Impact of Transient and Persistent Donor-Specific Antibodies in Lung Transplantation.

Lung transplantation (LuTx) is an established treatment for patients with end-stage lung diseases, however, outcomes are limited by acute and chronic rejection. One aspect that has received increasing attention is the role of the host's humoral alloresponse, particularly the formation of de novo donor-specific antibodies (dnDSAs). The aim of this study was to investigate the clinical significance of transient and persistent dnDSAs and to understand their impact on outcomes after LuTx. A retrospective analysis was conducted using DSA screening data from LuTx recipients obtained at the Medical University of Vienna between February 2016 and March 2021. Of the 405 LuTx recipients analyzed, 205 patients developed dnDSA during the follow-up period. Among these, 167 (81%) had transient dnDSA and 38 (19%) persistent dnDSA. Persistent but not transient dnDSAs were associated with chronic lung allograft dysfunction (CLAD) and antibody-mediated rejection (AMR) (p < 0.001 and p = 0.006, respectively). CLAD-free survival rates for persistent dnDSAs at 1-, 3-, and 5-year post-transplantation were significantly lower than for transient dnDSAs (89%, 59%, 56% vs. 91%, 79%, 77%; p = 0.004). Temporal dynamics of dnDSAs after LuTx have a substantial effect on patient outcomes. This study underlines that the persistence of dnDSAs poses a significant risk to graft and patient survival.

The neurophenomenology of early psychosis: An integrative empirical study.

BACKGROUND: The integration of various domains or levels of analysis (clinical, neurobiological, genetic, etc.) has been a challenge in schizophrenia research. A promising approach is to use the core phenomenological features of the disorder as an organising principle for other levels of analysis. Minimal self-disturbance (fragility in implicit first-person perspective, presence and agency) is emerging as a strong candidate to play this role. This approach was adopted in a previously described theoretical neurophenomenological model that proposed that source monitoring deficits and aberrant salience may be neurocognitive/neurobiological processes that correlate with minimal self-disturbance on the phenomenological level, together playing an aetiological role in the onset of schizophrenia spectrum disorders. The current paper presents full cross-sectional data from the first empirical test of this model. METHODS: Fifty ultra-high risk for psychosis patients, 39 first episode psychosis patients and 34 healthy controls were assessed with a variety of clinical measures, including the Examination of Anomalous Self-Experience (EASE), and neurocognitive and neurophysiological (EEG) measures of source monitoring deficits and aberrant salience. RESULTS: Linear regression indicated that source monitoring (composite score across neurocognitive and neurophysiological measures), with study group as an interaction term, explained 39.8% of the variance in EASE scores (R2 = 0.41, F(3,85) = 14.78, p < 0.001), whereas aberrant salience (composite score) explained only 6% of the variance in EASE scores (R2 = 0.06, F(3,85) = 1.44, p = 0.93). Aberrant salience measures were more strongly related to general psychopathology measures, particularly to positive psychotic symptoms, than to EASE scores. DISCUSSION: A neurophenomenological model of minimal self-disturbance in schizophrenia spectrum disorders may need to be expanded from source monitoring deficits to encompass other relevant constructs such as temporal processing, intermodal/multisensory integration, and hierarchical predictive processing. The cross-sectional data reported here will be expanded with longitudinal analysis in subsequent reports. These data and other related recent research show an emerging picture of neuro-features of core phenomenological aspects of schizophrenia spectrum disorders beyond surface-level psychotic symptoms.

Interrelationships between obesity, obstructive sleep apnea syndrome and cardiovascular risk in obese adolescents.

BACKGROUND/OBJECTIVES: Obstructive sleep apnea syndrome (OSAS) may be a cardiovascular disease (CVD) risk factor independently of obesity in adults. Pediatric studies have associated OSAS with endothelial dysfunction, but few studies have examined relationships between OSAS and macrovascular sequelae. Our objective was to examine OSAS's independent contribution to macrovascular CVD risk measures in obese adolescents. SUBJECTS/METHODS: This cross-sectional observational study was conducted at Children's Hospital of Philadelphia Clinical Research and Academic Sleep Centers, and University of Pennsylvania Vascular Research Unit. Thirty-one obese non-diabetic adolescents underwent anthropometric measurements, overnight polysomnography, fasting laboratory draw and cardiovascular imaging. Cardiovascular outcome measures included maximal carotid intima-media thickness (cIMTmax), a measure of carotid structural changes, and carotid-femoral pulse wave velocity (CFPWV), an aortic stiffness measure whose relationship vis-à-vis OSAS in children has not been previously examined. Carotid diameter and augmentation index (AIx, measuring central pressure augmentation from wave reflections) were assessed. Potential confounding variables examined included blood pressure, lipoproteins, high-sensitivity C-reactive protein, insulin and glucose. RESULTS: The apnea hypopnea index, a primary OSAS measure, was not associated with cIMTmax, carotid diameter, CFPWV or AIx. body mass index (BMI) associated positively with cIMTmax (r=0.52, P=0.006) and CFPWV (r=0.45, P=0.01). Mean asleep end-tidal CO2 was negatively associated with carotid diameter (r=-0.63, P<0.0005). Insulin levels were negatively associated with AIx (r=-0.53, P=0.02). CONCLUSIONS: OSAS did not predict carotid structural changes or arterial stiffness independently of BMI in obese adolescents. Higher insulin levels associated with lower central pressure wave augmentation. Finally, long-term hypercapnia may predispose to carotid narrowing.

Disturbances of basic self and prodromal symptoms among non-psychotic help-seeking adolescents.

BACKGROUND: The goal of this study was to explore the notion that anomalies of self-experience (ASE) are a core, 'not-yet-psychotic' clinical phenotype of emerging schizophrenia and its spectrum. Method To accomplish this goal, we examined the relationship between ASE and commonly accepted risk markers in a sample of 87 help-seeking, non-psychotic adolescents (aged 14-18 years). ASE were assessed with the Examination of Anomalous Self-Experience (EASE), subclinical psychotic symptoms were assessed with the Prodromal Questionnaire and the Structured Interview for Prodromal Syndromes, deterioration in psychosocial functioning was assessed with the Social and Role Functioning Scales, and level of distress with the Mood and Anxiety Symptoms Questionnaire. RESULTS: About 82 participants completed the entire EASE interview. The number of participants who reported ASE at a clinically meaningful level (n = 18, 22%) was smaller than that who met diagnostic criteria for a prodromal syndrome (n = 28, 34%). The degree of overlap between the two conditions was moderate but statistically significant (χ2 (1) = 7.01, p = 0.008). An exploratory factor analysis revealed that ASE load on a different factor than prodromal symptoms and deterioration in functioning, but that there is a moderate correlation between the three factors. CONCLUSIONS: These results suggest that ASE are prevalent among non-psychotic help-seeking adolescents, yet at a considerably lower rate than prodromal symptoms. In addition, they suggest that ASE and prodromal symptoms constitute distinct but moderately related dimensions of potential risk. Taken together, they provide preliminary support for the clinical usefulness of supplementing and refining the methods of early detection of risk with assessment of ASE.

Loss of high-molecular-weight von Willebrand factor multimers mainly affects platelet aggregation in patients with aortic stenosis.

Severe aortic stenosis is associated with a haemostatic abnormality that resembles acquired von Willebrand syndrome type 2. It is assumed that high shear conditions render large von Willebrand factor (VWF) multimers accessible to cleavage by ADAMTS-13. However, whether loss of these large multimers affects platelet function by impairing adhesion, aggregate formation, or both has not been evaluated in clinical studies. We prospectively enrolled 47 patients with severe aortic stenosis, and studied them prior to aortic valve surgery and at a median of six months after valve replacement. We investigated levels of large VWF multimers, platelet function under high shear conditions, and residual response to suboptimal concentrations of ADP to express P-selectin. As expected, there was a significant reduction of VWF large multimers before surgery that resolved thereafter in most patients (p<0.0001). The closure time of the ADP cartridge of the PFA-100 was also corrected in most patients after the operation (p<0.0001). We used the cone and plate(let) analyser Impact-R to differentiate between adhesion and aggregation. Both adhesion (p=0.03) and ADP-inducible platelet aggregation (p=0.002) improved considerably after valve replacement. Consequently, ADP-inducible expression of P-selectin was higher after valve replacement (p=0.001). We conclude that reduced levels of large VWF multimers associated with aortic stenosis lead to impairment of both adhesion and, especially, ADP-inducible platelet aggregation.

Monitoring survival and function of transfused platelets in Glanzmann thrombasthenia by flow cytometry and thrombelastography.

Patients with Glanzmann thrombasthenia (GT) may form isoantibodies which induce refractoriness or inhibition of function of transfused platelets. We monitored the survival and function of transfused platelets by flow cytometry and thrombelastography in a patient with GT. Gating on CD42a+ allowed identification of even a few transfused platelets. Only by gating on these CD41+ CD42a+ cells were we able to demonstrate their capability to bind fibrinogen and PAC-1 upon activation. Platelets were rapidly cleared from the circulation as a result of boosted isoantibodies. The contribution of transfused platelets to clot formation was also demonstrated by thrombelastography by blocking their function with abciximab.

Frequencies of maternal platelet alloantibodies and autoantibodies in suspected fetal/neonatal alloimmune thrombocytopenia, with emphasis on human platelet antigen-15 alloimmunization.

BACKGROUND AND OBJECTIVES: Serological evaluation of maternal sera for platelet antibodies in suspected fetal/neonatal alloimmune thrombocytopenia (FNAITP) discloses in only approximately 30% of individuals a platelet-specific antibody. Transfusion-induced alloimmunization against human platelet antigen-15 (HPA-15) has been reported to be about as common as against HPA-5, the second most common platelet antibody. Thus, anti-HPA-15 may also contribute significantly to yet-unclear cases of FNAITP. MATERIALS AND METHODS: In this retrospective analysis, we provide data on maternal platelet antibodies from 309 mothers who delivered an offspring with suspected FNAITP. RESULTS: Genotyping maternal and paternal samples (together n = 573) revealed a gene frequency of 0.496 for HPA-15a and a gene frequency of 0.504 for HPA-15b. HPA-15 antibodies were detected in 2% of all samples. Anti-HPA-15a and -15b were detected in two and three samples, respectively. One serum reacted equally with HPA-15a and -15b platelets. The most frequent platelet-specific antibodies were anti-HPA-1a (22%), but anti-HPA-5b (8.4%) were more frequent than anti-HPA-15. In addition, panreactive (5.5%) or autoreactive (5.2%) anti-GPIIb/IIIa or anti-GPIb/IX were detectable in maternal samples. CONCLUSIONS: These data indicate that HPA-15 alloimmunization needs only to be considered in subjects with suspected FNAITP if no other platelet-specific antibody is detectable. The presence of panreactive or autoreactive antibodies should also be considered in neonatal thrombocytopenia.

The adequacy of the MMPI-2 Harris-Lingoes subscales: a cross-cultural factor analytic study of Scales D, Hy, Pd, Pa, Sc, and Ma.

The authors investigated cross-culturally the factor structure of Scales D, Hy, Pd, Pa, Sc, and Ma of the Minnesota Multiphasic Personality Inventory--2 (S. R. Hathaway & J. C. McKinley, 1989) to examine the adequacy of the Harris-Lingoes (HL) subscales developed for these scales. A combined sample of 1,896 Israeli outpatients and inpatients and a sample of 1,020 American outpatients were used. Each scale was factor analyzed separately in the Israeli and U.S. samples and, within each sample, by gender. The results did not support the structural adequacy of the HL subscales for Scales D, Pd, Sc, and Ma but generally supported their suitability for Scales Hy and Pa. In addition, the results also suggested that all clinical scales share a common element of general distress akin to A. Tellegen's (1985) negative affectivity. These findings highlight the need for developing and validating a new set of subscales for most of the clinical scales, using external measures of relevant clinical and personality domains for which the current scales may serve as a basis.

Long term course of chronic posttraumatic stress disorder in traffic accident victims: a three-year prospective follow-up study.

The purpose of the present study was to gather prospective longitudinal data on the long-term course and outcome of chronic posttraumatic stress disorder (PTSD). The target population for this study was 74 injured traffic accident victims who had been previously followed-up for one year after the trauma. Nineteen of the original 24 PTSD subjects (79%) and 39 of the original 50 Non-PTSD subjects (78%) were available for this study, which took place during the fourth year after the accident. Our results show that 10 (53%) of the 19 patients with PTSD at one-year still suffered from PTSD after another two-year follow-up interval, while 9 recovered from PTSD during this follow-up period. Only 2 of the 39 without PTSD at one year developed delayed onset PTSD. The best predictor of recovery from chronic PTSD was the initial level of posttraumatic reaction immediately after the accident. These results demonstrate that spontaneous recovery from PTSD can occur even among patients who are currently considered chronic. Severity of initial reaction to the trauma appears to be a major risk factor for non-remitting chronic PTSD.

Neuropsychological effects of prefrontal slow rTMS in normal volunteers: a double-blind sham-controlled study.

Recent reports have suggested that repetitive transcranial magnetic stimulation (rTMS) is effective in major depression. Unlike ECT, rTMS does not involve a seizure and is associated with minimal side-effects, including cognitive difficulties. However, the effect of rTMS on cognitive functioning has not been systematically evaluated. This study was designed to examine the neuropsychological effects of slow rTMS in normal volunteers. Forty-six normal volunteers were randomly assigned to receive one session of right (N = 16) or left prefrontal (N = 15), or sham (N = 15) rTMS at 1 HZ. Patients were assessed before and after stimulation by a computerized neurospychological battery. All three groups showed significant improvement over time in processing speed (reaction time) and efficiency (correct responses per unit of time). However, no time by group interaction was found for any of the neuropsychological tests. These findings suggest that a single session of slow rTMS does not interfere with neurospychological functioning in normal volunteers, supporting clinical reports of no adverse cognitive effects.

Right prefrontal slow repetitive transcranial magnetic stimulation in schizophrenia: a double-blind sham-controlled pilot study.

BACKGROUND: The aim of this study was to extend our previous work on the therapeutic efficacy of repetitive transcranial magnetic stimulation (rTMS) in major depression to patients with schizophrenia. METHODS: Thirty-five inpatients with schizophrenia were randomly assigned to either right prefrontal rTMS or sham treatment and were rated before and after treatment for positive, negative, and depressive symptoms. RESULTS: Thirty-one subjects (rTMS = 16, sham = 15) completed a 2-week treatment protocol. No serious adverse effects were reported; however, rTMS was not superior to sham treatment on any of the clinical ratings. CONCLUSIONS: In contrast to our previous positive findings in major depression, right prefrontal slow rTMS does not appear to have a beneficial effect for actively psychotic patients with schizophrenia.

Therapeutic efficacy of right prefrontal slow repetitive transcranial magnetic stimulation in major depression: a double-blind controlled study.

BACKGROUND: Transcranial magnetic stimulation (TMS), a noninvasive technique for stimulation of the brain, has recently been suggested to be effective for the treatment of major depression. We conducted a double-blind, placebo-controlled study to assess the efficacy of slow repetitive TMS (rTMS) in patients with major depression. METHODS: Seventy patients with major depression (53 women, 17 men; mean age, 58.7 years; SD, 17.2 years) were randomly assigned to receive rTMS or sham rTMS in a double-blind design. Treatment was administered in 10 daily sessions during a 2-week period. Severity of depression was blindly assessed before, during, and after completion of the treatment protocol. RESULTS: All patients completed the first week of treatment and 67 completed the entire protocol. Patients who received rTMS had a significantly greater improvement in depression scores compared with those who received sham treatment. At the end of 2 weeks, 17 of 35 patients in the rTMS group, but only 8 of 32 in the sham-treated group, had an improvement of greater than 50% in their depression ratings. CONCLUSIONS: This controlled study provides evidence for the short-term efficacy of slow rTMS in patients with recurrent major depression. Additional studies will be necessary to assess the efficacy of rTMS as compared with electroconvulsive therapy as well as the long-term outcome of this treatment in major depression and possibly other psychiatric disorders.

Acute stress response and posttraumatic stress disorder in traffic accident victims: a one-year prospective, follow-up study.

OBJECTIVE: This study was designed to assess the natural course of posttraumatic symptoms formation, as well as the degree to which acute stress reactions predict later posttraumatic stress disorder (PTSD) in injured traffic accident victims. METHOD: A prospective, 1-year follow-up study was carried out on 74 injured traffic accident victims and a comparison group of 19 patients who were hospitalized for elective orthopedic surgery. Participants were interviewed within the first week following the accident, and follow-up interviews were performed 1, 3, 6, and 12 months after the accident. At 12 months, a structured clinical interview was administered to determine a formal DSM-III-R diagnosis of PTSD. RESULTS: Twenty-four (32%) of the 74 traffic accident victims, but none of the 19 comparison subjects, met DSM-III-R criteria for PTSD at 1 year. Traffic accident victims who developed PTSD had higher levels of premorbid and comorbid psychopathology. Levels of posttraumatic symptoms were significantly higher from the outset in the subjects who developed PTSD and worsened progressively over the first 3 months, in contrast to subjects without PTSD, who manifested gradual amelioration of symptoms during this time. Existence of posttraumatic symptoms immediately after the accident was a better predictor of later PTSD than was accident or injury severity. CONCLUSIONS: In this study, a significant portion of injured traffic accident victims manifested PTSD 1 year after the event. The development of PTSD at 1 year can be predicted as early as 1 week after the accident on the basis of the existence and severity of early PTSD-related symptoms. However, the first 3 months following the accident appear to be the critical period for the development of PTSD.

Screening for platelet auto-antibodies by flow cytometry and their evaluation by the MAIPA technique.

The determination of platelet antibodies assists in the diagnosis of immune thrombocytopenia. Among the various techniques which have been used two major ways for the determination of these antibodies have entered the routine use, determination of in vivo platelet bound total IgG, termed platelet-associated IgG, PAIgG, and that of specifically to particular platelet glycoproteins bound IgG, GP-IgG. The former has been found to be non-specific, and the evaluation of the latter is rather laborious. Furthermore, both require a large number of platelets. By flowcytometry, however, PAIgG can be determined even if platelet counts are very low. We therefore evaluated in 30 patients' samples if the flowcytometric determination of PAIgG can serve to screen for platelet antibodies. Positive samples subsequently are evaluated by a glycoprotein-specific detection technique (MAIPA). We show that in patients with suspected autoimmune thrombocytopenia (AITP) and in secondary AITP PAIgG is elevated in 83%. However, only 30% of patients' samples have detectable antibodies by the MAIPA technique. Based on the findings that by the MAIPA technique antibodies were only detectable in samples which had also elevated levels of PAIgG we consider the flowcytometric determination of PAIgG useful for screening, prior to the more laborious investigation by the MAIPA assay.

Are there sex differences in neuropsychological functions among patients with schizophrenia?

OBJECTIVE: Studies of sex differences in neuropsychological performance in schizophrenia report inconsistent results, due in part to methodological artifacts. The study presented here was specifically designed to examine sex differences in neuropsychological performance. It was hypothesized that schizophrenic women would exhibit fewer neuropsychological deficits than schizophrenic men and that their performance would be more similar to that of normal women than schizophrenic men's performance would be to that of normal men. METHOD: Thirty-one outpatients with DSM-III-R-defined schizophrenia were systematically sampled from an extensive service network serving a large urban catchment area for seriously mentally ill persons. Twenty-seven normal comparison subjects were matched within sex on the basis of age, parental socioeconomic status, ethnicity, and handedness. An extensive neuropsychological test battery was administered, and multivariate analysis of variance was used to test for the effects of sex and group and sex-by-group interactions. RESULTS: Male patients were significantly impaired across all functions in comparison with normal male subjects and on tests of attention, verbal memory, and executive functions in comparison with female patients. Female patients performed significantly worse than female normal comparison subjects only on tests of attention, executive functions, visual memory, and motor functions. CONCLUSIONS: The findings suggest that women with schizophrenia may be less vulnerable to particular cognitive deficits, especially those involving verbal processing, than schizophrenic men.

IQ decline during childhood and adult psychotic symptoms in a community sample: a 19-year longitudinal study.

OBJECTIVE: The goal of this study was to examine cognitive antecedents of psychosis by determining whether variability in IQ during childhood was predictive of psychotic symptoms in adulthood. METHOD: Deviant responder analyses were used to examine prospectively the relationship of IQ at ages 4 and 7 to psychotic symptoms at age 23 in 547 offspring from a community sample (National Collaborative Perinatal Project) that was unselected for psychiatric illness. The authors compared three hypotheses: that 1) low IQ, 2) large IQ fluctuations regardless of direction, or 3) large IQ declines would predict the presence of adult psychotic symptoms. RESULTS: The 10% of individuals with substantially larger than expected IQ declines from age 4 to 7 had a rate of psychotic, but not other psychiatric, symptoms at age 23 that was nearly seven times as high as the rate for other persons. Parental socioeconomic status and IQ at age 7 also predicted adult psychotic symptoms. However, when IQ at age 7, IQ decline between ages 4 and 7, and socioeconomic status were all included in a logistic regression analysis, only IQ decline remained significant. CONCLUSIONS: There is an increased likelihood of developing psychotic symptoms in adulthood for a subgroup of individuals with substantially greater than expected IQ declines during childhood. IQ decline is specific for psychotic symptoms, but follow-up assessment when the study participants are further into the age of risk will be necessary to determine specificity for schizophrenia. The authors discuss the implications of this early cognitive downturn for a neurodevelopmental view of schizophrenia.

Factor structure of the Wisconsin Card Sorting Test: dimensions of deficit in schizophrenia.

The aim of this study was to explore the factorial structure of the Wisconsin Card Sorting Test (WCST) and to identify the dimensions of deficit in schizophrenia. WCST scores in patients with schizophrenia and schizophrenia-related psychosis (n = 292), 1st degree relatives of schizophrenic patients (n = 91), and normal controls (n = 141) were subjected to a principal factor analysis followed by orthogonal rotation. This led to 3 factors, perseveration, failure to maintain set, and idiosyncratic sorting. The detected factor structure was found to be invariant across the schizophrenic and control subsamples. Moreover, it replicated previous findings from 2 smaller samples. Only perseverations and, to a lesser degree, idiosyncratic sorting appeared to differentiate schizophrenic patients from comparisons. Only perseveration had good sensitivity and specificity, as well as the most robust significant correlations with estimates of IQ, attention, and other measures of executive functioning. Thus, perseveration appears to be the most diagnostically useful and characteristic WCST feature of schizophrenia.

Sex differences in olfactory identification and Wisconsin Card Sorting performance in schizophrenia: relationship to attention and verbal ability.

We investigated the hypothesis that different prefrontal brain systems (i.e., dorsal vs. ventral) and sex contribute differentially to cognitive deficit in schizophrenia. Performance was assessed among clinically stable, chronic schizophrenic outpatients and matched normal control subjects on olfactory identification [on the University of Pennsylvania Smell Identification Test (UPSIT)] and on executive functions [using the Wisconsin Card Sorting Test (WCST)]. Patients were impaired on both tests compared to controls, and male schizophrenics were impaired on the WCST compared to female schizophrenics. The pattern of results suggests that gender differences on the UPSIT are mildly accentuated in schizophrenia. The data support our previous study indicating that UPSIT performance is largely independent of the executive or attentional deficits typically associated with schizophrenia, with the exception of verbal ability. Further research with larger samples is required to test the hypothesis that there is a severely impaired subgroup of male patients with diffuse prefrontal dysfunctions.

Affect regulation and affective experience: individual differences, group differences, and measurement using a Q-sort procedure.

This article describes the development of, and preliminary findings with, the Affect Regulation and Experience Q-Sort (the AREQ), an observer-based assessment of affect regulation and experience. In Study 1, 31 clinicians provided Q-sort descriptions of 90 patients. Factor scores correlated in predicted ways with criteria such as suicide attempts and hospitalizations, as well as with clinicians' ratings of functioning in a variety of domains. Correlations between prototype Q-sorts and actual Q-sort profiles for patients sharing a diagnosis (dysthymia, borderline personality disorder, and narcissistic personality disorder) also provided evidence for convergent and discriminant validity. The data also suggested the importance of distinguishing 2 kinds of negative affect that have very different correlates. Study 2 showed that the AREQ can be applied reliably using an interview that avoids many of the problems of self-report.