Adjunctive canakinumab reduces peripheral inflammation markers and improves positive symptoms in people with schizophrenia and inflammation: A randomized control trial.

BACKGROUND: Clinical trials of anti-inflammatories in schizophrenia do not show clear and replicable benefits, possibly because patients were not recruited based on elevated inflammation status. Interleukin 1-beta (IL-1ß) mRNA and protein levels are increased in serum, plasma, cerebrospinal fluid, and brain of some chronically ill patients with schizophrenia, first episode psychosis, and clinical high-risk individuals. Canakinumab, an approved anti-IL-1ß monoclonal antibody, interferes with the bioactivity of IL-1ß and interrupts downstream signaling. However, the extent to which canakinumab reduces peripheral inflammation markers, such as, high sensitivity C-reactive protein (hsCRP) and symptom severity in schizophrenia patients with inflammation is unknown. TRIAL DESIGN: We conducted a randomized, placebo-controlled, double-blind, parallel groups, 8-week trial of canakinumab in chronically ill patients with schizophrenia who had elevated peripheral inflammation. METHODS: Twenty-seven patients with schizophrenia or schizoaffective disorder and elevated peripheral inflammation markers (IL-1ß, IL-6, hsCRP and/or neutrophil to lymphocyte ratio: NLR) were randomized to a one-time, subcutaneous injection of canakinumab (150 mg) or placebo (normal saline) as an adjunctive antipsychotic treatment. Peripheral blood hsCRP, NLR, IL-1ß, IL-6, IL-8 levels were measured at baseline (pre injection) and at 1-, 4- and 8-weeks post injection. Symptom severity was assessed at baseline and 4- and 8-weeks post injection. RESULTS: Canakinumab significantly reduced peripheral hsCRP over time, F(3, 75) = 5.16, p = 0.003. Significant hsCRP reductions relative to baseline were detected only in the canakinumab group at weeks 1, 4 and 8 (p's = 0.0003, 0.000002, and 0.004, respectively). There were no significant hsCRP changes in the placebo group. Positive symptom severity scores were significantly reduced at week 8 (p = 0.02) in the canakinumab group and week 4 (p = 0.02) in the placebo group. The change in CRP between week 8 and baseline (b = 1.9, p = 0.0002) and between week 4 and baseline (b = 6.0, p = 0.001) were highly significant predictors of week 8 change in PANSS Positive Symptom severity scores. There were no significant changes in negative symptoms, general psychopathology or cognition in either group. Canakinumab was well tolerated and only 7 % discontinued. CONCLUSIONS: Canakinumab quickly reduces peripheral hsCRP serum levels in patients with schizophrenia and inflammation; after 8 weeks of canakinumab treatment, the reductions in hsCRP are related to reduced positive symptom severity. Future studies should consider increased doses or longer-term treatment to confirm the potential benefits of adjunctive canakinumab in schizophrenia. Australian and New Zealand Clinical Trials Registry number: ACTRN12615000635561.

Resuscitators' opinions on using a respiratory function monitor during neonatal resuscitation.

AIM: The aim of this study was to assess the resuscitators' opinions of the usefulness and clinical value of using a respiratory function monitor (RFM) when resuscitating extremely preterm infants with positive pressure ventilation. METHODS: The link to an online survey was sent to 106 resuscitators from six countries who were involved in a multicentre trial that compared the percentage of inflations within a predefined target range with and without the RFM. The resuscitators were asked to assess the usefulness and clinical value of the RFM. The survey was online for 4 months after the trial ended in May 2019. RESULTS: The survey was completed by 74 (70%) resuscitators of which 99% considered the RFM to be helpful during neonatal resuscitation and 92% indicated that it influenced their decision-making. The majority (76%) indicated that using the RFM improved their practice and made resuscitation more effective, even when the RFM was not available. Inadequate training was the key issue that limited the effectiveness of the RFM: 45% felt insufficiently trained, and 78% felt more training in using and interpreting the RFM would have been beneficial. CONCLUSION: Resuscitators considered the RFM to be helpful to guide neonatal resuscitation, but sufficient training was required to achieve the maximum benefit.

Decreasing Intubation for Ineffective Ventilation after Birth for Very Low Birth Weight Neonates.

Despite recommendations promoting noninvasive delivery room (DR) ventilation, local historical preterm DR noninvasive ventilation rates were low (50%-64%). Project aims were to improve DR noninvasive ventilation rate in very low birth weight (VLBW) neonates (<1500 g) with a focus on decreasing DR intubations for ineffective positive pressure ventilation (PPV). Methods: We addressed drivers for improving noninvasive ventilation and decreasing intubations for ineffective PPV through plan-do-study-act cycles. Outcome measures were intubation for ineffective PPV (defined as intubation for heart rate <100 despite ongoing PPV) and final respiratory support in the DR. Our process measure was adherence to division-wide DR-intubation guidelines. Balancing measures were maximum FiO2 and hypothermia. We analyzed data using statistical process control charts and special cause variation rules. Results: There were 139 DR intubations among 521 VLBW neonates between January 2015 and February 2020. The noninvasive ventilation rate upon intensive care nursery admission was higher than historically reported at 73% and sustained throughout the project. The intubation rate for ineffective PPV was 10% and did not change. The number of VLBW neonates between intubations for ineffective PPV increased from 6.1 to 8.0. Ten intubations did not comply with guidelines. Balancing measures were unaffected. Conclusions: Noninvasive ventilation rates were higher than historically reported and remained high. After plan-do-study-act cycles, the number of VLBW neonates between intubations for ineffective PPV increased without impacting balancing measures. Our data demonstrate that effective ventilation (heart rate > 100) using noninvasive support is possible in up to 90% of VLBW infants but requires ongoing PPV training.

Perinatal COVID-19 maternal and neonatal outcomes at two academic birth hospitals.

OBJECTIVE: Describe 1-month outcomes among newborns of persons with perinatal COVID-19. STUDY DESIGN: Prospective observational study of pregnant persons who tested positive for SARS-CoV-2 between 14 days before and 3 days after delivery and their newborns, from 3/2020 to 3/2021 at two urban high-risk academic hospitals. Phone interviews were conducted to determine 1-month newborn outcomes. RESULTS: Among 9748 pregnant persons, 209 (2.1%) tested positive for perinatal SARS-CoV-2. Symptomatically infected persons were more likely to have a preterm delivery due to worsening maternal condition and their newborns were more likely to test positive for SARS-CoV-2 compared with asymptomatic persons. Six of 191 (3.1%) infants tested were positive for SARS-CoV-2; none had attributable illness before discharge. Of 169 eligible families, 132 (78.1%) participated in post-discharge interviews; none reported their newborn tested positive for SARS-CoV-2 by 1 month of age. CONCLUSION: Symptomatic perinatal COVID-19 had a substantial effect on maternal health but no apparent short-term effect on newborns.

A multi-centre randomised controlled trial of respiratory function monitoring during stabilisation of very preterm infants at birth.

AIM: To determine whether the use of a respiratory function monitor (RFM) during PPV of extremely preterm infants at birth, compared with no RFM, leads to an increase in percentage of inflations with an expiratory tidal volume (Vte) within a predefined target range. METHODS: Unmasked, randomised clinical trial conducted October 2013 - May 2019 in 7 neonatal intensive care units in 6 countries. Very preterm infants (24-27 weeks of gestation) receiving PPV at birth were randomised to have a RFM screen visible or not. The primary outcome was the median proportion of inflations during manual PPV (face mask or intubated) within the target range (Vte 4-8 mL/kg). There were 42 other prespecified monitor measurements and clinical outcomes. RESULTS: Among 288 infants randomised (median (IQR) gestational age 26+2 (25+3-27+1) weeks), a total number of 51,352 inflations were analysed. The median (IQR) percentage of inflations within the target range in the RFM visible group was 30.0 (18.0-42.2)% vs 30.2 (14.8-43.1)% in the RFM non-visible group (p = 0.721). There were no differences in other respiratory function measurements, oxygen saturation, heart rate or FiO2. There were no differences in clinical outcomes, except for the incidence of intraventricular haemorrhage (all grades) and/or cystic periventricular leukomalacia (visible RFM: 26.7% vs non-visible RFM: 39.0%; RR 0.71 (0.68-0.97); p = 0.028). CONCLUSION: In very preterm infants receiving PPV at birth, the use of a RFM, compared to no RFM as guidance for tidal volume delivery, did not increase the percentage of inflations in a predefined target range. TRIAL REGISTRATION: Dutch Trial Register NTR4104, clinicaltrials.gov NCT03256578.

Intubation Competence During Neonatal Fellowship Training.

OBJECTIVES: To characterize neonatal-perinatal medicine fellows' progression toward neonatal intubation procedural competence during fellowship training. METHODS: Multi-center cohort study of neonatal intubation encounters performed by neonatal-perinatal medicine fellows between 2014 through 2018 at North American academic centers in the National Emergency Airway Registry for Neonates. Cumulative sum analysis was used to characterize progression of individual fellows' intubation competence, defined by an 80% overall success rate within 2 intubation attempts. We employed multivariable analysis to assess the independent impact of advancing quarter of fellowship training on intubation success. RESULTS: There were 2297 intubation encounters performed by 92 fellows in 8 hospitals. Of these, 1766 (77%) were successful within 2 attempts. Of the 40 fellows assessed from the start of training, 18 (45%) achieved procedural competence, and 12 (30%) exceeded the deficiency threshold. Among fellows who achieved competence, the number of intubations to meet this threshold was variable, with an absolute range of 8 to 46 procedures. After adjusting for patient and practice characteristics, advancing quarter of training was independently associated with an increased odds of successful intubation (adjusted odds ratio: 1.10; 95% confidence interval 1.07-1.14). CONCLUSIONS: The number of neonatal intubations required to achieve procedural competence is variable, and overall intubation competence rates are modest. Although repetition leads to skill acquisition for many trainees, some learners may require adjunctive educational strategies. An individualized approach to assess trainees' progression toward intubation competence is warranted.

Delivery room oxygen physiology and respiratory interventions for newborns with cyanotic congenital heart disease.

OBJECTIVE: To characterize pulse oxygen saturation (SpO2) trajectories and respiratory interventions after birth for newborns with cyanotic congenital heart disease (CCHD). STUDY DESIGN: Retrospective single-site study of newborns ≥32 weeks gestation with CCHD: single ventricle with critical aortic obstruction (SV-CAO), critical pulmonic obstruction (CPO), transposition of the great arteries (TGA). Minute-to-minute SpO2 values and respiratory interventions were summarized and compared. RESULTS: Two hundred infants were enrolled. SpO2 at each minute differed across groups (p < 0.01), with the lowest values in TGA. All interventions were most frequent in TGA (p < 0.01). Continuous positive airway pressure was provided in 22% SV-CAO, 23% CPO, and 66% TGA. Positive pressure ventilation occurred in 7% SV-CAO, 14% CPO, and 33% TGA. Intubation occurred in 4% SV-CAO, 10% CPO, and 53% TGA. CONCLUSION: We defined SpO2 trajectories and delivery room respiratory interventions for three CCHD phenotypes. These results inform delivery room management of these high-risk populations.

Provider visual attention on a respiratory function monitor during neonatal resuscitation.

BACKGROUND: A respiratory function monitor (RFM) provides real-time positive pressure ventilation feedback. Whether providers use RFM during neonatal resuscitation is unknown. METHODS: Ancillary study to the MONITOR(NCT03256578) randomised controlled trial. Neonatal resuscitation leaders at two centres wore eye-tracking glasses, and visual attention (VA) patterns were compared between RFM-visible and RFM-masked groups. RESULTS: 14 resuscitations (6 RFM-visible, 8 RFM-masked) were analysed. The median total gaze duration on the RFM was significantly higher with a visible RFM (29% vs 1%, p<0.01), while median total gaze duration on other physical objects was significantly lower with a visible RFM (3% vs 8%, p=0.02). Median total gaze duration on the infant was lower with RFM visible, although not statistically significantly (29% vs 46%, p=0.05). CONCLUSION: Providers' VA patterns differed during neonatal resuscitation when the RFM was visible, emphasising the importance of studying the impact of additional delivery room technology on providers' behaviour.

Corrective steps to enhance ventilation in the delivery room.

OBJECTIVE: The clinical impact of ventilation corrective steps for delivery room positive pressure ventilation (PPV) is not well studied. We aimed to characterise the performance and effect of ventilation corrective steps (MRSOPA (Mask adjustment, Reposition airway, Suction mouth and nose, Open mouth, Pressure increase and Alternative airway)) during delivery room resuscitation of preterm infants. DESIGN: Prospective observational study of delivery room PPV using video and respiratory function monitor recordings. SETTING: Tertiary academic delivery hospital. PATIENTS: Preterm infants <32 weeks gestation. MAIN OUTCOME MEASURE: Mean exhaled tidal volume (Vte) of PPV inflations before and after MRSOPA interventions, categorised as inadequate (<4 mL/kg); appropriate (4-8 mL/kg), or excessive (>8 mL/kg). Secondary outcomes were leak (>30%) and obstruction (Vte <1 mL/kg), and infant heart rate. RESULTS: There were 41 corrective interventions in 30 infants, with a median duration of 15 (IQR 7-29) s. The most frequent intervention was a combination of Mask/Reposition and Suction/Open. Mean Vte was inadequate before 16/41 interventions and became adequate following 6/16. Mean Vte became excessive after 6/41 interventions. Mask leak, present before 13/41 interventions, was unchanged after 4 and resolved after 9. Obstruction was present before five interventions and was subsequently resolved only once. MRSOPA interventions introduced leak in two cases and led to obstruction in one case. The heart rate was <100 beats per minute before 31 interventions and rose to >100 beats per minute after 14/31 of these. CONCLUSIONS: Ventilation correction interventions improve tidal volume delivery in some cases, but lead to ineffective or excessive tidal volumes in others. Mask leak and obstruction can be induced by MRSOPA manoeuvres.

Initiating resuscitation before umbilical cord clamping in infants with congenital diaphragmatic hernia: a pilot feasibility trial.

BACKGROUND: Infants with congenital diaphragmatic hernia (CDH) often experience hypoxaemia with acidosis immediately after birth. The traditional approach in the delivery room is immediate cord clamping followed by intubation. Initiating resuscitation prior to umbilical cord clamping (UCC) may support this transition. OBJECTIVES: To establish the safety and feasibility of intubation and ventilation prior to UCC for infants with CDH. To compare short-term outcomes between trial participants and matched controls treated with immediate cord clamping before intubation and ventilation. DESIGN: Single-arm, single-site trial of infants with CDH and gestational age ≥36 weeks. Infants were placed on a trolley immediately after birth and underwent intubation and ventilation, with UCC performed after qualitative CO2 detection. The primary feasibility endpoint was successful intubation prior to UCC. Prespecified safety and physiological outcomes were compared with historical controls matched for prognostic variables using standard bivariate tests. RESULTS: Of 20 enrolled infants, all were placed on the trolley, and 17 (85%) infants were intubated before UCC. The first haemoglobin and mean blood pressure at 1 hour of life were significantly higher in trial participants than controls. There were no significant differences between groups for subsequent blood pressure values, vasoactive medications, inhaled nitric oxide or extracorporeal membrane oxygenation. Blood gas and oxygenation index values did not differ between groups at any point. CONCLUSIONS: Intubation and ventilation prior to UCC is safe and feasible among infants with CDH. The impact of this approach on clinically relevant outcomes deserves investigation in a randomised trial.

The Impact of Childhood Adversity on Cognitive Development in Schizophrenia.

Childhood adversity, such as physical, sexual, and verbal abuse, as well as neglect and family conflict, is a risk factor for schizophrenia. Such adversity can lead to disruptions of cognitive function during development, undermining intellectual capabilities and academic achievement. Schizophrenia is a neurodevelopmental disorder that is associated with cognitive impairments that may become evident during childhood. The Australian Schizophrenia Research Bank database comprises a large community cohort (N = 1169) in which we previously identified 3 distinct cognitive groups among people with schizophrenia: (1) Compromised, current, and estimated premorbid cognitive impairment; (2) Deteriorated, substantial decline from estimated premorbid function; and (3) Preserved, performing in the normal cognitive range without decline. The compromised group displayed the worst functional and symptom outcomes. Here, we extend our previous work by assessing the relationship among these categories of cognitive abilities and reported childhood adversity in 836 patients and healthy controls. Exploratory factor analysis of the Childhood Adversity Questionnaire revealed 3 factors (lack of parental involvement; overt abuse; family breakdown and hardship). People with schizophrenia reported significantly more childhood adversity than healthy controls on all items and factors. People with schizophrenia in the compromised group reported significantly more lack of parental involvement and family breakdown and hardship and lower socioeconomic status than those in the deteriorated group. The cognitive groups were not related to family history of psychosis. These findings identify specific social and family factors that impact cognition, highlighting the important role of these factors in the development of cognitive and functional abilities in schizophrenia.

Accuracy of real-time delivery room resuscitation documentation.

OBJECTIVE: To assess the accuracy of real-time delivery room resuscitation documentation. DESIGN: Retrospective observational study. SETTING: Level 3 academic neonatal intensive care unit. PARTICIPANTS: Fifty infants with video recording of neonatal resuscitation. MAIN OUTCOME MEASURES: Vital sign assessments and interventions performed during resuscitation. The accuracy of written documentation was compared with video gold standard. RESULTS: Timing of initial heart rate assessment agreed with video in 44/50 (88%) records; the documented heart rate was correct in 34/44 (77%) of these. Heart rate and oxygen saturation were documented at 5 min of life in 90% of resuscitations. Of these, 100% of heart rate and 93% of oxygen saturation values were correctly recorded. Written records accurately reflected the mode(s) of respiratory support for 89%-100%, procedures for 91%-100% and medications for 100% of events. CONCLUSION: Real-time documentation correctly reflects interventions performed during delivery room resuscitation but is less accurate for early vital sign assessments.

Visual attention patterns of team leaders during delivery room resuscitation.

AIM: To assess visual attention of neonatal team leaders during delivery room resuscitation of preterm infants using eye tracking glasses. METHODS: Prospective observational eye tracking study. Gaze fixations and sequences were captured, categorized, and mapped during the first 5 min of the resuscitations. Gaze fixation metrics of total gaze duration, visit count, and visit duration were summarized and compared based on interventions performed and provider training level. Fixation sequences were compared between attending neonatologists and fellows. RESULTS: During 18 eye tracking recordings, practitioners focused most of their cumulative visual attention on the infant (median total gaze duration 57%, interquartile range [IQR] 38-61%), followed by monitors (24%, IQR 13-46%), clinical staff (5%, IQR 1-8%), other physical objects (4%, IQR 3-6%), T-piece resuscitator (2%, IQR 0-4%) and the Apgar timer (1%, IQR 0-2%). Visual attention parameters varied according to intervention, with higher visit counts on the infant during corrective ventilation steps than during Continuous Positive Airway Pressure (CPAP) or Positive Pressure Ventilation (PPV), and longer visit durations on monitors during PPV. Time and frequency-based measures of visual attention did not significantly differ by provider training level, but patterned fixation sequences were identified among attending neonatologists that were not observed in fellows. CONCLUSION: Team leaders predominantly gazed upon the infant and monitors during resuscitation, and visual attention parameters varied depending on the respiratory interventions performed. Attending neonatologists exhibited patterned fixation sequences that were not observed in fellows. Study results may have implications for optimizing delivery room design and training novice providers.

Visual attention on a respiratory function monitor during simulated neonatal resuscitation: an eye-tracking study.

OBJECTIVE: A respiratory function monitor (RFM) may improve positive pressure ventilation (PPV) technique, but many providers do not use RFM data appropriately during delivery room resuscitation. We sought to use eye-tracking technology to identify RFM parameters that neonatal providers view most commonly during simulated PPV. DESIGN: Mixed methods study. Neonatal providers performed RFM-guided PPV on a neonatal manikin while wearing eye-tracking glasses to quantify visual attention on displayed RFM parameters (ie, exhaled tidal volume, flow, leak). Participants subsequently provided qualitative feedback on the eye-tracking glasses. SETTING: Level 3 academic neonatal intensive care unit. PARTICIPANTS: Twenty neonatal resuscitation providers. MAIN OUTCOME MEASURES: Visual attention: overall gaze sample percentage; total gaze duration, visit count and average visit duration for each displayed RFM parameter. Qualitative feedback: willingness to wear eye-tracking glasses during clinical resuscitation. RESULTS: Twenty providers participated in this study. The mean gaze sample captured wa s 93% (SD 4%). Exhaled tidal volume waveform was the RFM parameter with the highest total gaze duration (median 23%, IQR 13-51%), highest visit count (median 5.17 per 10 s, IQR 2.82-6.16) and longest visit duration (median 0.48 s, IQR 0.38-0.81 s). All participants were willing to wear the glasses during clinical resuscitation. CONCLUSION: Wearable eye-tracking technology is feasible to identify gaze fixation on the RFM display and is well accepted by providers. Neonatal providers look at exhaled tidal volume more than any other RFM parameter. Future applications of eye-tracking technology include use during clinical resuscitation.

Widespread Volumetric Reductions in Schizophrenia and Schizoaffective Patients Displaying Compromised Cognitive Abilities.

Objective: Progress toward understanding brain mechanisms in psychosis is hampered by failures to account for within-group heterogeneity that exists across neuropsychological domains. We recently identified distinct cognitive subgroups that might assist in identifying more biologically meaningful subtypes of psychosis. In the present study, we examined whether underlying structural brain abnormalities differentiate these cognitively derived subgroups. Method: 1.5T T1 weighted structural scans were acquired for 168 healthy controls and 220 patients with schizophrenia/schizoaffective disorder. Based on previous work, 47 patients were categorized as being cognitively compromised (impaired premorbid and current IQ), 100 as cognitively deteriorated (normal premorbid IQ, impaired current IQ), and 73 as putatively cognitively preserved (premorbid and current IQ within 1 SD of controls). Global, subcortical and cortical volume, thickness, and surface area measures were compared among groups. Results: Whole cortex, subcortical, and regional volume and thickness reductions were evident in all subgroups compared to controls, with the largest effect sizes in the compromised group. This subgroup also showed abnormalities in regions not seen in the other patient groups, including smaller left superior and middle frontal areas, left anterior and inferior temporal areas and right lateral medial and inferior frontal, occipital lobe and superior temporal areas. Conclusions: This pattern of more prominent brain structural abnormalities in the group with the most marked cognitive impairments-both currently and putatively prior to illness onset, is consistent with the concept of schizophrenia as a progressive neurodevelopmental disorder. In this group, neurodevelopmental and neurodegenerative factors may be important for cognitive function.

Cognitive Subtypes of Schizophrenia Characterized by Differential Brain Volumetric Reductions and Cognitive Decline.

IMPORTANCE: Cognitively distinct subgroups of schizophrenia have been defined based on premorbid and current IQ, but little is known about the neuroanatomical differences among these cognitive subgroups. OBJECTIVES: To confirm previous findings related to IQ-based subgroups of patients with schizophrenia in an independent sample and extend those findings to determine the extent to which brain volumetric differences correspond to the IQ-based subgroups. DESIGN, SETTING, AND PARTICIPANTS: A total of 183 participants were assessed at the outpatient settings of Neuroscience Research Australia and Lyell McEwin Hospital from September 22, 2009, to August 1, 2012. Patients were classified using cluster analysis on the basis of current and premorbid IQ differences. Regional magnetic resonance imaging (MRI) brain volumes were compared among the IQ-based subgroups using analysis of covariance with intracranial volume and age as covariates. MAIN OUTCOMES AND MEASURES: Wechsler Adult Intelligence Scale, third edition, scores; Wechsler Test of Adult Reading scores; Positive and Negative Syndrome Scale scores; and MRI brain volumes. RESULTS: Ninety-six outpatients (mean [SD] age, 35.7 [8.4] years; age range, 18-51 years; 59 men) with schizophrenia or schizoaffective disorder and 87 healthy controls (mean [SD] age, 31.9 [8.4] years; age range, 20-50 years; 46 men) were studied. Sixty-two patients and 67 healthy controls underwent structural MRI of the brain. Cluster analyses revealed 25 putatively preserved patients (26%), 33 moderately deteriorated patients (34%), 27 severely deteriorated patients (28%), and 11 compromised patients (12%). Negative symptom scores were significantly worse in the severely deteriorated group relative to the putatively preserved group (F2,82 = 13.8, P < .001, effect size [ES] = 1.40). Patient subgroups analyzed revealed significantly reduced inferior parietal volume relative to controls (F3,113 = 9.7, P < .001, ES = 0.85-1.24). The severely deteriorated group had significantly reduced total hippocampal (mean [SEM], 8309.6 [175.0] vs 9024.0 [145.5]; P = .01), lingual gyrus (mean [SEM], 11 996.0 [531.5] vs 13 838.1 [441.9]; P = .05), and superior temporal sulcus (mean [SEM], 4697.8 [192.0] vs 5446.0 [159.6]; P = .05) gray matter volumes relative to the putatively preserved group (ES = 0.91-1.10). CONCLUSIONS AND RELEVANCE: Using an independent sample, we obtained proportions in each IQ-based subgroup that were similar to our previous work. Inferior parietal volume reduction was characteristic of schizophrenia relative to controls, and the severely deteriorated IQ group had widespread volumetric reductions. Classifying cognitive heterogeneity in schizophrenia provides a platform to better characterize the neurobiological underpinnings of the illness and its treatment.

The impact of premorbid and current intellect in schizophrenia: cognitive, symptom, and functional outcomes.

BACKGROUND: Cognitive heterogeneity among people with schizophrenia has been defined on the basis of premorbid and current intelligence quotient (IQ) estimates. In a relatively large, community cohort, we aimed to independently replicate and extend cognitive subtyping work by determining the extent of symptom severity and functional deficits in each group. METHODS: A total of 635 healthy controls and 534 patients with a diagnosis of schizophrenia or schizoaffective disorder were recruited through the Australian Schizophrenia Research Bank. Patients were classified into cognitive subgroups on the basis of the Wechsler Test of Adult Reading (a premorbid IQ estimate) and current overall cognitive abilities into preserved, deteriorated, and compromised groups using both clinical and empirical (k-means clustering) methods. Additional cognitive, functional, and symptom outcomes were compared among the resulting groups. RESULTS: A total of 157 patients (29%) classified as 'preserved' performed within one s.d. of control means in all cognitive domains. Patients classified as 'deteriorated' (n=239, 44%) performed more than one s.d. below control means in all cognitive domains except estimated premorbid IQ and current visuospatial abilities. A separate 138 patients (26%), classified as 'compromised,' performed more than one s.d. below control means in all cognitive domains and displayed greater impairment than other groups on symptom and functional measures. CONCLUSIONS: In the present study, we independently replicated our previous cognitive classifications of people with schizophrenia. In addition, we extended previous work by demonstrating worse functional outcomes and symptom severity in the compromised group.

Comparative semantic profiles in semantic dementia and Alzheimer's disease.

Patients with the semantic variant of primary progressive aphasia, also known as semantic dementia, and Alzheimer's disease have deficits in semantic memory. However, few comparative studies have been performed to determine whether these patient groups have distinct semantic memory impairments. We asked 15 patients with semantic variant primary progressive aphasia and 57 patients with Alzheimer's disease to judge semantic category membership of coloured photos and printed words that are members of familiar natural and manufactured categories, and we related performance to grey matter atrophy. We found that both semantic variant primary progressive aphasia and Alzheimer's disease are significantly impaired on this task. Moreover, patients with semantic variant primary progressive aphasia had a significantly more prominent deficit for natural objects than their own deficit judging manufactured objects. Both semantic variant primary progressive aphasia and Alzheimer's disease had atrophy that included portions of the left temporal lobe. Regression analyses related performance in semantic variant primary progressive aphasia to ventral and medial portions of the left temporal lobe, while regression analyses in Alzheimer's disease related performance to these ventral and medial temporal areas as well as lateral temporal-parietal regions in the left hemisphere. We conclude that both semantic variant primary progressive aphasia and Alzheimer's disease are significantly impaired in a simple category membership judgement task and the selective impairment for natural kinds in semantic variant primary progressive aphasia is related in part to disease in visual association cortex in ventral-medial portions of the left temporal lobe. We discuss factors that may contribute to the semantic memory deficit in semantic variant primary progressive aphasia.

Differentiating primary progressive aphasias in a brief sample of connected speech.

OBJECTIVE: A brief speech expression protocol that can be administered and scored without special training would aid in the differential diagnosis of the 3 principal forms of primary progressive aphasia (PPA): nonfluent/agrammatic PPA, logopenic variant PPA, and semantic variant PPA. METHODS: We used a picture-description task to elicit a short speech sample, and we evaluated impairments in speech-sound production, speech rate, lexical retrieval, and grammaticality. We compared the results with those obtained by a longer, previously validated protocol and further validated performance with multimodal imaging to assess the neuroanatomical basis of the deficits. RESULTS: We found different patterns of impaired grammar in each PPA variant, and additional language production features were impaired in each: nonfluent/agrammatic PPA was characterized by speech-sound errors; logopenic variant PPA by dysfluencies (false starts and hesitations); and semantic variant PPA by poor retrieval of nouns. Strong correlations were found between this brief speech sample and a lengthier narrative speech sample. A composite measure of grammaticality and other measures of speech production were correlated with distinct regions of gray matter atrophy and reduced white matter fractional anisotropy in each PPA variant. CONCLUSIONS: These findings provide evidence that large-scale networks are required for fluent, grammatical expression; that these networks can be selectively disrupted in PPA syndromes; and that quantitative analysis of a brief speech sample can reveal the corresponding distinct speech characteristics.