Results of a randomized, double-blind, placebo-controlled trial of lorcaserin in cocaine use disorder.

BACKGROUND: Cocaine use disorder (CUD) is a major public health problem for which there is no approved pharmacotherapy. The primary purpose of this study was to evaluate the ability of lorcaserin, a 5-hydroxytryptamine2 C (5-HT2 C) receptor agonist, to facilitate abstinence in individuals seeking treatment for CUD. METHODS: This was a 12-site, randomized, parallel arm study with a 13-week Treatment Phase that included a 1-week, single-blind run-in period when all participants received twice daily 15mg acetazolamide capsules (a medication adherence marker), followed by randomization to either twice daily 10mg lorcaserin or placebo capsules for the remaining 12 weeks. Pre-randomization data were utilized in an enrichment strategy aimed at achieving high levels of medication adherence and low placebo response rates in a subgroup of participants that qualified for the "efficacy population." For lorcaserin vs. placebo, the primary efficacy endpoint was the proportion of participants in the efficacy population achieving abstinence during the last three weeks of treatment, as evidenced by self-report of no cocaine use, confirmed by urine testing. RESULTS: Within the efficacy population, 1.1% of 91 participants receiving lorcaserin and 4.3% of 92 receiving placebo achieved abstinence during the last 3 weeks of treatment. Among all randomized participants, 2.5% of 118 receiving lorcaserin and 5.6% of 124 receiving placebo achieved similar abstinence. Study participants receiving lorcaserin exhibited significantly greater reductions in body weight and BMI, indicating that medication adherence was sufficient to produce a pharmacological effect. CONCLUSIONS: Twice daily 10mg lorcaserin failed to demonstrate efficacy in the treatment of CUD.

Replacement of Antiretroviral Therapy with HIV Broadly Neutralizing Antibodies to Maximize the Effectiveness of Chemotherapy in HIV Patients with Lung Cancer.

Non-small cell lung cancer (NSCLC) is the most fatal non-AIDS defining cancer in people living with HIV (PWH) on antiretroviral therapy (ART). Treatment of malignancies in PWH requires concomitant cancer therapy and ART, which can lead to potential drug-drug interactions (DDIs) and overlapping toxicities. In this study, we hypothesize that replacement of ART with HIV broadly neutralizing antibodies (bNAbs) during cancer chemotherapy (chemo) may maintain HIV suppression and tumor inhibition while minimizing DDIs and overlapping toxicities. We compared HIV suppression, tumor inhibition, and toxicity between conventional treatment (ART plus chemo) and a new modality (bNAbs plus chemo) in humanized mice. Humanized mice infected with HIVYU2 and xenografted with human NSCLC A549 cells were treated with NSCLC chemo (cisplatin and gemcitabine) and first-line ART (dolutegravir, tenofovir disoproxil difumarate, and emtricitabine) or bNAbs (N49P9.6-FR and PGT 121) at human equivalent drug doses. We monitored plasma HIV RNA, tumor volume, and toxicities over five cycles of chemo. We found that chemo plus ART or bNAbs were equally effective at maintaining suppression of HIV viremia and tumor growth. Comparative analysis showed that mice on ART and chemo had significant reductions in body weight and significant increases in plasma creatinine concentrations compared with mice on bNAbs and chemo, which suggests that a combination of bNAbs and chemo produces less renal toxicity than an ART and chemo combination. These data suggest that bNAb therapy during concomitant chemo may be an improved treatment option over ART for PWH and NSCLC, and possibly other cancers, because bNAbs maintain HIV suppression while minimizing DDIs and toxicities.

Tolerability, user acceptance and preference for a novel reusable respirator among health care workers.

BACKGROUND: The CleanSpace Technology Halo respirator combines a clear face mask and a powered air supply, without belts or hoses. Although providing higher protection than other respirators used in health care, user acceptance of this device has not been assessed with validated tools. METHODS: We surveyed healthcare workers (HCWs) within a US medical system using Halo respirators in 2021. Subjects completed 3 surveys over 8 weeks, which included the Respirator Comfort, Wearing Experience, and Function Instrument (R-COMFI), a validated tool to assess respirator tolerability. The survey included additional questions about user acceptability and respirator preference. Responses were evaluated for change over time and for significant predictors. RESULTS: Of 113 HCWs who completed the initial survey (29% response rate), mean ± SD R-COMFI score was 9.1± 5.1, (scale 0-47, lower = more tolerable) and did not change over time (P = .42). Fewer years in healthcare significantly predicted better R-COMFI score (P = .01). Many users preferred Halo in both usual care (45%-52%) and care of patients with COVID-19 (60%-64%). DISCUSSION: Halo respirators received favorable tolerability scores by HCWs, who often preferred them, especially during care of patients with COVID-19. CONCLUSIONS: Given demand for respirator use in health care, the innovative design provides higher protection than other respirators with a favorable user experience.

Characteristics Associated With Health Care Worker Knowledge and Confidence in Elastomeric Half-Mask Respirator Use.

OBJECTIVE: This study evaluated health care workers' (HCWs') knowledge and confidence in using elastomeric half-mask respirator (EHMR) attributes known to influence usage. METHODS: Health care workers were surveyed regarding their EHMR donning and doffing experience. Respondents were categorized into competency categories based on their scores. Category differences were analyzed using χ 2 and multiple logistic regression. RESULTS: Seventy-two percent showed high levels of EHMR donning and doffing knowledge and confidence (mastery); however, 21% had greater confidence than knowledge (misinformed). Respiratory therapists had greater odds of mastery than other HCWs ( P < 0.05), whereas those working in medical/surgical and pediatric units had greater odds of doubt than other HCWs ( P < 0.01). CONCLUSIONS: Although most HCWs show high knowledge and confidence with EHMR use, strategies to confirm respirator use competency may ensure greater HCWs protection.

Physiological Impacts of Surgical Mask Coverage of Elastomeric Half-mask Respirator Exhalation Valves in Healthcare Workers.

OBJECTIVES: Elastomeric half-mask respirator (EHMR) use in healthcare increased significantly during the COVID-19 pandemic. Concern for potential release of infectious aerosols from EHMR exhalation valves prompted recommendations to cover them with surgical masks (SMs), thereby improving source control. The physiological and subjective effects of wearing a SM over the exhalation valve of an EHMR, however, are unknown. METHODS: Twelve healthy healthcare worker volunteers completed a 30-min series of simulated healthcare-related tasks, including resting, talking, walking, and bending, proning and supinating a weighted manikin, and performing cardiopulmonary resuscitation. This series recurred three times with different mask configurations-SM only, EHMR only, or EHMR with SM covering the exhalation valve. A transcutaneous sensor continuously measured carbon dioxide (tcPCO2), oxygen saturation (SpO2), and heart rate (HR) from each subject. Subjects scored their rates of perceived exertion (RPE) and levels of discomfort after each round. Physiological parameters and subjective scores were analyzed using mixed linear models with a fixed effect for mask type, activity, age, body mass index (BMI), and gender. Analysis also tested for interaction between mask type and activity. RESULTS: Physiological parameters remained within normal ranges for all mask configurations but varied by task. Statistically significant but small decreases in mean tcPCO2 (37.17 versus 37.88 mmHg, P < 0.001) and SpO2 (97.74 versus 97.94%, P < 0.001) were associated with wearing EHMR with SM over the exhalation valve compared with EHMR alone. Mean HR did not differ between these mask configurations. Wearing SM only was associated with lower RPE and level of discomfort compared with EHMR, but these subjective scores did not differ when comparing EHMR with SM to EHMR only. Age, BMI, and gender had no significant effect on any outcomes. CONCLUSIONS: Wearing a SM over an EHMR did not produce clinically significant changes in tcPCO2, SpO2, or HR compared with uncovered EHMR during healthcare-related tasks. Covered EHMR use also did not affect perceived exertion or discomfort compared with uncovered EHMR use. Covering the exhalation valve of an EHMR with a SM for source control purposes can be done safely.

Complications associated with the current sequential pharmacological management of early postnatal hypotension in extremely premature infants.

Early postnatal hypotension in premature infants is treated with escalating doses of vasopressor-inotropes (VI), followed by hydrocortisone if VI therapy fails. The adverse effects of this standard clinical practice have not been well reported. In a retrospective case-control study, we compared the complications associated with VI and hydrocortisone (HCVI) treatments in extremely low-birth-weight infants (≤1000 g) with contemporaneous normotensive medication-naïve controls via standard univariate and multivariate analyses. Birth weight, gestational age, and receipt of antenatal steroids did not differ between VI (n = 74) and control (n = 124) groups, while the occurrence of gestational diabetes mellitus and risks for patent ductus arteriosus, intraventricular-periventricular hemorrhage, spontaneous intestinal perforation, ventriculomegaly, and bronchopulmonary dsyplasia were higher in VI. Infants in the HCVI group (n = 69) had lower birth weight, gestational age, and receipt of antenatal steroids and higher risks for intraventricular-periventricular hemorrhage, bronchopulmonary dysplasia, air leaks, and patent ductus arteriosus than controls. Whereas the occurrences of spontaneous intestinal perforation, ventriculomegaly, and maternal diabetes mellitus did not differ, that of maternal hypertension trended to be lower in HCVI recipients (P = 0.06). In conclusion, hypotensive extremely low-birth-weight infants treated with VI or with HCVI are susceptible to intraventricular-periventricular hemorrhage, bronchopulmonary dysplasia, and patent ductus arteriosus. Furthermore, those who receive inotropes are at risk for spontaneous intestinal perforation and ventriculomegaly. Maternal diabetes mellitus increases the occurrence of hypotension, which responds to VI. Maternal hypertension does not contribute to VI responsive and tends to decrease the occurrence of VI-refractory hypotension.

Interhospital Transfers with Wide Variability in Emergency General Surgery.

Interhospital transfer of emergency general surgery (EGS) patients is a common occurrence. Modern individual hospital practices for interhospital transfers have unknown variability. A retrospective review of the Maryland Health Services Cost Review Commission database was undertaken from 2013 to 2015. EGS encounters were divided into three groups: encounters not transferred, encounters transferred from a hospital, and encounters transferred to a hospital. In total, 380,405 EGS encounters were identified, including 12,153 (3.2%) encounters transferred to a hospital, 10,163 (2.7%) encounters transferred from a hospital, and 358,089 (94.1%) encounters not transferred. For individual hospitals, percentage of encounters transferred to a hospital ranged from 0 to 30.05 per cent, encounters transferred from a hospital from 0.02 to 14.62 per cent, and encounters not transferred from 69.25 to 99.95 per cent of total encounters at individual hospitals. Percentage of encounters transferred from individual hospitals was inversely correlated with annual EGS hospital volume (P < 0.001, r = -0.59), whereas percentage of encounters transferred to individual hospitals was directly correlated with annual EGS hospital volume (P < 0.001, r = 0.51). Individual hospital practices for interhospital transfer of EGS patients have substantial variability. This is the first study to describe individual hospital interhospital transfer practices for EGS.

Percentage of Mortal Encounters Transferred in Emergency General Surgery.

BACKGROUND: Despite the frequent occurrence of interhospital transfers in emergency general surgery (EGS), rates of transfer of complications are undescribed. Improved understanding of hospital transfer patterns has a multitude of implications, including quality measurement. The objective of this study was to describe individual hospital transfer rates of mortal encounters. MATERIALS AND METHODS: A retrospective review was undertaken from 2013 to 2015 of the Maryland Health Services Cost Review Commission database. Two groups of EGS encounters were identified: encounters with death following transfer and encounters with death without transfer. The percentage of mortal encounters transferred was defined as the percentage of EGS hospital encounters with mortality initially presenting to a hospital transferred to another hospital before death at the receiving hospital. RESULTS: Overall, 370,242 total EGS encounters were included, with 17,003 (4.6%) of the total EGS encounters with mortality. Encounters with death without transfer encompassed 15,604 (91.8%) of mortal EGS encounters and encounters with death following transfer 1399 (8.2%). EGS disease categories of esophageal varices or perforation, necrotizing fasciitis, enterocutaneous fistula, and pancreatitis had over 10% of these total mortal encounters with death following transfer. For individual hospitals, percentage of mortal encounters transferred ranged from 0.8% to 35.2%. The percentage of mortal encounters transferred was inversely correlated with annual EGS hospital volume for all state hospitals (P < 0.001, r = -0.57). CONCLUSIONS: Broad variability in individual hospital practices exists for mortality transferred to other institutions. Application of this knowledge of percentage of mortal encounters transferred includes consideration in hospital quality metrics.

Corrigendum: A randomized synbiotic trial to prevent sepsis among infants in rural India.

This corrects the article DOI: 10.1038/nature23480.

A randomized synbiotic trial to prevent sepsis among infants in rural India.

Sepsis in early infancy results in one million annual deaths worldwide, most of them in developing countries. No efficient means of prevention is currently available. Here we report on a randomized, double-blind, placebo-controlled trial of an oral synbiotic preparation (Lactobacillus plantarum plus fructooligosaccharide) in rural Indian newborns. We enrolled 4,556 infants that were at least 2,000 g at birth, at least 35 weeks of gestation, and with no signs of sepsis or other morbidity, and monitored them for 60 days. We show a significant reduction in the primary outcome (combination of sepsis and death) in the treatment arm (risk ratio 0.60, 95% confidence interval 0.48-0.74), with few deaths (4 placebo, 6 synbiotic). Significant reductions were also observed for culture-positive and culture-negative sepsis and lower respiratory tract infections. These findings suggest that a large proportion of neonatal sepsis in developing countries could be effectively prevented using a synbiotic containing L. plantarum ATCC-202195.

A comparative analysis of ante- and postnatal clinical characteristics of extremely premature neonates suffering from refractory and non-refractory hypotension: Is early clinical differentiation possible?

BACKGROUND: About 25% of hypotensive ELBW infants are refractory to intravascular volume expansion and inotropic drugs (VI) and require hydrocortisone (HC). Such neonates suffer from complications of prolonged hypotension and extended therapy with VI. ELBW infants with refractory hypotension (RH) are clinically and biochemically indistinguishable from those who respond to VI. OBJECTIVE: Early identification and differentiation of ELBW infants susceptible to steroid dependent hypotension from those who respond to inotropic medications. METHODS: In a retrospective study the ante- and postnatal clinical characteristics of ELBW infants who received hydrocortisone (HC) for refractory hypotension (RH) were compared to those who responded to volume-inotropes (VI). RESULTS: Infants in HC group had lower birth weight (BW, 675±121g) and gestational age (GA, 25.1±1.3weeks) and higher mean airway pressure and oxygen requirements, all independent of antenatal steroid (ANS) exposure. The receipt of ANS (p 0.01) and occurrences of maternal diabetes mellitus (GDM, p 0.01) were lower in HC group. ANS (OR 0.5, 95% CI 0.2-0.9, p 0.01) and GDM (OR 0.3, 95% CI 0.09-0.9, p 0.04) reduced the risk for RH. HC group had higher risk for IVH (OR 2.1, 95% CI 1.02-4.2 p=0.04) which declined in the multivariate analysis. A trend towards lower risk of ventriculomegaly (VM) was noted in HC group (OR 0.3, 95% CI 0.1-1.1), which became significant after controlling for BW (OR 0.2 95% CI 0.07-0.9, p 0.04). Similar trend was noted for maternal hypertension. CONCLUSION: Hypotension in ELBW infants who are ≤25wks of GA and unexposed to ANS and GDM is refractory to VI therapy. Such neonates may benefit from an initial therapy with, or earlier institution of hydrocortisone. The trend towards a higher risk for VM with VI therapy needs validation in future studies.

Diffusion Tensor Imaging Parameter Obtained during Acute Blunt Cervical Spinal Cord Injury in Predicting Long-Term Outcome.

There are no reliable neuroimaging biomarkers to predict long-term outcome after spinal cord injury. This prospective longitudinal study evaluates diffusion tensor imaging (DTI) in predicting long-term outcome after cervical spinal cord injury (CSCI). We investigate the admission DTI parameters measured in 30 patients with CSCI, with 16 of them followed up to one year, and 15 volunteers serving as controls. All magnetic resonance imaging examinations were performed within 24 h of injury. The DTI parameters were measured in patients and controls, avoiding areas of hemorrhage in patients and at corresponding upper/middle/lower regions of the spinal cord in controls. Stepwise regression analysis was performed to find relevant parameters (normalized DTI values, age, sex, hemorrhagic contusion [HC or non-HC]) that correlated with two primary outcome measures: patient International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) motor and Spinal Cord Independence Measure (SCIM III) scores at one year. Among all DTI measures, axial diffusivity (AD) most strongly correlated with both motor (r2 = 0.76, p < 0.01) and SCIM III scores (r2 = 0.77, p < 0.01) at one year. Further stepwise regression indicated that including AD (p = 0.0001) and presence of HC (p < 0.0001) in the regression model provided the best model fit for one year ISNCSCI (r2 = 0.93). The AD is a more specific parameter for axonal injury than radial diffusivity; this may indicate that axonal injury in the cord is the main factor affecting patient recovery. Our study demonstrates DTI measurement at the CSCI is a potential neuroimaging biomarker in predicting long-term neurological and functional outcome in blunt CSCI.

Mechanistic insight of platelet apoptosis leading to non-surgical bleeding among heart failure patients supported by continuous-flow left ventricular assist devices.

Non-surgical bleeding (NSB) is the most common clinical complication in heart failure (HF) patients supported by continuous-flow left ventricular assist devices (CF-LVADs). In this study, oxidative stress and alteration of signal pathways leading to platelet apoptosis were investigated. Thirty-one HF patients supported by CF-LVADs were divided into bleeder (n = 12) and non-bleeder (n = 19) groups. Multiple blood samples were collected at pre-implant (baseline) and weekly up to 1-month post-implant. A single blood sample was collected from healthy subjects (reference). Production of reactive oxygen species (ROS) in platelets, total antioxidant capacity (TAC), oxidized low-density lipoproteins (oxLDL), expression of Bcl-2 and Bcl-xL, Bax and release of cytochrome c (Cyt.c), platelet mitochondrial membrane potential (Δψ m), activation of caspases, gelsolin cleavage and platelet apoptosis were examined. Significantly elevated ROS, oxLDL and depleted TAC were evident in the bleeder group compared to non-bleeder group (p < 0.05). Platelet pro-survival proteins (Bcl-2, Bcl-xL) were significantly reduced in the bleeder group in comparison to the non-bleeder group (p < 0.05). Translocation of Bax into platelet mitochondria membrane and subsequent release of Cyt.c were more prevalent in the bleeder group. Platelet mitochondrial damage, activation of caspases, gelsolin cleavage, and ultimate platelet apoptosis in the bleeder group were observed. Oxidative stress and activation of both intrinsic and extrinsic pathways of platelet apoptosis may be linked to NSB in CF-LVAD patients. Additionally, biomarkers of oxidative stress, examination of pro-survivals and pro-apoptotic proteins in platelets, mitochondrial damage, caspase activation, and platelet apoptosis may be used to help identify HF patients at high risk of NSB post-implant.

Blunt splenic injury: use of a multidetector CT-based splenic injury grading system and clinical parameters for triage of patients at admission.

PURPOSE: To assess the use of a dual-phase multidetector computed tomography (CT)-based grading system alone and in combination with assessment of clinical parameters at triage of patients with blunt splenic injury for determination of appropriate treatment (observation, splenic artery embolization [SAE], or splenic surgery). MATERIALS AND METHODS: This HIPAA-compliant retrospective study was approved by the institutional review board, and the requirement for informed consent was waived. Between January 2009 and July 2011, 171 hemodynamically stable patients with blunt splenic injury underwent multidetector CT at admission to the hospital. Images were reviewed by applying a multidetector CT-based grading system, and the amount of hemoperitoneum was quantified. Demographic data, vital signs, laboratory values, injury severity score, abbreviated injury severity, final treatment decision, and success of nonsurgical treatment were reviewed. Receiver operating characteristic curves and stepwise logistic regression analyses were performed to determine the optimal parameters for effective triage of patients. RESULTS: One hundred seventy one patients with splenic injury underwent multidetector CT. At triage, clinical treatment decisions were made, and patients received either observation (85 of 171 [50%]) or splenic intervention (surgery, 19 of 171 [11%] or splenic angiography, 67 of 171 [39%]). Four patients underwent SAE after unsuccessful observation. Six of 171 (3.5%) other patients received unsuccessful nonsurgical treatment with SAE. No patients who received observation required splenectomy. Areas under the receiver operating characteristic curve (AUCs) showed that the CT grading system was the best individual predictor of successful observation (AUC, 0.95), and stepwise logistic regression analysis results showed that multidetector CT grade and the abbreviated injury scale score (AUC, 0.97; P = .02) were the best combination of variables for selection of patients for observation versus splenic intervention. The combination of abbreviated injury scale score, systolic blood pressure reading, and serum glucose level was the best triage model for decision making between splenectomy and SAE (AUC, 0.84). CONCLUSION: The best individual predictor of successful observation in patients with blunt splenic injury was the CT-based grading system. Multidetector CT grade and abbreviated injury scale score were the best combination of variables for selection of patients for observation versus splenic intervention.

Intracranial pressure response after pharmacologic treatment of intracranial hypertension.

BACKGROUND: The accepted treatment of increased intracranial pressure (ICP) in patients experiencing severe traumatic brain injury is multimodal and algorithmic, obscuring individual effects of treatment. Using continuous vital signs monitoring, we sought to measure treatment effect and ascertain the accuracy of manual data recording. METHODS: Patients older than 17 years, admitted and requiring ICP monitoring between 2008 and 2010 at a high-volume urban trauma center, were retrospectively evaluated. Timing and dose of ICP-directed therapy were recorded from paper and electronic medical records. ICP data were collected automatically at 6-second intervals and from manual charts. A statistical mixed model was applied to all data to account for multiple sampling. RESULTS: A total of 117 patients met inclusion criteria; 450 treatments were administered when nursing records indicate an ICP greater than 20 mm Hg, while 968 treatments were given when ICP was greater than 20 mm Hg by automated data. Pharmacologic treatments identified include hypertonic saline (HTS), mannitol, barbiturates, and dose escalations of propofol or fentanyl infusions. Treatment with HTS resulted in the largest ICP decrease of the treatments examined, with a 1-hour ICP reduction of 8.8/9.9 mm Hg (for a small/large dose) according to manual data and a reduction of 3.0/2.4 mm Hg according to automated data. Propofol and fentanyl escalations resulted in smaller but significant ICP reductions. Mannitol (n = 8) resulted in statistically insignificant trends down in the first hour but rebounded by the second hour after administration. The average ICP in the hour before medication administration was higher for barbiturates (27 mm Hg) and mannitol (32 mm Hg) than for the other interventions (18-19 mm Hg). CONCLUSION: ICP fell after administration of HTS, mannitol, or barbiturates and showed continued improvement after 2 hours. ICP fell initially after treatment with short-acting propofol and fentanyl but trended back up after 2 hours. Manually recorded data consistently overestimated treatment effectiveness. Automated data collection gives a more accurate assessment of patient status and responsiveness to treatment. LEVEL OF EVIDENCE: Therapeutic study, level IV.

Automated prediction of early blood transfusion and mortality in trauma patients.

BACKGROUND: Prediction of blood transfusion needs and mortality for trauma patients in near real time is an unrealized goal. We hypothesized that analysis of pulse oximeter signals could predict blood transfusion and mortality as accurately as conventional vital signs (VSs). METHODS: Continuous VS data were recorded for direct admission trauma patients with abnormal prehospital shock index (SI = heart rate [HR] / systolic blood pressure) greater than 0.62. Predictions of transfusion during the first 24 hours and in-hospital mortality using logistical regression models were compared with DeLong's method for areas under receiver operating characteristic curves (AUROCs) to determine the optimal combinations of prehospital SI and HR, continuous photoplethysmographic (PPG), oxygen saturation (SpO2), and HR-related features. RESULTS: We enrolled 556 patients; 37 received blood within 24 hours; 7 received more than 4 U of red blood cells in less than 4 hours or "massive transfusion" (MT); and 9 died. The first 15 minutes of VS signals, including prehospital HR plus continuous PPG, and SpO2 HR signal analysis best predicted transfusion at 1 hour to 3 hours, MT, and mortality (AUROC, 0.83; p < 0.03) and no differently (p = 0.32) from a model including blood pressure. Predictions of transfusion based on the first 15 minutes of data were no different using 30 minutes to 60 minutes of data collection. SI plus PPG and SpO2 signal analysis (AUROC, 0.82) predicted 1-hour to 3-hour transfusion, MT, and mortality no differently from pulse oximeter signals alone. CONCLUSION: Pulse oximeter features collected in the first 15 minutes of our trauma patient resuscitation cohort, without user input, predicted early MT and mortality in the critical first hours of care better than the currently used VS such as combinations of HR and systolic blood pressure or prehospital SI alone. LEVEL OF EVIDENCE: Therapeutic/prognostic study, level II.

Cellular alterations in human traumatic brain injury: changes in mitochondrial morphology reflect regional levels of injury severity.

Mitochondrial dysfunction may be central to the pathophysiology of traumatic brain injury (TBI) and often can be recognized cytologically by changes in mitochondrial ultrastructure. This study is the first to broadly characterize and quantify mitochondrial morphologic alterations in surgically resected human TBI tissues from three contiguous cortical injury zones. These zones were designated as injury center (Near), periphery (Far), and Penumbra. Tissues from 22 patients with TBI with varying degrees of damage and time intervals from TBI to surgical tissue collection within the first week post-injury were rapidly fixed in the surgical suite and processed for electron microscopy. A large number of mitochondrial structural patterns were identified and divided into four survival categories: normal, normal reactive, reactive degenerating, and end-stage degenerating profiles. A tissue sample acquired at 38 hours post-injury was selected for detailed mitochondrial quantification, because it best exhibited the wide variation in cellular and mitochondrial changes consistently noted in all the other cases. The distribution of mitochondrial morphologic phenotypes varied significantly between the three injury zones and when compared with control cortical tissue obtained from an epilepsy lobectomy. This study is unique in its comparative quantification of the mitochondrial ultrastructural alterations at progressive distances from the center of injury in surviving TBI patients and in relation to control human cortex. These quantitative observations may be useful in guiding the translation of mitochondrial-based neuroprotective interventions to clinical implementation.

Computational gene mapping to analyze continuous automated physiologic monitoring data in neuro-trauma intensive care.

BACKGROUND: We asked whether the advanced machine learning applications used in microarray gene profiling could assess critical thresholds in the massive databases generated by continuous electronic physiologic vital signs (VS) monitoring in the neuro-trauma intensive care unit. METHODS: We used Class Prediction Analysis to predict binary outcomes (life/death, good/bad Extended Glasgow Outcome Score, etc.) based on data accrued within 12, 24, 48, and 72 hours after admission to the neuro-trauma intensive care unit. Univariate analyses selected "features," discriminator VS segments or "genes," in each individual's data set. Prediction models using these selected features were then constructed using six different statistical modeling techniques to predict outcome for other individuals in the sample cohort based on the selected features of each individual then cross-validated with a leave-one-out method. RESULTS: We gleaned complete sets of 588 VS monitoring segment features for each of four periods and outcomes from 52 of 60 patients with severe traumatic brain injury who met study inclusion criteria. Overall, intracranial pressures and blood pressures over time (e.g., intracranial pressure >20 mm Hg for 20 minutes) provided the best discrimination for outcomes. Modeling performed best in the first 12 hours of care and for mortality. The mean number of selected features included 76 predicting 14-day hospital stay in that period, 11 predicting mortality, and 4 predicting 3-month Extended Glasgow Outcome Score. Four of the six techniques constructed models that correctly identified mortality by 12 hours 75% of the time or higher. CONCLUSION: Our results suggest that valid prediction models after severe traumatic brain injury can be constructed using gene mapping techniques to analyze large data sets from conventional electronic monitoring data, but that this methodology needs validation in larger data sets, and that additional unstructured learning techniques may also prove useful.

Live colonocytes in newborn stool: surrogates for evaluation of gut physiology and disease pathogenesis.

Studies of gastrointestinal pathophysiology are not feasible by biopsies in human neonates. We examined the utility of live colonocytes in stool in studying cellular markers during early neonatal life. Expression of IgA, IgG, cluster of differentiation-45 cells (CD45), and toll-like receptors-2 and 4 (TLR2 and TLR4) were analyzed by flow cytometry. Colonocyte RNA extracts were used in quantitative real-time PCR (qRT-PCR) to examine the expression of cytokeratin-19, ribosomal protein-24, and tight-junction (Tj) protein zonula occludens-1 (ZO-1). Colonocyte yield varied between 5 × 104 to 2 × 106 cells/g of stool. Meconium samples yielded a highly enriched population of viable cells. Although low, all samples showed CD45-positive cells during the initial weeks of life. Starting as early as d 2, IgA expression was observed in 69% of the cells. Low to moderate expression of IgG was observed with a linear increase as the infants grew. There was an almost total lack of TLR2 staining; however, >55% of the colonocytes showed TLR4 expression. Although high levels of IgA in gut cells may serve as a natural protectant during neonatal period, increased TLR4 may provide a niche for lipopolysaccharide (LPS)-mediated epithelial damage. Use of stool colonocytes can be a valuable noninvasive approach for studying gut pathophysiology in the neonatal period.