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Introduction: Low-grade appendiceal mucinous neoplasms (LAMNs) are classified as non-perforated (pTis, pT3) or perforated (pT4), and considered precursors of pseudomyxoma peritonei (PMP). This study aims to quantify the risk of developing PMP from pTis and pT3 LAMNs., Materials and Methods: Retrospective analysis of a prospectively collected database identified LAMN patients referred to a specialist centre from 2004 to 2019. pT4 LAMNs and other appendix tumours were excluded. All patients had specialist review of their pathology, operation note, and a CT scan (at least 6 weeks post-operatively). Surveillance CTs were then performed at 6, 12, 24, 36, 48, & 60 months, with tumour markers (CEA, CA19-9, CA125)., Results: 193 pT3/pTis LAMN patients were included (pTis = 153, pT3 = 40). Median follow-up = 6.45 (3.91-22.13) years, M:F ratio = 1:1.57, and median age = 57 (23-83) years. Initial surgery included: appendicectomy (67 %), appendicectomy + visceral resection (6 %), and right hemicolectomy (27 %). R1 resections were identified in 5/193 patients (2.5 %). 3 R 1 patients underwent re-operation (2 caecal pole excision and 1 ileocecectomy), none of which had residual tumour. 8/193 patients (4 %) were lost to follow up. None of the remaining 185 developed PMP., Conclusion: This is the largest reported series of pTis/pT3 LAMNs with standardised follow-up in the literature. LAMNs correctly classified as pT3/pTis (after careful specialist review of pathology, operation note, and a baseline post-operative CT) have negligible risk of developing PMP and should have low intensity surveillance. If completely excised, further surgery is not indicated. R1 resections should be considered on an individual basis at a specialist centre., Competing Interests: Declaration of competing interest We the authors have no competing interests to declare regarding this submitted manuscript., (Copyright © 2024 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background and Aims: Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is an established treatment in selected patients with peritoneal metastases, delivered in the UK in specialist centres. HIPEC can be administered via the open coliseum technique as first described by Sugarbaker (O-HIPEC) or using a closed technique (C-HIPEC). Data comparing the safety and outcomes of these different approaches is limited. This study aims to compare morbidity and mortality rates of O-HIPEC and C-HIPEC following CRS for peritoneal metastases from colorectal cancer and appendiceal tumours., Methods: Consecutive patients undergoing CRS with open (05/2019-04/2020) and closed (05/2020-04/2021) HIPEC were identified from a prospectively maintained database. Baseline data including primary pathology, HIPEC agent and major operative procedures were analysed using Chi-squared and Fishers exact tests to ensure comparability of groups. Primary outcomes were 30- and 60-day postoperative mortality and morbidity (Common Terminology Criteria for Adverse Events, CTCAE). Secondary outcomes were length of critical care and overall hospital stay. In addition, morbidity and mortality were compared between HIPEC agents (mitomycin and oxaliplatin/5-fluorouracil)., Results: 99 patients (39.3%) and 153 patients (60.7%) underwent O-HIPEC, C-HIPEC respectively. Groups were well matched for baseline demographics, pathology, and HIPEC agent. In the O-HIPEC and C-HIPEC groups respectively, the incidence of 60-day complications (CTCAE 1-4) was 40.4% vs 39.3% (chi squared 0.94) and severe complications (CTCAE 3-4) 14% vs 13% (Fisher's exact p = 1) There was no perioperative mortality but one death in each group within the follow up period. There was no difference in morbidity or mortality between those receiving mitomycin or oxaliplatin., Conclusion: Closed administration of HIPEC is safe with no difference in post-operative morbidity or mortality compared to open HIPEC administration. Differences in longer term oncological outcomes including overall survival and disease-free survival between open and closed HIPEC techniques are yet to be determined., (Copyright © 2023 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Objective: The objectives of this nested study were to (1) assess whether changes in scores between rounds altered the final degree of consensus achieved in three Delphi surveys conducted as part of COS development projects (anal, gastric, and prostate cancer), and (2) explore participants' reasons for changing scores between rounds., Study Design and Setting: All Delphi surveys were conducted online using DelphiManager software and included healthcare professionals and participating patients. Participants were invited to give a free-text reason whenever they changed their score across an important threshold on a 1-9 Likert scale (1-3 not important, 4-5 important, 7-9 critically important). Reasons for score change were coded by four researchers independently using an inductive-iterative approach., Results: In all three Delphi surveys, the number of outcomes reaching criteria for consensus was greater in R2 than R1. Twelve themes and 23 subthemes emerged from 2298 discrete reasons given for score change. The most common reasons for the change were "time to reflect" (482 responses, 23%) and vicarious thinking (424, 21%), with 68% (291) of vicarious thinking attributed to seeing other participant's scores., Conclusion: Our findings support conducting a Delphi survey over the use of a single questionnaire where building consensus is the objective. Time to reflect and vicarious thinking, facilitated by seeing other participant's scores, were important drivers of score change. How results are presented to participants between rounds and the duration of and time between rounds in a Delphi survey may, therefore, influence the results and should be clearly reported., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Super Refined™ and Tween™ 20 HP polysorbate 20 (PS20) are two commercially available compendial grades of PS20 frequently used in biopharmaceutical formulations as protein stabilizing surfactants. PS20 degradation has been a major concern recently for potentially limiting drug product shelf life due to free fatty acid particle formation. This work is a side-by-side comparison of SR and HP PS20 in terms of PS20 degradation, particle formation and protein stability. The use of SR grade PS20 results in higher levels of oxidative PS20 degradation, protein oxidation, peroxides and protein aggregation, and therefore requires addition of methionine as an antioxidant to mitigate these issues. No clear root cause was identified as to why SR PS20 is more prone to oxidative degradation. This work also suggests that SR PS20 is less prone to particle formation than HP PS20 when there is preferential degradation of mono-esters of PS20, while more susceptible to particle formation when there is preferential degradation of higher order esters of PS20. Overall, this publication summarizes the potential risks and benefits of SR PS20 compared to HP PS20 to enable a formulator to make an informed decision when choosing between the two surfactant grades in their drug product formulations., (Copyright © 2020. Published by Elsevier Inc.)

Essentials The fibrinogen gene cluster is flanked by CCCTC-binding factor (CTCF) interaction sites. Chromatin looping of the fibrinogen cluster was demonstrated by chromosome conformation capture. Deleting a CTCF interaction site alters chromatin looping and halves fibrinogen expression. Looping of the human fibrinogen locus is functionally linked to fibrinogen gene expression., Summary: Background The coordinately regulated genes encoding human fibrinogen are clustered. This evolutionarily conserved configuration provides a possible mechanism for co-regulation whereby regulatory elements influence gene expression locally. The cluster is flanked by CCCTC-binding factor (CTCF) interaction sites that are candidate insulator regions mediating chromatin looping. Objectives To further our understanding of fibrinogen gene regulation, we aimed to investigate whether interactions exist between parts of the fibrinogen locus and how these contacts contribute to fibrinogen expression. Methods We used chromosome conformation capture in cultured cell lines to detect chromatin interactions at the fibrinogen gene cluster. We generated clonal cell lines where two CTCF interaction sites at one end of the locus were deleted using CRISPR-Cas9-mediated genome editing. Fibrinogen expression and protein production were measured using qRT-PCR and ELISA, respectively. Results We detected proximity between the ends of the fibrinogen locus, regardless of whether cells express fibrinogen. An interaction between the FGA promoter and the edge of the locus was more frequent in fibrinogen-expressing cells. Deletion of a CTCF site at one edge of the cluster altered chromatin interactions, reduced steady-state expression of FGB and FGG mRNA, and led to a halving of secreted fibrinogen. These phenotypes were completely restored by reintroduction of the CTCF interaction motif in previously motif-deleted clones. Conclusions Chromatin interactions are important for the coordinated regulation of the human fibrinogen genes. This finding furthers our comprehension of how fibrinogen is produced and identifies a possible source of variability in plasma fibrinogen levels seen in populations., (© 2018 International Society on Thrombosis and Haemostasis.)

Objectives: There is increasing recognition that insufficient attention has been paid to the choice of outcomes measured in clinical trials. The lack of a standardized outcome classification system results in inconsistencies due to ambiguity and variation in how outcomes are described across different studies. Being able to classify by outcome would increase efficiency in searching sources such as clinical trial registries, patient registries, the Cochrane Database of Systematic Reviews, and the Core Outcome Measures in Effectiveness Trials (COMET) database of core outcome sets (COS), thus aiding knowledge discovery., Study Design and Setting: A literature review was carried out to determine existing outcome classification systems, none of which were sufficiently comprehensive or granular for classification of all potential outcomes from clinical trials. A new taxonomy for outcome classification was developed, and as proof of principle, outcomes extracted from all published COS in the COMET database, selected Cochrane reviews, and clinical trial registry entries were classified using this new system., Results: Application of this new taxonomy to COS in the COMET database revealed that 274/299 (92%) COS include at least one physiological outcome, whereas only 177 (59%) include at least one measure of impact (global quality of life or some measure of functioning) and only 105 (35%) made reference to adverse events., Conclusions: This outcome taxonomy will be used to annotate outcomes included in COS within the COMET database and is currently being piloted for use in Cochrane Reviews within the Cochrane Linked Data Project. Wider implementation of this standard taxonomy in trial and systematic review databases and registries will further promote efficient searching, reporting, and classification of trial outcomes., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Reductions in agricultural pollution are essential for meeting nationally and internationally agreed policy targets for losses to both air and water. Numerous studies quantify the impact of relevant mitigation methods by field experimentation or computer modelling. The majority of these studies have addressed individual methods and frequently also individual pollutants. This paper presents a conceptual model for the synthesis of the evidence base to calculate the impact of multiple methods addressing multiple pollutants in order to identify least cost solutions for multiple policy objectives. The model is implemented as a farm scale decision support tool that quantifies baseline pollutant losses for identifiable sources, areas and pathways and incorporates a genetic algorithm based multi-objective procedure for determining optimal suites of mitigation methods. The tool is generic as baseline losses can be replaced with measured data and the default library of mitigation methods can be edited and expanded. The tool is demonstrated through application to two contrasting farm systems, using survey data on agricultural practices typical of England and Wales. These examples show how the tool could be used to help target the adoption of mitigation options for the control of diffuse pollution from agriculture. The feedback from workshops where Farmscoper was demonstrated is included to highlight the potential role of Farmscoper as part of the farm advisory process., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: Do demographics, clinical characteristics, care structures, mortality, and rehospitalization differ by region among a national sample of nursing home (NH) residents with heart failure (HF)?, Methods: Retrospective observational study of NH residents with HF by ICD-9 CM codes or Minimum Data Set (MDS) diagnosis, using the Linked Nursing Home/Skilled Nursing Facility Stay File, containing MDS, hospitalization, and mortality data for all residents in a 10% random sample of NHs (n = 1840) during 2003-2004. Facility characteristics, demographics, functional characteristics, comorbidity, and outcomes were described by geographic region. Baseline characteristics and care structures for subjects who experienced a subsequent HF hospitalization or death were compared with those who did not, using unadjusted odds ratios and chi-square tests or Fisher's exact tests for categorical, and t tests or Wilcoxon Rank Sum tests for continuous variables. Predictive logistic regression models for mortality in all subjects and HF hospitalization in subjects with a single NH stay of fewer than 90 days were developed. Time to first HF hospitalization in longer-stay subjects was analyzed using Cox models., Results: Mortality of NH residents with HF exceeds 45%; HF hospitalization exceeds 50% annually. Residing in a facility with 50 or fewer beds or in the rural South were both associated with lower risk of death. Older age and residing in the Midwest were associated with higher risk of HF hospitalization., Conclusion: Age, comorbidity, and functional impairment were not clinically different among regions of the country, but both mortality and HF hospitalization rates differed significantly by region., (Published by Elsevier Inc.)

Introduction: The aim of this study was to use an automated blood sampling technique to measure soluble hormones following an ovine corticotrophin releasing factor (oCRF) challenge using pharmacological doses that significantly inhibit brain CRF(1) receptors., Methods: A high throughput crude homogenate CRF(1) receptor binding assay was used to measure binding affinity, dose and time occupancy and exposure relationships in rat brain. From these studies a 30 mg/kg dose of DMP904 was selected to test in an oCRF challenged hormone release assay using an automated blood sampler., Results: DMP904 dose-dependently displaced [(125)I]oCRF ex vivo binding in crude rat cortex homogenates with a mean ID(50) of 0.4±0.08 mg/kg (n=4). DMP904 receptor occupancy remained greater than 90% over a 24h time period, despite a decrease in free plasma concentration. A dose of 30 mg/kg completely abolished an oCRF stimulated increase in plasma corticosterone and adrenocorticotropic hormone (ACTH), as measured by an automated blood sampler. There were no significant alterations to either basal or stimulated pituitary derived hormones measured., Discussion: In conclusion, we have shown for the first time, an automated blood sampling technique that can be incorporated to identify pharmacodynamic biomarkers in-vivo. This technology can be used successfully to reduce the number of animals and improve the quality of biomarker measures. Furthermore, at least for DMP904, to elicit a marked inhibition on plasma corticosterone levels, doses that produce greater than 95% brain occupancy are required., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: Determine whether a comprehensive approach to implementing national consensus guidelines for nursing home-acquired pneumonia (NHAP) affected hospitalization rates., Design: Quasi-experimental, mixed-methods, multifaceted, unblinded intervention trial., Setting: Sixteen nursing homes (NHs) from 1 corporation: 8 in metropolitan Denver, CO; 8 in Kansas and Missouri during 3 influenza seasons, October to April 2004 to 2007., Participants: Residents with 2 or more signs and symptoms of systemic lower respiratory tract infection (LRTI); NH staff and physicians were eligible., Intervention: Multifaceted, including academic detailing to clinicians, within-facility nurse change agent, financial incentives, and nursing education., Measurements: Subjects' NH medical records were reviewed for resident characteristics, disease severity, and care processes. Bivariate analysis compared hospitalization rates for subjects with stable and unstable vital signs between intervention and control NHs and time periods. Qualitative interviews were analyzed using content coding., Results: Hospitalization rates for stable residents in both NH groups remained low throughout the study. Few critically ill subjects in the intervention NHs were hospitalized in either the baseline or intervention period. In control NHs, 8.7% of subjects with unstable vital signs were hospitalized during the baseline and 33% in intervention year 2, but the difference was not statistically significant (P = .10). Interviews with nursing staff and leadership confirmed there were significant pressures for, and enablers of, avoiding hospitalization for treatment of acute infections., Conclusions: Secular pressures to avoid hospitalization and the challenges of reaching NH physicians via academic detailing are likely responsible for the lack of intervention effect on hospitalization rates for critically ill NH residents., (Published by Elsevier Inc.)

Objectives: Determine whether a comprehensive approach to implementing national consensus guidelines for nursing home acquired pneumonia (NHAP), including influenza and pneumococcal vaccination, improves resident subject and staff vaccination rates., Methods: Quasi-experimental, mixed-methods multifaceted intervention trial conducted at 16 nursing homes (NHs) from 1 corporation (8 in metropolitan Denver, Colorado; 8 in Kansas and Missouri) during 3 influenza seasons, October to April 2004 to 2007. Residents with 2 or more signs and symptoms of systemic lower respiratory tract infection (LRTI) and NH staff and physicians were eligible. Subjects' NH records were reviewed for vaccination. Each director of nursing (DON) completed a questionnaire assessing staffing and the number of direct care staff vaccinated against influenza. DONs and study liaison nurses were interviewed after the intervention. Bivariate analysis compared vaccination outcomes and covariates between intervention and control homes, and risk-adjusted models were fit. Qualitative interview transcripts were analyzed using content coding., Results: No statistically significant relationship between the intervention and improved resident vaccination rates was found, so other factors associated with improved rates were explored. Estimated direct patient care staff vaccination rates were better during the baseline and improved more in the intervention NHs. Qualitative results suggested that facility-specific factors and national policy changes impacted vaccination rates., Conclusions: External factors influence staff and resident vaccination rates, diluting the potential impact of a comprehensive program to improve care for NHAP on vaccination., (Published by Elsevier Inc.)

Background: Emerging data demonstrate important roles for tissue-type plasminogen activator (t-PA) in the central nervous system (CNS). In contrast to endothelial cells, little is known about the regulation of t-PA gene expression and secretion in astrocytes., Objectives: The aims of the present study were to investigate whether t-PA gene expression is regulated by retinoids and the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) in human astrocytes, and to study whether t-PA is stored and subject to regulated release from these cells, as with endothelial cells., Methods: Native human astrocytes were treated with RA and/or PMA. mRNA was quantified by real-time RT-PCR and protein secretion determined by ELISA. Intracellular t-PA immunoreactivity in astrocytes was examined by immunocyto- and histochemistry., Results: RA and/or PMA induced a time-dependent increase in t-PA mRNA and protein levels in astrocytes, reaching 10-fold after combined treatment. This was associated with increased amounts of t-PA storage in intracellular granular structures. Both forskolin and histamine induced regulated release of t-PA. The presence of t-PA in reactive astrocytes was confirmed in human brain tissue., Conclusions: These data show that RA and PKC activation induce a strong up-regulation of t-PA expression in astrocytes, and increased intracellular storage pools. Moreover, a regulated release of t-PA can be induced from these cells. This raises the possibility that astrocytes contribute to the regulation of extracellular t-PA levels in the CNS.

Background: Patients who survive a severe exacerbation of COPD are at high risk of rehospitalization for COPD and death. The objective of this study was to determine predictors of these events in a large cohort of Veterans Affairs (VA) patients., Methods: We identified 51,353 patients who were discharged after an exacerbation of COPD in the VA health-care system from 1999 to 2003, and determined the rates of rehospitalization for COPD and death from all causes. Potential risk factors were assessed with univariate and multivariate survival analysis., Results: On average, the cohort was elderly (mean age, 69 years), predominately white (78% white, 13% black, 3% other, and 6% unknown), and male (97%), consistent with the underlying VA population. The risk of death was 21% at 1 year, and 55% at 5 years. Independent risk factors for death were age, male gender, prior hospitalizations, and comorbidities including weight loss and pulmonary hypertension; nonwhite race and other comorbidities (asthma, hypertension, and obesity) were associated with decreased mortality. The risk of rehospitalization for COPD was 25% at 1 year, and 44% at 5 years, and was increased by age, male gender, prior hospitalizations, and comorbidities including asthma and pulmonary hypertension. Hispanic ethnicity and other comorbidities (diabetes and hypertension) were associated with a decreased risk of rehospitalization., Conclusions: Age, male gender, prior hospitalizations, and certain comorbid conditions were risk factors for death and rehospitalization in patients discharged after a severe COPD exacerbation. Nonwhite race and other comorbidities were associated with decreased risk.

Background: Blood-derived endothelial progenitor cells (EPC) have been used to treat ischemic disease. However, the number of EPC that can be obtained from adult blood is limited., Objective: To characterize endothelial-like cells obtained from human bone marrow and determine their ability to stimulate new blood vessel formation in vivo., Methods: Mononuclear cells (MNC) were isolated from human bone marrow or umbilical cord blood and cultured in endothelial growth medium (EGM-2). Mesenchymal stem cells (MSC) were isolated from bone marrow and induced to differentiate into endothelial-like cells (MSCE), or adipocytes or osteocytes by growth in EGM-2, adipogenic or osteogenic medium., Results: Cells obtained by culturing bone marrow MNC in EGM-2 formed cord- or tube-like structures when grown on Matrigel(TM) and expressed several endothelial marker proteins. However, cell morphology and the profile of endothelial marker protein expression were different from those of cord blood-derived EPC (cbEPC). Cells with a similar phenotype were obtained by differentiation of MSC into MSCE, which was accompanied by an increase of endothelial marker proteins and a diminished capacity to differentiate into adipocytes. Subcutaneous implantation of MSCE in collagen plugs in non-obese diabetic-severe combined immunodeficient (NOD-SCID) mice resulted in formation of functional blood vessels that had incorporated the MSCE., Conclusions: Our results show that MSCE and cbEPC are different cell types. The formation of functional blood vessels by MSCE, combined with high yields and a reduced capacity to differentiate into other cell types compared with MSC, makes these cells potentially useful for autologous therapy of ischemic disease.

Background: Older patients frequently receive care in multiple settings. However, there has been a paucity of studies that quantify the number of care transitions or that attempt to explain utilization patterns over a given time period. Furthermore, no studies have examined transitions based on method of payment., Objective: The objective of this study was to examine the number of different posthospital interinstitutional transfers (including hospital, inpatient rehabilitation facilities [IRF], and skilled nursing facilities [SNF]) by method of payment (managed Care [MC] or fee-for-service [FFS])., Design: Prospective cohort followed for 12 months., Method: A total of 1055 older patients were identified on transfer from an acute hospital to either an SNF or IRF. Utilization and mortality was tracked over 12 months through analysis of administrative data, chart review, nursing assessments, and patient interviews., Results: After 3 months, 65.3% of MC patients and 75.6% of FFS patients experienced between two and three transfers and an additional 13.8% of MC patients and 14.6% of FFS patients experienced between four and six transfers. Over the next 9 months, the frequency of patient transfers uniformly declined in both payment groups., Conclusion: This study demonstrates that interinstitutional transfers are common in older patients. The majority of these transfers occurred within the first 3 months after hospital discharge for both payment groups. Understanding the frequency and patterns of posthospital care transitions is an important step toward designing innovative approaches to improve the quality of care transitions and ensuring patient safety across settings.

A number of publications have presented recommendations for prolonged cardiac monitoring after electric injury. These recommendations are combined in this article to make criteria for monitoring that agree with the recommendations of most studies. It is generally agreed that cardiac monitoring is not needed unless there is an abnormal electrocardiogram or other suggestion of acute problems. Electric injury in pregnancy is also discussed, with recommendations for fetal monitoring after electric and mechanical trauma. Reports of fetal death after minor electric injury to the mother are described. Finally, selected aspects of lightning injury are described, including neurologic and vascular effects. This is the final article of a 3-part series on electric injury.

Electric injury can cause disruption of cardiac rhythm and breathing, burns, fractures, dislocations, rhabdomyolysis, eye and ear injury, oral and gastrointestinal injury, vascular damage, disseminated intravascular coagulation, peripheral and spinal cord injury, and Reflex Sympathetic Dystrophy. Secondary trauma from falls, fires, flying debris, and inhalation injury can complicate the clinical picture. Diagnostic and treatment considerations for electric injuries are described in this article, which is the second part of a three-part series on electric injuries.

Patients with electric injury present a significant challenge. Possible mechanisms of injury include electrical disruption of cardiac rhythm and breathing, burns of several types, and inhalation of gases from fires. Mechanical trauma may come from electric arc blast, explosion of gases, falls, and strong muscle contractions. Additionally, the patient may have multiple co-existent injuries, comorbidities, an abnormal mental status, and a severely disrupted acid-base balance. These factors can make diagnosis and treatment difficult. In addition, electric injury can cause a number of slowly developing and subtle sequelae that may be difficult, if not impossible, to diagnose on initial examination.

Measurements of extracellular pH (pHe) in vivo have shown that the microenvironment in tumours is more acidic than in normal tissue. However, both human and animal tumour cells have been shown to have an intracellular pH (pHi) on the alkaline side of neutrality (pH 7.1-7.2). This gives rise to a reversed pH gradient between tumours and normal tissue which implies that cells within solid tumours are capable of maintaining their level of pHi at physiological levels, despite lower than normal levels of pHe. In this paper the authors describe a mathematical model that provides a possible explanation for the altered pH gradient observed in tumours. The authors examine the influence of changes in the microenvironment on the activity of several membrane based ion transport systems. Using qualitative analysis the authors show that the pHi of tumour cells is less sensitive to external pH than for normal cells, because of their increased reliance on the inefficient glycolytic pathway for energy production. It is shown that under aerobic conditions the lactate-/H+ symporter could be the most active exchanger in the regulation of pHi in tumour cells. However, under more hypoxic conditions lactate extrusion is reduced, and so this exchanger has little effect on resting pHi in these regions. The authors also consider an extended model which incorporates the transfer of acids from the cytosol into acidic organelles. The model demonstrates that one of the major factors involved in the maintenance of cytosolic pH to physiological levels, despite an acidic extracellular pH in hypoxic areas of tumour tissue (median, 6.9-7.0), is enhanced sequestration of cytosolic protons into acidic cellular vesicles such as endoplasmic reticulum, golgi, endosomes, and lysosomes.

The professional standard of care has historically been defined in terms of the practice of reasonable, prudent physicians. In court, physicians are needed in most cases to testify as to what is the standard of practice and to verify the relevance of published materials that may be presented as being descriptive of the standard of care. Proposed standards have been published by many organizations and institutions. The medical literature also serves as a source of information concerning medical practices. Court cases may be decided in a way that suggests that the usual practices of physicians are inadequate.

Earlier parts of this series have discussed the physics, pathophysiology, and nature of electric injury. This part will discuss deliberately applied electric shocks and the treatment of electric injuries. Electric shocks are deliberately applied to persons during electroshock therapy and with stun guns, shock batons, and electric cattle prods. Electric injuries, whether a complication of deliberate electric shock or due to accidental injury, should be treated to preserve cardiac and respiratory function and to prevent further tissue damage. Safe extrication at the scene, rapid triage, and emergency medical treatment are discussed.

Background: Neuroretinitis is a distinct clinical entity consisting of moderate to severe visual loss, optic nerve head edema, macular exudate in a stellate pattern, and variable vitreous inflammation. Although the etiology is usually postviral or idiopathic, an acute infectious cause occasionally is demonstrated., Methods: Five juvenile or young adult patients with neuroretinitis are presented with serologic evidence of Toxoplasma gondii infection. Four of the five patients were treated with systemic antibiotics and corticosteroids; one patient was not treated., Results: With a mean follow-up period of 50 months, visual acuity returned to 20/25 or better in four patients, with one patient regaining visual acuity of 20/60. Two patients had one or more recurrent episodes of neuroretinitis, distinguishing toxoplasmosis from idiopathic neuroretinitis, which is usually a monophasic illness., Conclusion: Toxoplasmosis infection is a rare, but potentially treatable, form of neuroretinitis and should be included in the differential diagnosis of "Leber's idiopathic stellate retinopathy."

Virtually every part of the body can be injured by electric current. The extent of injury to any given tissue will depend on many factors, including the nature of the tissue and the amount and duration of the electric current. In addition, cardiac and respiratory arrest can be induced by a number of mechanisms with little or no immediate tissue damage. Burns can be caused by the heating of tissue by electric current and by other mechanisms. Secondary trauma may result from falls, explosions, and other events initiated by electric forces. Nervous tissue has the least resistance to current flow and is thus more easily damaged. Part II in this 3-part series will discuss nervous tissue damage first, followed by discussions of damage to tissues of increasingly greater electric resistance. These are blood vessels, muscle, skin, and bone. Less common injuries are discussed last.

Background: An experimental sustained release intraocular device has been designed to deliver ganciclovir over a long period of time. As part of an efficacy trial, the ganciclovir intraocular device was used to treat cytomegalovirus (CMV) retinitis in patients with acquired immune deficiency syndrome (AIDS)., Methods: All patients had active CMV retinitis that had progressed despite intravenous ganciclovir therapy. The ganciclovir intraocular device was inserted into the vitreous cavity by making an inferotemporal full-thickness circumferential sclerotomy and anchored to the incision. Intravenous therapy was then discontinued and patients were followed up at 2-week intervals until death. Seven eyes from five patients were obtained 2 to 10 hours postmortem and submitted for histopathologic examination. Light and electron microscopic studies were performed and correlated to the clinical outcome. Follow-up period after device placement ranged from 16 to 82 days (median, 70 days)., Results: All seven eyes showed clinical stabilization of the CMV retinitis. Light microscopy showed varying degrees of retinal atrophy with areas of gliosis. In addition, we observed syncytial megalic cells containing Cowdrey type A inclusions affecting all layers of the retina. Concurrent choroidal infections with Pneumocystis carinii (1) and Mycobacterium avium (2) also were seen. Electron microscopy showed virus particles located mostly at the junction of uninvolved and "healed" retinitis. No evidence of retinal toxic effects or inflammation at the site of ganciclovir intraocular device implant was noted., Conclusion: The ganciclovir intraocular device appeared to be effective in controlling the progression of CMV retinitis. The clinical and pathologic results are similar to those observed in the eyes of patients with intravenously administered ganciclovir. The lack of toxic effects and sustained levels of intravitreal ganciclovir may provide an improved therapeutic method of local treatment of CMV retinitis.

Electric shock causes injury and death through a variety of mechanisms. The proper treatment of a patient with electric shock depends upon the nature of the injuries sustained. The primary electric injuries to be expected depend in large part on the type of electric energy source, the amount and duration of current flow, and the parts of the body affected. Secondary injury can be caused by trauma associated with the electric accident such as falls and explosions.

A pregnant patient with a chief complaint of chest pain was found to have many characteristic findings of the HELLP syndrome. A number of pregnancy-related conditions have in common various degrees of hypertension, proteinuria, edema, hemolysis, elevated liver enzymes, and low platelets. Emergency physicians should search for clinical and laboratory signs of these conditions when evaluating ill pregnant patients.

Background: Epimacular membrane with pseudohole is an important vitreomacular disorder that belongs in the differential diagnosis of impending and established macular hole. To better characterize this lesion, the authors attempted to identify various features of eyes with epimacular membrane and pseudohole., Methods: Demographic, clinical, photographic, and fluorescein angiographic data for 14 eyes with epimacular membrane and pseudohole were reviewed. Horizontal and vertical diameters of the pseudoholes were measured, and the original diagnosis was recorded for each eye. Fluorescein angiography was performed in 11 eyes., Results: The mean age of patients with macular pseudoholes was 61.6 years, and median visual acuity for pseudohole eyes was 20/30. Mean horizontal and vertical diameters of the pseudoholes were 384 and 410 microns, respectively. None of the eyes with pseudoholes had the characteristic ophthalmoscopic features associated with full-thickness macular holes or impending macular holes. Results of fluorescein angiography showed three eyes with increased tortuosity or abnormal straightening of the perifoveal vessels; three eyes with a foveal window defect; and three eyes with late leakage from the perifoveal vessels. The original diagnosis of the initial examining physician was correct in only 43% of eyes with epimacular membrane and pseudohole., Conclusion: Epimacular membrane with pseudohole may be an underdiagnosed lesion and commonly mistaken for impending macular hole, full-thickness hole, or lamellar hole. These data may be of use as more patients are being considered for recently advocated surgical treatments for impending and established macular hole.

Residency programs routinely review cases involving "morbidity and mortality." It would be a valuable experience to similarly review medical malpractice cases and the associated testimony by medical experts. When available, the cases reviewed in residency programs would be those in which faculty members at the same institution had testified. The faculty member in such cases would be intimately familiar with the case and able to share the knowledge necessary to take part in the legal process. This case review process would expose residents to the legal realities of medical practice, provide a forum for peer review of legal testimony by experts, and show residents how to participate in the legal system should the need arise.

Emergency physicians as individuals, as groups, or as corporations, have medical and legal relationships with hospitals, other physicians, and nurses. These relationships sometimes result in liability for alleged negligence being applied in complex and unexpected ways. Emergency physicians may be held responsible for the acts of others. Conversely, other parties, such as hospitals, may be held liable for the acts of emergency physicians. This paper explores the history of hospital responsibility for patient care and examines how hospital policies and actions often impact on emergency care.

In east central Illinois over the last three years, three hospitals in which the authors were contracted as emergency physicians have been in various stages of merger with nearby hospitals. In all, six hospitals will be merged into three "medical centers." This is a basis of experience to be shared with other emergency physicians, as consolidation of health care facilities seems to be a wave of the future due to financial constraints of the health care setting. Lessons to be learned from these experiences involve many issues, including work contract, malpractice insurance payment, physician and nurse staffing, and public information problems.

Physicians have a responsibility to society, their peers, and patients to participate in malpractice litigation in a manner that ensures that medical malpractice cases are properly evaluated. Physicians are reluctant to involve themselves as expert witnesses in medical malpractice litigation because of not wanting to further any malpractice suits, mistrust of attorneys and misconceptions about expert witnesses and the legal system in general. The expert witness should be an impartial practicing physician who can select those suits that should or should not be filed and identify which parties were negligent in each case. If impartial physicians do not evaluate cases for attorneys, other more partisan and less objective physicians will.

The drawing of laboratory tests is often overlooked in the moribund patient. In patients with medical problems, potassium and other electrolyte abnormalities are often of significance and may be the cause of the arrest. Patients without circulation begin to develop severe abnormalities of PT, PTT, and potassium. These measurements will sometimes demonstrate that a patient's condition is hopeless. When laboratory tests show a situation to be hopeless, an early cessation of resuscitation efforts will be possible, and the justification for such actions will be documented. Laboratory tests drawn early in the resuscitation effort may prove that resuscitation could not have been successful.

A 19-year-old male with a bone disease that predisposes to pathological fractures was involved in an automobile accident. Although the physician must always look for multiple injuries in any trauma patient, this case illustrates that in the patient with bone disease, the probability of multiple fractures is extremely high. The differential diagnosis of dense-bone disease is discussed as are considerations relevant to caring for the trauma patient with bone disease.