Assessing the clinical significance of treatment outcomes for distressing voices in routine clinical practice

Determining reliable and clinically significant change is central to evidence‐based practice yet rarely used in routine clinical settings. This paper illustrates these methods in the context of an evaluation of cognitive behaviour therapy for distressing auditory hallucinations (“voices”). We used data from a clinical sample attending Perth Voices Clinic, a transdiagnostic outpatient service for distressing voices, and a previously published reference sample of healthy voice hearers. Our outcomes on the primary measure of voice distress, derived from a previous factor analysis of the Psychotic Symptom Rating Scale‐Auditory Hallucinations subscale, showed that 62.9% of clients were classified as Recovered/Improved, 35.5% were classified as Unchanged, and 0.02% were classified as Deteriorated. Partial support for the validity of these classifications was obtained from the scores on the Depression, Anxiety, Stress Scales (Lovibond & Lovibond, 1995) but not on the Social and Occupational Functional Assessment Scale (Goldman et al., 1992). Clients classified as Recovered showed better emotional functioning on the Depression, Anxiety, Stress Scales compared with those who did not make a clinically significant change in voice distress. A tool is provided to assist practitioners to evaluate whether individual clients have benefited from therapy for distressing voices or not, which can be used to guide future treatment decisions ( https://osf.io/gd9e5/ ).     

Genotype-phenotype correlation and molecular heterogeneity in pyruvate kinase deficiency

Pyruvate kinase (PK) deficiency is a rare recessive congenital hemolytic anemia caused by mutations in the PKLR gene. This study reports the molecular features of 257 patients enrolled in the PKD Natural History Study. Of the 127 different pathogenic variants detected, 84 were missense and 43 non-missense, including 20 stop-gain, 11 affecting splicing, five large deletions, four in-frame indels, and three promoter variants. Within the 177 unrelated patients, 35 were homozygous and 142 compound heterozygous (77 for two missense, 48 for one missense and one non-missense, and 17 for two non-missense variants); the two most frequent mutations were p.R510Q in 23% and p.R486W in 9% of mutated alleles. Fifty-five (21%) patients were found to have at least one previously unreported variant with 45 newly described mutations. Patients with two non-missense mutations had lower hemoglobin levels, higher numbers of lifetime transfusions, and higher rates of complications including iron overload, extramedullary hematopoiesis, and pulmonary hypertension. Rare severe complications, including lower extremity ulcerations and hepatic failure, were seen more frequently in patients with non-missense mutations or with missense mutations characterized by severe protein instability. The PKLR genotype did not correlate with the frequency of complications in utero or in the newborn period. With ICCs ranging from 0.4 to 0.61, about the same degree of clinical similarity exists within siblings as it does between siblings, in terms of hemoglobin, total bilirubin, splenectomy status, and cholecystectomy status. Pregnancy outcomes were similar across genotypes in PK deficient women. This report confirms the wide genetic heterogeneity of PK deficiency.     

Characterization of the oncogenic activity of the novel TRIM59 gene in mouse cancer models

A novel TRIM family member, TRIM59 gene was characterized to be upregulated in SV40 Tag oncogene-directed transgenic and knockout mouse prostate cancer models as a signaling pathway effector. We identified two phosphorylated forms of TRIM59 (p53 and p55) and characterized them using purified TRIM59 proteins from mouse prostate cancer models at different stages with wild-type mice and NIH3T3 cells as controls. p53/p55-TRIM59 proteins possibly represent Ser/Thr and Tyr phosphorylation modifications, respectively. Quantitative measurements by ELISA showed that the p-Ser/Thr TRIM59 correlated with tumorigenesis, whereas the p-Tyr-TRIM59 protein correlated with advanced cancer of the prostate (CaP). The function of TRIM59 was elucidated using short hairpin RNA (shRNA)-mediated knockdown of the gene in human CaP cells, which caused S-phase cell-cycle arrest and cell growth retardation. A hit-and-run effect of TRIM59 shRNA knockdown was observed 24 hours posttransfection. Differential cDNA microarrray analysis was conducted, which showed that the initial and rapid knockdown occurred early in the Ras signaling pathway. To confirm the proto-oncogenic function of TRIM59 in the Ras signaling pathway, we generated a transgenic mouse model using a prostate tissue-specific gene (PSP94) to direct the upregulation of the TRIM59 gene. Restricted TRIM59 gene upregulation in the prostate revealed the full potential for inducing tumorigenesis, similar to the expression of SV40 Tag, and coincided with the upregulation of genes specific to the Ras signaling pathway and bridging genes for SV40 Tag-mediated oncogenesis. The finding of a possible novel oncogene in animal models will implicate a novel strategy for diagnosis, prognosis, and therapy for cancer.     

Comparison of the correlation of the Selvester QRS scoring system with cardiac contrast-enhanced magnetic resonance imaging-measured acute myocardial infarct size in patients with and without thrombolytic therapy

Background

After an acute myocardial infarction (MI), it is important to define the infarct size because it is related to mortality and morbidity. The Selvester QRS Score is an electrocardiographic (ECG) method that has been developed for estimating MI size. It has been shown to correlate well with postmortem anatomically measured sizes of single MI in patients who did not receive thrombolytic therapy. The aim of this study was to test the hypothesis that correlation between Selvester QRS Score-estimated MI size and contrast-enhanced magnetic resonance imaging (ceMRI)-measured MI size is equivalent in patients who did vs those who did not receive thrombolytic therapy.

Methods

Thirty-six patients with MI (24 with thrombolytic therapy and 12 without) received ceMRI and ECG at admission and at 1 or 6 months after admission. Indeed, in 23 of the patients, the therapy was intravenous only. The Selvester QRS Score was calculated using the 1-month ECG or, if not available, the 6-month ECG. The correlation between the 2 measures of MI size was determined for all patients and for the 2 groups separately.

Results

The mean MI size in the group that did not receive thrombolytic therapy was 8.5% ± 6.4% estimated by the Selvester QRS Score and 11.7% ± 10.2% measured by ceMRI. For the group that received thrombolytic therapy, Selvester QRS Score was 13.9% ± 11.1% and ceMRI was 20.2% ± 11.3%. The mean MI size in both groups combined was 12.1% ± 10.0% estimated by the Selvester QRS Score and 17.3% ± 11.5% measured by ceMRI. The Spearman rank correlation coefficient between Selvester QRS Score and ceMRI was 0.74 (P < .0001) for all patients, 0.74 (P < .0001) for the group that received thrombolytic therapy, and 0.64 (P = .024) for the group that did not receive thrombolytic therapy.

Conclusions

The associations between Selvester QRS Score and ceMRI-based MI were statistically significant and similar in both groups.     

Pain sensitivity is normalized after a repeated bout of eccentric exercise

Purpose

The purpose of this study was to investigate the effect of repeated bouts of eccentric exercise on the nociceptive withdrawal reflex (NWR) threshold, a measure of sensitivity in the spinal nociceptive system.

Methods

Sixteen healthy students (age 25.7 ± 0.6 years, BMI 24.8 ± 1 kg m^?2) participated in this randomized, controlled, crossover study. Two identical bouts of high-intensity eccentric exercises were performed on the tibialis anterior muscle 7 days apart. Control sessions involving no exercise were performed 4 weeks apart the exercise sessions. Pressure pain thresholds (PPT) and the NWR threshold were recorded before, immediately after, and 1 day after both bouts of exercise.

Results

Pressure pain thresholds decreased significantly at two of the muscle belly sites on the day after initial bout compared with baseline. NWR threshold decreased by 25 ± 4 % immediately after initial bout and by 30 ± 5 % the next day (p < 0.05) as an indication of generalized pain hypersensitivity. On the contrary, no changes were found in both pain thresholds after second bout of eccentric exercise indicating that both localized and generalized pain sensitivity were normalized.

Conclusion

In conclusion, this study for the first time documented that an initial bout of unaccustomed high-intensity eccentric exercise, which results in muscle soreness can induce central sensitization. A repeated bout of exercise, however, facilitates inherent protective spinal mechanisms against the development of muscle soreness.