Evolution of the intracranial features of congenital cytomegalovirus on MRI.

AIM: To describe the evolution of the intracranial features of congenital cytomegalovirus (cCMV) on magnetic resonance imaging (MRI). MATERIALS AND METHODS: Sixteen infants with polymerase chain reaction (PCR)-confirmed cCMV who had undergone at least two MRI examinations of the brain were identified. Two paediatric neuroradiologists reviewed the baseline studies retrospectively for intracranial features of cCMV, including white matter signal abnormalities, subependymal cysts, malformations of cortical development, and intracranial calcification. The subsequent MRI studies were then reviewed and directly compared to the baseline examinations. RESULTS: White matter signal abnormalities were seen on all 16 baseline studies (100%); these persisted on all subsequent examinations but were patchier, more focal, and associated with an interval reduction in white matter volume. Subependymal cysts were present on 11 (69%) of the baseline scans; these almost universally regressed (in 10 of the 11 cases [91%]), with no new cysts appreciable on subsequent imaging. Malformations of cortical development, exclusively in the form of polymicrogyria, were seen in six (38%) patients and persisted, unchanged, on subsequent imaging. Intracranial calcification was seen in a minority of baseline studies (4 [25%]) and remained stable on subsequent scans. CONCLUSION: Children with cCMV who present later in life without an established or suspected underlying pathology can pose a challenge to the assessing radiologist. The radiological sequelae of cCMV can be non-specific; in some cases, white matter signal abnormalities and focal loss of white matter volume may be the only intracranial features. It is therefore important that radiologists are aware of cCMV as a potential differential for these findings.

Prediction of lithium response using clinical data.

OBJECTIVE: Promptly establishing maintenance therapy could reduce morbidity and mortality in patients with bipolar disorder. Using a machine learning approach, we sought to evaluate whether lithium responsiveness (LR) is predictable using clinical markers. METHOD: Our data are the largest existing sample of direct interview-based clinical data from lithium-treated patients (n = 1266, 34.7% responders), collected across seven sites, internationally. We trained a random forest model to classify LR-as defined by the previously validated Alda scale-against 180 clinical predictors. RESULTS: Under appropriate cross-validation procedures, LR was predictable in the pooled sample with an area under the receiver operating characteristic curve of 0.80 (95% CI 0.78-0.82) and a Cohen kappa of 0.46 (0.4-0.51). The model demonstrated a particularly low false-positive rate (specificity 0.91 [0.88-0.92]). Features related to clinical course and the absence of rapid cycling appeared consistently informative. CONCLUSION: Clinical data can inform out-of-sample LR prediction to a potentially clinically relevant degree. Despite the relevance of clinical course and the absence of rapid cycling, there was substantial between-site heterogeneity with respect to feature importance. Future work must focus on improving classification of true positives, better characterizing between- and within-site heterogeneity, and further testing such models on new external datasets.

Larger right inferior frontal gyrus volume and surface area in participants at genetic risk for bipolar disorders.

BACKGROUND: Larger grey matter volume of the inferior frontal gyrus (IFG) is among the most replicated biomarkers of genetic risk for bipolar disorders (BD). However, the IFG is a heterogeneous prefrontal region, and volumetric findings can be attributable to changes in cortical thickness (CT), surface area (SA) or gyrification. Here, we investigated the morphometry of IFG in participants at genetic risk for BD. METHODS: We quantified the IFG cortical grey matter volume in 29 affected, 32 unaffected relatives of BD probands, and 42 controls. We then examined SA, CT, and cortical folding in subregions of the IFG. RESULTS: We found volumetric group differences in the right IFG, with the largest volumes in unaffected high-risk and smallest in control participants (F2,192 = 3.07, p = 0.01). The volume alterations were localized to the pars triangularis of the IFG (F2,97 = 4.05, p = 0.02), with no differences in pars opercularis or pars orbitalis. Pars triangularis volume was highly correlated with its SA [Pearson r(101) = 0.88, p < 0.001], which significantly differed between the groups (F2,97 = 4.45, p = 0.01). As with volume, the mean SA of the pars triangularis was greater in unaffected (corrected p = 0.02) and affected relatives (corrected p = 0.05) compared with controls. We did not find group differences in pars triangularis CT or gyrification. CONCLUSIONS: These findings strengthen prior knowledge about the volumetric findings in this region and provide a new insight into the localization and topology of IFG alterations. The unique nature of rIFG morphology in BD, with larger volume and SA early in the course of illness, could have practical implications for detection of participants at risk for BD.

COVID-19 Stroke Apical Lung Examination Study 2: a national prospective CTA biomarker study of the lung apices, in patients presenting with suspected acute stroke (COVID SALES 2).

BACKGROUND: Apical ground-glass opacification (GGO) identified on CT angiography (CTA) performed for suspected acute stroke was developed in 2020 as a coronavirus-disease-2019 (COVID-19) diagnostic and prognostic biomarker in a retrospective study during the first wave of COVID-19. OBJECTIVE: To prospectively validate whether GGO on CTA performed for suspected acute stroke is a reliable COVID-19 diagnostic and prognostic biomarker and whether it is reliable for COVID-19 vaccinated patients. METHODS: In this prospective, pragmatic, national, multi-center validation study performed at 13 sites, we captured study data consecutively in patients undergoing CTA for suspected acute stroke from January-March 2021. Demographic and clinical features associated with stroke and COVID-19 were incorporated. The primary outcome was the likelihood of reverse-transcriptase-polymerase-chain-reaction swab-test-confirmed COVID-19 using the GGO biomarker. Secondary outcomes investigated were functional status at discharge and survival analyses at 30 and 90 days. Univariate and multivariable statistical analyses were employed. RESULTS: CTAs from 1,111 patients were analyzed, with apical GGO identified in 8.5 % during a period of high COVID-19 prevalence. GGO showed good inter-rater reliability (Fleiss κ = 0.77); and high COVID-19 specificity (93.7 %, 91.8-95.2) and negative predictive value (NPV; 97.8 %, 96.5-98.6). In subgroup analysis of vaccinated patients, GGO remained a good diagnostic biomarker (specificity 93.1 %, 89.8-95.5; NPV 99.7 %, 98.3-100.0). Patients with COVID-19 were more likely to have higher stroke score (NIHSS (mean +/- SD) 6.9 +/- 6.9, COVID-19 negative, 9.7 +/- 9.0, COVID-19 positive; p = 0.01), carotid occlusions (6.2 % negative, 14.9 % positive; p = 0.02), and larger infarcts on presentation CT (ASPECTS 9.4 +/- 1.5, COVID-19 negative, 8.6 +/- 2.4, COVID-19 positive; p = 0.00). After multivariable logistic regression, GGO (odds ratio 15.7, 6.2-40.1), myalgia (8.9, 2.1-38.2) and higher core body temperature (1.9, 1.1-3.2) were independent COVID-19 predictors. GGO was associated with worse functional outcome on discharge and worse survival after univariate analysis. However, after adjustment for factors including stroke severity, GGO was not independently predictive of functional outcome or mortality. CONCLUSION: Apical GGO on CTA performed for patients with suspected acute stroke is a reliable diagnostic biomarker for COVID-19, which in combination with clinical features may be useful in COVID-19 triage.

Comparison of the production, quality, and in vitro maturation capacity of oocytes from untreated cycling and intermediate phase equine serum gonadotropin-treated fat-tailed dunnarts (Sminthopsis crassicaudata).

This study describes ovarian changes during the natural and stimulated reproductive cycle of breeding (< or =12 month) and retired (>12 month) fat-tailed dunnarts, Sminthopsis crassicaudata. Increased urinary cornified epithelial cells and the influx of leukocytes defined day 0, at which time the naturally cycling females had already ovulated; at day 16 females had no antral follicles, but by day 20 antral follicles had begun to develop. There was no difference between naturally cycling breeding and retired females. Females were stimulated with 1 IU equine serum gonadotropin (eSG) during the intermediate phase on day 16 and killed 3, 4, or 5 days later. Stimulation resulted in a significant increase in the number of growing antral follicles but retired females demonstrated a reduced response. Upon collection from breeding females 4 days following eSG stimulation, 100% of oocytes were at the first polar body (PB1) stage, those collected from retired females were immature upon collection but within 48 h 98.2+/-1.9% were cultured to the PB1 stage. The rate of ovulation was high in breeding females 5 days following stimulation but retired females were less reliable, and in both groups all oocytes were degraded. This is the first study to describe a reliable technique, involving ovarian stimulation during the intermediate phase and segregation of age groups, allowing the collection of a large number of healthy PB1 stage oocytes from S. crassicaudata. This is important for the development of further assisted reproductive techniques for this species and threatened dasyurids.

Exercise capacity and quality of life in the treatment of heart failure.

In a double-blind study comparing two active treatments (digoxin and xamoterol) and placebo in patients with heart failure, improvements in exercise capacity and quality of life were observed in all three groups, with no significant differences. The substantial benefits seen in the placebo group were probably the result of increased attention from the medical and research staff and suggest the therapeutic value of special heart failure clinics. The relationship between exercise and symptomatic/functional status has been unclear. We developed quantitative measures of quality-of-life variables and examined their relationship with exercise capacity. There were significant relationships between change in exercise duration and changes in breathlessness, tiredness, chest pain, walking difficulty, rate of walking, difficulty with daily tasks, speed of daily tasks, mood, and sleeping. This study confirms the validity of measuring change in exercise capacity and demonstrates that specific measurements of quality of life make an important contribution to the evaluation of the treatment of heart failure.

Application of the soluble antigen fluorescent antibody (SAFA) test to the serodiagnosis of rabies.

The adaptation and evaluation of the Soluble Antigen Fluorescent Antibody (SAFA) test for the serologic diagnosis of rabies is described. Evaluation of the SAFA test was based on a comparison between serum titers obtained in the SAFA test, the mouse Serum Neutralization (SN) test and in the Indirect Fluorescent Antibody (IFAT) test. Dog, fox, raccoon and skunk sera were used for the comparison with mouse SN titers. Human serum was used for the comparison with the IFAT titer. The purity and concentration of the test antigen is a crucial factor in determining the efficiency of the SAFA test for rabies serodiagnosis. Viral antigen obtained by the AIPO4 gel method for rabies virus purification and concentration was found to be sufficiently purified and concentrated for use in the SAFA test. Conjugate dilution decreased the level of non-specific staining. Although specific activity was also decreased, there was a statistically significant difference (P less than or equal to 0.05; Student's t test) between the rabies positive and the rabies negative serum samples at all conjugate dilutions for all species studied. In three cases (fox, raccoon, skunk) SAFA titers were greater than mouse SN titers. In one case (dog) the SAFA titer was less than the mouse SN titer. The IFAT titer of the human serum sample was greater than the SAFA titer. Comparison of Fluorometer Dial Readings (FDR) of sera obtained in separate protocols demonstrated satisfactory reproducibility of the SAFA test for rabies serodiagnosis.

A double blind comparative study of lisinopril and enalapril in patients with essential hypertension.

The efficacy and safety profiles of lisinopril (10-40 mg) and enalapril (5-20 mg) were compared in 169 hypertensive patients during 12 weeks' treatment in a randomised double-blind parallel group study. BP was measured hourly for the first 8 hours following the first dose of lisinopril 10 mg and enalapril 5 mg. The peak reduction in sitting systolic and diastolic BP occurred approximately 6 hours post dose in both groups. At 8 hours post dose lisinopril had reduced sitting systolic and diastolic BP by 2.9 mmHg and 3.5 mmHg (P = 0.02) respectively, more than enalapril with similar results for standing BP. One patient on enalapril developed first dose postural hypotension. After 12 weeks' therapy lisinopril produced a greater decrease (P less than 0.05) in BP than enalapril. Sitting BP decreased by 25/15 mmHg on lisinopril and 17/12 mmHg with enalapril. Standing BP decreased by 24/14 mmHg compared with 16/10 mmHg on enalapril. Eighteen patients did not complete the study, 8 on lisinopril (6 adverse events, 1 uncontrolled BP, 1 protocol violator) and 10 on enalapril (8 adverse events, 1 uncontrolled BP, 1 protocol violator). Overall, the results indicated that while both drugs are well tolerated, the dose range of lisinopril 10-40 mg may produce a greater antihypertensive effect than enalapril 5-20 mg.

Cardiac failure: symptoms and functional status.

The associations between exercise capacity, symptoms and specific aspects of quality of life were examined in subjects participating in a trial of the treatment of heart failure. Patients were assessed on entry and after three months treatment. The principle symptoms were fatigue, breathlessness and chest pain. These limited the extent and speed of physical activities, restricted social, leisure and family life and were associated with emotional distress. There were associations between baseline exercise capacity and measures of quality of life. Change in exercise capacity during three months treatment was correlated with changes in measures of symptoms, limitation of activity and quality of life. The findings confirm the value of change in exercise capacity as a measure of functional status and suggest that it should be supported by a limited number of specific measures of quality of life.

The effect of repeated administration of diftalone on enzyme induction.

Plasma concentrations of diftalone have been examined in normal volunteers after a single dose (500 mg) and after 500 mg doses given twice daily for one week. An increase in post dosing urinary excretion of D-glucaric acid showed a correlation with the ratio of calculated to observed areas under the plasma concentration, time curve following the final dose in the multiple dosing studies, indicating that hepatic microsomal enzymes are induced after repeated administration of the drug. Single dose studies in the presence of aluminium hydroxide and sodium bicarbonate showed that the antacids had no significant effect on the absorption of diftalone.

Estimating normal and pathological dynamic responses in cerebral blood flow velocity to step changes in end-tidal pCO2.

The regulation of cerebral blood flow (CBF) following changes in arterial blood pressure (ABP) and end-tidal pCO2 (EtCO2) are of clinical interest in assessing cerebrovascular reserve capacity. Linear finite-impulse-response modelling is applied to ABP, EtCO2 and CBF velocity (CBFV, from transcranial Doppler measurements), which allows the CBFV response to ideal step changes in EtCO2 to be estimated from clinical data showing more sluggish, and additional random variations. The confounding effects of ABP changes provoked by hypercapnia on the CBFV are also corrected for. Data from 56 patients suffering from stenosis of the carotid arteries (with normal or diminished cerebrovascular reactivity to EtCO2 changes--CVRCO2) were analysed. The results show the expected significant differences (p < 0.05) between EtCO2 steps up and down, the significant contribution from ABP variation, and also differences in the dynamic responses of patients with reduced CVRCO2 (p < 0.01 after 10 s). For the latter the CBFV response appears exhausted after about 15 s, whereas for normals CBFV continues to increase. While dispersion of individual step responses remains large, the method gives encouraging results for the non-invasive study of compromised haemodynamics in different patient groups.

Comparison of erythromycin ethyl succinate, stearate and estolate treatments of group A streptococcal infections of the upper respiratory tract.

The microbiologic and clinical responses of acute Group A beta-hemolytic streptococcal infections of the upper respiratory tract to oral treatment with erythromycin ethyl succinate, stearate, and estolate were studied in 303 patients. Streptococcal M and T typing was done on all positive cultures. The overall cure rate was 95.4 per cent, with no statistically significant differences in clearing organisms from the pharynx. Of the 285 cured patients who completed the prescribed follow-up period, 11 had recurrences between the 12th and 31st day after initiation of therapy, and five developed new infections. No cases of rheumatic fever or glomerulonephritis were encountered during a follow-up study. Eight gastrointestinal reactions and one transient rash occurred. Results with these forms of erythromycin compare favorably with published results for similar infections treated with oral penicillins.

[Contribution of perindopril to the treatment of chronic congestive cardiac insufficiency. Multicenter pilot double blind study versus placebo]. / Apport du perindopril au traitement de l'insuffisance cardiaque chronique congestive. Etude pilote multicentrique en double aveugle contre placebo.

Cardiac decompensation occurred in three patients of the placebo group, but not in the perindopril group. The effectiveness of perindopril in heart failure was demonstrated by the improvement observed in exercise test and severity score and by the decrease of cardiothoracic ratio. Changes in SAP, and serum creatinine levels, in particular, showed that the drug was well tolerated.

Retrospective study of intra-operative testing with the Nucleus CI24M cochlear implant and use of the back-up device.

The combined use of integrity testing (IT) and impedance telemetry (ImTe) intra-operatively is evaluated. One hundred and fifty children implanted with the Nucleus device were studied. In 81% of patients, normal results were obtained on all electrodes from both ImTe and IT. In seven cases where the back-up device was used, the intra-operative analysis of the device and subsequent postoperative quality assurance testing did not always correlate. In conclusion, intra-operatively, only ImTe is needed to verify the function of the implant if all impedance values are normal. However, in the case of abnormal ImTe results, additional IT data provide valuable assistance with the decision of whether to leave the implant in place or to use the backup device.

Some observations on informed consent in non-therapeutic research.

The quality of the consent obtained from 41 volunteer subjects in eight experiments is evaluated. Five subjects (all physicians) gave informed consent; 22 subjects gave partially informed consent; and 14 subjects merely gave consent. It is argued that 'informed' consent is obtainable only from medically trained people, and that lip service to this concept in laymen should cease. The concept of medical competence should instead be introduced and a personal medical referee appointed to adjudicate on behalf of the volunteer.

Comparison of the efficacy of nicardipine, a new calcium channel blocker, with nifedipine in the treatment of mild to moderate essential hypertension.

Thirty-nine patients with mild to moderate essential hypertension participated in a parallel, single-blind study comparing 6 weeks' treatment of nicardipine hydrochloride (90 mg/day) with nifedipine (40 mg/day). Nicardipine-treated patients commenced therapy with a significantly higher mean supine diastolic blood pressure than the nifedipine-treated patients. There was a statistically significant fall in blood pressure (systolic and diastolic) on both treatments at the 3 and 6 week follow-up visits. On adjusting the results for the baseline inequality, no statistically significant differences were found between treatment groups. Seven patients withdrew from nifedipine therapy and six patients withdrew from nicardipine therapy due to adverse events. The results show that nicardipine hydrochloride at 90 mg/day is an effective anti-hypertensive agent. The incidence and nature of adverse events were similar on the two treatments.

The effect of buffered aspirin on plasma indomethacin.

Plasma indomethacin levels have been compared in 10 subjects following 100 mg of indomethacin from two different formulations, with similar disintegration and dissolution profiles. In four of these ten subjects plasma indomethacin levels were estimated after pretreatment with, and concurrent administration of, a buffered aspirin. The percentage of protein binding of indomethacin in the presence of salicylate was also estimated. No significant differences between peak plasma indomethacin levels with or without buffered aspirin were detected, but the rate of indomethacin absorption as shown by plasma levels, was significantly increased by pretreatment with and concurrent administration of, buffered aspirin. This was associated with a marked increase in side effects.

Audit of 5-year post-implantation routine integrity tests performed on paediatric cochlear implantees.

The Nottingham Paediatric Cochlear Implant Programme (NPCIP) specializes in the implantation of children under 5 years of age. Subsequent tuning of the device and identification of changes in device function for these young children, who may have additional disabilities, can often be challenging. Thus, an objective measure to assess the integrity of the device is desirable. This study compares the device function by both objective and behavioural techniques in 30 children (age at implantation 3-11 years) at five years post-implantation. All children were implanted with the Nucleus Mini 22 device. Objective data were collected from integrity testing (IT) which allowed examination of the functioning of the implant by measuring the electrical stimulus artefact. This does not require the child to give a behavioural response. A protocol for a five-year post-implantation IT is suggested which examines common ground, monopolar and bipolar modes of operation. Behavioural data in the form of threshold (T) and comfort (C) levels were obtained by use of developmental age-appropriate techniques at 5 years post-implantation. Results demonstrate that 43.3% of patients had no electrode faults, 23.3% had potential faults on both behavioural and integrity testing, 6.7% were difficult to assess in terms of defining electrode faults due to partial electrode insertions, 13.3% had potential faults on behavioural testing only and 13.3% of patients had potential faults on IT only. In conclusion, IT is valuable in the identification of faulty electrodes, especially in young children and those with additional disabilities. Implementation of the five-year routine IT affected the management of 30% of patients. This study demonstrates that objective and behavioural techniques are complementary procedures in the ongoing management of paediatric patients.