Should health professionals screen women for domestic violence? : systematic review

Objective To assess the evidence for the acceptability and effectiveness of screening women for domestic violence in healthcare settings. Design Systematic review of published quantitative studies. Search strategy Three electronic databases (Medline, Embase, and CINAHL) were searched for articles published in the English language up to February 2001. Included studies Surveys that elicited the attitudes of women and health professionals on the screening of women in health settings; comparative studies conducted in healthcare settings that measured rates of identification of domestic violence in the presence and absence of screening; studies measuring outcomes of interventions for women identified in health settings who experience abuse from a male partner or ex­partner compared with abused women not receiving an intervention. Results 20 papers met the inclusion criteria. In four surveys, 43­85% of women respondents found screening in healthcare settings acceptable. Two surveys of health professionals' views found that two thirds of physicians and almost half of emergency department nurses were not in favour of screening. In nine studies of screening compared with no screening, most detected a greater proportion of abused women identified by healthcare professionals. Six studies of interventions used weak study designs and gave inconsistent results. Other than increased referral to outside agencies, little evidence exists for changes in important outcomes such as decreased exposure to violence. No studies measured quality of life, mental health outcomes, or potential harm to women from screening programmes. Conclusion Although domestic violence is a common problem with major health consequences for women, implementation of screening programmes in healthcare settings cannot be justified. Evidence of the benefit of specific interventions and lack of harm from screening is needed

Myosin II-Mediated Focal Adhesion Maturation Is Tension Insensitive

Myosin II motors drive changes in focal adhesion morphology and composition in a “maturation process” that is crucial for regulating adhesion dynamics and signaling guiding cell adhesion, migration and fate. The underlying mechanisms of maturation, however, have been obscured by the intermingled effects of myosin II on lamellar actin architecture, dynamics and force transmission. Here, we show that focal adhesion growth rate stays constant even when cellular tension is reduced by 75%. Focal adhesion growth halts only when myosin stresses are sufficiently low to impair actin retrograde flow. Focal adhesion lifetime is reduced at low levels of cellular tension, but adhesion stability can be rescued at low levels of force by over-expression of α-actinin or constitutively active Dia1. Our work identifies a minimal myosin activity threshold that is necessary to drive lamellar actin retrograde flow is sufficient to permit focal adhesion elongation. Above this nominal threshold, myosin-mediated actin organization and dynamics regulate focal adhesion growth and stability in a force-insensitive fashion.</p

Screening for primary aldosteronism- normal ranges for aldosterone and renin in three South African population groups

Objective. To establish normal ranges for plasma aldosterone, renin and aldosterone / renin (A/ R) ratio in South African normotensives under typical ou tpatient conditions, and to estimate the prevalence of primary aldosteronism (PA) among hypertensives in primary care settings.Design and methods. One hundred and thirty-six normotensive subjects and 154 sex- and age-matched hypertensives at three primary care clinics had measurements of blood pressure, plasma creatinine, K+, aldosterone, plasma renin activity, and spot urine for urinary Na+/ creatinine ratio. Medication was not withdrawn before testing.Results. Mean plasma renin activity in black normotensive subjects (0.95 ± 1.25 ng/ ml/ h, mean± standard deviation (SD)) was significantly lower than in white (2.09 ± 1.12 ng/ ml/ h; P &lt; 0.0001) and coloured (1.81 ± 1.86 ng/ ml/ h, P = 0.013) normotensives. Mean plasma aldosterone in black normotensives (306 ± 147 pmol/ 1) was also significantly lower than in white (506 ± 324 pmol/1, P = 0.0002) and coloured (418 ± 304 pmol/1, P = 0.0148) normotensives. In hypertensives, there were no significant differences in renin or aldosterone levels between the three population groups. Urinary Na+ /creatinine ratios, an index of Na+ intake, were not significantly different in the three population groups. None of the normotensives had an A/R ratio ≥ 1 000 plus aldosterone ≥ 750, while 7.1% of hypertensives exceeded these levels, suggesting that they are appropriate criteria for screening for PA.Conclusions. A large fraction of black normotensive subjects had low renin and aldosterone levels compared with whites, suggesting a salt-retaining tendency in black subjects. These results have important implications for the interpretation of plasma renin and aldosterone levels in hypertensive patients. In primary care settings, 7.1% of hypertensives had biochemical results indicating the need for investigation of PA

Orthogonal pipelines for lipid nanoparticle evaluation

Ribonucleic acid (RNA) drugs pose promising candidates for gene therapy in treatment resistant conditions and rare diseases. The FDA approval of siRNA Onpattro® in 2018 mRNA-LNP Spikevax® and Comirnaty® COVID-19 vaccinations in 2021[1] ignited research interests as these were the first siRNA and mRNA candidates to utilize lipid nanoparticles (LNPs) as a drug delivery platform. As the RNA-LNP research field is rapidly growing, robust, high-resolution separation techniques coupled to in-line detectors are required to analyze particle key quality attributes and accelerate the successful clinical translation of RNA-LNP therapies. Asymmetric-Flow Field Flow Fraction (AF4) and Size Exclusion Chromatography (SEC) are robust approaches for the characterization of oligo-LNPs [2, 3]. AF4 utilizes perpendicular field induction and particle diffusion-based separation, whereas SEC uses LNP-stationary phase interactions for separation. The goal of this study was to develop separation pipelines for the high-resolution analysis of LNPs. Briefly, we prepared (6Z,9Z,28Z,31Z)-heptatriaconta6,9,28,31-tetraen-19-yl-4-(dimethylamino)- butanoate:cholesterol: 1,2-distearoyl-sn-glycero-3-phosphocholine: 1,2-dimyristoyl-rac-glycero-3- methoxypolyethylene glycol-2000 (MC3:CHOL:DSPC:DMG-PEG2000) LNPs and 8-[(2- hydroxyethyl)[6-oxo-6-(undecyloxy)hexyl]amino]-octanoic acid, 1-octylnonyl ester:cholesterol: 1,2-distearoyl-sn-glycero-3-phosphocholine: 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (SM-102:CHOL:DSPC:DMG-PEG2000) using microfluidics at 50:38.5:10:1.5 mol% ratio. Here, we performed AF4, combined with in-line dynamic light scattering, multi-angle light scattering, and UV detection. Using these detectors, we measured key particle quality attributes including particle size, polydispersity index (PDI), and shape factor. The properties were evaluated alongside oligo-LNP samples that had not been subjected to separation. Manufacture of LNPs using microfluidics-based analysis led to PolyA MC3-LNPs in the 56.5 nm ± 1.2 nm size range with a corresponding PDI of 0.12 ± 0.02, and PolyA SM-102-LNPs of 48.5 nm ± 1.1 nm with a PDI of 0.10 ± 0.01. Our findings show the presence of sub-populations within LNP samples, which cannot be detected using routine particle metrology techniques such as nanoparticle tracking analysis and dynamic light scattering. Our results highlight the need for developing more high-resolution approaches for the analysis of LNPs and linking these to input materials and process parameter design

Go with the flow- High resolution lipid nanoparticle metrology

Asymmetric-Flow Field Flow Fraction (AF4) is a rapidly growing analytical technique for the separation and in-line analysis of RNA-loaded lipid nanoparticles (RNA-LNPs). This high resolution, robust technique will facilitate the clinical translation of new RNA-LNP formulations by evaluating nanoparticle critical quality attributes (CQAs) and enhance the knowledge between RNA-LNP design, manufacture, and associated physical chemical properties [1]. The use of high-resolution analytical techniques can bridge existing knowledge gaps and accelerate the successful clinical translation of RNA-LNP therapies. The aim of this work was to develop a method for the characterization of RNA-LNPs using Frit Inlet (FI) AF4-Multi angle light scattering (MALS)-UV to determine LNP particle size distribution

Higher or lower? : the resolution of analytical pipelines for the evaluation of lipid nanoparticle critical quality attributes

Dynamic light scattering (DLS) is a routinely used analytical technique to measure the size distribution of a colloidal sample. Nanoparticle tracking analysis (NTA) has more recently emerged as an orthogonal technique to determine particle size and estimated concentration, although widespread use of NTA for lipid nanoparticle (LNP) analysis is not reported. Here, we use DLS and NTA to screen the stability of oligonucleotide drug loaded lipid nanoparticles (oligo-LNPs) at ultra-low storage temperatures (-80 °C) in the presence and absence of a cryoprotectant (20 % sucrose, w/v) as a case study to highlight differences in technique resolution. NTA was able to detect additional LNP subpopulations samples for all measured samples, whereas DLS was unable to detect these subpopulations. Our study conveys that the use of orthogonal sizing techniques can support early-stage product development, where a more in-depth analysis of formulation and process parameters on LNP stability would support comprehensive understanding of variable defining product stability

Evaluation of the critical quality attributes of lipid nanoparticles stored under different conditions

Lipid nanoparticles (LNPs) are emerging new modalities for mRNA therapeutics which have been in the spotlight for the past decade. Since these are relatively new drug delivery systems compared to conventional medicines, new analytical techniques for the robust characterization of their critical quality attributes (CQAs) are needed [1]. It has been reported that several stimuli can affect the stability of the LNPs such as leakage of the nucleic acid cargo from the nanoparticle and LNP aggregation, resulting in low translation efficiency. Hence, understanding the duration of stability is key during formulation development. The aim of the present study is to evaluate the stability of PolyA-LNPs: 1) Stored at different temperatures (4oC and 25oC); 2) Dialysed in the absence and presence of cryoprotectant sucrose. We measured the impact of the above storage conditions on LNP physicochemical parameters

Physicochemical characterisation of poly(A) lipid nanoparticles : effect of cryoprotectant and temperature storage conditions

Lipid nanoparticles (LNPs) are emerging new modalities for mRNA therapeutics which have been in the spotlight for the past decade. Since these are relatively new drug delivery systems compared to conventional medicines, new analytical techniques for the robust characterization of their critical quality attributes (CQAs) are needed [1]. It has been reported that several stimuli can affect the stability of the LNPs such as leakage of the nucleic acid cargo from the nanoparticle and LNP aggregation, resulting in low translation efficiency [2]. Hence, understanding the duration of stability is key during formulation development. The aim of the present study is to evaluate the stability of PolyA-LNPs: 1) Stored at different temperatures (4oC and 25oC); 2) Dialysed in the absence and presence of cryoprotectant sucrose. We measured the impact of the above storage conditions on LNP physicochemical parameters

The anxiety and ethanol intake controlling GAL5.1 enhancer is epigenetically modulated by, and controls preference for, high-fat diet

Excess maternal fat intake and obesity increase offspring susceptibility to conditions such as chronic anxiety and substance abuse. We hypothesised that environmentally modulated DNA methylation changes (5mC/5hmC) in regulatory regions of the genome that modulate mood and consumptive behaviours could contribute to susceptibility to these conditions. We explored the effects of environmental factors on 5mC/5hmC levels within the GAL5.1 enhancer that controls anxiety-related behaviours and alcohol intake. We first observed that 5mC/5hmC levels within the GAL5.1 enhancer differed significantly in different parts of the brain. Moreover, we noted that early life stress had no significant effect of 5mC/5hmC levels within GAL5.1. In contrast, we identified that allowing access of pregnant mothers to high-fat diet (&gt; 60% calories from fat) had a significant effect on 5mC/5hmC levels within GAL5.1 in hypothalamus and amygdala of resulting male offspring. Cell transfection-based studies using GAL5.1 reporter plasmids showed that 5mC has a significant repressive effect on GAL5.1 activity and its response to known stimuli, such as EGR1 transcription factor expression and PKC agonism. Intriguingly, CRISPR-driven disruption of GAL5.1 from the mouse genome, although having negligible effects on metabolism or general appetite, significantly decreased intake of high-fat diet suggesting that GAL5.1, in addition to being epigenetically modulated by high-fat diet, also actively contributes to the consumption of high-fat diet suggesting its involvement in an environmentally influenced regulatory loop. Furthermore, considering that GAL5.1 also controls alcohol preference and anxiety these studies may provide a first glimpse into an epigenetically controlled mechanism that links maternal high-fat diet with transgenerational susceptibility to alcohol abuse and anxiety