Perception of cure in prostate cancer: human-led and artificial intelligence-assisted landscape review and linguistic analysis of literature, social media and policy documents.

BACKGROUND: Understanding stakeholders' perception of cure in prostate cancer (PC) is essential to preparing for effective communication about emerging treatments with curative intent. This study used artificial intelligence (AI) for landscape review and linguistic analysis of definition, context and value of cure among stakeholders in PC. MATERIALS AND METHODS: Subject-matter experts (SMEs) selected cure-related key words using Elicit, a semantic literature search engine, and extracted hits containing the key words from Medline, Sermo and Overton, representing academic researchers, health care providers (HCPs) and policymakers, respectively. NetBase Quid, a social media analytics and natural language processing tool, was used to carry out key word searches in social media (representing the general public). NetBase Quid analysed linguistics of key word-specific hit sets for key word count, geolocation and sentiments. SMEs qualitatively summarised key word-specific insights. Contextual terms frequently occurring with key words were identified and quantified. RESULTS: SMEs identified seven key words applicable to PC (number of acquired hits) across four platforms: Cure (12429), Survivor (6063), Remission (1904), Survivorship (1179), Curative intent (432), No evidence of disease (381) and Complete remission (83). Most commonly used key words were Cure by the general public and HCPs (11815 and 224 hits), Survivorship by academic researchers and Survivor by policymakers (378 hits each). All stakeholders discussed Cure and cure-related key words primarily in early-stage PC and associated them with positive sentiments. All stakeholders defined cure differently but communicated about it in relation to disease measurements (e.g. prostate-specific antigen) or surgery. Stakeholders preferred different terms when discussing cure in PC: Cure (academic researchers), Cure rates (HCPs), Potential cure and Survivor/Survivorship (policymakers) and Cure and Survivor (general public). CONCLUSION: This human-led, AI-assisted large-scale qualitative language-based research revealed that cure was commonly discussed by academic researchers, HCPs, policymakers and the general public, especially in early-stage PC. Stakeholders defined and contextualised cure in their communications differently and associated it with positive value.

Current advances in serological and molecular diagnosis of Schistosoma mekongi infection.

Schistosomiasis, a neglected tropical disease, caused by blood flukes belonging to the genus Schistosoma; it persists as a public health problem in selected regions throughout Africa, South America, and Asia. Schistosoma mekongi, a zoonotic schistosome species endemic to the Mekong River in Laos and Cambodia, is one of the significant causes of human schistosomiasis along with S. japonicum, S. mansoni, S. haematobium and S. intercalatum. Since its discovery, S. mekongi infection has been highly prevalent in communities along the Mekong River. Although surveillance and control measures have shown success in recent years, more robust diagnostic tools are still needed to establish more efficient control and prevention strategies to achieve and sustain an elimination status. Diagnosis of S. mekongi infection still relies on copro-parasitological techniques, commonly made by Kato-Katz stool examination. Serological techniques such as enzyme-linked immunosorbent assay (ELISA) may also be applicable but in a limited setting. Targeted molecular and serological tools specific to the species, on the other hand, have been limited. This is due, in part, to the limited research and studies on the molecular biology of S. mekongi since genome information of this species has not yet been released. In this review, current advances, and gaps and limitations in the molecular and immunological diagnosis of S. mekongi are discussed.

The Association Between State Minimum Wage and Firearm Homicides, 2000-2020.

INTRODUCTION: Recent research has indicated an association between both poverty and income inequality and firearm homicides. Increased minimum wages may serve as a strategy for reducing firearm violence by increasing economic security among workers earning low wages and reducing the number of families living in poverty. This study aimed to examine the association between state minimum wage and firearm homicides in the U.S. between 2000 and 2020. METHODS: State minimum wage, obtained from Temple's Law Atlas and augmented by legal research, was conceptualized using the Kaitz Index. State-level homicide counts were obtained from 2000 to 2020 multiple-cause-of death mortality data from the National Vital Statistics System. Log-linear regressions were conducted to model the associations between state minimum wage and firearm homicides, stratifying by demographic groups. Analyses were conducted in 2023. RESULTS: A 1% point increase in a state's Kaitz Index was associated with a 1.3% (95% CI: -2.1% to -0.5%) decrease in a state's firearm homicide rate. When interacted with quartile of firearm ownership, the Kaitz Index was associated with decreases in firearm homicide in all except the lowest quartile. These findings were largely consistent across stratifications. CONCLUSIONS: Changing a state's minimum wage, whereby a full-time minimum wage worker's salary is closer to a state's median income, may be an option for reducing firearm homicides.

Trends in the surgical management of proximal humerus fractures in Ireland from 2009 to 2022: An increasing usage of reverse shoulder arthroplasty.

BACKGROUND: Proximal humeral fractures are a common injury accounting for a significant workload across orthopaedic departments. Though often managed non-operatively, surgical management is indicated for a proportion of patients. AIMS: The aim of this study is to examine the trends in the management of proximal humeral fractures within Ireland over the past 13 years. METHODS: A retrospective review of Irish Hospital In-Patient Enquiry (HIPE) data was performed between January 2009 and December 2022. Information regarding demographics including age and gender, along with procedure type were collated after patients with proximal humerus fractures, were identified using relevant ICD 10 codes. RESULTS: Demographic details remained stable with females and those within the 55-69 year age bracket accounting for the highest proportion of patients. The mean annual number of procedures performed across the study period was 365 (273-508), with an increase from 288 cases in 2009 to 441 in 2022. Open reduction and internal fixation were the most common procedures accounting for 76.4% of cases. There has been a rising usage of total shoulder arthroplasty for fixation with an increase from < 5 cases in 2016 to 84 in 2022. A decrease in the usage of hemiarthroplasty and closed reduction internal fixation was also observed. CONCLUSIONS: There has been an increasing volume of operatively managed proximal humeral fractures in Ireland, which sustained despite the 2015 publication of the highly publicised PROPHER trial. The increasing utilisation of total shoulder arthroplasty in acute trauma management is notable and necessitates appropriate training for trauma theatre personnel.

Modulating tumoral exosomes and fibroblast phenotype using nanoliposomes augments cancer immunotherapy.

Cancer cells program fibroblasts into cancer associated fibroblasts (CAFs) in a two-step manner. First, cancer cells secrete exosomes to program quiescent fibroblasts into activated CAFs. Second, cancer cells maintain the CAF phenotype via activation of signal transduction pathways. We rationalized that inhibiting this two-step process can normalize CAFs into quiescent fibroblasts and augment the efficacy of immunotherapy. We show that cancer cell-targeted nanoliposomes that inhibit sequential steps of exosome biogenesis and release from lung cancer cells block the differentiation of lung fibroblasts into CAFs. In parallel, we demonstrate that CAF-targeted nanoliposomes that block two distinct nodes in fibroblast growth factor receptor (FGFR)-Wnt/ß-catenin signaling pathway can reverse activate CAFs into quiescent fibroblasts. Co-administration of both nanoliposomes significantly improves the infiltration of cytotoxic T cells and enhances the antitumor efficacy of αPD-L1 in immunocompetent lung cancer-bearing mice. Simultaneously blocking the tumoral exosome-mediated activation of fibroblasts and FGFR-Wnt/ß-catenin signaling constitutes a promising approach to augment immunotherapy.

Advanced child tax credit payments and national child abuse hotline contacts, 2019-2022.

BACKGROUND: Children in households experiencing poverty are disproportionately exposed to maltreatment. Income support policies have been associated with reductions in child abuse and neglect. The advance child tax credit (CTC) payments may reduce child maltreatment by improving the economic security of some families. No national studies have examined the association between advance CTC payments and child abuse and neglect. This study examines the association between the advance CTC payments and child abuse and neglect-related contacts to the Childhelp National Child Abuse Hotline. METHODS: A time series study of contacts to the Childhelp National Child Abuse Hotline between January 2019 and December 2022 was used to examine the association between the payments and hotline contacts. An interrupted time series (ITS) exploiting the variation in the advance CTC payments was estimated using fixed effects. RESULTS: The CTC advance payments were associated with an immediate 13.8% (95% CI -17.5% to -10.0%) decrease in contacts to the hotline in the ITS model. Following the expiration of the advance CTC payments, there was a significant and gradual 0.1% (95% CI +0.0% to +0.2%) daily increase in contacts. Sensitivity analyses found significant reductions in contacts following each payment, however, the reductions were associated with the last three of the six total payments. CONCLUSION: These findings suggest the advance CTC payments may reduce child abuse and neglect-related hotline contacts and continue to build the evidence base for associations between income-support policies and reductions in child abuse and neglect.

Molecular detection and internal transcribed spacer-1 sequence diversity of Trypanosoma evansi in goats from Cavite, Philippines.

Goat production is an important source of livelihood and food. Goats may serve as reservoir of surra affecting livestock production. Here, forty-two free-roaming goats from Cavite, Philippines were screened using two primer sets, Trypanosoma brucei minisatellite chromosome for initial detection and the internal transcribed spacer 1 (ITS-1) to determine phylogeny. Initial PCR detection showed that 19/42 (45%) goats were positive, much higher than the rate previously reported in goats from Cebu (34%). The infectivity rate was higher in male (56%) than in female (42%) and the rate was higher in young ≤1 year old (100%) than in adult >1 year old (43%). Phylogenetic analysis of the ITS-1 sequences between T. evansi goat samples and other isolates indicate potential interspecies transmission.

Establishing an early warning surveillance system in jails in Calabarzon, the Philippines, 2021

@#The Philippines’ Republic Act 11332 (2020) mandates prisons, jails and detention centres to participate in disease surveillance, but currently no surveillance system exists in these facilities. This report aims to describe the piloting of an early warning disease surveillance system in 21 selected jails in Calabarzon from July to September 2021. Sites were selected based on congestion, proximity to health facilities and logistical capacity. Data sources, collection mechanisms and reporting tools were determined and health personnel were trained in the operation of the system. During the implementation period, the system detected 10 health events, with influenza-like illness and foodborne illness being the most common. Nine of these events were reported within 24 hours. The local health unit provided medications for clinical management and instructed jail nurses on infection prevention and control measures, including active case finding, the isolation of cases and the inspection of food handling. Twelve sites reported over 8 of the 10 weeks, with all sites reporting zero cases promptly. The challenges identified included insufficient workforce, slow internet speed and multitasking. It was concluded that the jail-based early warning surveillance system is feasible and functional, but the perceived benefits of jail management are crucial to the acceptability and ownership of the system. It is recommended to replicate the surveillance system in other penitentiaries nationwide.

Patients' experiences of a suppoRted self-manAGeMent pAThway In breast Cancer (PRAGMATIC): quality of life and service use results.

PURPOSE: To describe trends and explore factors associated with quality of life (QoL) and psychological morbidity and assess breast cancer (BC) health service use over a 12-month period for patients joining the supported self-management (SSM)/patient-initiated follow-up (PIFU) pathway. METHODS: Participants completed questionnaires at baseline, 3, 6, 9 and 12 months that measured QoL (FACT-B, EQ 5D-5L), self-efficacy (GSE), psychological morbidity (GHQ-12), roles and responsibilities (PRRS) and service use (cost diary). RESULTS: 99/110 patients completed all timepoints; 32% (35/110) had received chemotherapy. The chemotherapy group had poorer QoL; FACT-B total score mean differences were 8.53 (95% CI: 3.42 to 13.64), 5.38 (95% CI: 0.17 to 10.58) and 8.00 (95% CI: 2.76 to 13.24) at 6, 9 and 12 months, respectively. The odds of psychological morbidity (GHQ12 >4) were 5.5-fold greater for those treated with chemotherapy. Financial and caring burdens (PRRS) were worse for this group (mean difference in change at 9 months 3.25 (95% CI: 0.42 to 6.07)). GSE and GHQ-12 scores impacted FACT-B total scores, indicating QoL decline for those with high baseline psychological morbidity. Chemotherapy patients or those with high psychological morbidity or were unable to carry out normal activities had the highest service costs. Over the 12 months, 68.2% participants phoned/emailed breast care nurses, and 53.3% visited a hospital breast clinician. CONCLUSION: The data suggest that chemotherapy patients and/or those with heightened psychological morbidity might benefit from closer monitoring and/or supportive interventions whilst on the SSM/PIFU pathway. Reduced access due to COVID-19 could have affected service use.

Living with metastatic breast cancer (LIMBER): experiences, quality of life, gaps in information, care and support of patients in the UK.

PURPOSE: To determine the experiences, information, support needs and quality of life of women in the UK living with metastatic breast cancer (MBC) to provide content for educational materials. METHODS: An online survey, hosted for 3 months on a UK MBC charity website, comprised sections covering issues such as communication about MBC treatment and management, helpful and less helpful things that healthcare professionals, family and friends did or said and completion of the Patient Roles and Responsibilities Scale (PRRS). RESULTS: A total of 143 patients participated; 48/143(33%) presented de novo; 54/143(38%) had been living with MBC > 2 years. PRRS analysis revealed that MBC imposed a serious impact upon most respondents' own caring abilities and social lives. A majority 98/139 (71%) wished they had known more about MBC before their diagnosis; 63/134(47%) indicated that they still did not fully understand their illness; merely 78/139(56%) had access to a specialist nurse and only 69/135(51%) had been offered any additional support. Respondents reported little consideration given to their lifestyle/culture during consultations and inconsistent information, support services, continuity of care or access to clinical trials. They commented upon things health care professionals/friends and family did or said that were useful and cited other behaviours that were especially unhelpful. CONCLUSIONS: MBC exerted a deleterious impact upon patients' activities of daily living which were exacerbated in part by significant gaps in support, communication and information. IMPLICATIONS FOR CANCER SURVIVORS: LIMBER results are informing the content of educational materials currently being developed for patients' formal and informal carers.

Lipid Bilayer Strengthens the Cooperative Network of a Membrane-Integral Enzyme.

Lipid bilayer provides a two-dimensional hydrophobic solvent milieu for membrane proteins in cells. Although the native bilayer is widely recognized as an optimal environment for folding and function of membrane proteins, the underlying physical basis remains elusive. Here, employing the intramembrane protease GlpG of Escherichia coli as a model, we elucidate how the bilayer stabilizes a membrane protein and engages the protein's residue interaction network compared to the nonnative hydrophobic medium, micelles. We find that the bilayer enhances GlpG stability by promoting residue burial in the protein interior compared to micelles. Strikingly, while the cooperative residue interactions cluster into multiple distinct regions in micelles, the whole packed regions of the protein act as a single cooperative unit in the bilayer. Molecular dynamics (MD) simulation indicates that lipids less efficiently solvate GlpG than detergents. Thus, the bilayerinduced enhancement of stability and cooperativity likely stems from the dominant intraprotein interactions outcompeting the weak lipid solvation. Our findings reveal a foundational mechanism in the folding, function, and quality control of membrane proteins. The enhanced cooperativity benefits function facilitating propagation of local structural perturbation across the membrane. However, the same phenomenon can render the proteins' conformational integrity vulnerable to missense mutations causing conformational diseases1,2.