Bridgeport Hospital

RATIONALE: Accurate, early identification of patients at risk for developing acute lung injury (ALI) provides the opportunity to test and implement secondary prevention strategies. OBJECTIVES: To determine the frequency and outcome of ALI development in patients at risk and validate a lung injury prediction score (LIPS). METHODS: In this prospective multicenter observational cohort study, predisposing conditions and risk modifiers predictive of ALI development were identified from routine clinical data available during initial evaluation. The discrimination of the model was assessed with area under receiver operating curve (AUC). The risk of death from ALI was determined after adjustment for severity of illness and predisposing conditions. MEASUREMENTS AND MAIN RESULTS: Twenty-two hospitals enrolled 5,584 patients at risk. ALI developed a median of 2 (interquartile range 1-4) days after initial evaluation in 377 (6.8%; 148 ALI-only, 229 adult respiratory distress syndrome) patients. The frequency of ALI varied according to predisposing conditions (from 3% in pancreatitis to 26% after smoke inhalation). LIPS discriminated patients who developed ALI from those who did not with an AUC of 0.80 (95% confidence interval, 0.78-0.82). When adjusted for severity of illness and predisposing conditions, development of ALI increased the risk of in-hospital death (odds ratio, 4.1; 95% confidence interval, 2.9-5.7). CONCLUSIONS: ALI occurrence varies according to predisposing conditions and carries an independently poor prognosis. Using routinely available clinical data, LIPS identifies patients at high risk for ALI early in the course of their illness. This model will alert clinicians about the risk of ALI and facilitate testing and implementation of ALI prevention strategies. Clinical trial registered with www.clinicaltrials.gov (NCT00889772).

Increased intrahepatic resistance in cirrhotic livers is in part caused by increased vascular tone. Several morphological abnormalities have been described in the sinusoidal endothelial cells of cirrhotic livers, but the functional impact of these abnormalities on the intrahepatic vascular tone has not been studied. The aim of this study was to investigate the intrahepatic endothelial function and the role of nitric oxide (NO) with regard to vascular tone in cirrhotic livers. Isolated rat liver perfusions were performed in cirrhotic rats (induced by chronic carbon tetrachloride inhalation) and weight-matched normal controls. After preconstricting the intrahepatic microcirculation with methoxamine (10(-4) mol/L), response to cumulative doses of receptor-mediated endothelial agonist, acetylcholine (10(-7) mol/L-10(-5) mol/L), was obtained. In another series, response to the receptor-independent endothelial agonist, calcium ionophore A23187 (10(-7) mol/L and 3 x 10(-7) mol/L), was obtained in the absence and presence of Nomega-nitro-L-arginine (NNA) and indomethacin. In a third series of rats, nitrate and nitrite production was measured in the perfusate of perfused normal and cirrhotic livers. There was significantly less vasorelaxation in cirrhotic livers as compared with normal livers in response to acetylcholine and calcium ionophore A23187 (P < .0001). The impaired vasorelaxation was a result of a decrease in both NO-mediated and non-NO-mediated components of vasorelaxation. Cirrhotic livers from ascitic rats had significantly less vasorelaxation as compared with livers from nonascitic rats (P < .005). There was significantly less production of nitrates and nitrites in cirrhotic livers (P < .05). The liver microcirculation of cirrhotic livers is characterized by endothelial dysfunction that results in impaired release of endothelial relaxing factors including NO.

BACKGROUND: Intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) are known to occur in patients after major abdominal surgery. The incidence of IAH and ACS in the burn population is not known. METHODS: We prospectively recorded the intra-abdominal pressures of major burn patients admitted to our burn center from February 1999 to September 1999. A bladder pressure greater than 25 mm Hg was diagnosed as IAH. ACS was diagnosed when pulmonary compliance decreased in association with persistent IAH and was treated with abdominal decompression. RESULTS: Ten patients were placed on the protocol; of these, seven developed IAH. Five responded to conservative treatment. Two patients with 80% body surface area burns developed ACS and required decompression. CONCLUSIONS: IAH occurs commonly in major burn patients, and ACS is seen regularly in patients with more than 70% body surface area burns. We recommend bladder pressure measurements after infusion of more than 0.25 L/kg during the acute resuscitation phase and for peak inspiratory pressures greater than 40 cm H2O. Whereas ACS warrants surgical decompression of the abdominal cavity, IAH usually responds to conservative therapy.

OBJECTIVE: The Acute Kidney Injury Network's proposed definition for acute kidney injury (increment of serum creatinine > or = 0.3 mg/dL or 50% from baseline within 48 hrs or urine output < 0.5 mL/kg/hr for > 6 hrs despite fluid resuscitation when applicable) predicts meaningful clinical outcomes. DESIGN: Retrospective cohort study. SETTING: A 350-bed community teaching hospital. PATIENTS: The study population consisted of 471 patients with no recent history of renal replacement therapy who were admitted to the medical intensive care unit during 1 yr. INTERVENTIONS: Medical records of all patients were reviewed using a data abstraction tool. Demographic information, diagnoses, risk factors for acute kidney disease, physiologic and laboratory data, and outcomes were recorded. MEASUREMENTS AND MAIN RESULTS: Of 496 patients, 471 were not receiving renal replacement therapy in the weeks before medical intensive care unit admission; 213 had changes > or = .3 mg/dL in serum creatinine within 48 hrs and/or urine output of < or = .5 mL/kg/hr for > 6 hrs. Detailed fluid challenge information was available for only 123 patients, who met acute kidney injury criteria, and three patients reversed after administration of > or = 500 mL of intravenous fluid and/or blood products. All patients whose creatinine increased > or = 50% also had increments > or = 0.3 mg/dL. The 120 patients with acute kidney injury were older (mean +/- SE: 69.3 +/- 1.7 vs. 62.9 +/- 1.3, p < .01), were more ill (Acute Physiology and Chronic Health Evaluation II score 18.7 +/- .6 vs. 13.3 +/- .4, p < .01), and had multiple comorbidities (two or more organs, 65% vs. 51.3%, p < .01) compared with those without acute kidney injury. The mortality rate of patients who met criteria for acute kidney injury was significantly higher than that of patients who did not have acute kidney injury (45.8 vs. 16.4%, p < .01). In multivariate logistic regression analyses, acute kidney injury was an independent predictor of mortality (adjusted odds ratio 3.7, 95% confidence interval 2.2-6.1). Acute kidney injury was a better predictor of in-hospital mortality than was Acute Physiology and Chronic Health Evaluation II score, advanced age, or presence of nonrenal organ failures. Median hospital stay was twice as long in patients with acute kidney injury (14 vs. 7 days, p < .01), and only patients with acute kidney injury required hemodialysis during hospitalization. The oliguria criterion of acute kidney injury did not affect the odds of in-hospital mortality. CONCLUSIONS: The Acute Kidney Injury Network definition of acute kidney injury predicts hospital mortality, need for renal replacement therapy, and prolonged hospital stay in critically ill patients. An increment of serum creatinine > or = 0.3 mg/dL in 48 hrs alone predicts clinical outcomes as well as the full Acute Kidney Injury Network definition.

Importance: Lipoprotein(a) (Lp[a]) is a low-density lipoprotein (LDL) cholesterol-like particle bound to apolipoprotein(a). This novel marker of cardiovascular disease acts through induction of vascular inflammation, atherogenesis, calcification, and thrombosis. While an absolute risk threshold remains to be universally accepted, an estimated 20% to 25% of the global population have Lp(a) levels of 50 mg/dL or higher, a level noted by the European Atherosclerosis Society to confer increased cardiovascular risk. Observations: Compelling evidence from pathophysiological, observational, and genetic studies suggest a potentially causal association between high Lp(a) levels, atherosclerotic cardiovascular disease, and calcific aortic valve stenosis. Additional evidence has demonstrated that elevated Lp(a) levels are associated with a residual cardiovascular risk despite traditional risk factor optimization, including LDL cholesterol reduction. These findings have led to the formulation of the Lp(a) hypothesis, namely that Lp(a) lowering leads to cardiovascular risk reduction, intensifying the search for Lp(a)-reducing therapies. The ineffectiveness of lifestyle modification, statins, and ezetimibe to lower Lp(a); the modest Lp(a) reduction with proprotein convertase subtilisin/kexin type 9 inhibitors; the adverse effect profile and unclear cardiovascular benefit of pharmacotherapies such as niacin and mipomersen; and the impracticality of regular lipoprotein apheresis represent major challenges to currently available therapies. Nevertheless, emerging nucleic acid-based therapies, such as the antisense oligonucleotide pelacarsen and the small interfering RNA olpasiran, are generating interest because of their potent Lp(a)-lowering effects. Assessment of new-onset diabetes in patients achieving very low Lp(a) levels will be important in future trials. Conclusions and Relevance: Epidemiologic and genetic studies suggest a potentially causal association between elevated Lp(a) levels, atherosclerotic cardiovascular disease, and aortic valve stenosis. Emerging nucleic acid-based therapies have potent Lp(a)-lowering effects and appear safe; phase 3 trials will establish whether they improve cardiovascular outcomes.

Four patients with quiescent inflammatory bowel disease had prompt exacerbations when given nonsteroidal anti-inflammatory drugs. Nonsteroidal anti-inflammatory drugs can have noxious effects on the distal intestine as well as on the proximal gut. Eight previous cases of exacerbation of ulcerative colitis have been reported, as have instances of de-novo colitis and ileitis in persons treated with nonsteroidal anti-inflammatory drugs who did not have preexisting inflammatory bowel disease. Nonsteroidal anti-inflammatory drug ingestion should be considered in the differential diagnosis of inflammatory bowel disease. These drugs should be administered to patients with inflammatory bowel disease only after consideration of their possible harmful effects.

OBJECTIVE: Most studies of contrast-induced nephropathy lack controls to distinguish it from nephropathy from other causes. We assessed the frequency and magnitude of serum creatinine changes in patients not receiving iodinated contrast material to compare with creatinine changes in publications regarding contrast nephropathy. MATERIALS AND METHODS: From the electronic medical records of an academic medical center, adults with creatinine determinations on five consecutive days who had not received contrast material during the previous 10 days were identified. The first creatinine level was compared with those on subsequent days. We calculated the frequency with which these levels exceeded thresholds used to identify contrast nephropathy in previous publications. RESULTS: Among 32,161 patients, more than half showed a change of at least 25% and more than two fifths, a change of at least 0.4 mg/dL. Among patients with baseline creatinine levels of 0.6-1.2 mg/dL, increases of at least 25%, 33%, and 50% occurred in 27%, 19%, and 11% of patients, respectively. Increases of 0.4, 0.6, and 1.0 mg/dL occurred in 13%, 7%, and 3% of patients. Among patients with baseline creatinine levels greater than 2.0 mg/dL, increases of at least 25%, 33%, and 50% occurred in 16%, 12%, and 7%. Increases of 0.4, 0.6, and 1.0 mg/dL occurred in 33%, 26%, and 18%. These increases were not different from the incidences of contrast nephropathy previously published. CONCLUSION: The creatinine level increases in patients who are not receiving contrast material as often as it does in published series of patients who are receiving contrast material. The role of contrast material in nephropathy may have been overestimated.

Background: The syndrome of 5-fluorouracil (5-FU)-associated cardiotoxicity remains poorly defined. Patients and methods: We performed a literature review (1969 – 2007) and compiled data derived from 377 evaluable cases out of 448 reported cases. Results: Patient age ranged from 14 to 86 years. Of the patients 65% were 55 years old and the male:female ratio was 1.5:1. The most commonly treated tumors were gastrointestinal (60%), head and neck (22%) and breast (4%). Of the patients 14% had a history of heart disease whereas cardiac risk factors were found in 37%. Mode of administration included: continuous infusion (72%); bolus (22.5%); intermediate infusion (3%); oral (2%); and intraperitoneal (1 patient). The dosages of 5-FU used were < 750 mg/m2/day (36%), 751 – 999 (16%), 1,000 (26%), 1,001 – 1,499 (4%) and 1,500 (16%). Of the patients 54% received 5-FU in combination with other chemotherapeutic agents (cisplatin 44%) whereas 51% received 5-FU alone or with leucovorin. Only 4% patients had undergone previous or concomitant radiation therapy to the mediastinum. Of cardiac incidents that happened 69% were seen during or within 72 h of the first cycle of 5-FU. Angina occurred in 45% of patients whereas myocardial infarction was seen in 22%, arrhythmias in 23, acute pulmonary edema in 5, cardiac arrest and pericarditis in 1.4 and heart failure in 2. Electro-cardiographic evidence of ischemia or ST-T changes were recorded in 69% of patients, but abnormal cardiac enzymes were found in only 12%. The cardiac symptoms were reproducible in 47%, including in one patient subsequently treated with 5-FU p.o. Symptoms were also elicited when the same patients were treated with lower doses or different schedules. Of the patients 68% responded to conservative anti-anginal therapy, although prophylactic coronary vasodilators had limited efficacy. Overall, 8% of patients showing cardiotoxicity on 5-FU administration died. Furthermore, 13% reexposed to 5-FU died. Conclusions: Our review suggests that 5-FU cardiotoxicity is an infrequent but real phenomenon that is independent of dose and may be related to a continuous infusion schedule. The presence of cardiac risk factors is not predictive. Patients should be observed closely and 5-FU administration discontinued if cardiac symptoms develop. A rechallenge with 5-FU should be reserved only for those patients in whom there is no reasonable alternative therapy and should be performed in the setting of aggressive prophylaxis and close monitoring.

OBJECTIVE: Postoperative pulmonary complications are a major contributor to the overall risk of surgery. We convened a patient safety summit to discuss ways to enhance physician awareness of postoperative pulmonary complications, advance postoperative pulmonary complications as a substantive public health concern demanding national attention, recommend strategies to reduce the deleterious impact of postoperative pulmonary complications on clinical outcomes and healthcare costs, and establish an algorithm that will help identify patients who are at increased risk for postoperative pulmonary complications. DATA SOURCES: We conducted PubMed searches for relevant literature on postoperative pulmonary complications in addition to using the summit participants' experience in the management of patients with postoperative pulmonary complications. DATA SYNTHESIS: Postoperative pulmonary complications are common, are associated with increased morbidity and mortality, and adversely affect financial outcomes in health care. A multifaceted approach is necessary to reduce the incidence of postoperative pulmonary complications. Identifying a measurable marker of risk will facilitate the targeted implementation of risk-reduction strategies. CONCLUSIONS: The most practicable marker that identifies patients at highest risk for postoperative pulmonary complications is the need for postoperative mechanical ventilation of a cumulative duration >48 hrs.

BACKGROUND: Lymphedema is a relatively frequent complication following the management of breast carcinoma. Numerous therapeutic interventions have been offered to treat this potentially disabling and disfiguring condition. Consensus has not been attained among oncologists, surgeons, psychiatrists, and physical therapists concerning the appropriate treatment of lymphedema. METHODS: This review provides an overview of those treatment regimens that have been used in the past and, in some instances, have gone on to provide the foundation for the most widely prescribed interventions currently employed for the management of upper extremity lymphedema following breast carcinoma treatment. The use of intermittent pneumatic compression pumps as a part of an integrated multidisciplinary treatment approach incorporating garments, exercises, and massage also is discussed. RESULTS: A review of available literature suggests that a variety of traditional and commonly available techniques, when used appropriately in a multidisciplinary fashion, may lessen the cosmetic and physical impairments associated with acquired lymphedema. The role of surgery is unclear. Pharmacotherapies are a promising adjunct to manual and mechanical therapies. CONCLUSIONS: The appropriate use of readily available treatment approaches may lessen the severity of acquired lymphedema following breast carcinoma therapy. A comprehensive therapeutic approach should be employed in the management of lymphedema, including attention to the functional, cosmetic, and emotional sequelae of this potentially disabling condition. To that end, a recommendation for a comprehensive treatment regimen is provided.

Since the terrorist attack of September 11, 2001, preparation by the health care system for an act of terrorism has been mandated by leaders of governments. Scenarios for terrorist acts involving radioactive material have been identified, and approaches to management (based on past experience from atomic weapons detonations and radiation accidents) have been developed. Because of their experience in managing patients with profound cytopenia and/or marrow aplasia, hematologists will be asked to play a significant role in evaluating and treating victims of mass accidental or deliberate exposure to radiation. This review provides a framework for understanding how radiation levels are quantified, how radiation alters the function of hematopoietic (and nonhematopoietic) cells and tissues, and how victims receiving a significant radiation dose can be identified and managed. In Section I, Dr. Nicholas Dainiak reviews four components of the Acute Radiation Syndrome: the hematopoietic, neurovascular, gastrointestinal and cutaneous subsyndromes. Clinical signs and symptoms are discussed for exposed individuals at the time of initial presentation (the prodromal phase) and during their course of disease (the manifest illness). In Section II, he presents clinical and laboratory methods to assess radiation doses, including time to onset and severity of vomiting, rate of decline in absolute blood lymphocyte count and the appearance of chromosome aberrations such as dicentrics and ring forms. Potential scenarios of a radiation terrorist event are reviewed, and methods for initial clinical assessment, triage, and early management of the acute radiation syndrome and its component subsyndromes are summarized. In Section III, Dr. Jamie Waselenko reviews the hematopoietic syndrome, and presents guidelines for the use of cytokine therapy, antibiotics, and supportive care that have been developed by the Strategic National Pharmaceutical Stockpile Working Group. Results of preclinical and clinical growth factor therapy studies with G-CSF, GM-CSF, pegylated G-CSF, SCF, and IL-3 are summarized. When and how potassium iodide should be used after exposure to radioiodines is also reviewed. In Section IV, Dr. James Armitage describes a narrow "window" of 7 to 10 Gy where therapy with stem cell transplantation may be appropriate. Victims who are candidates for allotransplantation should not have major trauma or significant injury to other (nonhematopoietic) tissues. Rarely, victims may have an identical sibling or autologous stored marrow or blood stem cells, in which case the threshold for transplantation is 4 Gy. In Section V, Dr. Thomas MacVittie describes new directions for therapy, using cytokines such as IL-7, keratinocyte growth factor, and FLT-3. The potential for combinations of cytokines to enhance hematopoietic recovery is also reviewed.

BACKGROUND AND AIMS: We sought to analyze whether response to a second-line biologic varies depending on the reason for discontinuation of the primary anti-TNF agent (primary non-response [PNR], secondary loss of response [LOR] after initial response, or intolerance), through a systematic review and meta-analysis. METHODS: Through a systematic search through May 31, 2017, we identified eight randomized controlled trials [RCTs] of biologics in patients with IBD with prior exposure to anti-TNF agents, that stratified response to second-line therapy by reason for discontinuing primary anti-TNF therapy [PNR vs. LOR vs. intolerance]. We estimated relative risk [RR] (and 95% confidence interval [CI]) of achieving clinical remission in patients with PNR as compared with patients with LOR, and intolerance, through random effects meta-analysis. RESULTS: As compared with patients who discontinued prior anti-TNF due to intolerance, patients with prior PNR were 24% less likely to achieve remission with second-line biologics (RR,0.76 [0.61-0.96]). As compared with patients who discontinued prior anti-TNF due to LOR, patients with prior PNR were 27% less likely to achieve remission with induction therapy with second-line biologics (RR,0.73 [0.56-0.97]), particularly to ustekinumab (RR,0.64 [0.52-0.80]). There was no difference in response to vedolizumab in patients with prior PNR or LOR to anti-TNF agents (RR,1.16 [0.85-1.58]). CONCLUSION: Patients with PNR to anti-TNF agents are less likely to respond to second-line non-TNF biologics, as compared with patients who discontinued therapy due to secondary LOR or intolerance. This may be attributed to underlying pharmacokinetics and pharmacodynamics of anti-TNF agents in patients with PNR.

BACKGROUND: Timely and comprehensive analyses of causes of death stratified by age, sex, and location are essential for shaping effective health policies aimed at reducing global mortality. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 provides cause-specific mortality estimates measured in counts, rates, and years of life lost (YLLs). GBD 2023 aimed to enhance our understanding of the relationship between age and cause of death by quantifying the probability of dying before age 70 years (70q0) and the mean age at death by cause and sex. This study enables comparisons of the impact of causes of death over time, offering a deeper understanding of how these causes affect global populations. METHODS: GBD 2023 produced estimates for 292 causes of death disaggregated by age-sex-location-year in 204 countries and territories and 660 subnational locations for each year from 1990 until 2023. We used a modelling tool developed for GBD, the Cause of Death Ensemble model (CODEm), to estimate cause-specific death rates for most causes. We computed YLLs as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. Probability of death was calculated as the chance of dying from a given cause in a specific age period, for a specific population. Mean age at death was calculated by first assigning the midpoint age of each age group for every death, followed by computing the mean of all midpoint ages across all deaths attributed to a given cause. We used GBD death estimates to calculate the observed mean age at death and to model the expected mean age across causes, sexes, years, and locations. The expected mean age reflects the expected mean age at death for individuals within a population, based on global mortality rates and the population's age structure. Comparatively, the observed mean age represents the actual mean age at death, influenced by all factors unique to a location-specific population, including its age structure. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 250-draw distribution for each metric. Findings are reported as counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2023 include a correction for the misclassification of deaths due to COVID-19, updates to the method used to estimate COVID-19, and updates to the CODEm modelling framework. This analysis used 55 761 data sources, including vital registration and verbal autopsy data as well as data from surveys, censuses, surveillance systems, and cancer registries, among others. For GBD 2023, there were 312 new country-years of vital registration cause-of-death data, 3 country-years of surveillance data, 51 country-years of verbal autopsy data, and 144 country-years of other data types that were added to those used in previous GBD rounds. FINDINGS: The initial years of the COVID-19 pandemic caused shifts in long-standing rankings of the leading causes of global deaths: it ranked as the number one age-standardised cause of death at Level 3 of the GBD cause classification hierarchy in 2021. By 2023, COVID-19 dropped to the 20th place among the leading global causes, returning the rankings of the leading two causes to those typical across the time series (ie, ischaemic heart disease and stroke). While ischaemic heart disease and stroke persist as leading causes of death, there has been progress in reducing their age-standardised mortality rates globally. Four other leading causes have also shown large declines in global age-standardised mortality rates across the study period: diarrhoeal diseases, tuberculosis, stomach cancer, and measles. Other causes of death showed disparate patterns between sexes, notably for deaths from conflict and terrorism in some locations. A large reduction in age-standardised rates of YLLs occurred for neonatal disorders. Despite this, neonatal disorders remained the leading cause of global YLLs over the period studied, except in 2021, when COVID-19 was temporarily the leading cause. Compared to 1990, there has been a considerable reduction in total YLLs in many vaccine-preventable diseases, most notably diphtheria, pertussis, tetanus, and measles. In addition, this study quantified the mean age at death for all-cause mortality and cause-specific mortality and found noticeable variation by sex and location. The global all-cause mean age at death increased from 46·8 years (95% UI 46·6-47·0) in 1990 to 63·4 years (63·1-63·7) in 2023. For males, mean age increased from 45·4 years (45·1-45·7) to 61·2 years (60·7-61·6), and for females it increased from 48·5 years (48·1-48·8) to 65·9 years (65·5-66·3), from 1990 to 2023. The highest all-cause mean age at death in 2023 was found in the high-income super-region, where the mean age for females reached 80·9 years (80·9-81·0) and for males 74·8 years (74·8-74·9). By comparison, the lowest all-cause mean age at death occurred in sub-Saharan Africa, where it was 38·0 years (37·5-38·4) for females and 35·6 years (35·2-35·9) for males in 2023. Lastly, our study found that all-cause 70q0 decreased across each GBD super-region and region from 2000 to 2023, although with large variability between them. For females, we found that 70q0 notably increased from drug use disorders and conflict and terrorism. Leading causes that increased 70q0 for males also included drug use disorders, as well as diabetes. In sub-Saharan Africa, there was an increase in 70q0 for many non-communicable diseases (NCDs). Additionally, the mean age at death from NCDs was lower than the expected mean age at death for this super-region. By comparison, there was an increase in 70q0 for drug use disorders in the high-income super-region, which also had an observed mean age at death lower than the expected value. INTERPRETATION: We examined global mortality patterns over the past three decades, highlighting-with enhanced estimation methods-the impacts of major events such as the COVID-19 pandemic, in addition to broader trends such as increasing NCDs in low-income regions that reflect ongoing shifts in the global epidemiological transition. This study also delves into premature mortality patterns, exploring the interplay between age and causes of death and deepening our understanding of where targeted resources could be applied to further reduce preventable sources of mortality. We provide essential insights into global and regional health disparities, identifying locations in need of targeted interventions to address both communicable and non-communicable diseases. There is an ever-present need for strengthened health-care systems that are resilient to future pandemics and the shifting burden of disease, particularly among ageing populations in regions with high mortality rates. Robust estimates of causes of death are increasingly essential to inform health priorities and guide efforts toward achieving global health equity. The need for global collaboration to reduce preventable mortality is more important than ever, as shifting burdens of disease are affecting all nations, albeit at different paces and scales. FUNDING: Gates Foundation.

OBJECTIVE: The lack of generally accepted diagnostic criteria for neuroleptic malignant syndrome (NMS) impedes research and clinical management of patients receiving antipsychotic medications. The purpose of this study was to develop NMS diagnostic criteria reflecting a broad consensus among clinical knowledge experts, represented by an international multispecialty physician panel. PARTICIPANTS: Eleven psychiatrists, 2 neurologists, 2 anesthesiologists, and 2 emergency medicine specialists participated in a formal Delphi consensus procedure. EVIDENCE: A core bibliography consisting of 12 prominent, current reviews of the NMS literature was identified by an objective, comprehensive electronic search strategy. Each panel member was given a copy of these references and asked to examine them before commencing the survey process. CONSENSUS PROCESS: After reviewing the core bibliography, panel members were asked to list any clinical signs or symptoms or diagnostic studies that they believed, on the basis of their knowledge and clinical experience, were useful in making a diagnosis of NMS. In subsequent survey rounds, panel members assigned priority points to these items, and items that failed to receive a minimum priority score were eliminated from the next round. Information about individual panel member responses was fed back to the group anonymously in the form of the group median or mean and the number of members who had ranked or scored each survey item. The a priori consensus endpoint was defined operationally as a change of 10% or less in the mean priority score for any individual item, and an average absolute value change of 5% or less across all items, between consecutive rounds. The survey was conducted from January 2009 through September 2009. RESULTS: Consensus was reached on the fifth round regarding the following criteria: recent dopamine antagonist exposure, or dopamine agonist withdrawal; hyperthermia; rigidity; mental status alteration; creatine kinase elevation; sympathetic nervous system lability; tachycardia plus tachypnea; and a negative work-up for other causes. The panel also reached a consensus on the relative importance of these criteria and on the following critical values for quantitative criteria: hyperthermia, > 100.4°F or > 38.0°C on at least 2 occasions; creatine kinase elevation, at least 4 times the upper limit of normal; blood pressure elevation, ≥ 25% above baseline; blood pressure fluctuation, ≥ 20 mm Hg (diastolic) or ≥ 25 mm Hg (systolic) change within 24 hours; tachycardia, ≥ 25% above baseline; and tachypnea, ≥ 50% above baseline. CONCLUSIONS: These diagnostic criteria significantly advance the field because they represent the consensus of an international multispecialty expert panel, include critical values, provide guidance regarding the relative importance of individual elements, and are less influenced by particular theoretical biases than most previously published criteria. They require validation before being applied in clinical settings.

PROBLEM: Women with antiphospholipid antibodies (aPL) are at risk for recurrent miscarriage, pre-eclampsia, and pre-term labor. aPL target the placenta directly by binding to beta(2)-glycoprotein I (beta(2)GPI) expressed on the surface of trophoblast cells. The objective of this study was to determine the effects of aPL on trophoblast function and the mechanisms involved. METHOD OF STUDY: First trimester trophoblast cells were treated with anti-beta(2)GPI monoclonal antibodies and patient-derived aPL, after which cell survival and function was evaluated. RESULTS: We report that anti-beta(2)GPI antibodies trigger an inflammatory response in trophoblast, characterized by increased secretion of interleukin (IL)-8, MCP-1, GRO-alpha, and IL-1beta, and that this occurs in a TLR-4/MyD88-dependent manner. At high concentrations, these antibodies also induce caspase-mediated cell death. This was attenuated upon disabling of the MyD88 pathway, suggesting that anti-beta(2)GPI-induced inflammatory mediators compromise trophoblast survival by acting in an autocrine/paracrine manner. Enhanced IL-8, GRO-alpha, and IL-1beta secretion also occurred when trophoblast cells were incubated with antibodies from patients with antiphospholipid syndrome. Heparin, which acts as a pro-survival factor in human trophoblast, attenuated the anti-beta(2)GPI antibody-mediated cell death, and also the pro-inflammatory response, but only at high concentrations. CONCLUSION: These findings demonstrate that aPL triggers a placental inflammatory response via the TLR-4/MyD88 pathway, which in turn compromises trophoblast survival. Thus, the TLR-4/MyD88 pathway may provide a new therapeutic target to improve pregnancy outcome in antiphospholipid syndrome patients.

This randomized, controlled trial was designed to document the effectiveness of Child FIRST (Child and Family Interagency, Resource, Support, and Training), a home-based, psychotherapeutic, parent-child intervention embedded in a system of care. Multirisk urban mothers and children, ages 6-36 months (N = 157) participated. At the 12-month follow-up, Child FIRST children had improved language (odds ratio [OR] = 4.4) and externalizing symptoms (OR= 4.7) compared to Usual Care children. Child FIRST mothers had less parenting stress at the 6-month follow-up (OR = 3.0), lower psychopathology symptoms at 12-month follow-up (OR = 4.0), and less protective service involvement at 3 years postbaseline (OR = 2.1) relative to Usual Care mothers. Intervention families accessed 91% of wanted services relative to 33% among Usual Care. Thus, Child FIRST is effective with multirisk families raising young children across multiple child and parent outcomes.

In the light of the increase in teenage sexual activity over the past decade, the authors review current social, psychological, and educational attitudes. Together with a summary of the legal ramifications, they provide recommendations for treatment of this patient group.

OBJECTIVE: The present umbrella review aims to collate and summarize the findings from previous meta-analyses on the Triglyceride and Glucose (TyG) Index, providing insights to clinicians, researchers, and policymakers regarding the usefulness of this biomarker in various clinical settings. METHODS: A comprehensive search was conducted in PubMed, Scopus, and Web of Science up to April 14, 2024, without language restrictions. The AMSTAR2 checklist assessed the methodological quality of the included meta-analyses. Statistical analyses were performed using Comprehensive Meta-Analysis (CMA) software. RESULTS: A total of 32 studies were finally included. The results revealed significant associations between the TyG index and various health outcomes. For kidney outcomes, a high TyG index was significantly associated with an increased risk of contrast-induced nephropathy (CIN) (OR = 2.24, 95% CI: 1.82-2.77) and chronic kidney disease (CKD) (RR = 1.46, 95% CI: 1.32-1.63). High TyG index was significantly associated with an increased risk of type 2 diabetes mellitus (T2DM) (RR = 3.53, 95% CI: 2.74-4.54), gestational diabetes mellitus (GDM) (OR = 2.41, 95% CI: 1.48-3.91), and diabetic retinopathy (DR) (OR = 2.34, 95% CI: 1.31-4.19). Regarding metabolic diseases, the TyG index was significantly higher in patients with obstructive sleep apnea (OSA) (SMD = 0.86, 95% CI: 0.57-1.15), metabolic syndrome (MD = 0.83, 95% CI: 0.74-0.93), and non-alcoholic fatty liver disease (NAFLD) (OR = 2.36, 95% CI: 1.88-2.97) compared to those without these conditions. In cerebrovascular diseases, a higher TyG index was significantly associated with an increased risk of dementia (OR = 1.14, 95% CI: 1.12-1.16), cognitive impairment (OR = 2.31, 95% CI: 1.38-3.86), and ischemic stroke (OR = 1.37, 95% CI: 1.22-1.54). For cardiovascular outcomes, the TyG index showed significant associations with an increased risk of heart failure (HF) (HR = 1.21, 95% CI: 1.12-1.30), atrial fibrillation (AF) (SMD = 1.22, 95% CI: 0.57-1.87), and hypertension (HTN) (RR = 1.52, 95% CI: 1.25-1.85). CONCLUSION: The TyG index is a promising biomarker for screening and predicting various medical conditions, particularly those related to insulin resistance and metabolic disorders. However, the heterogeneity and methodological quality of the included studies suggest the need for further high-quality research to confirm these findings and refine the clinical utility of the TyG index.

Magnetic resonance imaging (MRI) has been playing an increasingly important role in the spinal trauma patients due to high sensitivity for detection of acute soft tissue and cord injuries. More and more patients are undergoing MRI for spinal trauma in the emergency settings, thus necessitating the interpreting physicians to be familiar with MRI findings in spinal trauma. In this pictorial review, we will first describe the normal anatomy of various ligamentous structures. Indications of MRI in spinal trauma as well as the role of MRI in diagnosing spinal cord and soft tissue injuries will then be discussed. Illustrated cases are mainly of cervical spine trauma, but thoracolumbar spine injuries are also included where appropriate in our review.

Clinical presentations as well as radiological and histopathological findings in biopsies from patients with multiple sclerosis (MS) or other demyelinating disorders of the central nervous system are sometimes misleading, resulting in an erroneous diagnosis of brain or spinal cord tumor. We report 17 patients who presented with symptoms mimicking those of brain (14 cases) or spinal cord (three cases) tumors. Computerized tomography or magnetic resonance imaging studies or both were interpreted as consistent with a tumor in each case. All patients underwent surgery, and all 17 pathological specimens were eventually diagnosed as showing demyelinating disease, usually consistent with MS. In each case we examined a variety of histological features and immunohistochemical studies and addressed their relative importance in considering the diagnosis of MS. All cases showed perivascular lymphocytic inflammation with variable amounts of macrophage infiltration, necrosis, and edema. The hypercellularity of the lesions and the presence of atypical reactive astrocytes with mitotic figures were the disturbing features that might have led to the erroneous diagnosis of an astrocytic neoplasm. Immunohistochemistry for astrocytic (glial fibrillary acidic protein) and macrophage (HAM-56) markers are helpful in evaluating biopsies. Our results emphasize the need to perform special stains (i.e., for myelin and axons) that demonstrate myelin loss and relative preservation of axons and allow a correct diagnosis.