• infection control
• opportunist lung infections

• Humans
• Male
• Retrospective Studies
• Brain Injuries, Traumatic/complications
• Brain Injuries, Traumatic/mortality
• Female
• Middle Aged
• Intensive Care Units
• Adult
• Nomograms
• Risk Factors
• Aged
• Risk Assessment
• Respiratory Tract Infections/epidemiology
• Predictive Value of Tests
• ROC Curve

• Bacteria
• Controlled cortical impact
• Hospital-acquired infection
• Inflammation
• Pneumonia

• Animals
• Brain Injuries, Traumatic/microbiology
• Brain Injuries, Traumatic/complications
• Brain Injuries, Traumatic/pathology
• Mice
• Klebsiella pneumoniae
• Klebsiella Infections/pathology
• Klebsiella Infections/microbiology
• Female
• Disease Models, Animal
• Male
• Mice, Inbred C57BL
• Cytokines/metabolism
• Bronchoalveolar Lavage Fluid

• W81XWH-19-ERP-IDA U.S. Department of Defense
• W81XWH-19-ERP-IDA U.S. Department of Defense
• W81XWH-19-ERP-IDA U.S. Department of Defense
• W81XWH-19-ERP-IDA U.S. Department of Defense
• W81XWH-19-ERP-IDA U.S. Department of Defense
• National Health and Medical Research Council
• Veski

• animal model
• bacteria
• immunosuppression
• inflammation
• neurotrauma
• pneumonia
• traumatic brain injury

• Animals
• Humans
• Brain Injuries, Traumatic/complications
• Brain Injuries
• Cross Infection
• Disease Models, Animal
• Hospitals

• Acute respiratory distress syndrome
• Brain injury
• Lung injury
• Mechanical ventilation
• Prognostic factors

• Brain trauma
• Immune system disorders

• Humans
• Brain Injuries/complications
• Glasgow Coma Scale
• Biomarkers
• Immune System Diseases/complications

• Autonomic nervous system
• Baroreflex sensitivity
• Pressure reactivity index
• Prognosis
• Traumatic brain injury

• Hospital complications
• Neurocritical care
• Outcomes research
• Prediction score
• Traumatic brain injury

Procalcitonin (PCT) is an acknowledged marker of systemic inflammatory response. Previous studies have not reached agreement on the association between serum PCT and outcome of traumatic brain injury (TBI) patients. We designed this study to confirm the prognostic value of PCT in isolated TBI and those with extracranial injury, respectively.

Patients hospitalized in our hospital for moderate-to-severe TBI between March 2015 and December 2019 were included. Logistic regression analysis was performed to validate the association between PCT and in-hospital mortality in these patients. AUC (area under the receiver operating characteristics curve) of PCT and constructed model were calculated and compared.

Among the included 211 patients, 81 patients suffered a poor outcome, with a mortality rate of 38.4%. Non-survivors had a higher level of serum PCT (2.73 vs 0.72, p<0.001) and lower GCS (5 vs 7, p<0.001) on admission than survivors. AUC of single PCT for predicting mortality in isolated TBI and those with extracranial injury were 0.767 and 0.553, respectively. Multivariate logistic regression showed that GCS (OR=0.744, p=0.008), glucose (OR=1.236, p<0.001), cholesterol (OR=0.526, p=0.002), and PCT (OR=1.107, p=0.022) were independently associated with mortality of isolated TBI. The AUC of the prognostic model composed of GCS, glucose, cholesterol, and PCT was 0.868 in isolated TBI.

PCT is an efficient marker of outcome in isolated moderate-to-severe TBI but not those with extracranial injury. A prognostic model incorporating PCT is useful for clinicians to make early risk stratification for isolated TBI.

• 1·3·5 project for disciplines of excellence–Clinical Research Incubation Project, West China Hospital, Sichuan University
• Knowledge Innovation Program of the Chinese Academy of Sciences
• General Program of the National Natural Science Foundation of China

Pneumonia is one of the most common complications in intensive care units and is the most common nosocomial infection in this setting. Patients with neurocritical conditions who are admitted to ICUs are no exception, and in fact, are more prone to infections such as pneumonia because of factors such as swallow dysfunction, need for mechanical ventilation, longer length of stay in hospitals, etc. Common central nervous system pathologies such as ischemic stroke, traumatic brain injury, subarachnoid hemorrhage, intracerebral hemorrhage, neuromuscular disorders, status epilepticus, and demyelinating diseases can cause long in-hospital admissions and increase the risk of pneumonia each with a mechanism of its own. Brain injury-induced immunosuppression syndrome is usually considered the common mechanism through which patients with critical central nervous system conditions become susceptible to different kinds of infection including pneumonia. Evaluating the patients and assessment of the risk factors can lead our attention toward better infection control in this population and therefore decrease the risk of infections in central nervous system injuries.

• lung injury
• neurocritical care
• neurogenic pulmonary edema
• traumatic brain injuries
• ventilator-induced lung injury

• Acute brain injury
• Acute lung injury
• Acute respiratory distress syndrome
• Neurogenic pulmonary edema
• Traumatic brain injury

• Adolescent
• Adult
• Brain Injuries, Traumatic/complications
• Brain Injuries, Traumatic/epidemiology
• Brain Injuries, Traumatic/therapy
• Case-Control Studies
• Cohort Studies
• Female
• Humans
• Male
• Prevalence
• Respiratory Distress Syndrome/diagnosis
• Respiratory Distress Syndrome/epidemiology
• Respiratory Distress Syndrome/etiology

• K23 HL157610 NHLBI NIH HHS

During the last decade, experimental and clinical studies have demonstrated that isolated acute brain injury (ABI) may cause severe dysfunction of peripheral extracranial organs and systems. Of all potential target organs and systems, the lung appears to be the most vulnerable to damage after brain injury (BI). The pathophysiology of these brain–lung interactions are complex and involve neurogenic pulmonary oedema, inflammation, neurodegeneration, neurotransmitters, immune suppression and dysfunction of the autonomic system. The systemic effects of inflammatory mediators in patients with BI create a systemic inflammatory environment that makes extracranial organs vulnerable to secondary procedures that enhance inflammation, such as mechanical ventilation (MV), surgery and infections. Indeed, previous studies have shown that in the presence of a systemic inflammatory environment, specific neurointensive care interventions—such as MV—may significantly contribute to the development of lung injury, regardless of the underlying mechanisms. Although current knowledge supports protective ventilation in patients with BI, it must be born in mind that ABI-related lung injury has distinct mechanisms that involve complex interactions between the brain and lungs. In this context, the role of extracerebral pathophysiology, especially in the lungs, has often been overlooked, as most physicians focus on intracranial injury and cerebral dysfunction. The present review aims to fill this gap by describing the pathophysiology of complications due to lung injuries in patients with a single ABI, and discusses the possible impact of MV in neurocritical care patients with normal lungs.

• Acute respiratory distress syndrome
• Brain damage
• Brain–lung interactions
• Inflammation
• Mechanical ventilation
• Ventilator induced lung injury

• Brain injuries
• Critical care
• Cytokines
• Immunosuppression
• Infection

As population age, healthcare systems and providers are likely to experience a substantial increase in the proportion of elderly patients requiring emergency surgery. Emergency surgery, compared with planned surgery, is strongly associated with increased risks of adverse postoperative outcomes due to the short time available for diagnosis, optimization, and intervention in patients presenting with physiological derangement. These patient populations, who are often frail and burdened with a variety of co-morbidities, have lower reserves to deal with the stress of the acute condition and the required emergency surgical intervention. In this review article, we discuss topical areas where mitigation of the physiological stress posed by the acute condition and asociated surgical intervention may be feasible. We consider the impact of the adrenergic response and use of beta blockers for these high-risk patients and discuss common risk factors such as frailty and delirium. A proactive multidisciplinary approach to peri-operative care aimed at mitigation of the stress response and proactive management of common conditions in the older emergency surgical patient could yield more favorable outcomes.

• Beta-blockers
• Elderly
• Emergency surgery
• Geriatric
• Surgical stress

• COVID-19
• disorder of consciousness
• hospitals
• minimally conscious state
• neurological rehabilitation
• persistent vegetative state
• rehabilitation

• ARDS
• critical care
• multi-organ dysfunction
• traumatic brain injury

Traumatic brain injury leads to cellular damage which in turn results in the rapid release of damage-associated molecular patterns (DAMPs) that prompt resident cells to release cytokines and chemokines. These in turn rapidly recruit neutrophils, which assist in limiting the spread of injury and removing cellular debris. Microglia continuously survey the CNS (central nervous system) compartment and identify structural abnormalities in neurons contributing to the response. After some days, when neutrophil numbers start to decline, activated microglia and astrocytes assemble at the injury site—segregating injured tissue from healthy tissue and facilitating restorative processes. Monocytes infiltrate the injury site to produce chemokines that recruit astrocytes which successively extend their processes towards monocytes during the recovery phase. In this fashion, monocytes infiltration serves to help repair the injured brain. Neurons and astrocytes also moderate brain inflammation via downregulation of cytotoxic inflammation. Depending on the severity of the brain injury, T and B cells can also be recruited to the brain pathology sites at later time points.

• Cellular infiltration
• Microglial dynamics
• Neuroinflammation
• Traumatic brain injury

• Acute respiratory distress syndrome
• Brain injury
• Brain-heart crosstalk
• Brain-lung crosstalk
• Cardiomyopathy
• Neurogenic pulmonary œdema

Severe traumatic brain injury (TBI) patients often develop acute respiratory failure. Optimal ventilator strategies in this setting are not well established. We performed an international survey to investigate the practice in the ventilatory management of TBI patients with and without respiratory failure.

An electronic questionnaire, including 38 items and 3 different clinical scenarios [arterial partial pressure of oxygen (PaO₂)/inspired fraction of oxygen (FiO₂) > 300 (scenario 1), 150–300 (scenario 2), < 150 (scenario 3)], was available on the European Society of Intensive Care Medicine (ESICM) website between November 2018 and March 2019. The survey was endorsed by ESICM.

There were 687 respondents [472 (69%) from Europe], mainly intensivists [328 (48%)] and anesthesiologists [206 (30%)]. A standard protocol for mechanical ventilation in TBI patients was utilized by 277 (40%) respondents and a specific weaning protocol by 198 (30%). The most common tidal volume (TV) applied was 6–8 ml/kg of predicted body weight (PBW) in scenarios 1–2 (72% PaO₂/FIO₂ > 300 and 61% PaO₂/FiO₂ 150–300) and 4–6 ml/kg/PBW in scenario 3 (53% PaO₂/FiO₂ < 150). The most common level of highest positive end-expiratory pressure (PEEP) used was 15 cmH₂O in patients with a PaO₂/FiO₂ ≤ 300 without intracranial hypertension (41% if PaO₂/FiO₂ 150–300 and 50% if PaO₂/FiO₂ < 150) and 10 cmH₂O in patients with intracranial hypertension (32% if PaO₂/FiO₂ 150–300 and 33% if PaO₂/FiO₂ < 150). Regardless of the presence of intracranial hypertension, the most common carbon dioxide target remained 36–40 mmHg whereas the most common PaO₂ target was 81–100 mmHg in all the 3 scenarios. The most frequent rescue strategies utilized in case of refractory respiratory failure despite conventional ventilator settings were neuromuscular blocking agents [406 (88%)], recruitment manoeuvres [319 (69%)] and prone position [292 (63%)].

Ventilatory management, targets and practice of adult severe TBI patients with and without respiratory failure are widely different among centres. These findings may be helpful to define future investigations in this topic.

• Mechanical ventilation
• Respiratory failure
• Traumatic brain injury

• Lower respiratory tract infection
• Pneumonia
• Pulmonary infection
• Spleen
• TBI

• Animals
• Brain Injuries, Traumatic/complications
• Male
• Rats
• Rats, Sprague-Dawley
• Respiratory Tract Infections

• Cholinergic anti-inflammatory pathway
• Immunosuppression
• Pneumonia
• Splenectomy
• Traumatic brain injury

• Fibrin monomers
• Glasgow Outcome Scale
• Progressive hemorrhagic injury
• Severe traumatic brain injury
• Trauma-induced coagulopathy

• Catecholamines
• Cerebral autoregulation
• Creatine kinase
• Traumatic brain injury

• Animals
• Animals, Newborn
• Arterial Pressure/drug effects
• Brain Injuries, Traumatic/blood
• Brain Injuries, Traumatic/physiopathology
• Cerebrovascular Circulation/drug effects
• Creatine Kinase, MB Form/blood
• Creatine Kinase, MB Form/drug effects
• Dopamine/pharmacology
• Epinephrine/blood
• Female
• Heart/drug effects
• Heart/physiopathology
• Homeostasis/drug effects
• Intracranial Pressure
• Male
• Norepinephrine/blood
• Papaverine/pharmacology
• Phenylephrine/pharmacology
• Random Allocation
• Sex Factors
• Sus scrofa
• Swine
• Sympathomimetics/pharmacology
• Troponin I/blood
• Troponin I/drug effects
• Vasodilator Agents/pharmacology

• R01 NS090998 NINDS NIH HHS

• ARDS = acute respiratory distress syndrome
• CI = confidence interval
• CPP = cerebral perfusion pressure
• GCS = Glasgow Coma Scale
• GOS = Glasgow Outcome Scale
• IL = interleukin
• IMPACT = International Mission for Prognosis and Analysis of Clinical Trials
• ISS = Injury Severity Scale
• MODS = multiple organ dysfunction syndrome
• OR = odds ratio
• SOFA = Sequential Organ Failure Assessment
• TBI = traumatic brain injury
• TNF = tumor necrosis factor
• critical care
• cytokines
• multiple organ dysfunction syndrome
• prognosis
• sepsis
• traumatic brain injury

• Adolescent
• Adult
• Aged
• Biomarkers/blood
• Brain Injuries, Traumatic/blood
• Brain Injuries, Traumatic/diagnosis
• Brain Injuries, Traumatic/drug therapy
• Cytokines/blood
• Erythropoietin/therapeutic use
• Female
• Glasgow Outcome Scale/trends
• Humans
• Male
• Middle Aged
• Multiple Organ Failure/blood
• Multiple Organ Failure/diagnosis
• Multiple Organ Failure/drug therapy
• Probability
• Young Adult

Trauma-induced coagulopathy (TIC) is life-threatening in head injury patients, and there is a lack of Indian data on its incidence and outcome.

In this study, incidence and outcome related to coagulopathy were assessed in patients with moderate-to-severe isolated traumatic brain injury (iTBI).

A prospective observational study carried out in patients admitted within 24 h of injury.

One hundred patients with moderate-to-severe iTBI were included. Samples for coagulation tests (prothrombin time [PT], PT index [PTI], international normalization ratio [INR], activated partial thromboplastin time, and platelet count) were collected at 5 points of time for 72 h. TIC was diagnosed if any three readings were abnormal during this period. Patients were also followed up posthospital discharge using the Glasgow Outcome Score (GOS) at 1 and 3 months.

Data were analyzed using SPSS ver. 21. Logistic regression analysis was employed to determine individual coagulation test as best predictors for mortality. P < 0.05 was considered statistically significant.

The incidence of TIC was found to be 62%; it was 63.75% in severe head injury and 55% in moderate head injury patients. Deranged INR at the time of hospital admission (odds ratio [OR] 4.38) and PTI at 24 h (OR 3.913) are highly predictive of mortality. There was no significant difference in GOS score at 1 and 3 months.

The incidence of TIC in our study was 62% among iTBI patients. It contributes to increased mortality at 1 and 3 months. However, the neurological outcome was not different in between the groups.

• Coagulopathy
• GOS
• isolated head injury

Acute respiratory distress syndrome (ARDS) survivors experience a high prevalence of cognitive impairment with concomitantly impaired functional status and quality of life, often persisting months after hospital discharge. In this review, we explore the pathophysiological mechanisms underlying cognitive impairment following ARDS, the interrelations between mechanisms and risk factors, and interventions that may mitigate the risk of cognitive impairment. Risk factors for cognitive decline following ARDS include pre-existing cognitive impairment, neurological injury, delirium, mechanical ventilation, prolonged exposure to sedating medications, sepsis, systemic inflammation, and environmental factors in the intensive care unit, which can co-occur synergistically in various combinations. Detection and characterization of pre-existing cognitive impairment imparts challenges in clinical management and longitudinal outcome study enrollment. Patients with brain injury who experience ARDS constitute a distinct population with a particular combination of risk factors and pathophysiological mechanisms: considerations raised by brain injury include neurogenic pulmonary edema, differences in sympathetic activation and cholinergic transmission, effects of positive end-expiratory pressure on cerebral microcirculation and intracranial pressure, and sensitivity to vasopressor use and volume status. The blood-brain barrier represents a physiological interface at which multiple mechanisms of cognitive impairment interact, as acute blood-brain barrier weakening from mechanical ventilation and systemic inflammation can compound existing chronic blood-brain barrier dysfunction from Alzheimer’s-type pathophysiology, rendering the brain vulnerable to both amyloid-beta accumulation and cytokine-mediated hippocampal damage. Although some contributory elements, such as the presenting brain injury or pre-existing cognitive impairment, may be irreversible, interventions such as minimizing mechanical ventilation tidal volume, minimizing duration of exposure to sedating medications, maintaining hemodynamic stability, optimizing fluid balance, and implementing bundles to enhance patient care help dramatically to reduce duration of delirium and may help prevent acquisition of long-term cognitive impairment.

• ARDS
• Blood-brain barrier
• Cognitive impairment
• ICU delirium
• Inflammation
• Mechanical ventilation
• Outcomes
• Pathophysiological mechanisms

• Healthcare-associated infections
• Healthcare-associated meningitis and ventriculitis
• Infections in brain injury

• Brain Injuries/immunology
• Central Nervous System Infections/complications
• Central Nervous System Infections/diagnosis
• Central Nervous System Infections/therapy
• Cross Infection/complications
• Cross Infection/diagnosis
• Cross Infection/therapy
• Encephalitis/diagnosis
• Humans
• Infection Control
• Meningitis/diagnosis
• Neuroimmunomodulation

• In-hospital complications
• Older adults
• Sex differences
• Traumatic brain injury

• age
• brain injury
• cerebral autoregulation
• histopathology
• sex
• signal transduction
• vasopressor

Acute kidney injury following traumatic brain injury is associated with poor outcome. We investigated in vitro the effects of plasma of brain injured patients with acute tubular kidney injury on kidney tubular epithelial cell function. we performed a prospective observational clinical study in ICU in a trauma centre of the University hospital in Italy including twenty-three ICU patients with traumatic brain injury consecutively enrolled. Demographic data were recorded on admission: age 39 ± 19, Glasgow Coma Score 5 (3–8). Neutrophil Gelatinase-Associated Lipocalin and inflammatory mediators were measured in plasma on admission and after 24, 48 and 72 hours; urine were collected for immunoelectrophoresis having healthy volunteers as controls. Human renal proximal tubular epithelial cells were stimulated with patients or controls plasma. Adhesion of freshly isolated human neutrophils and trans-epithelial electrical resistance were assessed; cell viability (XTT assay), apoptosis (TUNEL staining), Neutrophil Gelatinase-Associated Lipocalin and Megalin expression (quantitative real-time PCR) were measured. All patients with normal serum creatinine showed increased plasmatic Neutrophil Gelatinase-Associated Lipocalin and increased urinary Retinol Binding Protein and α1-microglobulin. Neutrophil Gelatinase-Associated Lipocalin was significantly correlated with both inflammatory mediators and markers of tubular damage. Patient’ plasma incubated with tubular cells significantly increased adhesion of neutrophils, reduced trans-epithelial electrical resistance, exerted a cytotoxic effect and triggered apoptosis and down-regulated the endocytic receptor Megalin compared to control. Plasma of brain injured patients with increased markers of subclinical acute kidney induced a pro-inflammatory phenotype, cellular dysfunction and apoptotic death in tubular epithelial cells.

• dual-energy X-ray absorptiometry scan
• intracranial hemorrhages
• multi-detector computed tomography
• traumatic brain hemorrhage

• Adult
• Female
• Humans
• Intracranial Hemorrhage, Traumatic/diagnostic imaging
• Male
• Middle Aged
• Neuroimaging/methods
• Reproducibility of Results
• Retrospective Studies
• Tomography, X-Ray Computed/methods

• Norepinephrine
• Programmed cell death-1
• Sympathetic nervous system
• T cell dysfunction
• Traumatic brain injury

• Adrenergic beta-Antagonists/pharmacology
• Animals
• Brain Contusion/immunology
• Brain Injuries, Traumatic/immunology
• CD4-Positive T-Lymphocytes/drug effects
• CD4-Positive T-Lymphocytes/immunology
• CD8-Positive T-Lymphocytes/drug effects
• CD8-Positive T-Lymphocytes/immunology
• Flow Cytometry
• Immune Tolerance/immunology
• Interferon-gamma/immunology
• Leukocytes, Mononuclear/immunology
• Norepinephrine/metabolism
• Programmed Cell Death 1 Receptor/drug effects
• Programmed Cell Death 1 Receptor/immunology
• Propranolol/pharmacology
• Rats
• Sympathetic Nervous System/drug effects
• Sympathetic Nervous System/immunology
• Tumor Necrosis Factor-alpha/immunology
• Up-Regulation

• firearm epidemiology
• gunshot wound to the head
• penetrating brain injury
• traumatic brain injury

• craniotomy
• decompressive craniectomy
• glasgow coma scale
• glasgow outcome scale
• neurotrauma
• severe traumatic brain injury
• traumatic brain injury

• early cultures
• infection
• mortality
• positive cultures
• trauma
• ventilated

• Age
• Concussion
• Immunosenescence
• Infection
• Inflammation
• Polytrauma
• Sepsis
• Toxoplasma gondii

• Acute Disease
• Adult
• Aged
• Anti-Inflammatory Agents/adverse effects
• Anti-Inflammatory Agents/therapeutic use
• Databases, Factual
• Female
• Humans
• Incidence
• Male
• Middle Aged
• Pneumonia/complications
• Pneumonia/epidemiology
• Random Allocation
• Respiration, Artificial
• Respiratory Insufficiency/epidemiology
• Respiratory Insufficiency/etiology
• Respiratory Insufficiency/prevention & control
• Respiratory Insufficiency/therapy
• Risk Assessment/methods
• Subarachnoid Hemorrhage/complications
• Subarachnoid Hemorrhage/epidemiology
• Taiwan/epidemiology
• Valproic Acid/adverse effects
• Valproic Acid/therapeutic use

Coagulopathy is a common occurrence following traumatic brain injury (TBI). There are various studies showing incidence and risk factors of coagulopathy and their correlation with poor outcome in adult as well as paediatric age groups. Exact incidence, associated risk factors, treatment guideline for coagulopathy and its impact on outcome are still lacking. In our study we compared the adults and paediatric age groups TBI patients for incidence and risk factors of coagulopathy and its impact on outcome.

Prospective study of 200 patients including 152 adult patients (age > 18 years) and 48 paediatric (Age < 18 years) patients of TBI admitted in intensive care unit of trauma centre of a tertiary care centre was performed from august 2015 to march 2016. Both population were further subdivided into moderate TBI and severe TBI as per Glasgow coma score (GCS). Patient with long bone injury, chest injury and abdominal injuries, coagulation disorder, liver disease, medical disease like diabetes mellitus and hypertension were excluded from study. Coagulation profile were compared in the both groups (Adult and paediatric) and correlated with the outcome. Chi- Square test, student t test and Odds ratios were used for statistical analysis.

Mean age among the adult and paediatric population were 37.89 ± 11.88 years and 11.41 ± 5.90, respectively. Among the patient with moderate TBI, coagulopathy was seen in 30% patients of adult TBI whereas it was 12.5% among the paediatric TBI (P = 0.185). Among the severe TBI group coagulopathy was observed in 68.03% and 37.5% of adult and paediatric age group respectively (P = 0.0016). There was significant correlation found between midline shift and coagulopathy in the paediatric age group (P = 0.022; OR - 4.58). E. There was significant association of coagulopathy and contusion on CT scan among the adult population (P = 0.007; OR - 3.487) found whereas no such correlation were observed in paediatric population.

Coagulopathy was significantly higher among the adult patient with severe TBI as compare to paediatric patient with severe TBI. There was no statistically significant difference in mortality among patients of both the age groups with coagulopathy.

• Adult
• Glasgow coma score
• coagulopathy
• pediatric
• traumatic brain injury

• Complications
• neurocritical care
• nonneurological complications
• outcome
• systemic complications
• traumatic brain injury

• Coagulation
• Head injury
• Neuropsychology
• Trauma

• Brain Injuries, Traumatic/complications
• Brain Injuries, Traumatic/metabolism
• Brain Injuries, Traumatic/physiopathology
• Catecholamines/metabolism
• Humans
• Hypertension/etiology
• Hypertension/metabolism
• Hypertension/physiopathology
• Hypertension/therapy

• L30 NS084420 NINDS NIH HHS
• T32 GM086270 NIGMS NIH HHS