Optimal symptom combinations to aid COVID-19 case identification: Analysis from a community-based, prospective, observational cohort.

OBJECTIVES: Diagnostic work-up following any COVID-19 associated symptom will lead to extensive testing, potentially overwhelming laboratory capacity whilst primarily yielding negative results. We aimed to identify optimal symptom combinations to capture most cases using fewer tests with implications for COVID-19 vaccine developers across different resource settings and public health. METHODS: UK and US users of the COVID-19 Symptom Study app who reported new-onset symptoms and an RT-PCR test within seven days of symptom onset were included. Sensitivity, specificity, and number of RT-PCR tests needed to identify one case (test per case [TPC]) were calculated for different symptom combinations. A multi-objective evolutionary algorithm was applied to generate combinations with optimal trade-offs between sensitivity and specificity. FINDINGS: UK and US cohorts included 122,305 (1,202 positives) and 3,162 (79 positive) individuals. Within three days of symptom onset, the COVID-19 specific symptom combination (cough, dyspnoea, fever, anosmia/ageusia) identified 69% of cases requiring 47 TPC. The combination with highest sensitivity (fatigue, anosmia/ageusia, cough, diarrhoea, headache, sore throat) identified 96% cases requiring 96 TPC. INTERPRETATION: We confirmed the significance of COVID-19 specific symptoms for triggering RT-PCR and identified additional symptom combinations with optimal trade-offs between sensitivity and specificity that maximize case capture given different resource settings.

Optimal symptom combinations to aid COVID-19 case identification: analysis from a community-based, prospective, observational cohort.

OBJECTIVES: Diagnostic work-up following any COVID-19 associated symptom will lead to extensive testing, potentially overwhelming laboratory capacity whilst primarily yielding negative results. We aimed to identify optimal symptom combinations to capture most cases using fewer tests with implications for COVID-19 vaccine developers across different resource settings and public health. METHODS: UK and US users of the COVID-19 Symptom Study app who reported new-onset symptoms and an RT-PCR test within seven days of symptom onset were included. Sensitivity, specificity, and number of RT-PCR tests needed to identify one case (test per case [TPC]) were calculated for different symptom combinations. A multi-objective evolutionary algorithm was applied to generate combinations with optimal trade-offs between sensitivity and specificity. FINDINGS: UK and US cohorts included 122,305 (1,202 positives) and 3,162 (79 positive) individuals. Within three days of symptom onset, the COVID-19 specific symptom combination (cough, dyspnoea, fever, anosmia/ageusia) identified 69% of cases requiring 47 TPC. The combination with highest sensitivity (fatigue, anosmia/ageusia, cough, diarrhoea, headache, sore throat) identified 96% cases requiring 96 TPC. INTERPRETATION: We confirmed the significance of COVID-19 specific symptoms for triggering RT-PCR and identified additional symptom combinations with optimal trade-offs between sensitivity and specificity that maximize case capture given different resource settings.

Fronto-temporal vulnerability to disconnection in paediatric moderate and severe traumatic brain injury.

BACKGROUND: In patients with moderate and severe paediatric traumatic brain injury (TBI), we investigated the presence and severity of white matter (WM) tract damage, cortical lobar and deep grey matter (GM) atrophies, their interplay and their correlation with outcome rating scales. METHODS: Diffusion tensor (DT) and 3D T1-weighted MRI scans were obtained from 22 TBI children (13 boys; mean age at insult = 11.6 years; 72.7% in chronic condition) and 31 age-matched healthy children. Patients were tested with outcome rating scales and the Wechsler Intelligence Scale for Children (WISC). DT MRI indices were obtained from several supra- and infra-tentorial WM tracts. Cortical lobar and deep GM volumes were derived. Comparisons between patients and controls, and between patients in acute (<6 months from the event) vs. chronic (≥6 months) condition were performed. RESULTS: Patients showed a widespread pattern of decreased WM FA and GM atrophy. Compared to acute, chronic patients showed severer atrophy in the right frontal lobe and reduced FA in the left inferior longitudinal fasciculus and corpus callosum (CC). Decreased axial diffusivity was observed in acute patients versus controls in the inferior fronto-occipital fasciculus and CC. Chronic patients showed increased axial diffusivity in the same structures. Uncinate fasciculus DT MRI abnormalities correlated with atrophy in the frontal and temporal lobes. Hippocampal atrophy correlated with reduced WISC scores, whereas putamen atrophy correlated with lower functional independence measure scores. CONCLUSIONS: The study isolated a distributed fronto-temporal network of structures particularly vulnerable to axonal damage and atrophy that may contribute to cognitive deficits following TBI.

Conformational dependence of the circular dichroism spectra of single amino acids from plane-waves-based density functional theory calculations.

We study the conformational dependence of circular dichroism (CD) spectra of amino acid molecules by means of an efficient ab initio DFT approach which is free from the typical gauge invariance issues arising with the use of localized basis sets and/or real-space grids. We analyze the dependence of the chiroptical spectra on the backbone dihedrals in the specific case of alanine and consider the role of side chain degrees of freedom at the examples of leucine, phenylalanine, and serine, whose side chains have different physicochemical properties. The results allow one to identify the most diagnostic regions of the CD spectra and to critically compare the conformations which match the experimental CD data with conformations extracted from the rotamer library. The inclusion of a solvation shell of explicit water molecules and its effect on the CD spectrum are analyzed at the example of alanine.

Hemodynamic and EEG Time-Courses During Unilateral Hand Movement in Patients with Cortical Myoclonus. An EEG-fMRI and EEG-TD-fNIRS Study.

Multimodal human brain mapping has been proposed as an integrated approach capable of improving the recognition of the cortical correlates of specific neurological functions. We used simultaneous EEG-fMRI (functional magnetic resonance imaging) and EEG-TD-fNIRS (time domain functional near-infrared spectroscopy) recordings to compare different hemodynamic methods with changes in EEG in ten patients with progressive myoclonic epilepsy and 12 healthy controls. We evaluated O2Hb, HHb and Blood oxygen level-dependent (BOLD) changes and event-related desynchronization/synchronization (ERD/ERS) in the α and ß bands of all of the subjects while they performed a simple motor task. The general linear model was used to obtain comparable fMRI and TD-fNIRS activation maps. We also analyzed cortical thickness in order to evaluate any structural changes. In the patients, the TD-NIRS and fMRI data significantly correlated and showed a significant lessening of the increase in O2Hb and the decrease in BOLD. The post-movement ß rebound was minimal or absent in patients. Cortical thickness was moderately reduced in the motor area of the patients and correlated with the reduction in the hemodynamic signals. The fMRI and TD-NIRS results were consistent, significantly correlated and showed smaller hemodynamic changes in the patients. This finding may be partially attributable to mild cortical thickening. However, cortical hyperexcitability, which is known to generate myoclonic jerks and probably accounts for the lack of EEG ß-ERS, did not reflect any increased energy requirement. We hypothesize that this is due to a loss of inhibitory neuronal components that typically fire at high frequencies.

Coupling of fMRI and NIRS measurements in the study of negative BOLD response to intermittent photic stimulation.

Functional Magnetic Resonance Imaging (fMRI) in combination with Near Infrared Spectroscopy (NIRS) is finding widespread use in the analysis of brain function. While most of the studies deal with the detection of positive responses, here we focus on negative responses to visual stimulation. In a group fMRI study on Intermittent Photic Stimulation (IPS) we detected a sustained Negative BOLD Response (NBR) in the extrastriate visual cortex. To confirm and better characterize NBR, we repeated the same protocol during NIRS recordings. In this paper we show fMRI results and demonstrate the NBR on the basis of NIRS findings.

From neurovascular coupling to neurovascular cascade: a study on neural, autonomic and vascular transients in attention.

Mental processes bring about neural, vascular and autonomic changes in the brain cortex. Due to the different nature of these modifications, their onsets show no synchrony and time dynamics is often strongly dissimilar. After acquiring data from a group of 16 subjects, we estimated temporal correlation between task and signals in order to assess possible influences induced by an attentive task on electroencephalographic (EEG), heart rate variability (HRV), oxy- and deoxy-haemoglobin concentration signals. We also investigated correlations and time delays between couples of different biological signals. This allowed for the isolation of a subgroup of subjects showing similar tracks. Cardiac frequency and deoxy-haemoglobin signals displayed a strong positive correlation with the task design, while EEG alpha rhythm and oxygenation showed a negative correlation. Neural electrical response was nearly instantaneous with respect to the task progression, and autonomic response showed a mean delay of about 15 s and a slower hemodynamic response (mean delay above 20 s) was finally induced. Globally, the task elicited a cascade of responses, in which delays can be quantified.

Study of neurovascular and autonomic response in a divided attention test by means of EEG, ECG and NIRS signals.

We evaluated neurovascular and autonomic response to a Divided Attention task within a group of 16 healthy subjects, by means of Electroencephalography, Electrocardiography, functional Near Infrared Spectroscopy techniques, acquired simultaneously. We exctracted Alpha (8-13,5 Hz) and Beta (13,5-30 Hz) power rhythms with a spectral autoregressive residual model, and inter-beat-interval (RR series) and separated superficial (extracortical) and depth NIRS contribution. Cross Correlation Function at different time lags was then calculated between each signal and the task, modeled as a square wave and among couples of signals, in order to evaluate the sequence of activation of the different physiological districts involved and the common information shared. Results showed the presence of a cascade of responses and a strong influence by the block task on each signal, representative of the neurovascular coupling elicited by the cognitive cerebral activation.

Structural features and oxidative stress towards plasmid DNA of apramycin copper complex.

The interaction of apramycin with copper at different pH values was investigated by potentiometric titrations and EPR, UV-vis and CD spectroscopic techniques. The Cu(II)-apramycin complex prevailing at pH 6.5 was further characterized by NMR spectroscopy. Metal-proton distances derived from paramagnetic relaxation enhancements were used as restraints in a conformational search procedure in order to define the structure of the complex. Longitudinal relaxation rates were measured with the IR-COSY pulse sequence, thus solving the problems due to signal overlap. At pH 6.5 apramycin binds copper(II) with a 2 : 1 stoichiometry, through the vicinal hydroxyl and deprotonated amino groups of ring III. Plasmid DNA electrophoresis showed that the Cu(II)-apramycin complex is more active than free Cu(II) in generating strand breakages. Interestingly, this complex in the presence of ascorbic acid damages DNA with a higher yield than in the presence of H(2)O(2).

The relationship between malaria parasitaemia and availability of healthcare facility in Mpwapwa district, central Tanzania.

A study was carried out in six villages located at different altitudes in Mpwapwa district of central Tanzania to determine malaria parasitaemia and transmission levels in villages with or without health care facilities. A total of 1119 schoolchildren (age = 5.9-12.3 years) were examined for malaria parasitaemia. Plasmodiumfalciparum was the predominant malaria species accounting for 92.8% of all species. The average malaria prevalence rate among schoolchildren was 25.8% (range 1.5-53.8%). The geometric mean parasite densities for P.falciparum was 361 (N = 286). Higher malaria prevalence was observed in villages at lower (< 1000 m) than at intermediate (1000-1500m) or higher (> 1500m) altitudes. Schoolchildren in areas with health care facilities were less at risk of acquiring malaria by 33.4% as compared with those living in areas without health facilities. Mean packed cell volume in schoolchildren was 38.5% (range = 35.2-41.0%). Splenomegaly was observed in 18.1% (0-40.2%) of the schoolchildren examined and it was higher among those in villages without health care facilities. Anopheles gambiae sensu lato was the only malaria vector found in the district and was found in all villages and at all altitudes. Sporozoite rate in An. gambiae s.l. ranged from 0-10.5%, with the lowland villages recording the highest rates. This study indicates that altitude and geographical accessibility to healthcare service are important determinants of malaria infection among rural communities in Tanzania.

Molecular characterization of a variant of proviral bovine leukaemia virus (BLV).

Southern-blot hybridization and partial sequencing of the pol and env genes were used to characterize BLV-integrated provirus of seropositive cattle from two dairy herds in northern Italy. Comparison of the data obtained with those of previously characterized BLV strains from other geographic areas (Australia, Belgium, Japan and USA) revealed the presence of a viral variant (BLV-12), which showed both conserved and unique features. Regarding the gp51 envelope glycoprotein, the BLV-12 variant showed: 1. A high extent of conservation, which included potential glycosylation sites and cysteine residues; 2. Three unique amino acid residues not present in any of the other BLV strains analysed; and 3. Some variability at the level of one (G) of the three (F, G and H) conformational epitopes, which is probably important in the process of infection. These results agree with the suggestion that the sequence variability of the gp51 glycoprotein preferentially involves structures whose change is thought to underlie the phenomenon of escape from immune surveillance.

Expression of distinct conformations of free HLA-Cw4 heavy chains in transfected neuroblastoma cells.

Epitope mapping of HLA-Cw4 indicates that the two monoclonal antibodies (mAbs) L31 and M38, specific for beta 2-microglobulin (beta2m)-free HLA-C heavy chains, react preferentially with the KYK motif, located in the binding groove (alpha1 domain). Transfection of HLA-Cw4 cDNA into a neuroblastoma cell line, which normally expresses negligible HLA class I, resulted in the constitutive surface expression of molecules displaying different reactivities with the two mAbs. This cellular system was used to determine whether L31 and M38 recognize distinct conformations of beta2m-free HLA-C proteins, and to investigate their mechanism of expression. Interferon-gamma greatly enhanced the expression of L31-reactive free chains, while abolishing that of M38-reactive molecules. The cytokine-induced expression of L31-reactive molecules was inhibited by anti-sense oligonucleotides specific for beta2m mRNA, while constitutive expression of L31-reactive molecules was only partially affected. Exogenous beta2m resulted in a reduction of constitutive L31 reactivity, and in a concomitant increase of M38 reactivity. These results indicate that: 1) at the cell surface, L31 and M38 react with two distinct conformations of HLA-Cw4 beta2m-free heavy chains, of which the L31-reactive conformation is the least folded; 2) the expression of both conformers can be modulated by endogenous or exogenous beta2m; and (3) L31-reactive molecules exposed at the cell surface are likely to derive from the dissociation of empty HLA-Cw4/beta2m complexes.

Applicability of DNA isolated from syncytiotrophoblast vesicles to gene amplification and molecular analysis.

Maternal contamination of fetal DNA represents a major problem when highly sensitive molecular techniques are used in the prenatal diagnosis of genetic diseases. For this reason, we have studied the possibility of using DNA isolated from syncytiotrophoblast vesicles as a target of gene amplification (PCR). Three PCR systems were selected which included a repetitive 149 bp fragment of the Y chromosome, the VNTR locus D1S80, and a portion of the beta-globin gene. The results of these experiments indicate that DNA isolated from syncytiotrophoblast vesicles is free of maternal contamination and is suitable for gene amplification and DNA analysis.

Risk factors for multiple births.

STUDY OBJECTIVE: To analyze risk factors for multiple births. DESIGN: A case-control study. Cases were 103 women (median age 31 years, range 20-44) who delivered multiple births not related with treatment for infertility at the 'Clinica Luigi Mangiagalli' of Milan. A total of 27 women delivered monozygotic twins and 76 dizygotic ones. Controls were 308 women (median age 30, range 17-45) admitted for normal delivery on selected days to the same clinic where cases had been identified. RESULTS: Cases tended to be less educated than controls and the relative risk of multiple pregnancy, compared with women reporting seven years of schooling or less, was 0.4 in those reporting 7-11 and 12 or more years of education. When the analysis was done separately for dizygotic and monozygotic multiple pregnancies, this relationship was restricted to dizygotic multiple pregnancies (chi 2 (1) trend for dizygotic pregnancies = 3.82, p = 0.05). A family history of multiple pregnancies was reported in 36 women (48%) with dizygotic multiple pregnancy and 13 (52%) monozygotic ones and 88 (30%) controls. The corresponding relative risks (RR) were 2.2 and 2.5 respectively for dizygotic and monozygotic pregnancies. Compared with nulliparae, the estimated RR of dizygotic multiple pregnancies was 0.5 in women reporting two or more births, but the trend in risk with number of births was not statistically significant. No relationship emerged with spontaneous or induced abortions, body mass index, oral contraceptive or IUD use, age at menarche and risk of multiple pregnancies. CONCLUSIONS: This study confirms the role of familiarity in the risk of multiple pregnancies and suggests some different epidemiological characteristics in dizygotic and monozygotic multiple pregnancies.

[Ciclopiroxolamine in the topical treatment of vaginal mycoses]. / La ciclopiroxolamina nel trattamento topico delle micosi vaginali.

We have verified the local activity and tolerance of the antimycotic drug ciclopiroxolamine in an open trial. The study included 34 women suffering from clinically and mycologically diagnosed vulvovaginitis caused by Candida. The therapy consisted of inserting a 100 mg ovule of ciclopiroxolamine once a day for 3 days. The cultural examination was negative in 76.5% of cases at the 1st control after the treatment and in 82.3% of cases at the 2nd control after the treatment. All the considered subjective and objective symptoms showed a highly significant decrease of frequency and intensity. No chemical parameter was modified; only in one patient a very mild side effect was verified.