Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium.

Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.

Connectome architecture shapes large-scale cortical alterations in schizophrenia: a worldwide ENIGMA study.

Schizophrenia is a prototypical network disorder with widespread brain-morphological alterations, yet it remains unclear whether these distributed alterations robustly reflect the underlying network layout. We tested whether large-scale structural alterations in schizophrenia relate to normative structural and functional connectome architecture, and systematically evaluated robustness and generalizability of these network-level alterations. Leveraging anatomical MRI scans from 2439 adults with schizophrenia and 2867 healthy controls from 26 ENIGMA sites and normative data from the Human Connectome Project (n = 207), we evaluated structural alterations of schizophrenia against two network susceptibility models: (i) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; (ii) epicenter mapping, which identifies regions whose typical connectivity profile most closely resembles the disease-related morphological alterations. To assess generalizability and specificity, we contextualized the influence of site, disease stages, and individual clinical factors and compared network associations of schizophrenia with that found in affective disorders. Our findings show schizophrenia-related cortical thinning is spatially associated with functional and structural hubs, suggesting that highly interconnected regions are more vulnerable to morphological alterations. Predominantly temporo-paralimbic and frontal regions emerged as epicenters with connectivity profiles linked to schizophrenia's alteration patterns. Findings were robust across sites, disease stages, and related to individual symptoms. Moreover, transdiagnostic comparisons revealed overlapping epicenters in schizophrenia and bipolar, but not major depressive disorder, suggestive of a pathophysiological continuity within the schizophrenia-bipolar-spectrum. In sum, cortical alterations over the course of schizophrenia robustly follow brain network architecture, emphasizing marked hub susceptibility and temporo-frontal epicenters at both the level of the group and the individual. Subtle variations of epicenters across disease stages suggest interacting pathological processes, while associations with patient-specific symptoms support additional inter-individual variability of hub vulnerability and epicenters in schizophrenia. Our work outlines potential pathways to better understand macroscale structural alterations, and inter- individual variability in schizophrenia.

Mapping gray and white matter volume abnormalities in early-onset psychosis: an ENIGMA multicenter voxel-based morphometry study.

INTRODUCTION: Regional gray matter (GM) alterations have been reported in early-onset psychosis (EOP, onset before age 18), but previous studies have yielded conflicting results, likely due to small sample sizes and the different brain regions examined. In this study, we conducted a whole brain voxel-based morphometry (VBM) analysis in a large sample of individuals with EOP, using the newly developed ENIGMA-VBM tool. METHODS: 15 independent cohorts from the ENIGMA-EOP working group participated in the study. The overall sample comprised T1-weighted MRI data from 482 individuals with EOP and 469 healthy controls. Each site performed the VBM analysis locally using the standardized ENIGMA-VBM tool. Statistical parametric T-maps were generated from each cohort and meta-analyzed to reveal voxel-wise differences between EOP and healthy controls as well as the individual-based association between GM volume and age of onset, chlorpromazine (CPZ) equivalent dose, and other clinical variables. RESULTS: Compared with healthy controls, individuals with EOP showed widespread lower GM volume encompassing most of the cortex, with the most marked effect in the left median cingulate (Hedges' g = 0.55, p = 0.001 corrected), as well as small clusters of lower white matter (WM), whereas no regional GM or WM volumes were higher in EOP. Lower GM volume in the cerebellum, thalamus and left inferior parietal gyrus was associated with older age of onset. Deficits in GM in the left inferior frontal gyrus, right insula, right precentral gyrus and right superior frontal gyrus were also associated with higher CPZ equivalent doses. CONCLUSION: EOP is associated with widespread reductions in cortical GM volume, while WM is affected to a smaller extent. GM volume alterations are associated with age of onset and CPZ equivalent dose but these effects are small compared to case-control differences. Mapping anatomical abnormalities in EOP may lead to a better understanding of the role of psychosis in brain development during childhood and adolescence.

In vivo white matter microstructure in adolescents with early-onset psychosis: a multi-site mega-analysis.

Emerging evidence suggests brain white matter alterations in adolescents with early-onset psychosis (EOP; age of onset <18 years). However, as neuroimaging methods vary and sample sizes are modest, results remain inconclusive. Using harmonized data processing protocols and a mega-analytic approach, we compared white matter microstructure in EOP and healthy controls using diffusion tensor imaging (DTI). Our sample included 321 adolescents with EOP (median age = 16.6 years, interquartile range (IQR) = 2.14, 46.4% females) and 265 adolescent healthy controls (median age = 16.2 years, IQR = 2.43, 57.7% females) pooled from nine sites. All sites extracted mean fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) for 25 white matter regions of interest per participant. ComBat harmonization was performed for all DTI measures to adjust for scanner differences. Multiple linear regression models were fitted to investigate case-control differences and associations with clinical variables in regional DTI measures. We found widespread lower FA in EOP compared to healthy controls, with the largest effect sizes in the superior longitudinal fasciculus (Cohen's d = 0.37), posterior corona radiata (d = 0.32), and superior fronto-occipital fasciculus (d = 0.31). We also found widespread higher RD and more localized higher MD and AD. We detected significant effects of diagnostic subgroup, sex, and duration of illness, but not medication status. Using the largest EOP DTI sample to date, our findings suggest a profile of widespread white matter microstructure alterations in adolescents with EOP, most prominently in male individuals with early-onset schizophrenia and individuals with a shorter duration of illness.

Impact of intimate partner violence on quality of life and disease activity in women with systemic lupus erythematosus.

OBJECTIVE: Stress and trauma are psychosocial factors with an impact on the course of systemic lupus erythematosus (SLE). The influence of violence on SLE has not been entirely explored, even though women (including patients with rheumatic diseases) are a vulnerable population to any form of violence. This study aims to assess the prevalence and impact of intimate partner violence (IPV) on health-related quality of life in women with SLE. METHODS: An observational, cross-sectional, and analytical study was conducted at a rheumatology clinic of a university hospital from September 2022 and September 2023. We evaluated the presence of IPV in 85 women with SLE with the Hurt, Insulted, Threatened with Harm and Screamed at (HITS) questionnaire and the Index of Spouse Abuse (ISA), and quality of life with LupusQoL. RESULTS: The prevalence by HITS score of past-year IPV was 24.4% and of lifetime IPV was 36.5%. Past-year non-physical violence was present in 17.1% of patients by ISA, and 27.1% were victims in their lifetime. While in physical violence, 7.3% were victims in the previous year and 21.2% in their lifetime. The total quality of life and the emotional domain by LupusQoL were diminished in victims of past-year IPV, compared to those who weren't exposed (p = .018 and p = .036, respectively). Past-year HITS score correlated with the Physician Global Assessment (PGA) (rho = 0.301, p = .006), while lifetime HITS score correlated with PGA (rho = 0.329, p = .002) and SLEDAI-2K (rho = 0.277, p = .010). CONCLUSION: We found that one in four women suffered IPV in the previous year, and those who were exposed had diminished quality of life. Also, the severity of the abuse correlated with disease activity. Our findings emphasize the importance of comprehensive care for patients with SLE.

Sexual dysfunction and self-perceived sexual health in patients with rheumatoid arthritis and systemic lupus erythematosus: results from a cross-sectional survey.

Sexual dysfunction (SD) has been associated with worse quality of life and higher disease activity in patients with rheumatic diseases, yet it is still not regularly addressed during routine rheumatologic evaluations. This study aimed to determine the prevalence of sexual dysfunction in patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) and evaluate their perception of their sexual health. We performed a retrospective study in an outpatient rheumatology clinic to evaluate patients over 18 years old with a diagnosis of RA or SLE through the Spanish version of the Arizona Sexual Experiences Scale (ASEX) and the Sexual Health Perception Survey (SHEPS), a questionnaire of 6 items designed in our clinic. Additionally, we applied the Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F version 4) and the Hospital Anxiety and Depression Scale (HADS). A total of 567 patients were evaluated with SHEPS, most of whom were women with a median age of 50 years (IQR: 34) and a median disease duration of 5 years (IQR: 9). Through the ASEX, we found that 67% of the patients with RA and 60% of the patients with SLE experienced SD. Patients reported the level of sex drive, arousal, and the ability to achieve orgasms as the areas with the most difficulties. Most patients did not know their disease could affect their sexuality and had never addressed these issues with their rheumatologists, but almost all of them were willing to. Our findings highlight the importance of addressing sexual health issues regularly during rheumatologic evaluations.

Obesity and brain structure in schizophrenia - ENIGMA study in 3021 individuals.

Schizophrenia is frequently associated with obesity, which is linked with neurostructural alterations. Yet, we do not understand how the brain correlates of obesity map onto the brain changes in schizophrenia. We obtained MRI-derived brain cortical and subcortical measures and body mass index (BMI) from 1260 individuals with schizophrenia and 1761 controls from 12 independent research sites within the ENIGMA-Schizophrenia Working Group. We jointly modeled the statistical effects of schizophrenia and BMI using mixed effects. BMI was additively associated with structure of many of the same brain regions as schizophrenia, but the cortical and subcortical alterations in schizophrenia were more widespread and pronounced. Both BMI and schizophrenia were primarily associated with changes in cortical thickness, with fewer correlates in surface area. While, BMI was negatively associated with cortical thickness, the significant associations between BMI and surface area or subcortical volumes were positive. Lastly, the brain correlates of obesity were replicated among large studies and closely resembled neurostructural changes in major depressive disorders. We confirmed widespread associations between BMI and brain structure in individuals with schizophrenia. People with both obesity and schizophrenia showed more pronounced brain alterations than people with only one of these conditions. Obesity appears to be a relevant factor which could account for heterogeneity of brain imaging findings and for differences in brain imaging outcomes among people with schizophrenia.

"I'm Done": A patient's wish and will to die.

BACKGROUND: A desire for hastened death is commonly expressed by cancer patients. Although efforts to define and explore this issue have been undertaken, no standardized approach exists to address these desires. CASE DESCRIPTION: Ms. J expressed a wish for accelerated death and subsequently experienced unexpected clinical decline resulting in a quick, natural death. Our team experienced a mixture of both emotional distress and awe after witnessing the pragmatic approach our patient had to her impending decline, that we felt was worthy of further exploration. CONCLUSION: Most clinicians lack formal training in communication, potentially making cases like Ms. J's highly distressing. Clinicians should feel comfortable addressing and potentially inquiring about patients' desire to hasten death. While our initial reaction might be to correct this desire, we propose reframing this expression as an opportunity to explore more about our patients.

A meta-analysis of deep brain structural shape and asymmetry abnormalities in 2,833 individuals with schizophrenia compared with 3,929 healthy volunteers via the ENIGMA Consortium.

Schizophrenia is associated with widespread alterations in subcortical brain structure. While analytic methods have enabled more detailed morphometric characterization, findings are often equivocal. In this meta-analysis, we employed the harmonized ENIGMA shape analysis protocols to collaboratively investigate subcortical brain structure shape differences between individuals with schizophrenia and healthy control participants. The study analyzed data from 2,833 individuals with schizophrenia and 3,929 healthy control participants contributed by 21 worldwide research groups participating in the ENIGMA Schizophrenia Working Group. Harmonized shape analysis protocols were applied to each site's data independently for bilateral hippocampus, amygdala, caudate, accumbens, putamen, pallidum, and thalamus obtained from T1-weighted structural MRI scans. Mass univariate meta-analyses revealed more-concave-than-convex shape differences in the hippocampus, amygdala, accumbens, and thalamus in individuals with schizophrenia compared with control participants, more-convex-than-concave shape differences in the putamen and pallidum, and both concave and convex shape differences in the caudate. Patterns of exaggerated asymmetry were observed across the hippocampus, amygdala, and thalamus in individuals with schizophrenia compared to control participants, while diminished asymmetry encompassed ventral striatum and ventral and dorsal thalamus. Our analyses also revealed that higher chlorpromazine dose equivalents and increased positive symptom levels were associated with patterns of contiguous convex shape differences across multiple subcortical structures. Findings from our shape meta-analysis suggest that common neurobiological mechanisms may contribute to gray matter reduction across multiple subcortical regions, thus enhancing our understanding of the nature of network disorganization in schizophrenia.

Engineering a Lysin with Intrinsic Antibacterial Activity (LysMK34) by Cecropin A Fusion Enhances Its Antibacterial Properties against Acinetobacter baumannii.

Bacteriophage-encoded lysins are increasingly reported as alternatives to combat Acinetobacter baumannii infections, for which limited therapeutic options are available. Some lysins, such as LysMK34, have a C-terminal amphipathic helix allowing them to penetrate the otherwise-impermeable outer membrane barrier. Another approach to kill Gram-negative pathogens with lysins relies on fusion of a peptide with outer membrane-permeabilizing properties to the lysin. In this work, we aimed to leverage the intrinsic antibacterial activity of LysMK34 by fusing the peptide cecropin A to its N terminus via a linker of three Ala-Gly repeats, resulting in engineered LysMK34 (eLysMK34). The engineered lysin has an improved antibacterial activity compared to that of the parental lysin, LysMK34, in terms of MICs (0.45 to 1.2 µM), killing rate, and killing extent. eLysMK34 has a ≥2-fold-increased activity against stationary-phase cells, and the bactericidal effect becomes less dependent on the intracellular osmotic pressure. In particular, colistin-resistant strains become highly susceptible to eLysMK34, and enhanced antibacterial activity is observed in complement-deactivated human serum. These observations demonstrate that fusion of a lysin with intrinsic antibacterial activity with a selected outer membrane-permeabilizing peptide is a useful strategy to further improve the in vitro antibacterial properties of such lysins. IMPORTANCE Phage lysins are a new class of enzyme-based antibiotics that increasingly gain interest. Lysins kill cells through rapid degradation of the peptidoglycan layer, resulting in sudden osmotic lysis. Whereas Gram-positive bacteria are readily susceptible to the actions of lysins, Gram-negative bacteria are naturally resistant, as the outer membrane protects their peptidoglycan layer. This work reveals that fusing an outer membrane-permeabilizing peptide to a lysin with intrinsic antibacterial activity results in a superior lysin that shows improved robustness in its antibacterial activity, including against the most worrisome colistin-resistant A. baumannii strains.

Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group.

DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)-three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.

High-yield synthesis of CsPbBr3nanoparticles: diphenylphosphine as a reducing agent and its effect in Pb-seeding nucleation and growth.

Based on the reported nucleation mechanisms for CsPbX3and II-VI/IV-VI quantum dots, CsPbBr3nanoparticles with a higher reaction-yield (up to 393% mass-increment) were synthetized by the hot-injection method. The introduction of diphenylphosphine (DPP) as a reducing agent improved nanoparticle nucleation and growth, giving out evidence for Pb-seeding in CsPbBr3nanoparticles formation. Additionally, a clear influence of the DPP in a CsPbBr3-Cs4PbBr6incomplete phase transformation was observed, marked by the appearance of several PbBr2nanoparticles. This indicated the need for an improved ratio between the stabilizing agents and the precursors, due to the increased number of nucleation sites produced by DPP. The resulting CsPbBr3nanoparticles showed high quality, as they displayed 70%-90% photoluminescence quantum yield; narrow size distribution with an average nanoparticle size of∼10 nm; and the characteristic cubic morphology reported in previous works. This increment in CsPbBr3nanoparticles' reaction yield will contribute to making them a more attractive option for different optoelectronic applications.

A new model for the formation of an Enterococcus faecalis endodontic biofilm with nutritional restriction.

An in vitro model for the formation of an Enterococcus faecalis endodontic biofilm under nutritional restriction was established, simulating clinical conditions for the evaluation of antimicrobial substances. Biofilm formation in dentin was standardized using root quarters incubated with E. faecalis ATCC 29212 at 37°C without nutritional changes. Biofilms were evaluated at 7, 14, and 30 days, counting bacterial colony-forming units using conventional culture and verified scanning electron microscopy. Bacterial viability and biovolume were determined with confocal laser microscopy. Colonization of E. faecalis and biofilm formation on the dentinal surface was confirmed after 7 and 14 days, respectively. Microorganism colonization was homogeneous over the entire root surface at each time point, without significant differences in the viability percentage and biovolume. On the contrary, a decrease in viability and an increase in biovolume were observed when the time was increased. Compared with other incubation times, 14 days was found to be the best time for the establishment of the biofilm in terms of biovolume and bacterial viability. This in vitro model for the formation of endodontic biofilm will allow future evaluation of the efficacy of antimicrobial substances with a more adequate clinical approach.

Treatment Discontinuation Impact on Long-Term (10-Year) Weight Gain and Lipid Metabolism in First-Episode Psychosis: Results From the PAFIP-10 Cohort.

BACKGROUND: Patients with a first episode of psychosis (FEP) are at higher risk of gaining weight and presenting metabolic disturbances, partly related to antipsychotic exposure. Previous studies suggest that treatment discontinuation might have a positive impact on weight in schizophrenia. The aim of this study was to evaluate the effect of treatment discontinuation on weight and metabolic changes in a FEP cohort. METHODS: A total of 209 FEP patients and 57 healthy controls were evaluated at study entry and prospectively at 10-year follow-up. Anthropometric measures and, clinical, metabolic, and sociodemographic data were collected. RESULTS: Patients discontinuing antipsychotic treatment presented a significantly lower increase in weight and better metabolic parameter results than those still on antipsychotic treatment at 10-year follow-up. CONCLUSIONS: Treatment discontinuation had a positive effect on the weight and metabolic changes observed in FEP patients; however, this effect was not sufficient to reaching a complete reversal to normal levels.

Dissecting the functional outcomes of first episode schizophrenia spectrum disorders: a 10-year follow-up study in the PAFIP cohort.

BACKGROUND: The aim of the current study was to examine the heterogeneity of functional outcomes in first episode psychosis (FEP) patients and related clinical, neurocognitive and sociodemographic factors using a cluster analytic approach. METHOD: A large sample of FEP patients (N = 209) was functionally reassessed 10 years after the first contact with an early intervention service. Multiple baseline, 3-year and 10-year follow-up variables were explored. RESULTS: The cluster analysis emphasized the existence of six independent clusters of functioning: one cluster was normal overall (42.16%), two clusters showed moderate interpersonal (9.63%) or instrumental (12.65%) deficits, two clusters showed more severe interpersonal (12.05%) or interpersonal and instrumental (13.85%) deficits and there was a significantly overall impaired cluster (9.63%). Cluster comparisons showed that several baseline and follow-up factors were differentially involved in functional outcomes. CONCLUSIONS: The current study demonstrated that distinct clusters of functioning in FEP patients can be identified. The fact that a variety of profiles was observed contributes to a better understanding of the nature of the heterogeneity characterizing FEP patients and has clinical implications for developing individualized treatment plans.

Neuroanatomical abnormalities in first-episode psychosis across independent samples: a multi-centre mega-analysis.

BACKGROUND: Neuroanatomical abnormalities in first-episode psychosis (FEP) tend to be subtle and widespread. The vast majority of previous studies have used small samples, and therefore may have been underpowered. In addition, most studies have examined participants at a single research site, and therefore the results may be specific to the local sample investigated. Consequently, the findings reported in the existing literature are highly heterogeneous. This study aimed to overcome these issues by testing for neuroanatomical abnormalities in individuals with FEP that are expressed consistently across several independent samples. METHODS: Structural Magnetic Resonance Imaging data were acquired from a total of 572 FEP and 502 age and gender comparable healthy controls at five sites. Voxel-based morphometry was used to investigate differences in grey matter volume (GMV) between the two groups. Statistical inferences were made at p < 0.05 after family-wise error correction for multiple comparisons. RESULTS: FEP showed a widespread pattern of decreased GMV in fronto-temporal, insular and occipital regions bilaterally; these decreases were not dependent on anti-psychotic medication. The region with the most pronounced decrease - gyrus rectus - was negatively correlated with the severity of positive and negative symptoms. CONCLUSIONS: This study identified a consistent pattern of fronto-temporal, insular and occipital abnormalities in five independent FEP samples; furthermore, the extent of these alterations is dependent on the severity of symptoms and duration of illness. This provides evidence for reliable neuroanatomical alternations in FEP, expressed above and beyond site-related differences in anti-psychotic medication, scanning parameters and recruitment criteria.

Breastfeeding counseling based on formative research at primary healthcare Services in Mexico.

BACKGROUND: Breastfeeding rates in Mexico are far from World Health Organization (WHO) recommendations with 28.8% of Exclusive Breastfeeding (EBF) under 6 months of age, according to the 2018 National Health and Nutrition Survey. Formative research has shown that culturally appropriate counseling is an effective breastfeeding intervention. The objective of the current study was to evaluate the effect of interpersonal counseling on EBF in a primary healthcare center in Tijuana, México. METHODS: This was a randomized controlled trial pilot with a sample of mothers with infants under 4 months of age from a primary care center. Participants were randomized into two groups: 1) Control group, received counseling on immunizations and standard infant feeding information, and 2) Intervention group, receiving breastfeeding counseling using a socio-ecological framework. Changes in breastfeeding attitudes, self-efficacy and EBF were evaluated at 2 months post-intervention. RESULTS: A total of 80 mothers completed the 2 month follow up assessment (40 in each group). The mean age at baseline was 26.4 years for mothers and 1.4 months for infants. There was a 30% increase in EBF at 2 months follow up in the intervention group and 15% decrease in the control group post-intervention. We observed a significant improvement in breastfeeding attitudes (P = 0.0001), self-efficacy (P = 0.046) and EBF (P = 0.0001) in the intervention group. Reported obstacles were discomfort of breastfeeding in public (23%), infant dissatisfaction (23%), pain (19%), insufficient milk supply (15%) and returning to work (8%). CONCLUSIONS: Breastfeeding counseling based on previous formative research improved breastfeeding attitudes, self-efficacy and practices in this population. These findings suggest that the promotion of breastfeeding utilizing a socio-ecological framework may improve breastfeeding rates by addressing the needs of women within their varying sociocultural contexts. TRIAL REGISTRATION: ACTRN: ACTRN12621000915853 . Retrospectively registered.

'[The pediatrician] said that maybe my milk, instead of doing good, no longer helped': the ecology of infant formula in rural communities in Central Mexico.

OBJECTIVE: As Mexico continues to develop, an epidemiological and nutritional transition has led to an increase in infant formula use in its rural and indigenous communities. Our objective was to determine the social and cultural factors that influence the use of formula in such populations in Central Mexico. DESIGN: Qualitative study using a data collection instrument based on the socio-ecological framework. SETTING: Two rural and indigenous communities in Central Mexico. PARTICIPANTS: Mothers, fathers, grandparents and healthcare providers. RESULTS: Breast-feeding was favoured in both communities; however, several cultural traditions hindered exclusive breast-feeding. As these communities became more developed, emerging ideas of modernity led to negative connotations about breast-feeding and many mothers began to view formula as a complement for breast-feeding. Formula was seen as a convenient solution for breast pain, insufficient milk and body image. Healthcare providers promoted the use of formula through their own beliefs, information, communication and conflicts of interest with formula industry representatives. The recent social and economic changes in these communities combined with the increased advertising and availability of breast milk substitutes have facilitated the preference for formula. CONCLUSIONS: Women in rural, indigenous communities in Central Mexico are increasingly using formula. Efforts at the policy and institutional levels are needed to protect mothers and their children from the detrimental consequences of unregulated formula promotion and the formula culture that it brings with it.

Lysin LysMK34 of Acinetobacter baumannii Bacteriophage PMK34 Has a Turgor Pressure-Dependent Intrinsic Antibacterial Activity and Reverts Colistin Resistance.

The prevalence of extensively and pandrug-resistant strains of Acinetobacter baumannii leaves little or no therapeutic options for treatment for this bacterial pathogen. Bacteriophages and their lysins represent attractive alternative antibacterial strategies in this regard. We used the extensively drug-resistant A. baumannii strain MK34 to isolate the bacteriophage PMK34 (vB_AbaP_PMK34). This phage shows fast adsorption and lacks virulence genes; nonetheless, its narrow host spectrum based on capsule recognition limits broad application. PMK34 is a Fri1virus member of the Autographiviridae and has a 41.8-kb genome (50 open reading frames), encoding an endolysin (LysMK34) with potent muralytic activity (1,499.9 ± 131 U/µM), a typical mesophilic thermal stability up to 55°C, and a broad pH activity range (4 to 10). LysMK34 has an intrinsic antibacterial activity up to 4.8 and 2.4 log units for A. baumannii and Pseudomonas aeruginosa strains, respectively, but only when a high turgor pressure is present. The addition of 0.5 mM EDTA or application of an osmotic shock after treatment can compensate for the lack of a high turgor pressure. The combination of LysMK34 and colistin results in up to 32-fold reduction of the MIC of colistin, and colistin-resistant strains are resensitized in both Mueller-Hinton broth and 50% human serum. As such, LysMK34 may be used to safeguard the applicability of colistin as a last-resort antibiotic.IMPORTANCEA. baumannii is one of the most challenging pathogens for which development of new and effective antimicrobials is urgently needed. Colistin is a last-resort antibiotic, and even colistin-resistant A. baumannii strains exist. Here, we present a lysin that sensitizes A. baumannii for colistin and can revert colistin resistance to colistin susceptibility. The lysin also shows a strong, turgor pressure-dependent intrinsic antibacterial activity, providing new insights in the mode of action of lysins with intrinsic activity against Gram-negative bacteria.

Advanced engineering of third-generation lysins and formulation strategies for clinical applications.

One of the possible solutions for the current antibiotic resistance crisis may be found in (often bacteriophage-derived) peptidoglycan hydrolases. The first clinical trials of these natural enzymes, coined here as first-generation lysins, are currently ongoing. Moving beyond natural endolysins with protein engineering established the second generation of lysins. In second-generation lysins, the focus lies on improving antibacterial and biochemical properties such as antimicrobial activity and stability, as well as expanding their activities towards Gram-negative pathogens. However, solutions to particular key challenges regarding clinical applications are only beginning to emerge in the third generation of lysins, in which protein and biochemical engineering efforts focus on improving properties relevant under clinical conditions. In addition, increasingly advanced formulation strategies are developed to increase the bioavailability, antibacterial activity, and half-life, and to reduce pro-inflammatory responses. This review focuses on third-generation and advanced formulation strategies that are developed to treat infections, ranging from topical to systemic applications. Together, these efforts may fully unlock the potential of lysin therapy and will propel it as a true antibiotic alternative or supplement.