Molecular insights into an ancient form of Paget's disease of bone.

Paget's disease of bone (PDB) is a chronic skeletal disorder that can affect one or several bones in individuals older than 55 y of age. PDB-like changes have been reported in archaeological remains as old as Roman, although accurate diagnosis and natural history of the disease is lacking. Six skeletons from a collection of 130 excavated at Norton Priory in the North West of England, which dates to medieval times, show atypical and extensive pathological changes resembling contemporary PDB affecting as many as 75% of individual skeletons. Disease prevalence in the remaining collection is high, at least 16% of adults, with age at death estimations as low as 35 y. Despite these atypical features, paleoproteomic analysis identified sequestosome 1 (SQSTM1) or p62, a protein central to the pathological milieu of PDB, as one of the few noncollagenous human sequences preserved in skeletal samples. Targeted proteomic analysis detected >60% of the ancient p62 primary sequence, with Western blotting indicating p62 abnormalities, including in dentition. Direct sequencing of ancient DNA excluded contemporary PDB-associated SQSTM1 mutations. Our observations indicate that the ancient p62 protein is likely modified within its C-terminal ubiquitin-associated domain. Ancient miRNAs were remarkably preserved in an osteosarcoma from a skeleton with extensive disease, with miR-16 expression consistent with that reported in contemporary PDB-associated bone tumors. Our work displays the use of proteomics to inform diagnosis of ancient diseases such as atypical PDB, which has unusual features presumably potentiated by yet-unidentified environmental or genetic factors.

Effects of an anti-TSLP antibody on allergen-induced asthmatic responses.

BACKGROUND: Thymic stromal lymphopoietin (TSLP) is an epithelial-cell-derived cytokine that may be important in initiating allergic inflammation. AMG 157 is a human anti-TSLP monoclonal immunoglobulin G2λ that binds human TSLP and prevents receptor interaction. METHODS: In this double-blind, placebo-controlled study, we randomly assigned 31 patients with mild allergic asthma to receive three monthly doses of AMG 157 (700 mg) or placebo intravenously. We conducted allergen challenges on days 42 and 84 to evaluate the effect of AMG 157 in reducing the maximum percentage decrease in the forced expiratory volume in 1 second (FEV1). We also measured the fraction of nitric oxide in exhaled air, blood and sputum eosinophils, and airway hyperresponsiveness. The primary end point was the late asthmatic response, as measured 3 to 7 hours after the allergen challenge. RESULTS: AMG 157 attenuated most measures of allergen-induced early and late asthmatic responses. The maximum percentage decrease in the FEV1 during the late response was 34.0% smaller in the AMG-157 group than in the placebo group on day 42 (P=0.09) and 45.9% smaller on day 84 (P=0.02). In addition, patients receiving AMG 157 had significant decreases in levels of blood and sputum eosinophils before and after the allergen challenge and in the fraction of exhaled nitric oxide. There were 15 adverse events in the AMG-157 group, as compared with 12 in the placebo group; there were no serious adverse events. CONCLUSIONS: Treatment with AMG 157 reduced allergen-induced bronchoconstriction and indexes of airway inflammation before and after allergen challenge. These findings are consistent with a key role for TSLP in allergen-induced airway responses and persistent airway inflammation in patients with allergic asthma. Whether anti-TSLP therapeutics will have clinical value cannot be determined from these data. (Funded by Amgen; ClinicalTrials.gov number, NCT01405963.).

Clinical pharmacology of AMG 181, a gut-specific human anti-α4ß7 monoclonal antibody, for treating inflammatory bowel diseases.

AIMS: AMG 181 pharmacokinetics/pharmacodynamics (PK/PD), safety, tolerability and effects after single subcutaneous (s.c.) or intravenous (i.v.) administration were evaluated in a randomized, double-blind, placebo-controlled study. METHODS: Healthy male subjects (n= 68) received a single dose of AMG 181 or placebo at 0.7, 2.1, 7, 21, 70 mg s.c. (or i.v.), 210 mg s.c. (or i.v.), 420 mg i.v. or placebo. Four ulcerative colitis (UC) subjects (n= 4, male : female 2:2) received 210 mg AMG 181 or placebo s.c. (3:1). AMG 181 concentration, anti-AMG 181-antibody (ADA), α4 ß7 receptor occupancy (RO), target cell counts, serum C-reactive protein, fecal biomarkers and Mayo score were measured. Subjects were followed 3-9 months after dose. RESULTS: Following s.c. dosing, AMG 181 was absorbed with a median tmax ranging between 2-10 days and a bioavailability between 82% and 99%. Cmax and AUC increased dose-proportionally and approximately dose-proportionally, respectively, within the 70-210 mg s.c. and 70-420 mg i.v. ranges. The linear ß-phase t1/2 was 31 (range 20-48) days. Target-mediated disposition occurred at serum AMG 181 concentrations of less than 1 µg ml(-1) . The PD effect on α4 ß7 RO showed an EC50 of 0.01 µg ml(-1) . Lymphocytes, eosinophils, CD4+ T cells and subset counts were unchanged. AMG 181-treated UC subjects were in remission with mucosal healing at weeks 6, 12 and/or 28. The placebo-treated UC subject experienced colitis flare at week 6. No ADA or AMG 181 treatment-related serious adverse events were observed. CONCLUSIONS: AMG 181 has PK/PD, safety, and effect profiles suitable for further testing in subjects with inflammatory bowel diseases.

Research Priorities for Childhood Apraxia of Speech: A Long View.

This article introduces the Journal of Speech, Language, and Hearing Research Special Issue: Selected Papers From the 2022 Apraxia Kids Research Symposium. The field of childhood apraxia of speech (CAS) has developed significantly in the past 15 years, with key improvements in understanding of basic biology including genetics, neuroscience, and computational modelling; development of diagnostic tools and methods; diversity of evidence-based interventions with increasingly rigorous experimental designs; and understanding of impacts beyond impairment-level measures. Papers in this special issue not only review and synthesize the some of the substantial progress to date but also present novel findings addressing critical research gaps and adding to the overall body of knowledge. A second aim of this prologue is to report the current research needs in CAS, which arose from symposium discussions involving researchers, clinicians, and Apraxia Kids community members (including parents of children with CAS). Four primary areas of need emerged from discussions at the symposium. These were: (a) What questions should we ask? (b) Who should be in the research? (c) How do we conduct the research? and (d) How do we move from research to practice? Across themes, symposium attendees emphasized the need for CAS research to better account for the diversity of people with CAS and improve the timeliness of implementation of high-level evidence-based practice across the lifespan. It is our goal that the articles and prologue discussion in this special issue provide an appreciation of advancements in CAS research and an updated view of the most pressing needs for future research.

Preservation of whole antibodies within ancient teeth.

Archaeological remains can preserve some proteins into deep time, offering remarkable opportunities for probing past events in human history. Recovering functional proteins from skeletal tissues could uncover a molecular memory related to the life-history of the associated remains. We demonstrate affinity purification of whole antibody molecules from medieval human teeth, dating to the 13th-15th centuries, from skeletons with different putative pathologies. Purified antibodies are intact retaining disulphide-linkages, are amenable to primary sequences analysis, and demonstrate apparent immunoreactivity against contemporary EBV antigen on western blot. Our observations highlight the potential of ancient antibodies to provide insights into the long-term association between host immune factors and ancient microbes, and more broadly retain a molecular memory related to the natural history of human health and immunity.

Nightguard vital bleaching: side effects and patient satisfaction 10 to 17 years post-treatment.

STATEMENT OF THE PROBLEM: The long-term patient satisfaction and safety of nightguard vital bleaching (NGVB) requires further evaluation. PURPOSE OF THE STUDY: The purpose of this study was to evaluate patients' satisfaction and identify side effects of NGVB up to 17 years post-treatment. MATERIALS AND METHODS: Thirty-one participants who had completed previous NGVB studies using 10% carbamide peroxide were contacted at least 10 years post-treatment (range 10-17 years, average 12.3 years). Participants reported shade satisfaction (very satisfied [VS], partially satisfied [PS], or not satisfied [NS]) as well as potential complications. Participants had teeth # 6 to 11 examined for tooth vitality, gingival inflammation (Löe's Gingival Index [GI]), and radiographically for external cervical resorption (ECR). RESULTS: All of the participants had successful lightening of their teeth. Sixty-one percent (19) had not retreated their teeth. Of those who had not retreated their teeth and who responded to the question of whitening satisfaction, 31% (4/13) were VS, 54% (7/13) were PS, and 15% (2/13) were NS with their current shade. Of those who had retreated their teeth, all were VS or PS. Ninety-one percent of the examined teeth had GI = 0 (normal), 7% had GI = 1 (mild inflammation), and 2% had GI = 2 (moderate inflammation). Sixty-nine percent of teeth tested responded to a cold stimulus. Radiographs did not detect ECR or apical lesions. No participant reported having a gingival biopsy post-treatment, and 87% would whiten again. CONCLUSIONS: Patient satisfaction with NGVB may last as long as 12.3 years in average (range 10-17 years) post-treatment. GI and ECR findings were considered within the normal expectations for the sample studied, suggesting minimal clinical post-NGVB side effects up to 17 years. CLINICAL SIGNIFICANCE: Nightguard vital bleaching provides patient satisfaction with minimal side effects up to 17 years post-treatment.

Structure based evolution of a novel series of positive modulators of the AMPA receptor.

Starting from compound 1, we utilized biostructural data to successfully evolve an existing series into a new chemotype with a promising overall profile, exemplified by 19.

Challenges that healthcare practitioners experience in the comprehensive assessment of patients with non-communicable diseases: a preliminary investigation.

BACKGROUND: Resource allocation and access to comprehensive treatment in the public healthcare sector are always under pressure. This pressure takes the form of staff shortages, treatment models and the holistic care of patients, compromising basic healthcare in South Africa. OBJECTIVES: The study's aim was to determine the challenges that healthcare practitioners experience while assessing patients with non-communicable diseases, in private and public healthcare sectors in the Gauteng Province of South Africa. METHODS: The research design was exploratory and contextual. Qualitative data were collected through focus groups and semi-structured interviews among healthcare practitioners (n = 12). Data analysis took place using Atlas.ti 8.4 Windows (2020). Inter-rater reliability (r = 93.68%) was calculated to ensure the rigour and validity of the results. RESULTS: From the discussion, four themes emerged: 1) limited consultation time; 2) overwhelming economic impact and healthcare cost for facilities and patients; 3) holistic patient care encompassing physical, mental and socioeconomic components; and 4) lack of patient education due to time constraints experienced by healthcare practitioners. CONCLUSION: Consultation times are reduced due to a shortage of medical staff, patient numbers, equipment, and poor working conditions. By improving these conditions, patients across all socioeconomic groups will be better assisted, treated, and educated, benefiting from equal access and quality healthcare.

A novel series of positive modulators of the AMPA receptor: structure-based lead optimization.

Starting from lead compound 1, we demonstrate how X-ray structural data can be used to understand SAR and expediently optimize bioavailability in a novel series of AMPA receptor modulators, furnishing 5 with improved bioavailability and robust in vivo activity.

A novel series of positive modulators of the AMPA receptor: discovery and structure based hit-to-lead studies.

Starting from an HTS derived hit 1, application of biostructural data facilitated rapid optimization to lead 22, a novel AMPA receptor modulator. This is the first demonstration of how structure based drug design can be exploited in an optimization program for a glutamate receptor.

Childhood asthma: ED follow-up determinants.

INTRODUCTION: This comparative correlational study investigated families who use the emergency department for childhood asthma to identify determinants of follow-up care. The primary hypothesis was: families who obtain follow-up care differ in predisposing, enabling, and need characteristics from families who do not obtain follow-up care. METHOD: A convenience sample of 63 children presenting to the pediatric emergency department of a Central Florida hospital were enrolled. Logistic regression techniques were utilized to explicate the individual and combined effects of the variables that best predicted the outcome variable. The dichotomous dependent variable was follow-up care within 30 days of the ED visit. RESULTS: Sixty-seven percent of the children did not follow up as directed. Mother's level of education was significantly associated with no follow-up (P = .0282). Odds of no follow-up were higher for children with more severe asthma (odds ratio [OR] 12.44) or older mothers (OR 2.14). DISCUSSION: Follow-up is not occurring at desired levels. Although this study has clinical and research implications for health care providers, further research is needed to identify follow-up determinants and develop interventions to improve follow-up rates and asthma outcomes.

Donor Diabetes Mellitus Severity and Corneal Transplant Suitability in a US Eye Bank Donor Population.

PURPOSE: To determine whether donor diabetes mellitus (DM) severity is associated with differences in endothelial cell density (ECD) and surgically unsuitable tissue. METHODS: Raw data were obtained from Saving Sight Eye Bank (Kansas City, MO) including 10,454 donated eyes from 5346 eligible donors from July 2014 through May 2017. Donors were grouped into 5 categories by their insulin use and the presence of microvascular end-organ complications. The categories were non-DM (NDM), noninsulin-dependent DM without complications (NIDDMnc), noninsulin-dependent DM with complication (NIDDMc), insulin-dependent DM without complications, and insulin-dependent DM with complication. Outcome variables included ECD and tissue transplant suitability. Mixed effects models were used to adjust for the random effect of repeated measures and fixed effects of donor age, race, lens status, and death to refrigeration and death to preservation times. Interaction effects of DM severity group and donor age and DM severity group and lens status were included in the models. RESULTS: One thousand six hundred eighty-four (32.1%) donors had a diagnosis of DM. Six hundred fifty-eight donors were in the NIDDMnc group, 225 in the NIDDMc group, 404 in the insulin-dependent DM without complication group, and 397 in the insulin-dependent DM with complication group. Compared with non-DM, donors with DM were older (P < 0.001) and more likely to be pseudophakic (P < 0.001). DM severity groups did not affect adjusted ECD at mean donor age. There was no statistically significant ECD interaction between DM severity group and lens status. There was a statistically significant ECD crossover interaction with NIDDMnc and donor age (P < 0.001). In phakic eyes, NIDDMc was associated with a statistically significantly lower odds of transplant suitability (odds ratio 0.62, P = 0.006). CONCLUSIONS: DM severity does not affect lowering adjusted ECD at mean donor age. DM severity and pseudophakia were not associated with lower adjusted ECD. NIDDMnc was associated with an attenuation of the age-dependent decrease in ECD. NIDDMc was associated with decreased transplant suitability in phakic eyes. Future studies should include age, lens status, and interaction effects in their models of ECD and transplant suitability.

Innovative solutions: my heart is a what?! Creativity in critical care education.

Nurses teach patients, families, and other healthcare providers. All of us teach our neighbors and communities. Choosing strategies for teaching essential content is the challenge we face every day. This article describes some innovative ways to share knowledge using creativity and imagination.

Does radiotherapy around the time of pregnancy for Hodgkin's disease modify the risk of breast cancer?

PURPOSE: To determine whether the risk of secondary breast cancer after radiotherapy (RT) for Hodgkin's disease is greater among women who underwent RT around time of pregnancy. METHODS AND MATERIALS: The records of 382 women treated with RT for Hodgkin's disease were reviewed and divided into those who received RT around the time of pregnancy and those who were not pregnant. Comparisons of the overall incidence, actuarial rates, and latency to breast cancer between the two groups were made. Multivariate Cox regression modeling was performed to determine possible contributing factors. RESULTS: Of the 382 women, 14 developed breast cancer (3.7%). The increase in the overall incidence (16.0% vs. 2.3%, p = 0.0001) and the actuarial rate of breast cancer among the women in the pregnant group (p = 0.011) was statistically significant. The women treated around the time of pregnancy had a 10- and 15-year actuarial rate of breast cancer of 6.7% and 32.6%, respectively. The 10-year and 15-year actuarial rate for the nonpregnant women was 0.4% and 1.7%, respectively. The median latency from RT to the diagnosis of breast cancer was 13.1 and 18.9 years for women in the pregnant and nonpregnant groups, respectively. In the multivariate analysis, pregnancy around the time of RT was the only variable associated with an increased risk of breast cancer. The risk was dependent on the length of time from pregnancy to RT, with women receiving RT during pregnancy and within 1 month of pregnancy having an increased risk of breast cancer compared with nonpregnant women and women irradiated later than 1 month after pregnancy (hazard ratio, 22.49; 95% confidence interval, 5.56-90.88; p <0.001). CONCLUSION: The results of this study indicate that the risk of breast cancer after RT is greater with irradiation around the time of pregnancy. This suggests that pregnancy is a time of increased sensitivity of breast tissue to the carcinogenic effects of radiation. Because of the small sample size and limited follow-up, additional studies are recommended to confirm these findings.

Complex karyotypic abnormality in ovarian fibroma associated with Gorlin syndrome.

Nevoid basal cell carcinoma (NBCC) syndrome is an autosomal dominant disorder characterized by distinctive congenital malformations and a variety of benign and malignant neoplasms, including ovarian fibromas. We describe pathologic and cytogenetic findings in a large unilateral ovarian fibroma from a 12-year-old female with NBCC syndrome. The pathologic findings were characteristic for ovarian fibroma, but were unusual for the ovarian fibromas associated with NBCC syndrome because of the absence of calcification, the lack of bilaterality, and the presence of focal hypercellularity. The karyotype of tumor tissue showed complex numerical and structural abnormalities. Although there is frequent loss of heterozygosity of 9q22.3 and mutations in the PTCHgene in Gorlin syndrome, the ovarian fibroma in this case did not have cytogenetically detectable abnormalities of chromosome 9.

Scleredema adultorum of Buschke treated with radiation.

BACKGROUND: Scleredema adultorum of Buschke is an uncommon skin condition that may accompany diabetes mellitus. Current therapeutic options are poor, with only case reports and small series supporting their use. OBSERVATION: We describe 3 patients with severe restrictive scleredema associated with type 2 diabetes mellitus who responded to radiation therapy after other treatments had failed. Angle of shoulder abduction was used as an objective measurement of improvement, while the patients rated several subjective areas, including arm range of motion, ease of performing daily tasks, ease of breathing, and neck thickening. Objective improvement tended to plateau over time but remained well above baseline. The duration of subjective improvement was variable, lasting from a few months to the end of the observation time of 2 1/2 years. CONCLUSION: Though not consistently durable in its effect, radiation therapy appears to be a viable therapeutic option in extreme cases of this difficult-to-treat disease.

The application of electron beam delivery using dose rate variation and dynamic couch motion in conformal treatment of the cranial-spinal axis.

Radiation therapy to the cranial-spinal axis is typically targeted to the spinal cord and to the cerebrospinal fluid (CSF) in the subarachnoid space adjacent to the spinal cord and brain. Standard techniques employed in the treatment of the whole central nervous system do little to compensate for the varying depths of spinal cord along the length of the spinal field. Lateral simulation films, sagittal magnetic resonance imaging (MRI), or computerized tomography (CT) are used to estimate an average prescription depth for treatment along the spine field. However, due to the varying depth of the target along the spinal axis, even with the use of physical compensators, there can be considerable dose inhomogeneity along the spine field. With the advent of treatment machines that have full dynamic capabilities, a technique has been devised that will allow for more conformal dose distribution along the full length of the spinal field. This project simulates this technique utilizing computer-controlled couch motion to deliver multiple small electron beams of differing energies and intensities. CT planning determines target depth along the entire spine volume. The ability to conform dose along the complete length of the treatment field is investigated through the application of superpositioning of the fields as energies and intensities change. The positioning of each beam is registered with the treatment couch dynamic motion. This allows for I setup in the treatment room rather than multiple setups for each treatment position, which would have been previously required. Dose-volume histograms are utilized to evaluate the dose delivered to structures in the beam exit region. This technique will allow for precise localization and delivery of a homogeneous dose to the entire CSF space.

Evaluation of side effects and patients' perceptions during tooth bleaching.

OBJECTIVE: The objective of this nightguard vital bleaching (NGVB) study was to compare tooth sensitivity (TS), gingival irritation (GIr), and other side effects, as well as patients' perceptions during tooth bleaching, from treatment with experimental 5 and 7% hydrogen peroxide (HP) bleaching solutions with those of a commercially available 10% carbamide peroxide (CP) product. MATERIALS AND METHODS: Sixty-one participants completed the study wearing a scalloped maxillary treatment tray without reservoirs with the different concentrations of bleaching gels for 30 minutes twice a day for 7 days. Parameters evaluated were changes in gingival index (GI), nonmarginal gingival index, nongingival oral mucosal index, and tooth vitality. Participants were seen pretreatment, after 7 treatment days, and 1 week post-treatment. A daily log form to record TS and GIr was completed by each participant as well as a sensitivity questionnaire at each appointment. Additionally, at 10 months post-treatment, a questionnaire was sent to the participants concerning TS and GIr relative to the treatment process. RESULTS: Data from end-of-treatment questionnaires, daily log forms, and clinical examination revealed a statistical difference (p < or = 0.05) in the patients' ranking of and days of TS and GIr between group S (7% HP) and group T (10% CP, control group) at the end of active treatment. There also existed a statistical clinical change in the GI levels for groups R and S compared with the control group T. There was no statistical difference (p > 0.05) in any of the parameters evaluated among the three products at 7 days or 10 months post-treatment. CONCLUSIONS: Participants in group S reported significantly more TS, GIr, and days of each compared with the control. There also existed a significant clinical change in the GI levels for groups R and S compared with the control group T. There was no significant difference among the three products at 7 days post-treatment. After ending treatment, TS/GIr was resolved in 2 to 3 days and did not recur during the 10 months post-treatment. CLINICAL SIGNIFICANCE: The experimental HP bleaching solutions, as described in this study, can be used in NGVB with no long-term side effects as evaluated in this study for up to 10 months post-treatment.