Diverse molecular causes of unsolved autosomal dominant tubulointerstitial kidney diseases.

Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) is caused by mutations in one of at least five genes and leads to kidney failure usually in mid adulthood. Throughout the literature, variable numbers of families have been reported, where no mutation can be found and therefore termed ADTKD-not otherwise specified. Here, we aim to clarify the genetic cause of their diseases in our ADTKD registry. Sequencing for all known ADTKD genes was performed, followed by SNaPshot minisequencing for the dupC (an additional cytosine within a stretch of seven cytosines) mutation of MUC1. A virtual panel containing 560 genes reported in the context of kidney disease (nephrome) and exome sequencing were then analyzed sequentially. Variants were validated and tested for segregation. In 29 of the 45 registry families, mutations in known ADTKD genes were found, mostly in MUC1. Sixteen families could then be termed ADTKD-not otherwise specified, of which nine showed diagnostic variants in the nephrome (four in COL4A5, two in INF2 and one each in COL4A4, PAX2, SALL1 and PKD2). In the other seven families, exome sequencing analysis yielded potential disease associated variants in novel candidate genes for ADTKD; evaluated by database analyses and genome-wide association studies. For the great majority of our ADTKD registry we were able to reach a molecular genetic diagnosis. However, a small number of families are indeed affected by diseases classically described as a glomerular entity. Thus, incomplete clinical phenotyping and atypical clinical presentation may have led to the classification of ADTKD. The identified novel candidate genes by exome sequencing will require further functional validation.

A noninvasive diagnostic approach to retrospective donor HLA typing in kidney transplant patients using urine.

Antibody-mediated rejection (AMR) is a major obstacle to long-term kidney transplantation. AMR is mostly caused by donor specific HLA antibodies, which can arise before or any time after transplantation. Incomplete donor HLA typing and unavailability of donor DNA regularly preclude the assessment of donor-specificity of circulating anti-HLA antibodies. In our centre, this problem arises in approximately 20% of all post-transplant HLA-antibody assessments. We demonstrate that this diagnostic challenge can be resolved by establishing donor renal tubular cell cultures from recipient´s urine as a source of high-quality donor DNA. DNA was then verified for genetic origin and purity by fluorescence in situ hybridization and short tandem repeat analysis. Two representative cases highlight the diagnostic value of this approach which is corroborated by analysis of ten additional patients. The latter were randomly sampled from routine clinical care patients with available donor DNA as controls. In all 12 cases, we were able to perform full HLA typing of the respective donors confirmed by cross-comparison to results from the stored 10 donor DNAs. We propose that this noninvasive diagnostic approach for HLA typing in kidney transplant patients is valuable to determine donor specificity of HLA antibodies, which is important in clinical assessment of suspected AMR.

An evaluation of manual tidal volume and respiratory rate delivery during simulated resuscitation.

INTRODUCTION: Excessive minute ventilation during cardiac arrest may cause lung injury and decrease the effectiveness of cardiopulmonary resuscitation (CPR). However, little is known about how clinicians deliver tidal volumes and respiratory rates during CPR. METHODS: In this cross-sectional study, licensed practitioners attending an American Heart Association (AHA) Advanced Cardiac Life Support (ACLS) course performed CPR and manual ventilation on a high-fidelity simulator during the megacode portion of the course. Delivered tidal volumes and respiratory rates were measured on a monitor. During the first scenario, results were not displayed to participants, but were displayed during the second scenario. RESULTS: Fifty-two clinicians participated in this study. Average height was 169 (157,178) cm. Pre-monitor display tidal volumes delivered were larger in male participants compared to female participants (684.6 ± 134.4 vs 586.7 ± 167.6 ml, P = 0.05). Those using medium-sized gloves delivered smaller tidal volumes than those using small or large gloves. Twenty-two (42.3%) delivered tidal volume in the range of 5-8 ml/kg of predicted body weight for the simulation manikin, and 35 (67.3%) delivered tidal volumes with >20% variability among breaths. All participants met the target respiratory rate around 10 breaths/min. CONCLUSION: Tidal volume delivery varied greatly during manual ventilation and fewer than half participants delivered tidal volume at 5-8 ml/kg to the manikin. Sex and glove size appeared to impact tidal volume delivery when the participants were unaware of what they were delivering. Participants were able to meet the target respiratory rate around 10 without audio or visual feedback.

Alterations in Anatomical Covariance in the Prematurely Born.

Preterm (PT) birth results in long-term alterations in functional and structural connectivity, but the related changes in anatomical covariance are just beginning to be explored. To test the hypothesis that PT birth alters patterns of anatomical covariance, we investigated brain volumes of 25 PTs and 22 terms at young adulthood using magnetic resonance imaging. Using regional volumetrics, seed-based analyses, and whole brain graphs, we show that PT birth is associated with reduced volume in bilateral temporal and inferior frontal lobes, left caudate, left fusiform, and posterior cingulate for prematurely born subjects at young adulthood. Seed-based analyses demonstrate altered patterns of anatomical covariance for PTs compared with terms. PTs exhibit reduced covariance with R Brodmann area (BA) 47, Broca's area, and L BA 21, Wernicke's area, and white matter volume in the left prefrontal lobe, but increased covariance with R BA 47 and left cerebellum. Graph theory analyses demonstrate that measures of network complexity are significantly less robust in PTs compared with term controls. Volumes in regions showing group differences are significantly correlated with phonological awareness, the fundamental basis for reading acquisition, for the PTs. These data suggest both long-lasting and clinically significant alterations in the covariance in the PTs at young adulthood.

Cerebral Lateralization is Protective in the Very Prematurely Born.

Individuals born prematurely are at risk for developmental delay, and converging data suggest alterations in neural networks in the developing preterm brain. Nevertheless, those critical period processes such as cerebral lateralization that underlie these findings remain largely unexplored. To test the hypothesis that preterm birth alters the fundamental program of corticogenesis in the developing brain, we interrogated cerebral lateralization at rest in very prematurely born participants and term controls at young adulthood. Employing a novel, voxel-based measure of functional connectivity, these data demonstrate for the first time that cerebral lateralization of functional connectivity in right hemisphere language homologs is altered for very preterm participants. Very preterm participants with no evidence for severe brain injury exhibited a significant decrease in right hemisphere lateralization in the right parietal and temporal lobes in this data driven analysis. Further, for the very preterm participants, but not the term participants, these fundamental alterations in the cerebral lateralization for language significantly correlate with language scores. These findings provide evidence that cerebral asymmetry is both plastic and experiential, and suggest the need for further study of underlying environmental factors responsible for these changes.

Functional magnetic resonance connectivity studies in infants born preterm: suggestions of proximate and long-lasting changes in language organization.

Sophisticated neuroimaging strategies demonstrate alterations in functional connectivity at school age, adolescence, and young adulthood in individuals born preterm. Recent data suggest these alterations are present in the postnatal period prior to term-equivalent age in neonates born preterm. Likewise, functional organization increases across development, but the influence of preterm birth on this fundamental infrastructure is immediate and unchanging. This article briefly reviews the current methods of measuring functional connectivity throughout development in those born preterm, and the association of functional connectivity with language disorders. Taken together, these data suggest that the effects of preterm birth on the functional organization of language in the developing brain are both proximate and long-lasting.

From Theory to Practice: Implementation of a Resource Allocation Model in Health Departments.

OBJECTIVE: To develop a resource allocation model to optimize health departments' Centers for Disease Control and Prevention (CDC)-funded HIV prevention budgets to prevent the most new cases of HIV infection and to evaluate the model's implementation in 4 health departments. DESIGN, SETTINGS, AND PARTICIPANTS: We developed a linear programming model combined with a Bernoulli process model that allocated a fixed budget among HIV prevention interventions and risk subpopulations to maximize the number of new infections prevented. The model, which required epidemiologic, behavioral, budgetary, and programmatic data, was implemented in health departments in Philadelphia, Chicago, Alabama, and Nebraska. MAIN OUTCOME MEASURES: The optimal allocation of funds, the site-specific cost per case of HIV infection prevented rankings by intervention, and the expected number of HIV cases prevented. RESULTS: The model suggested allocating funds to HIV testing and continuum-of-care interventions in all 4 health departments. The most cost-effective intervention for all sites was HIV testing in nonclinical settings for men who have sex with men, and the least cost-effective interventions were behavioral interventions for HIV-negative persons. The pilot sites required 3 to 4 months of technical assistance to develop data inputs and generate and interpret the results. Although the sites found the model easy to use in providing quantitative evidence for allocating HIV prevention resources, they criticized the exclusion of structural interventions and the use of the model to allocate only CDC funds. CONCLUSIONS: Resource allocation models have the potential to improve the allocation of limited HIV prevention resources and can be used as a decision-making guide for state and local health departments. Using such models may require substantial staff time and technical assistance. These model results emphasize the allocation of CDC funds toward testing and continuum-of-care interventions and populations at highest risk of HIV transmission.

Adaptive mechanisms of developing brain: cerebral lateralization in the prematurely-born.

Preterm birth results in alterations in neural connectivity, but the impact of prematurity on the functional organization of the developing brain has yet to be explored. To test the hypothesis that preterm birth alters cortical organization during the late second and third trimesters of gestation, we interrogated cerebral lateralization at rest in 26 very preterm subjects (birth weight 500-1500g) with no evidence of brain injury and 25 healthy term control subjects at term equivalent age. Employing an unbiased voxel-based measure of functional connectivity, these data demonstrated that cerebral lateralization is impaired in the prematurely-born. At term equivalent age, preterm neonates showed significantly less lateralization in regions subserving both receptive and expressive language, left Brodmann (BA) areas insula-BA22-BA21 and L BA45-BA47 (p<0.05 corrected for multiple comparisons for both). Exploratory region of interest analyses demonstrated significantly less inter-hemispheric connectivity from L BA22 to R BA22 in preterm infants compared to term controls (p<0.005) and from R BA22 to its homolog (p<0.005). L BA22, Wernicke's area, was more strongly connected to R BA39, foreshadowing neural networks for language in preterm subjects at school age, adolescence and young adulthood. For these very preterm neonates born at less than 30weeks' PMA, the degree of prematurity had no influence on lateralization in these differential regions.

A cost-effectiveness analysis of HIV preexposure prophylaxis for men who have sex with men in Australia.

BACKGROUND: Antiretroviral therapy (ART) used as preexposure prophylaxis (PrEP) by human immunodeficiency virus (HIV)-seronegative individuals reduces the risk of acquiring HIV. However, the population-level impact and cost-effectiveness of using PrEP as a public health intervention remains debated. METHODS: We used a stochastic agent-based model of HIV transmission and progression to simulate the clinical and cost outcomes of different strategies of providing PrEP to men who have sex with men (MSM) in New South Wales (NSW), Australia. Model outcomes were reported as incremental cost-effectiveness ratios (ICERs) in 2013 Australian dollars per quality-adjusted life-year gained (QALYG). RESULTS: The use of PrEP in 10%-30% of the entire NSW MSM population was projected to cost an additional $316-$952 million over the course of 10 years, and cost >$400 000 per QALYG compared with the status quo. Targeting MSM with sexual partners ranging between >10 to >50 partners within 6 months cost an additional $31-$331 million dollars, and cost >$110 000 per QALYG compared with the status quo. We found that preexposure prophylaxis is most cost-effective when targeted for HIV-negative MSM in a discordant regular partnership. The ICERs ranged between $8399 and $11 575, for coverage ranging between 15% and 30%, respectively. CONCLUSIONS: Targeting HIV-negative MSM in a discordant regular partnership is a cost-effective intervention. However, this highly targeted strategy would not have large population-level impact. Other scenarios are unlikely to be cost-effective.

Adolescents born prematurely with isolated grade 2 haemorrhage in the early 1990s face increased risks of learning challenges.

AIM: To compare the impact of low-grade haemorrhage on neurocognitive function in 16-year-old adolescents born preterm, by grade of intraventricular haemorrhage, and term controls. METHODS: We evaluated 338 preterm adolescents (birth weight 600-1250 g) for intelligence, executive function and memory tasks. Eleven had grade 3-4 haemorrhage, 44 had grade 2, 31 had grade 1, and 251 had no haemorrhage. Group comparisons were made with 102 term age-matched controls, and regression models used to identify the risk that low-grade haemorrhage posed for cognitive, executive function and memory deficits. RESULTS: Preterm adolescents with grade 2 haemorrhage had higher deficit rates of verbal intelligence, receptive vocabulary, phonemic fluency, cognitive flexibility and phonological fluency than preterm adolescents with grade 1 or no haemorrhage, compared with term controls. After excluding preterm adolescents with both grade 2 haemorrhage and cystic periventricular leukomalacia, those with isolated grade 2 haemorrhage remained at greater risk of cognitive and executive function deficits than term controls and of cognitive deficits than preterm adolescents with no haemorrhage. CONCLUSION: Our findings suggest that preterm adolescents born in the early 1990s with isolated grade 2 haemorrhage are at increased risk of learning challenges, including cognitive and executive function deficits.

Progressive Kidney Failure by Angiotensinogen Inactivation in the Germline.

BACKGROUND: Autosomal recessive renal tubular dysgenesis is a rare, usually fatal inherited disorder of the REN (renin)-angiotensin system. Herein, we report an adolescent individual experiencing an unknown chronic kidney disease and aim to provide novel insights into disease mechanisms. METHODS: Exome sequencing for a gene panel associated with renal disease was performed. The REN-angiotensin system was assessed by comprehensive biochemical analysis in blood. REN expression was determined in primary tubular cells by quantitative polymerase chain reaction and in situ hybridization on kidney biopsy samples. Allele frequencies of heterozygous and biallelic deleterious variants were determined by analysis of the Genomics England 100,000 Genomes Project. RESULTS: The patient was delivered prematurely after oligohydramnios was detected during pregnancy. Postnatally, he recovered from third-degree acute kidney injury but developed chronic kidney disease stage G3b over time. Exome sequencing revealed a previously reported pathogenic homozygous missense variant, p.(Arg375Gln), in the AGT (angiotensinogen) gene. Blood AGT concentrations were low, but plasma REN concentration and gene expression in kidney biopsy, vascular, and tubular cells revealed strong upregulation of REN. Angiotensin II and aldosterone in blood were not abnormally elevated. CONCLUSIONS: Renal tubular dysgenesis may present as chronic kidney disease with a variable phenotype, necessitating broad genetic analysis for diagnosis. Functional analysis of the renin-angiotensin system in a patient with AGT mutation revealed novel insights regarding compensatory upregulation of REN in vascular and tubular cells of the kidney and in plasma in response to depletion of AGT substrate as a source of Ang II (similarly observed with hepatic AGT silencing for the treatment of hypertension).

A left cerebellar pathway mediates language in prematurely-born young adults.

Preterm (PT) subjects are at risk for developmental delay, and task-based studies suggest that developmental disorders may be due to alterations in neural connectivity. Since emerging data imply the importance of right cerebellar function for language acquisition in typical development, we hypothesized that PT subjects would have alternate areas of cerebellar connectivity, and that these areas would be responsible for differences in cognitive outcomes between PT subjects and term controls at age 20 years. Nineteen PT and 19 term control young adults were prospectively studied using resting-state functional MRI (fMRI) to create voxel-based contrast maps reflecting the functional connectivity of each tissue element in the grey matter through analysis of the intrinsic connectivity contrast degree (ICC-d). Left cerebellar ICC-d differences between subjects identified a region of interest that was used for subsequent seed-based connectivity analyses. Subjects underwent standardized language testing, and correlations with cognitive outcomes were assessed. There were no differences in gender, hand preference, maternal education, age at study, or Peabody Picture Vocabulary Test (PPVT) scores. Functional connectivity (FcMRI) demonstrated increased tissue connectivity in the biventer, simple and quadrangular lobules of the L cerebellum (p<0.05) in PTs compared to term controls; seed-based analyses from these regions demonstrated alterations in connectivity from L cerebellum to both R and L inferior frontal gyri (IFG) in PTs compared to term controls. For PTs but not term controls, there were significant positive correlations between these connections and PPVT scores (R IFG: r=0.555, p=0.01; L IFG: r=0.454, p=0.05), as well as Verbal Comprehension Index (VCI) scores (R IFG: r=0.472, p=0.04). These data suggest the presence of a left cerebellar language circuit in PT subjects at young adulthood. These findings may represent either a delay in maturation or the engagement of alternative neural pathways for language in the developing PT brain.

Use of Immunization Information Systems in Ascertainment of COVID-19 Vaccinations for Claims-Based Vaccine Safety and Effectiveness Studies.

Importance: Safety and effectiveness studies of COVID-19 vaccines are being conducted using clinical data, including administrative claims. However, claims data only partially capture administered COVID-19 vaccine doses for numerous reasons, such as vaccination at sites that do not generate claims for reimbursement. Objective: To evaluate the extent to which Immunization Information Systems (IIS) data linked to claims data enhances claims-based COVID-19 vaccine capture for a commercially insured population and to estimate the magnitude of misclassification of vaccinated individuals as having unvaccinated status in the linked IIS and claims data. Design, Setting, and Participants: This cohort study used claims data from a commercial health insurance database and obtained vaccination data from IIS repositories in 11 US states. Participants were individuals younger than 65 years who resided in 1 of 11 states of interest and who were insured in health plans from December 1, 2020, through December 31, 2021. Main Outcomes and Measures: Estimated proportion of individuals with at least 1 dose of any COVID-19 vaccine and proportion of individuals with a completed vaccine series based on general population guidelines. Vaccination status estimates were calculated and compared using claims data alone and linked IIS and claims data. Remaining misclassification of vaccination status was assessed by comparing linked IIS and claims data estimates with estimates from external surveillance data sources (Centers for Disease Control and Prevention [CDC] and state Department of Health [DOH]) and capture-recapture analysis. Results: This cohort study included 5 112 722 individuals (mean [SD] age, 33.5 [17.6] years; 2 618 098 females [51.2%]) from 11 states. Characteristics of those who received at least 1 vaccine dose and those who completed a vaccine series were similar to the overall study population. The proportion with at least 1 vaccine dose increased from 32.8% using claims data alone to 48.1% when the data were supplemented with IIS vaccination records. Vaccination estimates using linked IIS and claims data varied widely by state. The percentage of individuals who completed a vaccine series increased from 24.4% to 41.9% after the addition of IIS vaccine records and varied across states. The percentages of underrecording using linked IIS and claims data were 12.1% to 47.1% lower than those using CDC data, 9.1% to 46.9% lower than the state DOH, and 9.2% to 50.9% lower than capture-recapture analysis. Conclusion and Relevance: Results of this study suggested that supplementing COVID-19 claims records with IIS vaccination records substantially increased the number of individuals who were identified as vaccinated, yet potential underrecording remained. Improvements in reporting vaccination data to IIS infrastructures could allow frequent updates of vaccination status for all individuals and all vaccines.

Investigating partner abuse among HIV-positive men who have sex with men.

High rates of partner abuse (PA) of all types-physical, sexual, and psychological-have been identified in studies of HIV-positive individuals. We examined both the prevalence and correlates of same-sex PA in HIV-positive men who have sex with men (MSM). Participants recruited from public outpatient HIV clinics (N = 168) completed CASI surveys about PA and current physical and mental health. Electronic medical record data were obtained for HIV biomarkers. Results indicate high rates of past year PA (physical, 19%; sexual, 17%; psychological, 51%; any, 54%), with rates comparable to, or higher than, those reported in recent studies of HIV-positive women and older studies of HIV-positive MSM. Overall, participants endorsing past year PA reported poorer mental but not physical health. Participants who endorsed past year physical PA, specifically, reported the largest number of mental health problems. HIV care providers should routinely assess PA, especially physical PA, in all MSM patients.

Consensual sex between men and sexual violence in Australian prisons.

Estimates of the incidence of sexual coercion in men's prisons are notoriously variable and fraught with conceptual and methodological problems. In 2006-2007, we conducted a computer-assisted telephone survey of a random sample of 2,018 male prisoners in New South Wales and Queensland. Of 2,626 eligible and available inmates, 76.8% consented and provided full responses. We asked about time in prison, sexual experience, attraction and (homo/bi/heterosexual) identity, attitudes, sexual contact with other inmates, reasons for having sex and practices engaged in, and about sexual coercion, including location and number of perpetrators. Most men (95.1%) identified as heterosexual. Of the total sample, 13.5% reported sexual contact with males in their lifetime: 7.8% only outside prison, 2.8% both inside and outside, and 2.7% only inside prison. Later in the interview, 144 men (7.1% of total sample) reported sexual contact with inmates in prison; the majority had few partners and no anal intercourse. Most did so for pleasure, but some for protection, i.e., to avoid assault by someone else. Before incarceration, 32.9% feared sexual assault in prison; 6.9% had been sexually threatened in prison and 2.6% had been sexually coerced ("forced or frightened into doing something sexually that [they] did not want"). Some of those coerced reported no same-sex contact. The majority of prisoners were intolerant of male-to-male sexual activity. The study achieved a high response rate and asked detailed questions to elicit reports of coercion and sex separately. Both consensual sex and sexual assault are less common than is generally believed.

Impact of the Comprehensive Care for Joint Replacement model on patient-reported outcomes.

OBJECTIVE: To determine whether the Comprehensive Care for Joint Replacement (CJR) model, a mandatory episode-based payment program for knee and hip replacement surgery, affected patient-reported measures of quality. DATA SOURCES: Surveys of Medicare fee-for-service beneficiaries who had hip or knee replacement surgery, collected between July 2018 and March 2019, secondary Medicare administrative data, the Provider of Services file, CJR and Bundled Payments for Care Improvement participant lists from the Centers for Medicare & Medicaid Services, and the Area Health Resource Files. STUDY DESIGN: In 2018, participation in the CJR model was mandatory for nearly all hospitals in 34 randomly selected, metropolitan statistical areas (MSAs) that had high historical Medicare payments for lower-extremity joint replacements surgery. The control group included 47 high-payment MSAs randomly assigned as controls. We estimated risk-adjusted differences in self-reported measures of functional status and pain, satisfaction with care, and caregiver help between respondents in CJR hospitals and respondents in hospitals located in the control group. DATA COLLECTION: We selected a census of CJR patients and an equal number of control patients to survey. We fielded two waves of surveys using a mail and phone protocol, yielding 8433 CJR and 9014 control respondents. PRINCIPAL FINDINGS: CJR respondents were slightly more likely to depend on caregivers for certain activities of daily living when they got home (either directly from the hospital or after an institutional post-acute care stay). On a 100-point scale, differences ranged from -2.6 points (p < 0.01) for help needed bathing to -1.7 points (p < 0.05) for help needed using the toilet. However, differences in eight measures of self-reported functional status approximately 90-120 days after hospital discharge were not statistically significant, ranging from -1.1% (p = 0.087) to 0.7% (p = 0.437). CONCLUSIONS: CJR did not harm patient health or affect patient satisfaction on average but did increase reliance on caregivers during recovery.

Prevalence of hereditary tubulointerstitial kidney diseases in the German Chronic Kidney Disease study.

Hereditary chronic kidney disease (CKD) appears to be more frequent than the clinical perception. Exome sequencing (ES) studies in CKD cohorts could identify pathogenic variants in ~10% of individuals. Tubulointerstitial kidney diseases, showing no typical clinical/histologic finding but tubulointerstitial fibrosis, are particularly difficult to diagnose. We used a targeted panel (29 genes) and MUC1-SNaPshot to sequence 271 DNAs, selected in defined disease entities and age cutoffs from 5217 individuals in the German Chronic Kidney Disease cohort. We identified 33 pathogenic variants. Of these 27 (81.8%) were in COL4A3/4/5, the largest group being 15 COL4A5 variants with nine unrelated individuals carrying c.1871G>A, p.(Gly624Asp). We found three cysteine variants in UMOD, a novel missense and a novel splice variant in HNF1B and the homoplastic MTTF variant m.616T>C. Copy-number analysis identified a heterozygous COL4A5 deletion, and a HNF1B duplication/deletion, respectively. Overall, pathogenic variants were present in 12.5% (34/271) and variants of unknown significance in 9.6% (26/271) of selected individuals. Bioinformatic predictions paired with gold standard diagnostics for MUC1 (SNaPshot) could not identify the typical cytosine duplication ("c.428dupC") in any individual, implying that ADTKD-MUC1 is rare. Our study shows that >10% of selected individuals carry disease-causing variants in genes partly associated with tubulointerstitial kidney diseases. COL4A3/4/5 genes constitute the largest fraction, implying they are regularly overlooked using clinical Alport syndrome criteria and displaying the existence of phenocopies. We identified variants easily missed by some ES pipelines. The clinical filtering criteria applied enriched for an underlying genetic disorder.

Preterm birth results in alterations in neural connectivity at age 16 years.

Very low birth weight preterm (PT) children are at high risk for brain injury. Employing diffusion tensor imaging (DTI), we tested the hypothesis that PT adolescents would demonstrate microstructural white matter disorganization relative to term controls at 16 years of age. Forty-four PT subjects (600-1250 g birth weight) without neonatal brain injury and 41 term controls were evaluated at age 16 years with DTI, the Wechsler Intelligence Scale for Children-III (WISC), the Peabody Picture Vocabulary Test-Revised (PPVT), and the Comprehensive Test of Phonological Processing (CTOPP). PT subjects scored lower than term subjects on WISC full scale (p=0.003), verbal (p=0.043), and performance IQ tests (p=0.001), as well as CTOPP phonological awareness (p=0.004), but scored comparably to term subjects on PPVT and CTOPP Rapid Naming tests. PT subjects had lower fractional anisotropy (FA) values in multiple regions including bilateral uncinate fasciculi (left: p=0.01; right: p=0.004), bilateral external capsules (left: p<0.001; right: p<0.001), the splenium of the corpus callosum (p=0.008), and white matter serving the inferior frontal gyrus bilaterally (left: p<0.001; right: p=0.011). FA values in both the left and right uncinate fasciculi correlated with PPVT scores (a semantic language task) in the PT subjects (left: r=0.314, p=0.038; right: r=0.336, p=0.026). FA values in the left and right arcuate fasciculi correlated with CTOPP Rapid Naming scores (a phonologic task) in the PT subjects (left: r=0.424, p=0.004; right: r=0.301, p=0.047). These data support for the first time that dual pathways underlying language function are present in PT adolescents. The striking bilateral dorsal correlations for the PT group suggest that prematurely born subjects rely more heavily on the right hemisphere than typically developing adults for performance of phonological language tasks. These findings may represent either a delay in maturation or the engagement of alternative neural pathways for language in the developing PT brain.

Psychological distress and experience of sexual and physical assault among Australian prisoners.

BACKGROUND: Prison populations are made up of individuals from disadvantaged, often abusive backgrounds, who are more likely to suffer from psychological problems than the general community. AIM: This study aimed to determine associations between current psychological distress and history of having experienced sexual coercion and/or physical assault among prisoners in two Australian states (Queensland and New South Wales). METHODS: We conducted a random sample survey of prisoners by computer-assisted telephone interview. Prisoners were asked about forced sexual encounters in or outside prison, and physical assault in prison. Psychological distress was estimated using a dichotomised score obtained from the Kessler 6-Item Psychological Distress Scale (K6), and a logistic regression analysis was employed to investigate associations. RESULTS: A total of 2426 prisoners were interviewed of 3055 prisoners invited to participate, a response rate of 79%. We categorised 236 men (12%) and 63 women (19%) as 'severely' psychologically distressed according to the K6, and 13% of the men and 60% of the women reported that they had been sexually coerced prior to imprisonment. Physical assault in prison was common, reported by 34% of the men and 24% of the women. On multivariate analysis, prisoners were more likely to be psychologically distressed if they had ever been threatened with sexual assault in prison or physically assaulted in prison. Sexual coercion outside prison was an important associate of psychological distress among men but not among women. CONCLUSIONS: As psychological distress and experiences of assault are closely statistically linked among male prisoners and both are very common among female prisoners, their screening for psychological distress should include efforts to find out about sexual and violent assaults against them both before and during imprisonment. Further, longitudinal research with prisoners is required to establish causal relationships.

Functional connectivity to a right hemisphere language center in prematurely born adolescents.

Prematurely born children are at increased risk for language deficits at school age and beyond, but the neurobiological basis of these findings remains poorly understood. Thirty-one PT adolescents (600-1250g birth weight) and 36 T controls were evaluated using an fMRI passive language task and neurodevelopmental assessments including: the Wechsler Intelligence Scale for Children-III (WISC-III), the Peabody Picture Vocabulary Test-Revised (PPVT-R), the Comprehensive Test of Phonological Processing (CTOPP) and the Test of Word Reading Efficiency (TOWRE) at 16years of age. Neural activity was assessed for language processing and the data were evaluated for connectivity and correlations to cognitive outcomes. PT subjects scored significantly lower on all components of the WISC-III (p<0.05) compared to term subjects, but there was no significant difference in PPVT-R scores between the groups. Functional connectivity (fcMRI) between Wernicke's area (left BA 22) and the right supramarginal gyrus (BA 40) was increased in preterm subjects relative to term controls (p=0.03), and the strength of this connection was inversely related to performance on both the PPVT-R (R(2)=0.553, p=0.002), and the verbal comprehension index (R(2)=0.439, p=0.019). Preterm adolescents engage a dorsal right hemisphere region for language at age 16years. Those with the greatest cognitive deficits demonstrate increasing reliance on this alternate pathway.