Comorbidities Associated with Worse Outcomes Among Inpatients Admitted for Acute Gastrointestinal Bleeding.

BACKGROUND: Multimorbidity increases healthcare resource utilization. Little is known on specific comorbidity combinations. AIMS: To identify comorbidities associated with increased resource utilization among inpatients admitted for gastrointestinal bleeding (GIB). METHODS: This retrospective cross-sectional study, 1/2010-5/2018 at the University Hospital Zurich, Switzerland, analyzed electronic health records of patients with upper (UGIB) and lower (LGIB) GIB, focusing on length of stay (LOS) and 30-day readmissions for resource use and clinical outcomes, investigated by multivariable regression adjusted for antithrombotics. RESULTS: Of 1101 patients, 791 had UGIB and 310 LGIB, most often melena and bleeding diverticula, respectively. In UGIB, thromboembolic events showed a trend toward 27% increased LOS (1.27; 95% confidence interval [CI] 1.00-1.61), antithrombotics independently associated with 46% increased LOS (1.46; 95% CI 1.32-1.62). Cancer (odds ratio [OR] 2.86; 95% CI 1.68-4.88) independently associated with 30-day readmissions, anemia showed a trend (OR 1.68; 95% CI 1.00-2.84). In LGIB, none of the investigated comorbidities associated with increased LOS, but antithrombotics independently associated with 25% increased LOS (1.25; 95% CI 1.07-1.46). Atrial fibrillation/flutter (OR 2.69; 95% CI 1.06-6.82) and cancer (OR 4.76; 95% CI 1.40-16.20) associated strongly with 30-day readmissions. CONCLUSIONS: In both groups, cancer associated with 30-day readmissions, antithrombotics with increased LOS. Thromboembolic events and anemia showed clinically important trends in UGIB. Atrial fibrillation/flutter associated with 30-day readmissions in LGIB. Prospective studies are needed to investigate these complex multimorbid populations and establish appropriate guidelines.

Embedded research: a promising way to create evidence-informed impact in public health?

Background: Embedded research (ER) is recognized as one way to strengthen the integration of evidence into public health (PH) practice. In this paper, we outline a promising example of the co-production of research evidence between Fuse, the UKCRC Centre for Translational Research in Public Health and a local authority (LA) in north east England. Methods: We critically examine attempts to share and use research findings to influence decision-making in a LA setting, drawing on insights from PH practitioners, managers, commissioners and academic partners involved in this organizational case study. We highlight what can be achieved as a co-located embedded researcher. Results: The benefits and risks of ER are explored, alongside our reflections on the added value of this approach and the institutional prerequisites necessary for it to work. We argue that while this is not a new methodological approach, its application in PH as a way to facilitate evidence use is novel, and raises pragmatic and theoretical questions about the nature of impact and the extent to which it can be engineered. Conclusion: With increased situated understanding of organizational culture and norms and greater awareness of the socio-political realities of PH, ER enables new co-produced solutions to become possible.

"It was the whole picture" a mixed methods study of successful components in an integrated wellness service in North East England.

BACKGROUND: A growing number of Local Authorities (LAs) have introduced integrated wellness services as part of efforts to deliver cost effective, preventive services that address the social determinants of health. This study examined which elements of an integrated wellness service in the north east of England were effective in improving health and wellbeing (HWB). METHODS: The study used a mixed-methods approach. In-depth semi-structured interviews (IVs) were conducted with integrated wellness service users (n = 25) and focus groups (FGs) with group based service users (n = 14) and non-service users (n = 23) to gather the views of stakeholders. Findings are presented here alongside analysis of routine monitoring data. The different data were compared to examine what each data source revealed about the effectiveness of the service. RESULTS: Findings suggest that integrated wellness services work by addressing the social determinants of health and respond to multiple complex health and social concerns rather than single issues. The paper identifies examples of 'active ingredients' at the heart of the programme, such as sustained relationships, peer support and confidence building, as well as the activities through which changes take place, such as sports and leisure opportunities which in turn encourage social interaction. Wider wellbeing outcomes, including reduced social isolation and increased self-efficacy are also reported. Practical and motivational support helped build community capacity by encouraging community groups to access funding, helped navigate bureaucratic systems, and promoted understanding of marginalised communities. Fully integrated wellness services could support progression opportunities through volunteering and mentoring. CONCLUSIONS: An integrated wellness service that offers a holistic approach was valued by service users and allowed them to address complex issues simultaneously. Few of the reported health gains were captured in routine data. Quantitative and qualitative data each offered a partial view of how effectively services were working.

'It is not a quick fix' structural and contextual issues that affect implementation of integrated health and well-being services: a qualitative study from North East England.

OBJECTIVE: The objective of this article is to examine the factors affecting the design, commissioning and delivery of integrated health and well-being services (IHWSs), which seek to address multiple health-related behaviours, improve well-being and tackle health inequalities using holistic approaches. STUDY DESIGN: Qualitative studies embedded within iterative process evaluations. METHODS: Semi-structured interviews conducted with 16 key informants as part of two separate evaluations of IHWSs in North East England, supplemented by informal observations of service delivery. Transcripts and fieldnotes were analysed thematically. RESULTS: The study findings identify a challenging organisational context in which to implement innovative service redesign, as a result of budget cuts and changes in NHS and local authority capacity. Pressures to demonstrate outcomes affected the ability to negotiate the practicalities of joint working. Progress is at risk of being undermined by pressures to disinvest before the long-term benefits to population health and well-being are realised. The findings raise important questions about contract management and relationships between commissioners and providers involved in implementing these new ways of working. CONCLUSIONS: These findings provide useful learning in terms of the delivery and commissioning of similar IHWSs, contributing to understanding of the benefits and challenges of this model of working.

[Multimorbidity management and the physician's daily clinical dilemma]. / Multimorbiditätsmanagement im Alltagsdilemma.

About 20-25% of all persons and about 90% of all patients who are acutely hospitalized in internal medicine departments have multiple acute or chronic diseases. They are multimorbid. The encounter with multimorbid patients has become the most common situation in the health care system. Theoretically, multimorbidity results in an innumerable potential disease constellations. In addition, the likelihood of interactions between diseases (disease-disease interactions, DDI) and the complexity increases overproportionately with each additional disease. However, multimorbidity often occurs in typical diadic, triadic, or higher characteristic combinations, in "disease clusters", e. g., vascular risk factors, heart and lung diseases, Frailty and dementia, psychiatric and somatic disorders. Such combinations lead to a worsening of the overall prognosis. In addition, DDIs are often difficult to treat or are life-threatening. Examples of DDIs include the following: anticoagulation and simultaneous severe bleeding, pain treatment and hypertension or renal insufficiency, depression and reduced medication adherence, chronic obstructive pulmonary disease and depression, Frailty and neurodepressant drugs and frequent falls, and combined psychiatric and somatic disorders. Such DDIs are common. Nevertheless, there are few studies and clinical guidelines that address these issues. The care of multimorbid patients is, therefore, heavily reliant upon guidelines developed mostly for single diseases. However, multimorbidity and serious DDIs are usually not addressed in these. Clinical guidelines can thus inadvertently jeopardize the safety of persons suffering from multiple diseases. In addition, stressful dilemmas arise for physicians encountering DDIs because of difficult treatment decisions.

Association of day-case rates with post COVID-19 recovery of elective laparoscopic cholecystectomy activity across England.

INTRODUCTION: The aim of this study was to investigate the safety of day-case laparoscopic cholecystectomy, and the association between day-case rates and, post the COVID-19 pandemic, recovery of activity to prepandemic levels for integrated care boards (ICBs) in England. METHODS: This was a retrospective observational study of the Hospital Episodes Statistics (HES) data set. Elective laparoscopic cholecystectomies for the period 1 January 2019 to 31 December 2022 were identified. Activity levels for 2022 were compared with those for the whole of 2019 (baseline). Day-case activity was identified where the length of stay recorded in the HES was zero days. RESULTS: Data were available for 184,252 patients across the 42 ICBs in England, of which 120,408 (65.3%) were day-case procedures. By December 2022, activity levels for the whole of England had returned to 88.2% of prepandemic levels. The South West region stood out as having recovered activity levels to the greatest extent, with activity at 97.3% of prepandemic levels during 2022. The South West also had the highest postpandemic day-case rate at 74.9% of all patients seen as a day-case during 2022; this compares with an England average of 65.3%. At an ICB level, there was a significant correlation between day-case rates and postpandemic activity levels (r = 0.362, p = 0.019). There was no strong or consistent evidence that day-case surgery had poorer patient outcomes than inpatient surgery. CONCLUSIONS: Recovery of elective laparoscopic cholecystectomy activity has been better in South West England than in other regions. Increasing day-case rates may be important if ICBs in other regions are to increase activity levels up to and beyond prepandemic levels.

Factors associated with conversion from day-case to in-patient elective inguinal hernia repair surgery across England: an observational study using administrative data.

PURPOSE: Elective primary inguinal hernia repair surgery is increasingly being conducted as a day-case procedure. However, some patients planned for day-case surgery have to stay in hospital for at least one night. The aim of this study was to identify the factors associated with conversion from day-case to in-patient management for elective inguinal hernia repair surgery. METHODS: This was an exploratory retrospective analysis of observational data from the Hospital Episode Statistics dataset for England. All patients aged ≥ 17 years undergoing a first elective inguinal hernia repair between 1st April 2014 and 31st March 2022 that was planned as day-case surgery were identified. The exposure of interest was discharged on the day of admission (day-case) or requiring overnight stay. The primary outcome of interest was 30-day emergency readmission with an overnight stay. For reporting, providers were aggregated to an Integrated Care Board (ICB) level. RESULTS: A total of 351,528 planned day-case elective primary inguinal hernia repairs were identified over the eight-year study period. Of these, 45,305 (12.9%) stayed in hospital for at least one night and were classed as day-case to in-patient stay conversions. Patients who converted to in-patient stay were older, had more comorbidities, and were more likely to have bilateral surgery and be operated on by a low-annual volume surgeon. Post-procedural complications were strongly associated with conversion. Across the 42 ICBs in England, model-adjusted conversion rates varied from 3.3% to 21.3%. CONCLUSIONS: There was considerable variation in conversion to in-patient stay rates for inguinal hernia repair across ICBs in England. Our findings should help surgical teams to better identify patients suitable for day-case inguinal hernia repair and plan discharge services more effectively. This should help to reduce the variation in conversion rates.

Day-case and in-patient elective inguinal hernia repair surgery across England: an observational study of variation and outcomes.

PURPOSE: Elective primary inguinal hernia repair surgery is increasingly being conducted as a day-case procedure. However, in England there is evidence of wide variation in day-case rates across hospitals. Reducing the extent of this variation has the potential to support more efficient use of resources (e.g., clinician time, hospital beds) and help the recovery of elective surgical activity following the COVID-19 pandemic. The aims of this study were to explore the extent of variation in day-case rates across healthcare providers in England and to evaluate the safety of day-case elective primary inguinal hernia repair surgery. METHODS: This was an exploratory, retrospective analysis of observational data from the Hospital Episode Statistics data set for England. All patients aged ≥ 17 years undergoing a first elective inguinal hernia repair between 1st April 2014 and 31st March 2022 were identified. The exposure of interest was day-case or in-patient stay, and the primary outcome of interest was 30-day emergency readmission with an overnight stay. For reporting, providers were aggregated to an Integrated Care Board (ICB) level. RESULTS: A total of 413,059 elective primary inguinal hernia repairs were identified over the 8-year study period. Of these, 326,833 (79.1%) were day-case procedures. During the most recent financial year (2021-22), the highest day-case rate for an ICB was 93.8% and the lowest 66.1%. After adjusting for covariates, day-case surgery was associated with significantly lower rates of 30-day emergency readmission (odds ratio (OR) 0.61, 95% confidence interval (CI) 0.58-0.64, p < 0.001) and for the secondary outcomes 180-day mortality and haemorrhage, infection and pain at 30-day post-discharge. Rates of 30-day emergency readmission were significantly lower in ICBs with high rates of day-case surgery (OR 0.84, 95% CI 0.74-0.96, p < 0.001) than in ICBs with low rates of day-case surgery, although rates of post-procedural haemorrhage within 30 days of discharge were significantly higher in trusts with high day-case rates (OR 1.20, 95% CI 1.04-1.40, p = 0.015). CONCLUSIONS: For the outcomes studied, we found no consistent evidence that day-case elective inguinal hernia repair was unsafe for selected patients. Currently, there is substantial variation between ICBs in terms of delivering day-case surgery. Reducing this variability may help address the current pressures on the NHS in elective surgery.

Eupatilin improves cilia defects in human CEP290 ciliopathy models.

The photoreceptor outer segment is a highly specialized primary cilium essential for phototransduction and vision. Biallelic pathogenic variants in the cilia-associated gene CEP290 cause non-syndromic Leber congenital amaurosis 10 (LCA10) and syndromic diseases, where the retina is also affected. While RNA antisense oligonucleotides and gene editing are potential treatment options for the common deep intronic variant c.2991+1655A>G in CEP290 , there is a need for variant-independent approaches that could be applied to a broader spectrum of ciliopathies. Here, we generated several distinct human models of CEP290 -related retinal disease and investigated the effects of the flavonoid eupatilin as a potential treatment. Eupatilin improved cilium formation and length in CEP290 LCA10 patient-derived fibroblasts, in gene-edited CEP290 knockout (CEP290 KO) RPE1 cells, and in both CEP290 LCA10 and CEP290 KO iPSCs-derived retinal organoids. Furthermore, eupatilin reduced rhodopsin retention in the outer nuclear layer of CEP290 LCA10 retinal organoids. Eupatilin altered gene transcription in retinal organoids, by modulating the expression of rhodopsin, and by targeting cilia and synaptic plasticity pathways. This work sheds light into the mechanism of action of eupatilin, and supports its potential as a variant-independent approach for CEP290 -associated ciliopathies.

Mobilisation, alteration, and redistribution of monosulfidic sediments in inland river systems.

The accumulation of monosulfidic sediments in inland waterways is emerging as a major environmental issue. Mobilisation and suspension of monosulfidic sediments can result in deoxygenation, acidification of the water column and mobilisation of trace metals. The controls on monosulfidic sediment mobilisation and the critical thresholds for its scour and entrainment have not been established. This study examines the effect of a minor flood event (average return interval of 5 years) on sulfidic sediment scour in the Wakool River in southern NSW, Australia. Five profiles were sampled within a small (~300 m) reach before and after a minor flood event to determine the degree of sediment scour and transport. The results indicate substantial scour of both monosulfidic sediments and underlying bed sediments (approximately 2100 m(3)). Changes in the sediment geochemistry suggest large concentrations of monosulfidic sediments had been suspended in the water column, partially-oxidised and redeposited. This is supported by (210)Pb results from one of the profiles. These results suggest that these monosulfidic sediments can move as bed load during minor flood events.

Parallel processing in human visual cortex revealed through the influence of their neural responses on the visual evoked potential.

The neural response in the human visual system is composed of magno-, parvo- and koniocellular input from the retina. Signal differences from functional imaging between health and individuals with a cognitive weakness are attributed to a dysfunction of a specific retinal input. Yet, anatomical interconnections within the human visual system obscure individual contribution to the neural response in V1. Deflections in the visual evoked potential (VEP) arise from an interaction between electric dipoles, their strength determined by the size of the neural population active during temporal - and spatial luminance contrast processing. To investigate interaction between these neural responses, we recorded the VEP over visual cortex of 14 healthy adults viewing four series of windmill patterns. Within a series, the relative area white in a pattern varied systematically. Between series, the number of sectors across which this area was distributed doubled. These patterns were viewed as pattern alternating and on-/off stimuli. P100/P1 amplitude increased linearly with the relative area white in the pattern, while N135/N1 and P240/P2 amplitude increased with the number of sectors of which the area white was distributed. The decreases P100 amplitude with increasing number of sectors is attributed to an interaction between electric dipoles located in granular and supragranular layers of V1. Differences between the VEP components obtained during a pattern reversing display and following pattern onset are accounted for by the transient and sustained nature of neural responses processing temporal - and spatial luminance contrast and ability of these responses to manifest in the VEP.

Depression is independently associated with increased length of stay and readmissions in multimorbid inpatients.

BACKGROUND: Little is known about the impact of depression across a broad range of multimorbid patients hospitalized for reasons other than depression. The objective of the study was to investigate in a large sample of multimorbid inpatients whether ancillary depression is associated with increased length of stay (LOS) and readmissions, two important clinical outcomes with implications for healthcare utilization and costs. METHODS: We retrospectively analyzed a cohort of 253,009 multimorbid inpatients aged ≥18 at an academic medical center, 8/2009-8/2017. PRIMARY OUTCOME: LOS. SECONDARY OUTCOMES: LOS related to different main diagnoses, readmissions within 1, 3, 6, 12, and 24-months after discharge. RESULTS: Multivariable linear regression showed 24% longer LOS in patients with ancillary depression (1.24; 95% confidence interval [CI]: 1.22, 1.25). Females stayed 22% longer (1.22; 95% CI: 1.20, 1.25), males 24% (1.24; 95% CI: 1.22, 1.27). We identified 16 main diagnosis clusters in which ancillary depression was associated with significant LOS increases, with associations being strongest for "Failure and rejection of transplanted organs and tissues", "Other noninfective gastroenteritis and colitis", and "Other soft tissue disorders, not elsewhere classified". Multivariable logistic and Poisson regression showed independent associations of ancillary depression with increased readmission odds and frequencies at 1, 3, 6, 12, and 24 months. CONCLUSIONS: Ancillary depression was independently associated with increased LOS and more readmissions across a broad range of multimorbid inpatients.

DnaJB6 is present in the core of Lewy bodies and is highly up-regulated in parkinsonian astrocytes.

DnaJ/Hsp40 chaperones determine the activity of Hsp70s by stabilizing their interaction with substrate proteins. We have predicted, based on the in silico analysis of a brain-derived whole-genome transcriptome data set, an increased expression of DnaJ/Hsp40 homologue, subfamily B, member 6 (DnaJB6) in Parkinson's disease (PD; Moran et al. [2006] Neurogenetics 7:1-11). We now show that DnaJB6 is a novel component of Lewy bodies (LBs) in both PD substantia nigra and PD cortex and that it is strongly up-regulated in parkinsonian astrocytes. The presence of DnaJB6 in the center of LBs suggests an early and direct involvement of this chaperone in the neuronal disease process associated with PD. The strong concomitant expression of DnaJB6 in astrocytes emphasizes the involvement of glial cells in PD and could indicate a route for therapeutic intervention. Extracellular alpha-synuclein originating from intravesicular alpha-synuclein is prone to aggregation and the potential source of extracellular aggregates (Lee [2008] J. Mol. Neurosci. 34:17-22). The observed strong expression of DnaJB6 by astrocytes could reflect a protective reaction, so reducing the neuronal release of toxic alpha-synuclein and supporting the astrocyte response in PD might limit the progression of the disease process.

Homocysteine-induced endoplasmic reticulum protein (herp) is up-regulated in parkinsonian substantia nigra and present in the core of Lewy bodies.

BACKGROUND: Recent studies highlight the role of endoplasmic reticulum (ER) stress and aberrant protein degradation in the pathogenesis of neurodegenerative disorders. Herp which is encoded by the HERPUD 1 (homocysteine-inducible, endoplasmic reticulum stress-inducible, ubiquitin-like domain member 1) gene is a stress-response protein localized in the ER membrane of neurons and other cell types. Herp has been suggested to improve ER-folding, decrease ER protein load, and participate in ER-associated degradation (ERAD) of proteins. METHODS: Based on microarray expression profiling results we have predicted an increased expression of HERPUD1 in the substantia nigra of Parkinson's disease (PD) patients. We have now used brain tissue of some of the same and additional cases of sporadic PD to localize Herp mRNA and protein in individual cell types. RESULTS: We found expression of Herp in neurons and in glial cells including astrocytes. These findings were corroborated by in situ hybridization. Accumulation of Herp protein was also detected in the core of Lewy bodies suggesting a role in their formation. Hierarchical clustering analysis identified TWINKLE (PEO1) as the gene whose expression profile was most similar to that of Herp across the PD cohort. CONCLUSIONS: The nigral glial cells that expressed Herp at a high level resembled TUNEL-positive glia. While some of these cells likely undergo degeneration, the strong up-regulation of Herp in glia could help to explain the inflammation-like changes observed in PD ("neuroinflammation") as it has been shown that the unfolded protein response serves as an important regulator of inflammatory genes in other organs.

Hsp40 Molecules That Target to the Ubiquitin-proteasome System Decrease Inclusion Formation in Models of Polyglutamine Disease.

We studied the ability of heat shock, DnaJ-like-1 (HSJ1) proteins (which contain DnaJ and ubiquitin-interacting motifs) to reduce polyglutamine-mediated inclusion formation. The experiments demonstrated that expression of heat shock protein 70 (hsp70), hsp40, HSJ1a, and HSJ1b significantly reduced protein inclusion formation in a model of spinal and bulbar muscular atrophy (SBMA). HSJ1a also mediated a significant decrease in the number of inclusions formed in a primary neuronal model of protein aggregation. Studies to elucidate the mechanisms underlying these reductions showed that hsp70 and hsp40 increased chaperone-mediated refolding. In contrast, expression of HSJ1 proteins did not promote chaperone activity but caused an increase in ubiquitylation. Furthermore, HSJ1a was associated with a ubiquitylated luciferase complex, and in the presence of HSJ1a but not an HSJ1a UIM mutant (HSJ1a-ΔUIM) there was a reduction in luciferase protein levels. Together these results show that HSJ1 proteins mediated an increase in target protein degradation via the ubiquitin-proteasome system (UPS). We also found that the expression of HSJ1a significantly decreased the number of neurons containing inclusions in an in vivo model of polyglutamine disease. These findings indicate that targeted modification of the UPS to facilitate degradation of misfolded proteins may represent a highly effective therapeutic avenue for the treatment of polyglutamine disease.

Urea-mediated anomalous diffusion in supported lipid bilayers.

Diffusion in biological membranes is seldom simply Brownian motion; instead, the rate of diffusion is dependent on the time scale of observation and so is often described as anomalous. In order to help better understand this phenomenon, model systems are needed where the anomalous diffusion of the lipid bilayer can be tuned and quantified. We recently demonstrated one such model by controlling the excluded area fraction in supported lipid bilayers (SLBs) through the incorporation of lipids derivatized with polyethylene glycol. Here, we extend this work, using urea to induce anomalous diffusion in SLBs. By tuning incubation time and urea concentration, we produce bilayers that exhibit anomalous behaviour on the same scale as that observed in biological membranes.

A novel missense mutation in HSF4 causes autosomal-dominant congenital lamellar cataract in a British family.

PurposeInherited cataract, opacification of the lens, is the most common worldwide cause of blindness in children. We aimed to identify the genetic cause of isolated autosomal-dominant lamellar cataract in a five-generation British family.MethodsWhole exome sequencing (WES) was performed on two affected individuals of the family and further validated by direct sequencing in family members.ResultsA novel missense mutation NM_001040667.2:c.190A>G;p.K64E was identified in the DNA-binding-domain of heat-shock transcription factor 4 (HSF4) and found to co-segregate with disease.ConclusionWe have identified a novel mutation in HSF4 in a large British pedigree causing dominant congenital lamellar cataract. This is the second mutation in this gene found in the British population. This mutation is likely to be dominant negative and affect the DNA-binding affinity of HSF4.

Cytosolic and ER J-domains of mammalian and parasitic origin can functionally interact with DnaK.

Both prokaryotic and eukaryotic cells contain multiple heat shock protein 40 (Hsp40) and heat shock protein 70 (Hsp70) proteins, which cooperate as molecular chaperones to ensure fidelity at all stages of protein biogenesis. The Hsp40 signature domain, the J-domain, is required for binding of an Hsp40 to a partner Hsp70, and may also play a role in the specificity of the association. Through the creation of chimeric Hsp40 proteins by the replacement of the J-domain of a prokaryotic Hsp40 (DnaJ), we have tested the functional equivalence of J-domains from a number of divergent Hsp40s of mammalian and parasitic origin (malarial Pfj1 and Pfj4, trypanosomal Tcj3, human ERj3, ERj5, and Hsj1, and murine ERj1). An in vivo functional assay was used to test the functionality of the chimeric proteins on the basis of their ability to reverse the thermosensitivity of a dnaJ cbpA mutant Escherichia coli strain (OD259). The Hsp40 chimeras containing J-domains originating from soluble (cytosolic or endoplasmic reticulum (ER)-lumenal) Hsp40s were able to reverse the thermosensitivity of E. coli OD259. In all cases, modified derivatives of these chimeric proteins containing an His to Gln substitution in the HPD motif of the J-domain were unable to reverse the thermosensitivity of E. coli OD259. This suggested that these J-domains exerted their in vivo functionality through a specific interaction with E. coli Hsp70, DnaK. Interestingly, a Hsp40 chimera containing the J-domain of ERj1, an integral membrane-bound ER Hsp40, was unable to reverse the thermosensitivity of E. coli OD259, suggesting that this J-domain was unable to functionally interact with DnaK. Substitutions of conserved amino acid residues and motifs were made in all four helices (I-IV) and the loop regions of the J-domains, and the modified chimeric Hsp40s were tested for functionality using the in vivo assay. Substitution of a highly conserved basic residue in helix II of the J-domain was found to disrupt in vivo functionality for all the J-domains tested. We propose that helix II and the HPD motif of the J-domain represent the fundamental elements of a binding surface required for the interaction of Hsp40s with Hsp70s, and that this surface has been conserved in mammalian, parasitic and bacterial systems.

Anatomical siting of the splenic flexure using computed tomography.

INTRODUCTION Often, left-sided colorectal surgery requires splenic flexure mobilisation (SFM) to allow a tension-free anastomosis to be carried out. This step is difficult and not without risk. We investigated a system of anatomical siting of the splenic flexure using computed tomography (CT). METHODS The Shrewsbury Splenic Flexure Siting (SSFS) system involves siting of the splenic flexure using the vertebral level (VL) as a reference point. We asked three surgical registrars (SRs) to analyse 20 CT scans of patients undergoing colonic resection to ascertain the anatomical site of the splenic flexure using the SSFS system. The distance from the centre of the vertebral body to the lateral edge (CVBL) of the splenic flexure was measured, as was the distance from the centre of the vertebral body to the inner abdominal wall (CVBI) along the same line, on axial images. RESULTS VL assessment demonstrated substantial inter-observer agreement with a kappa (κ) value of 0.742 (95% confidence interval (CI), 0.463-0.890). CVBL and CVBI demonstrated very strong inter-observer agreement (CVBL: κ = 0.905 (95% CI, 0.785-0.961); CVBI: 0.951 (0.890-0.979) (p<0.001). Overall, there was strong correlation between assessments by all three SRs across the three variables measured. CONCLUSIONS The SSFS system is an accurate method to site the splenic flexure anatomically using CT. We can use the SSFS system to develop a validated scoring system to help colorectal surgeons assess the difficulty of SFM.

Sex differences in the splenic flexure.

INTRODUCTION Anecdotally, surgeons claim splenic flexure mobilisation is more difficult in male patients. There have been no scientific studies to confirm or disprove this hypothesis. The implications in colorectal surgery could be profound. The aim of this study was to assess quantitatively whether there is an anatomical difference in the position of the splenic flexure between men and women using computed tomography (CT). METHODS Portal venous phase CT performed for preoperative assessment of colorectal malignancy was analysed using the hospital picture archiving and communication system. The splenic flexure was compared between men and women using two variables: anatomical height corresponding to the adjacent vertebral level (converted to ordinal values between 1 and 17) and distance from the midline. RESULTS In total, 100 CT images were analysed. Sex distribution was even. The mean ages of the male and female patients were 68.1 years and 66.7 years respectively (p=0.630). The mean vertebral level for men was 8.88, equating to the inferior half of the T11 vertebral body (range: 1-17 [superior half of T9 to inferior half of L2]), and 11.36 for women, equating to the inferior half of the T12 vertebral body (range: 4-16 [superior half of T10 to superior half of L2]). This difference was statistically significant (p=0.0001) and is equivalent to one whole vertebra. The mean distance from the midline was 160.8mm (range: 124-203mm) for men and 138.2mm (range: 107-185mm) for women (p<0.0001). CONCLUSIONS The splenic flexure is both higher and further from the midline in men than in women. This provides one theory as to why mobilising the splenic flexure may be more difficult in male patients.