Inhibitory systems in brain evolution: pathways of vulnerability in neurodevelopmental disorders.

BACKGROUND: The evolution of the primate brain has been characterized by the reorganization of key structures and circuits underlying derived specializations in sensory systems, as well as social behavior and cognition. Among these, expansion and elaboration of the prefrontal cortex has been accompanied by alterations to the connectivity and organization of subcortical structures, including the striatum and amygdala, underlying advanced aspects of executive function, inhibitory behavioral control, and socioemotional cognition seen in our lineages. At the cellular level, the primate brain has further seen an increase in the diversity and number of inhibitory GABAergic interneurons. A prevailing hypothesis holds that disruptions in the balance of excitatory to inhibitory activity in the brain underlies the pathophysiology of many neurodevelopmental and psychiatric disorders. SUMMARY: This review highlights the evolution of inhibitory brain systems and circuits, and suggests that recent evolutionary modifications to GABAergic circuitry may provide the substrate for vulnerability to aberrant neurodevelopment. We further discuss how modifications to primate and human social organization and life history may shape brain development in ways that contribute to neurodivergence and the origins of neurodevelopmental disorders. KEY MESSAGES: Many brain systems have seen functional reorganization in the mammalian, primate, and human brain. Alterations to inhibitory circuitry in frontostriatal and frontoamygdalar systems support changes in social behavior and cognition. Increased complexity of inhibitory systems may underlie vulnerabilities to neurodevelopmental and psychiatric disorders, including autism and schizophrenia. Changes observed in Williams syndrome may further elucidate the mechanisms by which alterations in inhibitory systems lead to changes in behavior and cognition. Developmental processes, including altered neuroimmune function and age-related vulnerability of inhibitory cells and synapses, may lead to worsening symptomatology in neurodevelopmental and psychiatric disorders.

Less restrictions in daily life: a clinical practice guideline for children with cancer.

PURPOSE: In current clinical practice, recommendations regarding restrictions in daily life for children with cancer are often lacking or not evidence-based. Critically reviewing the evidence and formulating recommendations are therefore of great importance as social restrictions (e.g., swimming, school attendance, sports) can impair the quality of life of these children severely. Therefore, our aim was to develop a clinical practice guideline for clinicians, children, and their parents regarding social restrictions in children with cancer. METHODS: A comprehensive multidisciplinary panel was assembled, comprising 21 professionals and patient representatives. A systematic literature review was performed, including dual appraisal of all citations. The GRADE methodology was used to extract, summarize, and assess the evidence. Multiple in-person meetings were held to rank outcomes, discuss evidence, complete evidence-to-decision frameworks, and formulate recommendations. Final recommendations were unanimously supported by all panel members. RESULTS: Six studies, including 758 children, formed the evidence base for the recommendations. Given the scarcity of the available evidence and various designs of studies in children with cancer, additional evidence was extracted from adult oncology guidelines, and shared expert opinions were utilized. In total, 14 recommendations were formulated of which multiple result in changes in current policy and standard of practice in the Netherlands. Topics covered in this guideline are swimming, having pets, visiting the zoo or farm, performing sports or high-velocity events, attending school or kindergarten, and use of public transport. This guideline is not intended to provide recommendations for patients after end of treatment, for palliative care settings, or for children undergoing a stem cell transplantation. CONCLUSIONS: In this clinical practice guideline, we provide recommendations regarding restrictions in daily life in children with cancer. These include evidence-based recommendations and, in the absence of sufficient evidence, recommendations based on expert evidence. With these recommendations, we provide guidance for clinicians, children, and parents and contribute to improving quality of life for children with cancer.

Less restrictions in daily life: a clinical practice guideline for children with cancer

In current clinical practice, recommendations regarding restrictions in daily life for children with cancer are often lacking or not evidence-based. Critically reviewing the evidence and formulating recommendations are therefore of great importance as social restrictions (e.g., swimming, school attendance, sports) can impair the quality of life of these children severely. Therefore, our aim was to develop a clinical practice guideline for clinicians, children, and their parents regarding social restrictions in children with cancer. A comprehensive multidisciplinary panel was assembled, comprising 21 professionals and patient representatives. A systematic literature review was performed, including dual appraisal of all citations. The GRADE methodology was used to extract, summarize, and assess the evidence. Multiple in-person meetings were held to rank outcomes, discuss evidence, complete evidence-to-decision frameworks, and formulate recommendations. Final recommendations were unanimously supported by all panel members. Six studies, including 758 children, formed the evidence base for the recommendations. Given the scarcity of the available evidence and various designs of studies in children with cancer, additional evidence was extracted from adult oncology guidelines, and shared expert opinions were utilized. In total, 14 recommendations were formulated of which multiple result in changes in current policy and standard of practice in the Netherlands. Topics covered in this guideline are swimming, having pets, visiting the zoo or farm, performing sports or high-velocity events, attending school or kindergarten, and use of public transport. This guideline is not intended to provide recommendations for patients after end of treatment, for palliative care settings, or for children undergoing a stem cell transplantation. In this clinical practice guideline, we provide recommendations regarding restrictions in daily life in children with cancer. These include evidence-based recommendations and, in the absence of sufcient evidence, recommendations based on expert evidence. With these recommendations, we provide guidance for clinicians, children, and parents and contribute to improving quality of life for children with cancer.

Impact of post-COVID-19 condition on health status and activities of daily living: the PRIME post-COVID study.

OBJECTIVE: To assess health and activities of daily living (ADL) in SARS-CoV-2-positive adults with and without post-COVID-19 condition (PCC) and compare this with negative tested individuals. Furthermore, different PCC case definitions were compared with SARS-CoV-2-negative individuals. METHODS: All adults tested PCR positive for SARS-CoV-2 at the Public Health Service South Limburg (Netherlands) between June 2020 and November 2021 (n=41 780) and matched PCR negative individuals (2:1, on age, sex, year-quarter test, municipality; n=19 875) were invited by email. Health (five-level EuroQol five-dimension (EQ5D) index and EuroQol visual analogue scale (EQVAS)) and ADL impairment were assessed. PCC classification was done using the WHO case definition and five other common definitions. RESULTS: In total, 8409 individuals (6381 SARS-CoV-2 positive; 53±15 years; 57% female; 9 (7-11) months since test) were included. 39.4% of positives had PCC by the WHO case definition (EQVAS: 71±20; EQ5D index: 0.800±0.191; ADL impairment: 30 (10-70)%) and perceived worse health and more ADL impairment than negatives, that is, difference of -8.50 points (95% CI -9.71 to -7.29; p<0.001) for EQVAS, which decreased by 1.49 points (95% CI 0.86 to 2.12; p<0.001) in individuals with PCC for each comorbidity present, and differences of -0.065 points (95% CI -0.074 to -0.056; p<0.001) for EQ5D index, and +16.72% (95% CI 15.01 to 18.43; p<0.001) for ADL impairment. Health and ADL impairment were similar in negatives and positives without PCC. Replacing the WHO case definition with other PCC definitions yielded comparable results. CONCLUSIONS: Individuals with PCC have substantially worse health and more ADL impairment than negative controls, irrespective of the case definition. Authorities should inform the public about the associated burden of PCC and enable adequate support.

Prevalence of Long-term Symptoms Varies When Using Different Post-COVID-19 Definitions in Positively and Negatively Tested Adults: The PRIME Post-COVID Study.

Background: Long-term symptoms after a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (ie, post-coronavirus disease 2019 [COVID-19] condition or long COVID) constitute a substantial public health problem. Yet, the prevalence remains currently unclear as different case definitions are used, and negatively tested controls are lacking. We aimed to estimate post-COVID-19 condition prevalence using 6 definitions. Methods: The Prevalence, Risk factors, and Impact Evaluation (PRIME) post-COVID-19 condition study is a population-based sample of COVID-19-tested adults. In 2021, 61 655 adults were invited to complete an online questionnaire, including 44 symptoms plus a severity score (0-10) per symptom. Prevalence was calculated in both positively and negatively tested adults, stratified by time since their COVID-19 test (3-5, 6-11, or ≥12 months ago). Results: In positive individuals (n = 7405, 75.6%), the prevalence of long-term symptoms was between 26.9% and 64.1% using the 6 definitions, while in negative individuals (n = 2392, 24.4%), the prevalence varied between 11.4% and 32.5%. The prevalence of long-term symptoms potentially attributable to COVID-19 ranged from 17.9% to 26.3%. Conclusions: There is a (substantial) variation in prevalence estimates when using different post-COVID-19 condition definitions, as is current practice; there is limited overlap between definitions, indicating that the essential post-COVID-19 condition criteria are still unclear. Including negatives is important to determine long-term symptoms attributable to COVID-19. Trial registration: ClinicalTrials.gov Identifier: NCT05128695.

High proportions of post-exertional malaise and orthostatic intolerance in people living with post-COVID-19 condition: the PRIME post-COVID study.

Background: Exercise-based treatments can worsen/exacerbate symptoms in people who were SARS-CoV-2 positive and living with post-COVID-19 condition (PL-PCC) and who have post-exertional malaise (PEM) or orthostatic intolerance (OI). Nevertheless, PEM and OI are not routinely assessed by clinicians. We estimated PEM and OI proportions in PL-PCC, as well as in people not living with PCC (PnL-PCC) and negatives (i.e., never reported a SARS-CoV-2 positive test), and identified associated factors. Methods: Participants from the Prevalence, Risk factors, and Impact Evaluation (PRIME) post-COVID-19 condition study were included. PEM and OI were assessed using validated questionnaires. PCC was defined as feeling unrecovered after SARS-CoV-2 infection. Multivariable regression analyses to study PEM and OI were stratified for sex. Results: Data from 3,783 participants were analyzed. In PL-PCC, the proportion of PEM was 48.1% and 41.2%, and the proportion of OI was 29.3% and 27.9% in women and men, respectively. Proportions were higher in PL-PCC than negatives, for PEM in women OR=4.38 [95%CI:3.01-6.38]; in men OR = 4.78 [95%CI:3.13-7.29]; for OI in women 3.06 [95%CI:1.97-4.76]; in men 2.71 [95%CI:1.75-4.21]. Associated factors were age ≤ 60 years, ≥1 comorbidities, and living alone. Conclusion: High proportions of PEM and OI are observed in PL-PCC. Standard screening for PEM and OI is recommended in PL-PCC to promote appropriate therapies.

Sex and age differences in the proportion of experienced symptoms by SARS-CoV-2 serostatus in a community-based cross-sectional study.

We examined the possible sex and age differences in the proportion of experienced Coronavirus Disease 2019 (COVID-19) symptoms in unaware (previously) infected adults, and their uninfected counterparts, estimated by serostatus prior to vaccination, at the end of 2020 (Wuhan strain). A cross-sectional community-based study using a convenience sample of 10 001 adult inhabitants of a southern Dutch province, heavily affected by COVID-19, was conducted. Participants donated a blood sample to indicate past infection by serostatus (positive/negative). Experienced symptoms were assessed by questionnaire, before the availability of the serological test result. Only participants without confirmed SARS-CoV-2 infection were included (n = 9715, age range 18-90 years). The seroprevalence was comparable between men (17.3%) and women (18.0%), and participants aged 18-60 years (17.3%) and aged 60 years and older (18.6%). We showed sex and age differences in the proportion experienced symptoms by serostatus in a large cohort of both unaware (untested) seropositive compared with seronegative reference participants. Irritability only differed by serostatus in men (independent of age), while stomach ache, nausea and dizziness only differed by serostatus in women aged 60 years and older. Besides, the proportion of experiencing pain when breathing and headache differed by serostatus in men aged 18-60 years only. Our study highlights the importance of taking possible sex and age differences into account with respect to acute and long-term COVID-19 outcomes. Identifying symptom profiles for sex and age subgroups can contribute to timely identification of infection, gaining importance once governments currently move away from mass testing again.

Exposure factors associated with SARS-CoV-2 seroprevalence during the first eight months of the COVID-19 pandemic in the Netherlands: A cross-sectional study.

BACKGROUND: The availability of valid Severe Acute Respiratory Syndrome Coronvirus-2 (SARS-CoV-2) serological tests overcome the problem of underestimated cumulative Coronavirus Disease 2019 (COVID-19) cases during the first months of the pandemic in The Netherlands. The possibility to reliably determine the number of truly infected persons, enabled us to study initial drivers for exposure risk in the absence of routine testing. Numerous activities or circumstances can accelerate virus spread, here defined as exposure factors. Hence, we aimed to evaluate a wide variety of demographic, behavioural and social exposure factors associated with seropositivity during the first eight months of the pandemic in Limburg, The Netherlands. METHODS: SARS-CoV-2 point-seroprevalence was determined cross-sectionally to indicate previous infection in a convenience sample of minimal 10,000 inhabitants of the study province. All adult (18+ years) inhabitants of the study province were eligible to register themselves for participation. Once the initial 10,000 registrations were reached, a reserve list was kept to ensure sufficient participants. Possible exposure factors were mapped by means of an extensive questionnaire. Associated exposure factors were determined using univariable and multivariable logistic regression models. RESULTS: Seropositivity was established in 19.5% (n = 1,948) of the 10,001 participants (on average 49 years old (SD = 15; range 18-90 years), majority women (n = 5,829; 58.3%). Exposure factors associated with seropositivity included current education, working in healthcare and not working from home, and being a member of three or four associations or clubs. Specifically for February-March 2020, visiting an après-ski bar during winter sports in Austria, travelling to Spain, celebrating carnival, and participating in a singing activity or ball sport were associated with seropositivity. CONCLUSIONS: Our results confirm that relevant COVID-19 exposure factors generally reflected circumstances where social distancing was impossible, and the number and duration of contacts was high, in particular for indoor activities.

Design and recruitment of a large-scale cohort study on prevalence, risk factors and impact evaluation of post-COVID-19 condition and its wider long-term social, mental, and physical health impact: The PRIME post-COVID study.

Background: Persistent symptoms, described as long COVID or post-COVID-19 condition, pose a potential public health problem. Here, the design and recruitment of the PRIME post-COVID study is described. PRIME post-COVID is a large-scale population-based observational study that aims to improve understanding of the occurrence, risk factors, social, physical, mental, emotional, and socioeconomic impact of post-COVID-19 condition. Methods: An observational open cohort study was set up, with retrospective and prospective assessments on various health-conditions and health-factors (medical, demographic, social, and behavioral) based on a public health COVID-19 test and by self-report (using online questionnaires in Dutch language). Invited for participation were, as recorded in a public health registry, adults (18 years and older) who were tested for COVID-19 and had a valid Polymerase Chain Reaction (PCR) positive or negative test result, and email address. In November 2021, 61,655 individuals were invited by email to participate, these included all eligible adults who tested PCR positive between 1 June 2020 and 1 November 2021, and a sample of adults who tested negative (2:1), comparable in distribution of age, sex, municipality of residence and year-quarter of testing. New recruitment periods are planned as well. Participants are followed over time by regular follow-up measurements. Data are analyzed using the appropriate data-analyses methods. Discussion: The PRIME post-COVID study will provide insights into various health-related aspects of post-COVID-19 condition in the context of various stages of the COVID-19 pandemic. Results will inform practical guidance for society, clinical and public health practice for the prevention and care for long-term impact of COVID-19. Trial registration ClinicalTrialsgov identifier: NCT05128695.

Biologic TNF-α inhibitors reduce microgliosis, neuronal loss, and tau phosphorylation in a transgenic mouse model of tauopathy.

BACKGROUND: Tumor necrosis factor-α (TNF-α) plays a central role in Alzheimer's disease (AD) pathology, making biologic TNF-α inhibitors (TNFIs), including etanercept, viable therapeutics for AD. The protective effects of biologic TNFIs on AD hallmark pathology (Aß deposition and tau pathology) have been demonstrated. However, the effects of biologic TNFIs on Aß-independent tau pathology have not been reported. Existing biologic TNFIs do not cross the blood-brain barrier (BBB), therefore we engineered a BBB-penetrating biologic TNFI by fusing the extracellular domain of the type-II human TNF-α receptor (TNFR) to a transferrin receptor antibody (TfRMAb) that ferries the TNFR into the brain via receptor-mediated transcytosis. The present study aimed to investigate the effects of TfRMAb-TNFR (BBB-penetrating TNFI) and etanercept (non-BBB-penetrating TNFI) in the PS19 transgenic mouse model of tauopathy. METHODS: Six-month-old male and female PS19 mice were injected intraperitoneally with saline (n = 12), TfRMAb-TNFR (1.75 mg/kg, n = 10) or etanercept (0.875 mg/kg, equimolar dose of TNFR, n = 10) 3 days/week for 8 weeks. Age-matched littermate wild-type mice served as additional controls. Blood was collected at baseline and 8 weeks for a complete blood count. Locomotion hyperactivity was assessed by the open-field paradigm. Brains were examined for phosphorylated tau lesions (Ser202, Thr205), microgliosis, and neuronal health. The plasma pharmacokinetics were evaluated following a single intraperitoneal injection of 0.875 mg/kg etanercept or 1.75 mg/kg TfRMAb-TNFR or 1.75 mg/kg chronic TfRMAb-TNFR dosing for 4 weeks. RESULTS: Etanercept significantly reduced phosphorylated tau and microgliosis in the PS19 mouse brains of both sexes, while TfRMAb-TNFR significantly reduced these parameters in the female PS19 mice. Both TfRMAb-TNFR and etanercept treatment improved neuronal health by significantly increasing PSD95 expression and attenuating hippocampal neuron loss in the PS19 mice. The locomotion hyperactivity in the male PS19 mice was suppressed by chronic etanercept treatment. Equimolar dosing resulted in eightfold lower plasma exposure of the TfRMAb-TNFR compared with etanercept. The hematological profiles remained largely stable following chronic biologic TNFI dosing except for a significant increase in platelets with etanercept. CONCLUSION: Both TfRMAb-TNFR (BBB-penetrating) and non-BBB-penetrating (etanercept) biologic TNFIs showed therapeutic effects in the PS19 mouse model of tauopathy.

Acute and Chronic Dosing of a High-Affinity Rat/Mouse Chimeric Transferrin Receptor Antibody in Mice.

Non-invasive brain delivery of neurotherapeutics is challenging due to the blood-brain barrier. The revived interest in transferrin receptor antibodies (TfRMAbs) as brain drug-delivery vectors has revealed the effect of dosing regimen, valency, and affinity on brain uptake, TfR expression, and Fc-effector function side effects. These studies have primarily used monovalent TfRMAbs with a human constant region following acute intravenous dosing in mice. The effects of a high-affinity bivalent TfRMAb with a murine constant region, without a fusion partner, following extravascular dosing in mice are, however, not well characterized. Here we elucidate the plasma pharmacokinetics and safety of a high-affinity bivalent TfRMAb with a murine constant region following acute and chronic subcutaneous dosing in adult C57BL/6J male mice. Mice received a single (acute dosing) 3 mg/kg dose, or were treated for four weeks (chronic dosing). TfRMAb and control IgG1 significantly altered reticulocyte counts following acute and chronic dosing, while other hematologic parameters showed minimal change. Chronic TfRMAb dosing did not alter plasma- and brain-iron measurements, nor brain TfR levels, however, it significantly increased splenic-TfR and -iron. Plasma concentrations of TfRMAb were significantly lower in mice chronically treated with IgG1 or TfRMAb. Overall, no injection related reactions were observed in mice.

Eliminating Fc N-Linked Glycosylation and Its Impact on Dosing Consideration for a Transferrin Receptor Antibody-Erythropoietin Fusion Protein in Mice.

Erythropoietin (EPO), a hematopoietic growth factor and a promising therapy for Alzheimer's disease, has low permeability across the blood-brain barrier. The transferrin receptor antibody fused to EPO (TfRMAb-EPO) is a chimeric monoclonal antibody that ferries EPO into the brain via the transvascular route. However, TfRMAbs have Fc-effector function-related adverse effects including reticulocyte suppression. To overcome this, we recently developed an effectorless TfRMAb-EPO fusion protein, designated TfRMAb-N292G-EPO, by eliminating the Fc N-linked glycosylation site at position 292 of the antibody heavy chain. The mutant fusion protein showed enhanced plasma clearance and dramatically reduced plasma concentrations compared with the wild-type (WT) nonmutant fusion protein. This increased clearance of the aglycosylated TfRMAb is expected to increase the injection dose of the mutant fusion protein. To provide a basis for future therapeutic uses of this IgG-neurotrophin fusion protein, the current study aimed to characterize the pharmacokinetic profile of this effectorless TfRMAb-N292G-EPO at different doses following different routes of administration in the mouse. Adult C57BL/6J male mice were injected with a single dose (3, 6, 9, or 20 mg/kg; n = 3-6 per dose) of TfRMAb-N292G-EPO through either the subcutaneous (SQ) or intraperitoneal (IP) route. TfRMAb-N292G-EPO plasma concentrations were determined using an enzyme-linked immunosorbent assay. Mice were sacrificed 24 h after injection, and terminal blood was used for a complete blood count. Brain concentrations in the WT- and mutant fusion protein-treated mice were compared. We observed stark differences in the plasma pharmacokinetics of TfRMAb-N292G-EPO between the IP and SQ routes of administration. Dose escalation from 3 to 20 mg/kg increased the plasma Cmax only 3.5-fold for the SQ route, compared with a 35-fold increase for the IP route. The plasma Cmax was 15.0 ± 2.0, 21.3 ± 4.1, 21.3 ± 6.4, and 52.8 ± 27.9 ng/mL following SQ injection and 288 ± 47, 389 ± 154, 633 ± 194, and 10,066 ± 7059 ng/mL following IP injection for 3, 6, 9, and 20 mg/kg doses, respectively. The plasma Cmax following the SQ route was therefore 19- to 190-fold lower than that following the IP route. This finding is consistent with a 31-fold higher apparent clearance following the SQ route compared with the IP route at the highest dose administered. The brain concentrations in the mice treated with a 3 mg/kg dose of the mutant fusion protein were lower than those in the nonmutant WT-treated mice. No reticulocyte suppression was observed at the 3 mg/kg SQ dose of TfRMAb-N292G-EPO. However, reticulocyte suppression increased with an increase in dose and area under the plasma concentration-time curve (AUC) for both the IP and SQ routes. Overall, elimination of Fc N-linked glycosylation, to mitigate TfRMAb effector function side effects, has a profound effect on the plasma exposure of TfRMAb-N292G-EPO at therapeutic as well as high doses (3-20 mg/kg). This effect is more pronounced following SQ injection. The low plasma concentrations of the mutant fusion protein following a 3 mg/kg dose resulted in negligible brain uptake. The beneficial rescue of reticulocyte reduction by the N292G mutation is a function of AUC and is negated at high doses of the N292G mutant.

Decreased density of cholinergic interneurons in striatal territories in Williams syndrome.

Williams syndrome (WS) is a rare neurodevelopmental disorder caused by the hemideletion of approximately 25-28 genes at 7q11.23. Its unusual social and cognitive phenotype is most strikingly characterized by the disinhibition of social behavior, in addition to reduced global IQ, with a relative sparing of language ability. Hypersociality and increased social approach behavior in WS may represent a unique inability to inhibit responses to specific social stimuli, which is likely associated with abnormalities of frontostriatal circuitry. The striatum is characterized by a diversity of interneuron subtypes, including inhibitory parvalbumin-positive interneurons (PV+) and excitatory cholinergic interneurons (Ch+). Animal model research has identified an important role for these specialized cells in regulating social approach behavior. Previous research in humans identified a depletion of interneuron subtypes associated with neuropsychiatric disorders. Here, we examined the density of PV+ and Ch+ interneurons in the striatum of 13 WS and neurotypical (NT) subjects. We found a significant reduction in the density of Ch+ interneurons in the medial caudate nucleus and nucleus accumbens, important regions receiving cortical afferents from the orbitofrontal and ventromedial prefrontal cortex, and circuitry involved in language and reward systems. No significant difference in the distribution of PV+ interneurons was found. The pattern of decreased Ch+ interneuron densities in WS differs from patterns of interneuron depletion found in other disorders.

Glucose Variability Assessed with Continuous Glucose Monitoring: Reliability, Reference Values, and Correlations with Established Glycemic Indices-The Maastricht Study.

Background: Glucose variability (GV) measured by continuous glucose monitoring (CGM) has become an accepted marker of glycemic control. Nevertheless, several methodological aspects of GV assessment require further study. We, therefore, investigated the minimum number of days needed to reliably measure GV, assessed GV reference values, and studied the correlation of GV with established glycemic indices (i.e., HbA1c, seven-point oral glucose tolerance test [OGTT]-derived indices). Methods: We used cross-sectional data from The Maastricht Study, an observational population-based cohort enriched with type 2 diabetes. Participants with more than 48 h of CGM (iPro2; Medtronic) were included for analysis (n = 851; age: 60 ± 9years; 49% women; 23% type 2 diabetes). We used mean sensor glucose (MSG), standard deviation (SD), and coefficient of variation (CV) as CGM-derived indices (the latter two for GV quantification). We calculated reliability using the Spearman-Brown prophecy formula, established reference values by calculating 2.5th-97.5th percentiles, and studied correlations using Spearman's rho. Results: Sufficient reliability (R > 0.80) was achieved with two (MSG and SD), or three monitoring days (CV). The reference ranges, assessed in individuals with normal glucose metabolism (n = 470), were 90.5-120.6 mg/dL (MSG), 7.9-24.8 mg/dL (SD), and 7.74%-22.45% (CV). For MSG, the strongest correlation was found with fasting plasma glucose (rho = 0.65 [0.61; 0.69]); for SD, with the 1-h OGTT value (rho = 0.61 [0.56; 0.65]); and for CV, with both the incremental glucose peak (IGP) during the OGTT (rho = 0.50 [0.45; 0.55]) and the 1-h OGTT value (rho = 0.50 [0.45; 0.55]). Conclusions: The reliability findings and reference values are relevant for studies that aim to investigate CGM-measured GV. One-hour OGTT and IGP values can be used as GV indices when CGM is unavailable.

Physical Mechanisms Providing Clinical Information From Ultrasound Lung Images: Hypotheses and Early Confirmations.

In standard B mode imaging, a set of ultrasound pulses is used to reconstruct a 2-D image even though some of the assumptions needed to do this are not fully satisfied. For this reason, ultrasound medical images show numerous artifacts which physicians recognize and evaluate as part of their diagnosis since even one artifact can provide clinical information. Understanding the physical mechanisms at the basis of the formation of an artifact is important to identify the physiopathological state of the biological medium which generated the artifact. Ultrasound lung images are a significant example of this challenge since everything that is represented beyond the thickness of the chest wall ( ≈ 2 cm) is artifactual information. A convincing physical explanation of the genesis of important ultrasound lung artifacts does not exist yet. Physicians simply base their diagnosis on a correlation observed over the years between the manifestation of some artifacts and the occurrence of particular lung pathologies. In this article, a plausible genesis of some important lung artifacts is suggested.

Oxygen permeability and oxidative stability of fish oil-loaded electrosprayed capsules measured by Electron Spin Resonance: Effect of dextran and glucose syrup as main encapsulating materials.

The oxygen permeability and oxidative stability of fish oil-loaded electrosprayed capsules were studied by Electron Spin Resonance (ESR). Electrosprayed capsules with dextran as main biopolymer showed a significantly faster broadening (ΔHpp) of 16-doxyl-stearate ESR spectrum when compared to glucose syrup capsules. This finding indicates a higher oxygen permeability of dextran capsules than glucose syrup capsules, which is explained by a reduced average free volume in the glucose syrup matrix than in the dextran shell. Moreover, glucose syrup capsules showed a significantly lower increase in the peak-to-peak amplitude of N-tert-butyl-α-phenylnitrone (PBN) ESR spectrum during storage when compared to dextran capsules. This implies a higher oxidative stability of glucose syrup capsules than dextran capsules, which correlated well with the lower oxygen permeability of the former. These results indicated the importance of the oxygen barrier properties of the wall materials when encapsulating long chain omega-3 polyunsaturated fatty acids by electrospraying.

Tetralogy of Fallot with absent pulmonary valve: a case complicated by bilateral relapsing pneumothorax.

We report a case of a neonate with tetralogy of Fallot with aneurysmal dilatation of the pulmonary artery, complicated by bilateral relapsing pneumothorax. The relapsing air leak made it necessary to place up to five chest drains and to switch from conventional ventilation to high frequency ventilation. In the course of 30 days, all drains were removed. Once other anatomical and functional malformations of the respiratory system had been appropriately excluded and reasonable haemodynamic stability had been achieved, the patient underwent successful radical corrective heart surgery in hypothermia and cardioplegia. We emphasize the advantage of resolving respiratory failure preoperatively to guarantee the success of corrective heart surgery and treatment of other surgically severe cases.

[Prevalence and costs of tuberculin screening performed at Altopiano di Asiago (Vicenza) during a decade]. / Prevalenza e costi di uno screening tubercolinico decennale eseguito sull'Altopiano di Asiago (Vicenza).

We determined the results of Tuberculosis Skin Test (TST) screening on pediatric population in the Asiago District, Italy, by means of Tine-test. During the period 1986-1995, all schoolchildren born between 1976 and 1988 were Tine-tested at least once. Furthermore all children, 6 months-14 years, hospitalized in the local General Hospital during the same period, 1986-1995, received one Mantoux-test; only the immunologically depressed ones and those who had undergone a Tine-test in the previous 6 months were excluded. A total of 5436 Tine-tests over 3220 schoolchildren were carried out; 1244 children were tested by Mantoux-test during hospitalization; 414 children underwent both of them by chance. 34 schoolchildren (1.07%) were Tine-test positive; only 3 out of them proved to be positive at the following Mantoux-test and therapy was carried out. 5 children out of 1244 proved to be Mantoux-positive during hospitalization; among them only 2 cases of tuberculosis were identified, less than 0,5% of all screned children. Tine-test identified 3 Mantoux-positive children; each of them costed about 9,850 US. It is a moot question if resources should then be directed only towards screening children at high risk of tuberculosis infection.