Real-world community hospital hyperglycemia management in noncritically ill, type 2 diabetic patients: a comparison between basal-bolus insulin and correctional insulin.

Purpose: This study evaluated the safety and efficacy of two insulin regimens for inpatient hyperglycemia management: combination short-plus long-acting insulin (basal-bolus insulin regimen, BBIR) vs. short-acting insulin only (correctional insulin only regimen, CIOR). Methods: Chart reviews identified noncritically ill patients with pre-existing type 2 diabetes mellitus receiving insulin injections. Study participants (N = 138) were divided into BBIR (N = 104) and CIOR (N = 34) groups. Data for the entire duration of each patient's stay were analyzed. Results: The primary outcome of percent hyperglycemic days was higher in BBIR vs. CIOR (3.97 ± 0.33% vs. 1.22 ± 0.38%). The safety outcome of percent hypoglycemic events was not different between BBIR and CIOR (0.78 ± 0.22% vs. 0.53 ± 0.37%). Regarding secondary outcomes, the percentage of euglycemic days was lower in BBIR vs. CIOR (26.74 ± 2.97% vs. 40.98 ± 5.91%). Overall blood glucose (BG) and daily insulin dose were higher in BBIR vs. CIOR (231.43 ± 5.37 vs. 195.55 ± 6.25 mg/dL and 41.36 ± 3.07 vs. 5.02 ± 0.68 units, respectively). Insulin regimen-associated differences in hyperglycemia and daily insulin dose persisted after adjusting for covariates. Conclusion: Our observations linking BBIR to worse glycemic outcomes differ from those reported in the randomized controlled Rabbit 2 and Rabbit 2 Surgery trials. This discrepancy can be partly explained by the fact that BBIR patients displayed worse glycemic baselines. Also, there was no diabetes stewardship team to monitor BG and modify insulin therapy, which is relevant since achieving euglycemia in BBIR patients requires more dose adjustments. This study highlights challenges with standard inpatient glycemic management and calls for further research assessing the benefits of pharmacist-led diabetes stewardship.

Focused deterrence: A protocol for a realist multisite randomised controlled trial for evaluating a violence prevention intervention in the UK.

INTRODUCTION: Focused deterrence (FD) is a frequently cited intervention for preventing violence, particularly against violent urban gangs. The Youth Endowment Fund (YEF) believes it could be effective in the UK, based primarily on research conducted in the US. However, we contend that these studies have inadequate methodological designs, lack of rigorous testing, and small sample sizes. Therefore, the evidence supporting focused deterrence as an effective method, particularly outside the US, is inconclusive. The aim of the protocol is to better understand the potential effects of FD in the context of the UK, using a multisite evaluation experimental design to more closely investigate the evidence of its likely impact. METHODS: We planned a realist randomised controlled trial. The design is focused on a multisite trial consisting of two-arm randomised experiments in five locations. Each trial location will test their implementation of a core programme specified by the funder. The multisite nature will allow us to understand differential impacts between locations, improving the external validity of the results. Participants will be randomly selected from a wider pool of eligible individuals for the intervention. We estimate a sample size of approximately N = 1,700 individuals is required. Based on this pooled sample size, a relative reduction of 26% would be detectable in 80% of trials. The trial is coupled with a formative process evaluation of delivery and fidelity. The formative evaluation will use a mixed methods design. The qualitative aspect will include semi-structured cross-sectional and longitudinal interviews with programme leads, programme delivery team, and programme participants, as well as observations of the meetings between the programme delivery team (i.e., community navigators/mentors) and programme participants. The quantitative data for the formative evaluation will be gathered by the sites themselves and consist of routine outcome performance monitoring using administrative data. Sampling for interviews and observations will vary, with the researchers aiming for a higher number of individuals included in the first round of cross-sectional interviews and retaining as many as possible for repeat interviews and observations. DISCUSSION: This protocol outlines the process and impact evaluation methodology for the most extensive multisite evaluation of focused deterrence to date in the UK. Spanning five distinct sites with seven trials, the evaluation includes a cohort of 2,000 individuals, marking it as the only multisite trial of focused deterrence. Employing an integrated realist evaluation framework, the study uses qualitative and quantitative research methods. The anticipated findings will offer pivotal insights for formulating future violence prevention policies in the UK. They are also expected to contribute significantly to the corpus of literature on violence prevention and intervention evaluation. TRIAL REGISTRATION: Protocol registration: ISRCTN: 11650008 4th June 2023.

Assessment of Cold Atmospheric Pressure Plasma (CAPP) Treatment for Degradation of Antibiotic Residues in Water.

The presence of antibiotic residues in water is linked to the emergence of antibiotic resistance globally and necessitates novel decontamination strategies to minimize antibiotic residue exposure in both the environment and food. A holistic assessment of cold atmospheric pressure plasma technology (CAPP) for ß-lactam antibiotic residue removal is described in this study. CAPP operating parameters including plasma jet voltage, gas composition and treatment time were optimized, with highest ß-lactam degradation efficiencies obtained for a helium jet operated at 6 kV. Main by-products detected indicate pH-driven peroxidation as a main mechanism of CAPP-induced decomposition of ß-lactams. No in vitro hepatocytotoxicity was observed in HepG2 cells following exposure to treated samples, and E. coli exposed to CAPP-degraded ß-lactams did not exhibit resistance development. In surface water, over 50% decrease in antibiotic levels was achieved after only 5 min of treatment. However, high dependence of treatment efficiency on residue concentration, pH and presence of polar macromolecules was observed.

Antibody Responses to the SARS-CoV-2 Ancestral Strain and Omicron Variants in Moderna mRNA-1273 Vaccinated Active-Duty US Navy Sailors and Marines.

Omicron and its subvariants have steadily gained greater capability of immune escape compared to other variants of concern, resulting in an increased incidence of reinfections even among vaccinated individuals. We evaluated the antibody response to Omicron BA.1, BA.2, and BA.4/5 in US military members vaccinated with the primary 2-dose series of Moderna mRNA-1273 in a cross-sectional study. While nearly all vaccinated participants had sustained spike (S) IgG and neutralizing antibodies (ND50) to the ancestral strain, only 7.7% participants had detectable ND50 to Omicron BA.1 at 8 months postvaccination. The neutralizing antibody response to BA.2 and BA.5 was similarly reduced. The reduced antibody neutralization of Omicron correlated with the decreased antibody binding to the receptor-binding domain. The participants' seropositivity to the nuclear protein positively correlated with ND50. Our data emphasizes the need for continuous vigilance in monitoring for emerging variants and the need to identify potential alternative targets for vaccine design.

Aggregation chimeras provide evidence of in vivo intercellular correction in ovine CLN6 neuronal ceroid lipofuscinosis (Batten disease).

The neuronal ceroid lipofuscinoses (NCLs; Batten disease) are fatal, mainly childhood, inherited neurodegenerative lysosomal storage diseases. Sheep affected with a CLN6 form display progressive regionally defined glial activation and subsequent neurodegeneration, indicating that neuroinflammation may be causative of pathogenesis. In this study, aggregation chimeras were generated from homozygous unaffected normal and CLN6 affected sheep embryos, resulting in seven chimeric animals with varied proportions of normal to affected cells. These sheep were classified as affected-like, recovering-like or normal-like, based on their cell-genotype ratios and their clinical and neuropathological profiles. Neuropathological examination of the affected-like animals revealed intense glial activation, prominent storage body accumulation and severe neurodegeneration within all cortical brain regions, along with vision loss and decreasing intracranial volumes and cortical thicknesses consistent with ovine CLN6 disease. In contrast, intercellular communication affecting pathology was evident at both the gross and histological level in the normal-like and recovering-like chimeras, resulting in a lack of glial activation and rare storage body accumulation in only a few cells. Initial intracranial volumes of the recovering-like chimeras were below normal but progressively recovered to about normal by two years of age. All had normal cortical thicknesses, and none went blind. Extended neurogenesis was evident in the brains of all the chimeras. This study indicates that although CLN6 is a membrane bound protein, the consequent defect is not cell intrinsic. The lack of glial activation and inflammatory responses in the normal-like and recovering-like chimeras indicate that newly generated cells are borne into a microenvironment conducive to maturation and survival.

"Indirect development" increases reproductive plasticity and contributes to the success of scyphozoan jellyfish in the oceans.

Ecologists and evolutionary biologists have been looking for the key(s) to the success of scyphomedusae through their long evolutionary history in multiple habitats. Their ability to generate young medusae (ephyrae) via two distinct reproductive strategies, strobilation or direct development from planula into ephyra without a polyp stage, has been a potential explanation. In addition to these reproductive modes, here we provide evidence of a third ephyral production which has been rarely observed and often confused with direct development from planula into ephyra. Planulae of Aurelia relicta Scorrano et al. 2017 and Cotylorhiza tuberculata (Macri 1778) settled and formed fully-grown polyps which transformed into ephyrae within several days. In distinction to monodisk strobilation, the basal polyp of indirect development was merely a non-tentaculate stalk that dissolved shortly after detachment of the ephyra. We provide a fully detailed description of this variant that increases reproductive plasticity within scyphozoan life cycles and is different than either true direct development or the monodisk strobilation. Our observations of this pattern in co-occurrence with mono- and polydisk strobilation in Aurelia spp. suggest that this reproductive mode may be crucial for the survival of some scyphozoan populations within the frame of a bet-hedging strategy and contribute to their long evolutionary success throughout the varied conditions of past and future oceans.

SARS-CoV-2 seropositivity and subsequent infection risk in healthy young adults: a prospective cohort study.

BACKGROUND: Whether young adults who are infected with SARS-CoV-2 are at risk of subsequent infection is uncertain. We investigated the risk of subsequent SARS-CoV-2 infection among young adults seropositive for a previous infection. METHODS: This analysis was performed as part of the prospective COVID-19 Health Action Response for Marines study (CHARM). CHARM included predominantly male US Marine recruits, aged 18-20 years, following a 2-week unsupervised quarantine at home. After the home quarantine period, upon arrival at a Marine-supervised 2-week quarantine facility (college campus or hotel), participants were enrolled and were assessed for baseline SARS-CoV-2 IgG seropositivity, defined as a dilution of 1:150 or more on receptor-binding domain and full-length spike protein ELISA. Participants also completed a questionnaire consisting of demographic information, risk factors, reporting of 14 specific COVID-19-related symptoms or any other unspecified symptom, and brief medical history. SARS-CoV-2 infection was assessed by PCR at weeks 0, 1, and 2 of quarantine and participants completed a follow-up questionnaire, which included questions about the same COVID-19-related symptoms since the last study visit. Participants were excluded at this stage if they had a positive PCR test during quarantine. Participants who had three negative swab PCR results during quarantine and a baseline serum serology test at the beginning of the supervised quarantine that identified them as seronegative or seropositive for SARS-CoV-2 then went on to basic training at Marine Corps Recruit Depot-Parris Island. Three PCR tests were done at weeks 2, 4, and 6 in both seropositive and seronegative groups, along with the follow-up symptom questionnaire and baseline neutralising antibody titres on all subsequently infected seropositive and selected seropositive uninfected participants (prospective study period). FINDINGS: Between May 11, 2020, and Nov 2, 2020, we enrolled 3249 participants, of whom 3168 (98%) continued into the 2-week quarantine period. 3076 (95%) participants, 2825 (92%) of whom were men, were then followed up during the prospective study period after quarantine for 6 weeks. Among 189 seropositive participants, 19 (10%) had at least one positive PCR test for SARS-CoV-2 during the 6-week follow-up (1·1 cases per person-year). In contrast, 1079 (48%) of 2247 seronegative participants tested positive (6·2 cases per person-year). The incidence rate ratio was 0·18 (95% CI 0·11-0·28; p<0·001). Among seropositive recruits, infection was more likely with lower baseline full-length spike protein IgG titres than in those with higher baseline full-length spike protein IgG titres (hazard ratio 0·45 [95% CI 0·32-0·65]; p<0·001). Infected seropositive participants had viral loads that were about 10-times lower than those of infected seronegative participants (ORF1ab gene cycle threshold difference 3·95 [95% CI 1·23-6·67]; p=0·004). Among seropositive participants, baseline neutralising titres were detected in 45 (83%) of 54 uninfected and in six (32%) of 19 infected participants during the 6 weeks of observation (ID50 difference p<0·0001). INTERPRETATION: Seropositive young adults had about one-fifth the risk of subsequent infection compared with seronegative individuals. Although antibodies induced by initial infection are largely protective, they do not guarantee effective SARS-CoV-2 neutralisation activity or immunity against subsequent infection. These findings might be relevant for optimisation of mass vaccination strategies. FUNDING: Defense Health Agency and Defense Advanced Research Projects Agency.

A Radiographic Sizing Algorithm for Tibial Plateau Osteochondral Allografts.

OBJECTIVE: Tibial plateau osteochondral allograft transplantation is a promising treatment for symptomatic chondral damage of the proximal tibia due to a variety of etiologies. The purpose of this investigation is to develop an accurate and reproducible algorithm for sizing tibial plateau allografts based on recipient radiographs. DESIGN: A cadaveric study was performed in which radiographs of 10 fresh frozen cadaveric knees were compared to measured digital photographs of the disarticulated specimens. By comparing the average distance between standard anatomical landmarks on the radiographs to the gross specimens, a correlation factor was calculated that could be applied to recipient radiograph measurements for more accurate sizing of tibial plateau allografts. RESULTS: In the coronal plane there were no differences between the mean radiographic and mean morphologic measurements of either the medial or lateral tibial plateau. However, in the sagittal plane the anatomic specimens of the medial and lateral plateau were 90% and 80%, respectively, of the measurements made from the lateral radiograph. CONCLUSIONS: This cadaveric investigation is the first to propose a sizing algorithm for tibial plateau osteochondral allografts. Based on the results, an anteroposterior radiograph can reliably measure the width of both the medial and lateral tibial plateau without any correction needed. The average morphological lengths of the medial and lateral tibial plateau, on the other hand, were found to be 90% and 80%, respectively, of the radiographically measured lengths. Without correction, this would lead to the implantation of oversized grafts that may contribute to early failure.

SARS-CoV-2 Transmission among Marine Recruits during Quarantine.

BACKGROUND: The efficacy of public health measures to control the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has not been well studied in young adults. METHODS: We investigated SARS-CoV-2 infections among U.S. Marine Corps recruits who underwent a 2-week quarantine at home followed by a second supervised 2-week quarantine at a closed college campus that involved mask wearing, social distancing, and daily temperature and symptom monitoring. Study volunteers were tested for SARS-CoV-2 by means of quantitative polymerase-chain-reaction (qPCR) assay of nares swab specimens obtained between the time of arrival and the second day of supervised quarantine and on days 7 and 14. Recruits who did not volunteer for the study underwent qPCR testing only on day 14, at the end of the quarantine period. We performed phylogenetic analysis of viral genomes obtained from infected study volunteers to identify clusters and to assess the epidemiologic features of infections. RESULTS: A total of 1848 recruits volunteered to participate in the study; within 2 days after arrival on campus, 16 (0.9%) tested positive for SARS-CoV-2, 15 of whom were asymptomatic. An additional 35 participants (1.9%) tested positive on day 7 or on day 14. Five of the 51 participants (9.8%) who tested positive at any time had symptoms in the week before a positive qPCR test. Of the recruits who declined to participate in the study, 26 (1.7%) of the 1554 recruits with available qPCR results tested positive on day 14. No SARS-CoV-2 infections were identified through clinical qPCR testing performed as a result of daily symptom monitoring. Analysis of 36 SARS-CoV-2 genomes obtained from 32 participants revealed six transmission clusters among 18 participants. Epidemiologic analysis supported multiple local transmission events, including transmission between roommates and among recruits within the same platoon. CONCLUSIONS: Among Marine Corps recruits, approximately 2% who had previously had negative results for SARS-CoV-2 at the beginning of supervised quarantine, and less than 2% of recruits with unknown previous status, tested positive by day 14. Most recruits who tested positive were asymptomatic, and no infections were detected through daily symptom monitoring. Transmission clusters occurred within platoons. (Funded by the Defense Health Agency and others.).

Combined deletion of Glut1 and Glut3 impairs lung adenocarcinoma growth.

Glucose utilization increases in tumors, a metabolic process that is observed clinically by 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET). However, is increased glucose uptake important for tumor cells, and which transporters are implicated in vivo? In a genetically-engineered mouse model of lung adenocarcinoma, we show that the deletion of only one highly expressed glucose transporter, Glut1 or Glut3, in cancer cells does not impair tumor growth, whereas their combined loss diminishes tumor development. 18F-FDG-PET analyses of tumors demonstrate that Glut1 and Glut3 loss decreases glucose uptake, which is mainly dependent on Glut1. Using 13C-glucose tracing with correlated nanoscale secondary ion mass spectrometry (NanoSIMS) and electron microscopy, we also report the presence of lamellar body-like organelles in tumor cells accumulating glucose-derived biomass, depending partially on Glut1. Our results demonstrate the requirement for two glucose transporters in lung adenocarcinoma, the dual blockade of which could reach therapeutic responses not achieved by individual targeting.

Smoking-associated interstitial lung disease: update and review.

INTRODUCTION: Smoking-associated interstitial lung disease manifests as several heterogeneous disorders involving the airways, pleura, and lung parenchyma with various radiological patterns. The clinical history, radiologic, and pathologic findings are important to distinguish these more uncommon diseases. A multidisciplinary approach is recommended for diagnosis and to manage these conditions appropriately. AREAS COVERED: This review provides an overview of the epidemiology, risk factors, pathogenesis, clinical features, diagnosis, and treatment of acute eosinophilic pneumonia, e-cigarettes, or vaping associated lung injury, respiratory bronchiolitis interstitial lung disease, desquamative interstitial pneumonitis, pulmonary Langerhans cell histiocytosis, idiopathic pulmonary fibrosis, and combined pulmonary fibrosis emphysema. EXPERT OPINION: Cigarette smoking is associated with a variety of pathologic conditions that affect the airways and lungs. E-cigarette use and vaping present new challenges to the clinician. Consensus between the clinical, radiographic, and pathologic findings is important in identifying and differentiating between the various entities to properly diagnose smoking-related interstitial lung diseases discussed in this review.

Dysfunction of homeostatic control of dopamine by astrocytes in the developing prefrontal cortex leads to cognitive impairments.

Astrocytes orchestrate neural development by powerfully coordinating synapse formation and function and, as such, may be critically involved in the pathogenesis of neurodevelopmental abnormalities and cognitive deficits commonly observed in psychiatric disorders. Here, we report the identification of a subset of cortical astrocytes that are competent for regulating dopamine (DA) homeostasis during postnatal development of the prefrontal cortex (PFC), allowing for optimal DA-mediated maturation of excitatory circuits. Such control of DA homeostasis occurs through the coordinated activity of astroglial vesicular monoamine transporter 2 (VMAT2) together with organic cation transporter 3 and monoamine oxidase type B, two key proteins for DA uptake and metabolism. Conditional deletion of VMAT2 in astrocytes postnatally produces loss of PFC DA homeostasis, leading to defective synaptic transmission and plasticity as well as impaired executive functions. Our findings show a novel role for PFC astrocytes in the DA modulation of cognitive performances with relevance to psychiatric disorders.

Author Correction: Identification of Exo1-Msh2 interaction motifs in DNA mismatch repair and new Msh2-binding partners.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Frequency-dependent impedance and surface waves on the boundary of a stratified dielectric medium.

We analyse waves propagating along the interface between half-spaces filled with a perfect dielectric and a Lorentz material. We show that the corresponding interface condition leads to a generalization of the classical Leontovich condition on the boundary of a dielectric half-space. We study when this condition supports propagation of (dispersive) surface waves. We derive the related dispersion relation for waves along the boundary of a stratified half-space and determine the relationship between the loss parameter, frequency and wavenumber for which interfacial waves exist. This article is part of the theme issue 'Modelling of dynamic phenomena and localization in structured media (part 1)'.

Atmospheric pressure non-thermal plasma exposure reduces Pseudomonas aeruginosa lipopolysaccharide toxicity in vitro and in vivo.

Lipopolysaccharide (LPS) is an endotoxin composed of a polysaccharide and lipid component. It is intrinsically responsible for the pathogenicity of Gram-negative bacteria and is involved in the development of bacterial sepsis. Atmospheric pressure non-thermal plasma is proposed as a potential new approach for the treatment of infected tissue such as chronic wounds, with both antibacterial and wound-healing activities extensively described. Using both the RAW264.7 murine macrophage cell line in vitro assays and the Galleria mellonella insect in vivo toxicity model, the effect non-thermal plasma exposure on LPS-mediated toxicity has been characterised. Short (60 s) non-thermal plasma exposures of Pseudomonas aeruginosa conditioned growth media, membrane lysates and purified P. aeruginosa LPS, resulted in a substantial detoxification and reduction of LPS-induced cytotoxicity in RAW264.7 murine macrophages. Non-thermal plasma exposure (60 s) of purified P. aeruginosa LPS led to a significant (p < 0.05) improvement in the G. mellonella health index (GHI) score, a measure of in vivo toxicity. These findings demonstrate the ability of short plasma exposures to significantly reduce LPS-induced cytotoxicity both in vitro and in vivo; attenuating the toxicity of this important virulence factor intrinsic to the pathogenicity of Gram-negative bacteria.

A holistic study to understand the detoxification of mycotoxins in maize and impact on its molecular integrity using cold atmospheric plasma treatment.

The need for safe and quality food, free from the presence of hazardous contaminants such as mycotoxins is an on-going and complex challenge. Cold atmospheric pressure plasma (CAPP) has the potential to contribute to achieving this goal. Decontamination efficacy of CAPP against six of the most common mycotoxins found in foods and feedstuffs was assessed herein. Concentration reduction of up to 66% was achieved in maize for both aflatoxin B1 and fumonisin B1. Degradation products were detected only in the case of aflatoxin B1 and zearalenone and were tested on human hepatocarcinoma cells with no increase in cytotoxicity observed. Analysis of treated maize revealed substantial changes to small molecular mass components of the matrix. While CAPP shows promise in terms of mycotoxin detoxification important questions concerning potential changes to the nutritional and safety status of the food matrix require further investigations.

Neurophysiological Characterization of a Non-Human Primate Model of Traumatic Spinal Cord Injury Utilizing Fine-Wire EMG Electrodes.

This study aims to characterize traumatic spinal cord injury (TSCI) neurophysiologically using an intramuscular fine-wire electromyography (EMG) electrode pair. EMG data were collected from an agonist-antagonist pair of tail muscles of Macaca fasicularis, pre- and post-lesion, and for a treatment and control group. The EMG signals were decomposed into multi-resolution subsets using wavelet transforms (WT), then the relative power (RP) was calculated for each individual reconstructed EMG sub-band. Linear mixed models were developed to test three hypotheses: (i) asymmetrical volitional activity of left and right side tail muscles (ii) the effect of the experimental TSCI on the frequency content of the EMG signal, (iii) and the effect of an experimental treatment. The results from the electrode pair data suggested that there is asymmetry in the EMG response of the left and right side muscles (p-value < 0.001). This is consistent with the construct of limb dominance. The results also suggest that the lesion resulted in clear changes in the EMG frequency distribution in the post-lesion period with a significant increment in the low-frequency sub-bands (D4, D6, and A6) of the left and right side, also a significant reduction in the high-frequency sub-bands (D1 and D2) of the right side (p-value < 0.001). The preliminary results suggest that using the RP of the EMG data, the fine-wire intramuscular EMG electrode pair are a suitable method of monitoring and measuring treatment effects of experimental treatments for spinal cord injury (SCI).

NANETS/SNMMI Procedure Standard for Somatostatin Receptor-Based Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE.

With the recent approval of 177Lu-DOTATATE for use in gastroenteropancreatic neuroendocrine tumors, access to peptide receptor radionuclide therapy is increasing. Representatives from the North American Neuroendocrine Tumor Society and the Society of Nuclear Medicine and Molecular Imaging collaborated to develop a practical consensus guideline for the administration of 177Lu-DOTATATE. In this paper, we discuss patient screening, maintenance somatostatin analog therapy requirements, treatment location and room preparation, drug administration, and patient release as well as strategies for radiation safety, toxicity monitoring, management of potential complications, and follow-up. Controversies regarding the role of radiation dosimetry are discussed as well. This document is designed to provide practical guidance on how to safely treat patients with this therapy.

Rehabilitation doxa and practitioner judgment. An analysis of symbolic violence on health care provision in the Scottish prison system.

This paper presents an analysis of the symbolic conditions which govern health care provision in the Scottish prison system. The paper considers the wider context of Scottish prisons, where health care provision follows a similar structure both in juvenile and adult prisons. Our intention is to provoke a debate about the doxa (Bourdieu, 1977), which underlies decision making in respect of health care in prison, in a political environment where pragmatism, allied to the 'pathologisation' of social policies, health and criminal justice has been a hegemonic force.

The properties of Msh2-Msh6 ATP binding mutants suggest a signal amplification mechanism in DNA mismatch repair.

DNA mismatch repair (MMR) corrects mispaired DNA bases and small insertion/deletion loops generated by DNA replication errors. After binding a mispair, the eukaryotic mispair recognition complex Msh2-Msh6 binds ATP in both of its nucleotide-binding sites, which induces a conformational change resulting in the formation of an Msh2-Msh6 sliding clamp that releases from the mispair and slides freely along the DNA. However, the roles that Msh2-Msh6 sliding clamps play in MMR remain poorly understood. Here, using Saccharomyces cerevisiae, we created Msh2 and Msh6 Walker A nucleotide-binding site mutants that have defects in ATP binding in one or both nucleotide-binding sites of the Msh2-Msh6 heterodimer. We found that these mutations cause a complete MMR defect in vivo The mutant Msh2-Msh6 complexes exhibited normal mispair recognition and were proficient at recruiting the MMR endonuclease Mlh1-Pms1 to mispaired DNA. At physiological (2.5 mm) ATP concentration, the mutant complexes displayed modest partial defects in supporting MMR in reconstituted Mlh1-Pms1-independent and Mlh1-Pms1-dependent MMR reactions in vitro and in activation of the Mlh1-Pms1 endonuclease and showed a more severe defect at low (0.1 mm) ATP concentration. In contrast, five of the mutants were completely defective and one was mostly defective for sliding clamp formation at high and low ATP concentrations. These findings suggest that mispair-dependent sliding clamp formation triggers binding of additional Msh2-Msh6 complexes and that further recruitment of additional downstream MMR proteins is required for signal amplification of mispair binding during MMR.