Optimization-Based Stable Balancing Weights Versus Propensity Score Weighting for Samples With High Covariate Imbalance.

PURPOSE: To compare the performance (covariate balance, effective sample size [ESS]) of stable balancing weights (SBW) versus propensity score weighting (PSW). Two applied cases were used to compare performance: (Case 1) extreme imbalance in baseline covariates between groups and (Case 2) substantial discrepancy in sample size between groups. METHODS: Using the Premier Healthcare Database, we selected patients who (Case 1) underwent a surgical procedure with one of two different bipolar forceps between January 2000 and June 2020, or (Case 2) a neurological procedure using one of two different nonabsorbable surgical sutures between January 2000 and March 2020. Average treatment effects on the treated (ATT) weights were generated based on selected covariates. SBW was implemented using two techniques: (1) "grid search" to find weights of minimum variance at the lowest target absolute standardized mean difference (SMD); (2) finding weights of minimum variance at prespecified SMD tolerance. PSW and SBW methods were compared on postweighting SMDs, the number of imbalanced covariates, and ESS of the ATT-weighted control group. RESULTS: In both studies, improved covariate balance was achieved with both SBW techniques. All methods suffered from postweighting ESS that was lower than the unweighted control group's original sample size; however, SBW methods achieved higher ESS for the control groups. Sensitivity analyses using SBW to apply variable-specific SMD thresholds increased ESS, outperforming PSW. CONCLUSIONS: In this applied example, the optimization-based SBW method provided ample flexibility with respect to prespecification of covariate balance goals and resulted in better postweighting covariate balance and larger ESS as compared with PSW.

Cigarette smoking and white matter microstructure in schizophrenia.

The majority of patients with schizophrenia smoke cigarettes. Both nicotine use and schizophrenia have been associated with alterations in brain white matter microstructure as measured by diffusion tensor imaging (DTI). The purpose of this study was to examine fractional anisotropy (FA) in smoking and non-smoking patients with schizophrenia and in healthy volunteers. A total of 43 patients (28 smoking and 15 non-smoking) with schizophrenia and 40 healthy, non-smoking participants underwent DTI. Mean FA was calculated in four global regions of interest (ROIs) (whole brain, cerebellum, brainstem, and total cortical) as well as in four regional ROIs (frontal, temporal, parietal and occipital lobes). The non-smoking patient group had a significantly higher intellectual quotient (IQ) compared with the patients who smoked, and our results varied according to whether IQ was included as a covariate. Without IQ correction, significant between-group effects for FA were found in four ROIs: total brain, total cortical, frontal lobe and the occipital lobe. In all cases the FA was lower among the smoking patient group, and highest in the control group. Smoking patients differed significantly from non-smoking patients in the frontal lobe ROI. However, these differences were no longer significant after IQ correction. FA differences between non-smoking patients and controls were not significant. Among smoking and non-smoking patients with schizophrenia but not healthy controls, FA was correlated with IQ. In conclusion, group effects of smoking on FA in schizophrenia might be mediated by IQ. Further, low FA in specific brain areas may be a neural marker for complex pathophysiology and risk for diverse problems such as schizophrenia, low IQ, and nicotine addiction.

A novel method for quantifying scanner instability in fMRI.

A method was developed to quantify the effect of scanner instability on functional MRI data by comparing the instability noise to endogenous noise present when scanning a human. The instability noise was computed from agar phantom data collected with two flip angles, allowing for a separation of the instability from the background noise. This method was used on human data collected at four 3 T scanners, allowing the physiological noise level to be extracted from the data. In a "well-operating" scanner, the instability noise is generally less than 10% of physiological noise in white matter and only about 2% of physiological noise in cortex. This indicates that instability in a well-operating scanner adds very little noise to functional MRI results. This new method allows researchers to make informed decisions about the maximum instability level a scanner can have before it is taken off line for maintenance or rejected from a multisite consortium. This method also provides information about the background noise, which is generally larger in magnitude than the instability noise.

Multi-site characterization of an fMRI working memory paradigm: reliability of activation indices.

Neuroimaging studies are facilitated significantly when it is possible to recruit subjects and acquire data at multiple sites. However, the use of different scanners and acquisition protocols is a potential source of variability in multi-site data. In this work we present a multi-site study of the reliability of fMRI activation indices, where 10 healthy volunteers were scanned at 4 different sites while performing a working memory paradigm. Our results indicate that, even with different scanner manufacturers and field strengths, activation variability due to site differences is small compared to variability due to subject differences in this cognitive task, provided we choose an appropriate activation measure.

The COMT Val108/158Met polymorphism and medial temporal lobe volumetry in patients with schizophrenia and healthy adults.

Abnormalities of the medial temporal lobe have been consistently demonstrated in schizophrenia. A common functional polymorphism, Val108/158Met, in the putative schizophrenia susceptibility gene, catechol-O-methyltransferase (COMT), has been shown to influence medial temporal lobe function. However, the effects of this polymorphism on volumes of medial temporal lobe structures, particularly in patients with schizophrenia, are less clear. Here we measured the effects of COMT Val108/158Met genotype on the volume of two regions within the medial temporal lobe, the amygdala and hippocampus, in patients with schizophrenia and healthy control subjects. We obtained MRI and genotype data for 98 schizophrenic patients and 114 matched controls. An automated atlas-based segmentation algorithm was used to generate volumetric measures of the amygdala and hippocampus. Regression analyses included COMT met allele load as an additive effect, and also controlled for age, intracranial volume, gender and acquisition site. Across patients and controls, each copy of the COMT met allele was associated on average with a 2.6% increase in right amygdala volume, a 3.8% increase in left amygdala volume and a 2.2% increase in right hippocampus volume. There were no effects of COMT genotype on volumes of the whole brain and prefrontal regions. Thus, the COMT Val108/158Met polymorphism was shown to influence medial temporal lobe volumes in a linear-additive manner, mirroring its effect on dopamine catabolism. Taken together with previous work, our data support a model in which lower COMT activity, and a resulting elevation in extracellular dopamine levels, stimulates growth of medial temporal lobe structures.

A phase I, pharmacokinetic, dosage escalation study of creatine monohydrate in subjects with amyotrophic lateral sclerosis.

Creatine monohydrate (creatine) has potential neuroprotective properties and is a commonly used supplement in amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Minimum therapeutic and maximum tolerated dosages of creatine are not yet known, nor is it known what systemic plasma concentrations result from specific dosage regimens. The objectives of this study were to establish steady-state plasma pharmacokinetics of creatine at several dosages, and to evaluate the effects of creatine on brain metabolites using proton magnetic resonance spectroscopy ((1)H-MRS). Six participants with ALS received creatine at three weekly escalating oral dosages (5, 10, and 15 g b.i.d.). Plasma creatine levels and MR spectra were obtained at baseline and with each dosage increase. Mean pre-dose steady-state creatine plasma concentrations were 20.3, 39.3, and 61.5 ug/ml at 5, 10, and 15 g b.i.d., respectively. Creatine spectra increased by 8% (p = 0.06) and glutamate + glutamine signals decreased by 17% (p = 0.039) at higher dosages. There were no safety concerns at any of the dosages. In conclusion, creatine plasma concentrations increased in a dose-dependent manner. Creatine appears to cross the blood-brain barrier, and oral administration of 15 g b.i.d. is associated with increased in vivo brain creatine concentrations and decreased glutamate concentrations.

Red vent syndrome in wild Atlantic salmon Salmo salar in Scotland is associated with Anisakis simplex sensu stricto (Nematoda: Anisakidae).

Simultaneous reports were received between June and July 2007 of wild Atlantic salmon Salmo salar with red, swollen, bloody vents returning to geographically diverse rivers in Scotland. By the end of September the condition, colloquially known as 'red vent syndrome' (RVS), was reported from >50 rivers across Scotland. Fish were generally in good overall condition but the vent area showed mild to severe lesions. External characteristics of the syndrome included a swollen, raised, haemorrhagic vent and surrounding tissues, with erosion of the skin, scale loss and moderate to severe bleeding in more advanced cases. Predominantly, the fish affected were 1-sea-winter grilse; however, RVS was also recorded in 2-sea-winter salmon and sea trout S. trutta. High numbers of the nematode Anisakis Type I larvae were found infesting the discrete region of the vent, a localisation that is reported as novel for the parasite. The hypothesis that this is a different species than that commonly found in the body cavity and viscera was investigated through molecular studies. These studies failed to show evidence that the parasites infesting the vent were different from those in the body cavity, i.e. all were identified as A. simplex sensu stricto. No other disease agent was found associated with the lesions or was isolated systemically, and no mortality or prevention of spawning was recorded during the 2007 season. Possible causes, including warming environments in the North Atlantic, are hypothesised as playing a role in the development of RVS in Atlantic salmon.

Aneurysm of antecubital vein: an unusual complication of peripheral intravenous cannulation.

BACKGROUND: Intravenous cannulation is a very common procedure. Venous aneurysm secondary to peripheral intravenous cannulation is extremely rare. Moreover, venous aneurysm can mimic other conditions and may confuse the issue. CASE PRESENTATION: We describe a case of a 45-year-old woman who was referred with the diagnosis of varicose vein of right arm. A history of intravenous cannulation at the same site was noted that raised suspicion. The swelling was compressible and turned out to be a venous aneurysm. The lesion was completely excised. Postoperative recovery was uneventful. Histology findings were in conformity with the preoperative diagnosis. CONCLUSION: Caution should be exercised in diagnosing varicose vein at a site that bears a history of intravenous cannulation. The case also raises an important issue regarding consent. Should patients undergoing peripheral intravenous cannulation be warned of this rare complication?

Smoking status as a potential confounder in the study of brain structure in schizophrenia.

Several but not all MRI studies have reported volume reductions in the hippocampus and dorsolateral prefrontal cortex (DLPFC) in patients with schizophrenia. Given the high prevalence of smoking among schizophrenia patients and the fact that smoking has also been associated with alterations in brain morphology, this study evaluated whether a proportion of the known gray matter reductions in key brain regions may be attributed to smoking rather than to schizophrenia alone. We examined structural MRI data of 112 schizophrenia patients (53 smokers and 59 non-smokers) and 77 healthy non-smoker controls collected by the MCIC study of schizophrenia. An automated atlas based probabilistic method was used to generate volumetric measures of the hippocampus and DLPFC. The two patient groups were matched with respect to demographic and clinical variables. Smoker schizophrenia patients showed significantly lower hippocampal and DLPFC volumes than non-smoker schizophrenia patients. Gray matter volume reductions associated with smoking status ranged between 2.2% and 2.8%. Furthermore, we found significant volume differences between smoker patients and healthy controls in the hippocampus and DLPFC, but not between non-smoker patients and healthy controls. Our data suggest that a proportion of the volume reduction seen in the hippocampus and DLPFC in schizophrenia is associated with smoking rather than with the diagnosis of schizophrenia. These results may have important implications for brain imaging studies comparing schizophrenia patients and other groups with a lower smoking prevalence.

Global white matter abnormalities in schizophrenia: a multisite diffusion tensor imaging study.

BACKGROUND: Emerging evidence implicates white matter (WM) abnormalities in the pathophysiology of schizophrenia. However, there is considerable heterogeneity in the presentation of WM abnormalities in the existing studies. The object of this study was to evaluate WM integrity in a large sample of patients with first-episode (FE) and chronic schizophrenia in comparison to matched control groups. Our goal was to assess whether WM findings occurred early in the illness or whether these abnormalities developed with the illness over time. METHODS: Participants included 114 patients with schizophrenia (31 FE and 83 chronic patients) and 138 matched controls. High-resolution structural and diffusion tensor images were obtained on all participants. Measures of fractional anisotropy (FA) were calculated for the 4 cortical lobes and the cerebellum and brain stem. RESULTS: FA was significant lower in patients vs controls in the whole brain and individually in the frontal, parietal, occipital, and temporal lobes. FA was not significantly different in the brain stem or cerebellum. FA differences were significant only in patients with chronic schizophrenia and not in the FE group. CONCLUSIONS: We found global differences in the WM microstructure in patients with chronic but not FE schizophrenia. These findings suggest progressive alterations in WM microstructure.

Structural differences in adult orbital and ventromedial prefrontal cortex predicted by infant temperament at 4 months of age.

CONTEXT: The term temperament refers to a biologically based predilection for a distinctive pattern of emotions, cognitions, and behaviors first observed in infancy or early childhood. High-reactive infants are characterized at age 4 months by vigorous motor activity and crying in response to unfamiliar visual, auditory, and olfactory stimuli, whereas low-reactive infants show low motor activity and low vocal distress to the same stimuli. High-reactive infants are biased to become behaviorally inhibited in the second year of life, defined by timidity with unfamiliar people, objects, and situations. In contrast, low-reactive infants are biased to develop into uninhibited children who spontaneously approach novel situations. OBJECTIVE: To examine whether differences in the structure of the ventromedial or orbitofrontal cerebral cortex at age 18 years are associated with high or low reactivity at 4 months of age. DESIGN: Structural magnetic resonance imaging in a cohort of 18-year-olds enrolled in a longitudinal study. Temperament was determined at 4 months of age by direct observation in the laboratory. SETTING: Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital. PARTICIPANTS: Seventy-six subjects who were high-reactive or low-reactive infants at 4 months of age. MAIN OUTCOME MEASURE: Cortical thickness. RESULTS: Adults with a low-reactive infant temperament, compared with those categorized as high reactive, showed greater thickness in the left orbitofrontal cortex. Subjects categorized as high reactive in infancy, compared with those previously categorized as low reactive, showed greater thickness in the right ventromedial prefrontal cortex. CONCLUSIONS: To our knowledge, this is the first demonstration that temperamental differences measured at 4 months of age have implications for the architecture of human cerebral cortex lasting into adulthood. Understanding the developmental mechanisms that shape these differences may offer new ways to understand mood and anxiety disorders as well as the formation of adult personality.