What supports and services post COVID-19 do children with disabilities and their parents need and want, now and into the future?

Introduction: Children and youth with disabilities and special healthcare needs, and their families, have been uniquely affected by the COVID-19 pandemic. However, the voices of children themselves are still not well represented in the existing literature. Methods: This qualitative descriptive study used a combination of visual methods and interviews to learn about the experiences of Canadian children with disabilities (n=18) and their parents (n=14) during the COVID pandemic and into the post-pandemic period. Data collection was carried out between January and July 2023. The aim was to identify the supports and services children and families need at present and moving forward. Results: Families' pandemic experiences were complex and nuanced. For many, the pandemic complicated and disrupted everyday activities and supports. These disruptions were largely buffered by parents. However, some families also identified unexpected benefits. Key themes pertaining to present and future needs included the need for services that are flexible; consistent; conducive to relationship-building; comprehensive; coordinated across sectors; and designed to support the needs of the whole family. Discussion: Implications for policy and practice are outlined.

Structural Plasticity of GABAergic Pallidothalamic Terminals in MPTP-Treated Parkinsonian Monkeys: A 3D Electron Microscopic Analysis.

The internal globus pallidus (GPi) is a major source of tonic GABAergic inhibition to the motor thalamus. In parkinsonism, the firing rate of GPi neurons is increased, and their pattern switches from a tonic to a burst mode, two pathophysiological changes associated with increased GABAergic pallidothalamic activity. In this study, we used high-resolution 3D electron microscopy to demonstrate that GPi terminals in the parvocellular ventral anterior nucleus (VApc) and the centromedian nucleus (CM), the two main GPi-recipient motor thalamic nuclei in monkeys, undergo significant morphometric changes in parkinsonian monkeys including (1) increased terminal volume in both nuclei; (2) increased surface area of synapses in both nuclei; (3) increased number of synapses/GPi terminals in the CM, but not VApc; and (4) increased total volume, but not number, of mitochondria/terminals in both nuclei. In contrast to GPi terminals, the ultrastructure of putative GABAergic nonpallidal terminals was not affected. Our results also revealed striking morphological differences in terminal volume, number/area of synapses, and volume/number of mitochondria between GPi terminals in VApc and CM of control monkeys. In conclusion, GABAergic pallidothalamic terminals are endowed with a high level of structural plasticity that may contribute to the development and maintenance of the abnormal increase in pallidal GABAergic outflow to the thalamus in the parkinsonian state. Furthermore, the evidence for ultrastructural differences between GPi terminals in VApc and CM suggests that morphologically distinct pallidothalamic terminals from single pallidal neurons may underlie specific physiological properties of pallidal inputs to VApc and CM in normal and diseased states.

Incidence, timing, presentation, treatment, and outcomes of second primary head and neck squamous cell carcinoma after oral cancer.

After their initial presentation of oral squamous cell carcinoma (SCC), patients have a lifelong risk of developing another new SCC of the head and neck. The aim of this study was to establish second primary rates, baseline characteristics (site, clinical or pathological stage, and smoking and alcohol history), timing, presentation, treatment, and outcomes. From the regional unit we analysed records of patients treated with curative intent for their first oral cancer between 2002 and 2007 inclusive. All patients had had at least 10 years of follow up either to death or the end of 2017. A total of 347 patients had been treated with curative intent, and of them, 29 had a second primary at a median (IQR) of 52 (30-79) months after the index operation. The incidence of developing a second primary tumour within two years was 1.7% (95% CI: 0.7% to 3.7%), within five years was 4.9% (95% CI: 2.9% to 7.7%), and within 10 years was 7.8% (95% CI: 5.1% to 11.1%). Early stage of first cancer was the only significant factor (p=0.001) for development of a second primary within 10 years, reflecting survivorship. Most second primaries (21 patients) were staged as early, and by visual inspection. Most (n=20) were within the oral cavity, one of which overlapped the oropharynx; eight others were in the oropharynx, and one in the larynx. Most patients (n=22) were treated by operation with curative intent. Three were treated palliatively. Patients need to be aware of the risk of a second primary and, as most are in the mouth or oropharynx, there is a role for surveillance by primary dental care practitioners.

CHD1 loss sensitizes prostate cancer to DNA damaging therapy by promoting error-prone double-strand break repair.

BACKGROUND: Deletion of the chromatin remodeler chromodomain helicase DNA-binding protein 1 (CHD1) is a common genomic alteration found in human prostate cancers (PCas). CHD1 loss represents a distinct PCa subtype characterized by SPOP mutation and higher genomic instability. However, the role of CHD1 in PCa development in vivo and its clinical utility remain unclear. PATIENTS AND METHODS: To study the role of CHD1 in PCa development and its loss in clinical management, we generated a genetically engineered mouse model with prostate-specific deletion of murine Chd1 as well as isogenic CHD1 wild-type and homozygous deleted human benign and PCa lines. We also developed patient-derived organoid cultures and screened patients with metastatic PCa for CHD1 loss. RESULTS: We demonstrate that CHD1 loss sensitizes cells to DNA damage and causes a synthetic lethal response to DNA damaging therapy in vitro, in vivo, ex vivo, in patient-derived organoid cultures and in a patient with metastatic PCa. Mechanistically, CHD1 regulates 53BP1 stability and CHD1 loss leads to decreased error-free homologous recombination (HR) repair, which is compensated by increased error-prone non-homologous end joining (NHEJ) repair for DNA double-strand break (DSB) repair. CONCLUSIONS: Our study provides the first in vivo and in patient evidence supporting the role of CHD1 in DSB repair and in response to DNA damaging therapy. We uncover mechanistic insights that CHD1 modulates the choice between HR and NHEJ DSB repair and suggest that CHD1 loss may contribute to the genomic instability seen in this subset of PCas.

Knowledge, attitudes, beliefs, and behaviors of university students, faculty, and staff during a meningococcal serogroup B outbreak vaccination program.

OBJECTIVES: During an outbreak of invasive meningococcal B disease on a university campus, we explored the knowledge, attitudes, beliefs, and behaviors of members of the university community in relation to the disease, the vaccine, and the vaccination program. DESIGN: All students, faculty and staff were invited by email to participate in a 71-item online survey, which was administered after completion of the mass clinics for the first and second doses of a meningococcal B vaccination program. RESULTS: A total of 404 individuals responded to the survey; 75.7% were students. Knowledge about meningococcal disease and vaccine was generally high; more than 70% correct responses were received on each knowledge question except for one question about the different meningococcal serogroups. Gender (female) and higher knowledge scores were significantly associated with either being immunized or intending to be immunized (p<0.05). Positive attitudes about immunization, concern about meningococccal infection, a sense of community responsibility, and trust in public health advice also correlated with being vaccinated or intending to be vaccinated (p<0.05). CONCLUSIONS: A successful mass vaccination program in a Nova Scotia university was associated with high levels of knowledge, positive attitudes toward vaccination, and positive attitudes toward public health recommendations.

Rapid surveillance for health events following a mass meningococcal B vaccine program in a university setting: A Canadian Immunization Research Network study.

An outbreak of Neisseria meningitidis serotype B infection occurred at a small residential university; public health announced an organizational vaccination program with the 4-component Meningococcal B (4CMenB) vaccine (Bexsero(TM), Novartis/GlaxoSmithKline Inc.) several days later. Since there were limited published data on reactogenicity of 4CMenB in persons over 17years of age, this study sought to conduct rapid surveillance of health events in vaccinees and controls using an online survey. Vaccine uptake was 84.7% for dose 1 (2967/3500) and 70% (2456/3500) for dose 2; the survey response rates were 33.0% (987/2967) and 18.7% (459/2456) in dose 1 and dose 1 recipients respectively, and 12% in unvaccinated individuals (63/533). Most students were 20-29years of age (vaccinees, 64.0%; controls, 74.0). A new health problem or worsening of an existing health problem was reported by 30.0% and 30.3% of vaccine recipients after doses 1 and 2 respectively; and by 15.9% of controls. These health problems interfered with the ability to perform normal activities in most vaccinees reporting these events (74.7% post dose 1; 62.6% post dose 2), and in 60% of controls. The health problems led to a health care provider visit (including emergency room) in 12.8% and 14.4% of vaccinees post doses 1 and 2, respectively and in 40% of controls. The most common reactions in vaccinees were injection site reactions (20.6% post dose 1, 16.1% post dose 20 and non-specific systemic complaints (22.6% post dose 1, 17.6% post dose 2). No hospitalizations were reported. An online surveillance program during an emergency meningococcal B vaccine program was successfully implemented, and detected higher rates of health events in vaccinees compared to controls, and high rates of both vaccinees and controls seeking medical attention. The types of adverse events reported by young adult vaccinees were consistent with those previously.

Methods to determine resistance to anthelmintics when continuing larval development occurs.

The in vivo faecal egg count reduction test (FECRT) is the most commonly used test to detect anthelmintic resistance (AR) in gastrointestinal nematodes (GIN) of ruminants in pasture based systems. However, there are several variations on the method, some more appropriate than others in specific circumstances. While in some cases labour and time can be saved by just collecting post-drench faecal worm egg counts (FEC) of treatment groups with controls, or pre- and post-drench FEC of a treatment group with no controls, there are circumstances when pre- and post-drench FEC of an untreated control group as well as from the treatment groups are necessary. Computer simulation techniques were used to determine the most appropriate of several methods for calculating AR when there is continuing larval development during the testing period, as often occurs when anthelmintic treatments against genera of GIN with high biotic potential or high re-infection rates, such as Haemonchus contortus of sheep and Cooperia punctata of cattle, are less than 100% efficacious. Three field FECRT experimental designs were investigated: (I) post-drench FEC of treatment and controls groups, (II) pre- and post-drench FEC of a treatment group only and (III) pre- and post-drench FEC of treatment and control groups. To investigate the performance of methods of indicating AR for each of these designs, simulated animal FEC were generated from negative binominal distributions with subsequent sampling from the binomial distributions to account for drench effect, with varying parameters for worm burden, larval development and drench resistance. Calculations of percent reductions and confidence limits were based on those of the Standing Committee for Agriculture (SCA) guidelines. For the two field methods with pre-drench FEC, confidence limits were also determined from cumulative inverse Beta distributions of FEC, for eggs per gram (epg) and the number of eggs counted at detection levels of 50 and 25. Two rules for determining AR: (1) %reduction (%R)<95% and lower confidence limit <90%; and (2) upper confidence limit <95%, were also assessed. For each combination of worm burden, larval development and drench resistance parameters, 1000 simulations were run to determine the number of times the theoretical percent reduction fell within the estimated confidence limits and the number of times resistance would have been declared. When continuing larval development occurs during the testing period of the FECRT, the simulations showed AR should be calculated from pre- and post-drench worm egg counts of an untreated control group as well as from the treatment group. If the widely used resistance rule 1 is used to assess resistance, rule 2 should also be applied, especially when %R is in the range 90 to 95% and resistance is suspected.

An unusual cause of lower abdominal pain in pubertal girls.

A rare cause of acute lower abdominal pain in pubertal girls is described. The diagnosis is often missed at initial presentation and this may result in multiple presentations to the emergency department or general practitioner. The clinical features, diagnosis, management and possible complications of this condition are discussed. The case illustrates the importance of keeping this diagnosis in mind when seeing teenage girls with lower abdominal pain.

Bluetongue virus: European Community inter-laboratory comparison tests to evaluate ELISA and RT-PCR detection methods.

European Community national reference laboratories participated in two inter-laboratory comparison tests in 2006 to evaluate the sensitivity and specificity of their 'in-house' ELISA and RT-PCR assays for the detection of bluetongue virus (BTV) antibodies and RNA. The first ring trial determined the ability of laboratories to detect antibodies to all 24 serotypes of BTV. The second ring trial, which included both antisera and EDTA blood samples from animals experimentally infected with the northern European strain of BTV-8, determined the ability of laboratories to detect BTV-8 antibodies and RNA, as well as the diagnostic sensitivity of the assays. A total of six C-ELISAs, six real-time RT-PCR and three conventional RT-PCR assays were used. All C-ELISAs were capable of detecting the BTV serotypes currently circulating in Europe (BTV-1, 2, 4, 8, 9 and 16), however some assays displayed inconsistencies in the detection of other serotypes, particularly BTV-19. All C-ELISAs detected BTV-8 antibodies in cattle and sheep by 21 dpi, while the majority of assays detected antibodies by 9 dpi in cattle and 8 dpi in sheep. All the RT-PCR assays were able to detect BTV-8, although the real-time assays were more sensitive compared to the conventional assays. The majority of real-time RT-PCR assays detected BTV RNA as early as 2 dpi in cattle and 3 dpi in sheep. These two ring trails provide evidence that national reference laboratories within the EC are capable of detecting BTV antibodies and RNA and provide specificity and sensitivity information on the detection methods currently available.

Supplementation with goldenseal (Hydrastis canadensis), but not kava kava (Piper methysticum), inhibits human CYP3A activity in vivo.

The effects of goldenseal (Hydrastis canadensis) and kava kava (Piper methysticum) supplementation on human CYP3A activity were evaluated using midazolam (MDZ) as a phenotypic probe. Sixteen healthy volunteers were randomly assigned to receive either goldenseal or kava kava for 14 days. Each supplementation phase was followed by a 30-day washout period. MDZ (8 mg, per os) was administered before and after each phase, and pharmacokinetic parameters were determined using standard non-compartmental methods. Comparisons of pre- and post-supplementation MDZ pharmacokinetic parameters revealed significant inhibition of CYP3A by goldenseal (AUC(0-infinity), 107.9+/-43.3 vs 175.3+/-74.8 ng x h/ml; Cl/F/kg, 1.26+/-0.59 vs 0.81+/-0.45 l/h/kg; T(1/2), 2.01+/-0.42 vs 3.15+/-1.12 h; Cmax, 50.6+/-26.9 vs 71.2+/-50.5 ng/ml). MDZ disposition was not affected by kava kava supplementation. These findings suggest that significant herb-drug interactions may result from the concomitant ingestion of goldenseal and CYP3A substrates.

Physical status of newborns and neonatal outcome.

OBJECTIVE: To determine the extent to which physical status at birth is associated with neonatal mortality and the causes of mortality vis-a-vis size at birth and gestational age. METHOD: 11,223 consecutive live births completing 26 weeks of gestation and weighing > or = 500 gm were included in the study. Birth weight and chest circumference were recorded as per WHO guidelines. Gestational age was calculated on the basis of L.M.P. and the new Ballard's score. Deaths occurring in the hospital within 28 days were recorded. Percentile values of gestational age specific birth weights were calculated separately for singletons and multiple births. Percentage of SGA was calculated with reference to WHO recommended values. Birth weight-gestational age-specific mortality rates were calculated at 2 wk and 500 gm intervals. RESULT: Low-birth-weight babies constituted 39.8% of the total, much in excess of WHO recommended figure of 15%. 76% deaths occurred among LBW babies and 56.2% among preterms. Mortality showed remarkable decline as the birth weight increased to 2,000 gm. The lowest mortality was among singletons weighing 2,500-3,000 gm and of 38-40 weeks gestation. Prevalence of SGA at 40 and 42 weeks were 73.7% and 83.6% respectively. But, if SGA babies not categorised as LBW were excluded, the values came down to 32% and 36% respectively. 36% of all deaths occurred during the first 24 hrs of birth; asphyxia and related causes contributing to 50% of it. CONCLUSION: Cut-off value of 2,000 gm instead of 2,500 gm for birth weight may be preferable in countries where most LBW babies are SGAs. Simultaneously, deaths in non-LBW babies due to perinatal causes contribute sgnificantly to total neonatal mortality and need due attention through sensitising obstetricians in essential newbom care and timely Intervention.

Another cause for bilateral haemorrhagic otorrhoea following trauma.

Bleeding from the external auditory meatus (haemorrhagic otorrhoea) following head trauma is usually attributed to a basal skull fracture. However, it may also result from unsuspected facial trauma. We describe a case that highlights an usual but important differential diagnosis for bilateral haemorrhagic otorrhoea.

Comorbidity in a clinical sample of substance abusers.

The sample consisted of 125 male inpatients admitted to one of two substance abuse treatment centers in Iowa. They were diagnosed by means of the Diagnostic Interview Schedule Screening Interview-Quick-DIS version, the Structural Interview for DSM-III-R Personality Disorder (PD), revised, and the Substance Abuse Reporting System. The most frequently diagnosed comorbid Axis I conditions were anxiety and mood disorders, while the most frequently observed Axis II disorders were in Cluster B, borderline PD, and antisocial PD followed by Cluster C, avoidant PD, passive-aggressive PD and obsessive-compulsive PD; and then Cluster A; schizoid PD. Subjects diagnosed with Borderline PD showed the highest rate of comorbid psychopathology, including Axis I disorders of generalized anxiety disorder, major depression, cocaine dependence, and inhalant dependence. The most likely comorbid diagnosis for antisocial PD subjects was bipolar disorder. The schizoid PD and the NoPD groups were less likely to meet criteria for other Axis I disorders. A high rate of comorbid Axis II pathology was also found. Polysubstance dependent subjects were more likely to be diagnosed with anxiety disorder or bipolar disorder than were those who were not polysubstance dependent or were dependent only on alcohol. Polysubstance dependent men were at highest risk for Axis II disorders: 56% of them met criteria for a Cluster B PD, with borderline PD and histrionic PD most frequent.

Up-regulation of WNT-4 signaling and dosage-sensitive sex reversal in humans.

Wnt-4, a member of the Wnt family of locally acting secreted growth factors, is the first signaling molecule shown to influence the sex-determination cascade. In mice, a targeted deletion of Wnt-4 causes the masculinization of XX pups. Therefore, WNT-4, the human homologue of murine Wnt-4, is a strong candidate gene for sex-reversal phenotypes in humans. In this article, we show that, in testicular Sertoli and Leydig cells, Wnt-4 up-regulates Dax1, a gene known to antagonize the testis-determining factor, Sry. Furthermore, we elucidate a possible mechanism for human XY sex reversal associated with a 1p31-p35 duplication including WNT-4. Overexpression of WNT-4 leads to up-regulation of DAX1, which results in an XY female phenotype. Thus, WNT-4, a novel sex-determining gene, and DAX1 play a concerted role in both the control of female development and the prevention of testes formation. These observations suggest that mammalian sex determination is sensitive to dosage, at multiple steps in its pathway.

Cross-cultural comparison of clinical samples of Norwegian and Iowan women with substance-related disorders.

The purpose of this study was to compare two clinical samples of women substance abusers, one from Iowa and one from Norway, along several dimensions: "substance abuse" history, current "abuse" pattern, parental and spouse drinking history, symptoms of psychological distress, and "vulnerability" to relapse. A higher percentage of women substance abusers from Iowa were divorced and lived alone, were "vulnerable" to relapse, and reported more life problems secondary to their substance use than women from Norway. The Iowa women had used more substances in addition to alcohol than had the Norwegian women. The Norwegian women reported greater intensity of emotional distress than the women from Iowa.

Repeated acetaminophen dosing in rats: adaptation of hepatic antioxidant system.

Repeated dosing of acetaminophen (paracetamol) to rats is reported to decrease their sensitivity to its hepatotoxic effects, which are associated with oxidative stress and glutathione depletion. We determined if repeated acetaminophen dosing produced adaptive response of key antioxidant system enzymes. Male rats (Sprague-Dawley, 10 weeks) were given 800, 1200, or 1600 mg/kg/day acetaminophen by oral gavage for 4 days. Liver was assayed for oxidative stress and antioxidant markers: malondialdehyde (MDA), thiobarbituric acid reactive substance (TBARS), total antioxidant status (TAS), glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPx), glucose-6-phosphate dehydrogenase (G6PD), catalase (CAT), and superoxide dismutase (SOD), and alanine transaminase (ALT) as a marker of hepatocellular injury. Acetaminophen at 1200/1600 mg/kg decreased GSH 26/47%, GPx 21/26%, CAT 35/28%, SOD 21/12%; and TAS 28/18% (correlated with CAT, r=0.91; SOD, r=0.66; GPx, r=0.45). Despite antioxidant deficiencies, and no TBARS change, MDA decreased 26%/33%/37% at 800/1200/1600 mg/kg, which correlated with increased GR (61%/62%/76%, r=0.77) and G6PD (130%/110%/190%, r=0.78). Both MDA (r=0.68) and G6PD (r=0.71) correlated with hepatic ALT, which decreased 27%/43%/48%, respectively. Resistance to acetaminophen hepatotoxicity produced by repeated exposure is partially attributable to upregulation of hepatic G6PD and GR activity as an adaptive and protective response to oxidative stress and glutathione depletion.

Peptide and peptide mimetic inhibitors of antigen presentation by HLA-DR class II MHC molecules. Design, structure-activity relationships, and X-ray crystal structures.

Molecular features of ligand binding to MHC class II HLA-DR molecules have been elucidated through a combination of peptide structure-activity studies and structure-based drug design, resulting in analogues with nanomolar affinity in binding assays. Stabilization of lead compounds against cathepsin B cleavage by N-methylation of noncritical backbone NH groups or by dipeptide mimetic substitutions has generated analogues that compete effectively against protein antigens in cellular assays, resulting in inhibition of T-cell proliferation. Crystal structures of four ternary complexes of different peptide mimetics with the rheumatoid arthritis-linked MHC DRB10401 and the bacterial superantigen SEB have been obtained. Peptide-sugar hybrids have also been identified using a structure-based design approach in which the sugar residue replaces a dipeptide. These studies illustrate the complementary roles played by phage display library methods, peptide analogue SAR, peptide mimetics substitutions, and structure-based drug design in the discovery of inhibitors of antigen presentation by MHC class II HLA-DR molecules.

Identity in adolescent survivors of childhood cancer.

OBJECTIVE: To investigate identify formation among adolescent survivors of childhood cancer. Family functioning, perceived emotional support from family and peers, life stress, and anxiety produced by the cancer experience also were examined as they influenced identity development. METHOD: Participants were 52 adolescent survivors and their mothers recruited from a medical center and 42 healthy adolescent counterparts and their mothers recruited from the community. RESULTS: A greater frequency of survivors than their healthy peers was found within the foreclosed identity status. Factors associated with the foreclosed identity status included the cancer diagnosis, symptoms of posttraumatic stress disorder (PTSD), and family functioning characterized by greater levels of conflict. CONCLUSIONS: Data were interpreted to suggest that the foreclosed identity status may serve a protective function in assisting survivors to cope with the stressors of the cancer experience.