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Background: Beta blockers, mainly propranalol, are usually administered to control heart rate in patients with thyrotoxicosis, especially when congestive heart failure presents. However, when thyrotoxicosis is not controlled, heart rate may be difficult to control even with maximal doses of propranolol. This presentation alerts physicians to the possibility of using ivabradine, a selective inhibitor of the sinoatrial pacemaker, for the control of heart rate. Case presentation: We present a 37-year-old woman with thyrotoxicosis and congestive heart failure whose heart rate was not controlled with a maximal dose of beta blockers during a thyroid storm. The addition of ivabradine, a selective inhibitor of the sinoatrial pacemaker, controlled her heart rate within 48 hours. Conclusion: Ivabradine should be considered in patients with thyrotoxicosis, including those with heart failure, in whom beta blockers are insufficient to control heart rate

OBJECTIVE: We aimed to develop a parent-reported outcome measure for febrile infants ≤60 days of age evaluated in the emergency department. METHODS: We conducted a three-part study: 1) individual, semi-structured interviews with parents of febrile infants ≤60 days of age to generate potential items for the measure; 2) expert review with pediatric emergency medicine physicians and member-checking with parents, who rated each item’s clarity and relevance using 4-point scales; and 3) cognitive interviews with a new sample of parents, who gave feedback and rated the measure’s ease of use on a 4-point scale. The measure was iteratively revised during each part of the development process. RESULTS: In part one, we interviewed 24 parents of 21 infants. Interviews revealed several themes: parents’ experiences with medical care, communication, and decision-making; parents’ emotions, particularly worry, fear, and stress; the infant’s outcomes valued by parents; and the impact of the infant’s illness on the family. From these themes, we identified 22 potential items for inclusion in the measure. In part two, 10 items were revised for clarity based on feedback from physicians and parents, primarily under the domains of parents’ emotions and the infant’s outcomes. In part three, we further revised the measure for clarity and added an item. The final measure included 23 items and was rated as excellent in its ease of use. CONCLUSIONS: The 23-item parent-reported outcome measure includes the experiences and outcomes important to parents. Further studies are needed to evaluate the measure’s psychometric properties.

Purpose Auditory feedback (AF) contributes to speech intelligibility (SI) which is vital in social interactions to examine AF effect on SI of adults with cochlear implant (CI). The relationship between age of CI implantation and AF on SI was examined as well. Method Twenty native Hebrew speaker pre-lingual adults with a hearing loss using CIs from ages 2 to 19 years. Participants were recorded reading excerpts from a book and word lists from MIDBAR test in two situations-with and without using their CIs. Sixteen judges listened to the recordings and rated the speech characteristics of the participants reading the excerpts using an adapted version of Speech Intelligibility Test and Intelligibility Questionnaire for Teachers. Results Significant differences were found between the SI of words of those who received CI before and after 3 years. AF effect was found only for the older implantation group. The questionnaire indicates good reliability among all the speech characteristics. The speech characteristics most affected by the AF are the disruption of consonants followed by the varied degrees of intonation precision and nasality. Conclusions AF affects speech characteristics differently and is vital to SI. The use of the adapted version of Speech Intelligibility Test and Intelligibility Questionnaire for Teachers can be used clinically to assess SI and rehabilitation of young adults with CI. AF accessed at a younger age decreases the dependency on AF in later years.

Background Patients with primary hyperparathyroidism (PHPT) treated surgically occasionally have normalized calcium, but persistently high parathyroid hormone (PTH). We hypothesized that a possible explanation for this phenomenon is an underlying hyperplasia rather than adenoma. Methods Retrospective cohort of patients who underwent parathyroidectomy for PHPT with biopsy of a normal‐appearing parathyroid gland were included. Cellularity level of each biopsy and of the adenoma's rim was determined. Results Forty‐seven patients were included. Of them, 19 (40%) had postoperative normocalcemia but elevated PTH. There was no correlation between cellularity either in the rim or of the normal‐appearing parathyroid gland and postoperative PTH. The postoperative high PTH group had higher preoperative PTH (P = 0.001) and larger adenomas (P = 0.025). Conclusions High PTH levels after successful parathyroidectomy in patients with primary hyperparathyroidism do not appear to result from underlying hyperplasia. A possible alternative explanation is that these patients have a higher preoperative burden of disease., Patients with Primary hyperparathyroidism treated surgically occasionally have normalized calcium, but persistently high PTH. We hypothesized that a possible explanation for this phenomenon is an underlying hyperplasia rather than adenoma.? Contrary to our hypothesis, there was no correlation between the cellularity of the normal‐appearing parathyroid glands and the parathyroid tissue surrounding the adenoma with PTH levels after surgery.

PURPOSE To point out the biomechanical changes of the topographically and tomographically normal partner eye (NPE) in patients with very asymmetrical corneal ectasia. SETTING Department of Ophthalmology, Saarland University Medical Center in Homburg/Saar, Germany. DESIGN Retrospective study. METHODS The topographical and tomographical results of the NPE were assessed using the Pentacam HR and the biomechanical corneal properties using the Ocular Response Analyzer (keratoconus match index [KMI], corneal hysteresis [CH], and corneal resistance factor [CRF]) and the Corvis ST (topographic biomechanical index [TBI] and Corvis biomechanical index) and compared those results with a normal control group (CG). RESULTS The clinical records of 26 patients recruited from the Homburg Keratoconus Center diagnosed with a very asymmetrical corneal ectasia were reviewed. The NPE (8.5 ± 1.5 mm Hg) showed a significantly more pathological CH (P < .001) compared with the CG. The CRF was also significantly more pathological (P = .04) for the NPE (8.3 ± 1.5 mm Hg) compared with the CG. The NPE (0.62 ± 0.32) showed a nonsignificant (P = .08) more pathological KMI compared with the CG. Nineteen (73.1%) of 26 NPE had a KMI less than 0.72 and were considered pathological. Compared with the CG, the TBI of the NPE (0.19 ± 0.25) did not differ significantly overall (P = .57). However, 5 (19.2%) of 26 eyes had a TBI more than 0.29 and were considered pathological. CONCLUSIONS Topographically and tomographically NPEs in very asymmetrical corneal ectasia frequently showed biomechanical changes. This should be considered before planning any type of refractive corneal surgery in such patients.

Background A shared decision-making (SDM) process for lung cancer screening (LCS) includes a discussion between clinicians and patients about benefits and potential harms. Expert-driven taxonomies consider mortality reduction a benefit and consider false-positives, incidental findings, overdiagnosis, overtreatment, radiation exposure, and direct and indirect costs of LCS as potential harms. Objective To explore whether patients conceptualize the attributes of LCS differently from expert-driven taxonomies. Design Cross-sectional study with semistructured interviews and a card-sort activity. Participants Twenty-three Veterans receiving primary care at a Veterans Affairs Medical Center, 55 to 73 y of age with 30 or more pack-years of smoking. Sixty-one percent were non-Hispanic African American or Black, 35% were non-Hispanic White, 4% were Hispanic, and 9% were female. Approach Semistructured interviews with thematic coding. Main Measures The proportion of participants categorizing each attribute as a benefit or harm and emergent themes that informed this categorization. Key Results In addition to categorizing reduced lung cancer deaths as a benefit (22/23), most also categorized the following as benefits: routine annual screening (8/9), significant incidental findings (20/23), follow-up in a nodule clinic (20/23), and invasive procedures (16/23). Four attributes were classified by most participants as a harm: false-positive (13/22), overdiagnosis (13/23), overtreatment (6/9), and radiation exposure (20/22). Themes regarding the evaluation of LCS outcomes were 1) the value of knowledge about body and health, 2) anticipated positive and negative emotions, 3) lack of clarity in terminology, 4) underlying beliefs about cancer, and 5) risk assessment and tolerance for uncertainty. Conclusions Anticipating discordance between patient- and expert-driven taxonomies of the benefits and harms of LCS can inform the development and interpretation of value elicitation and SDM discussions.

Contains fulltext : 245825.pdf (Publisher’s version ) (Closed access) BACKGROUND: Phaeochromocytoma or paraganglioma (collectively known as PPGL) in pregnant women can lead to severe complications and death due to associated catecholamine excess. We aimed to identify factors associated with maternal and fetal outcomes in women with PPGL during pregnancy. METHODS: We did a multicentre, retrospective study of patients with PPGL and pregnancy between Jan 1, 1980, and Dec 31, 2019, in the International Pheochromocytoma and Pregnancy Registry and a systematic review of studies published between Jan 1, 2005, and Dec 27, 2019 reporting on at least five cases. The inclusion criteria were pregnancy after 1980 and PPGL before or during pregnancy or within 12 months post partum. Eligible patients from the retrospective study and systematic review were included in the analysis. Outcomes of interest were maternal or fetal death and maternal severe cardiovascular complications of catecholamine excess. Potential variables associated with these outcomes were evaluated by logistic regression. FINDINGS: The systematic review identified seven studies (reporting on 63 pregnancies in 55 patients) that met the eligibility criteria and were of adequate quality. A further 197 pregnancies in 186 patients were identified in the International Pheochromocytoma and Pregnancy Registry. After excluding 11 pregnancies due to potential overlap, the final cohort included 249 pregnancies in 232 patients with PPGL. The diagnosis of PPGL was made before pregnancy in 37 (15%) pregnancies, during pregnancy in 134 (54%), and after delivery in 78 (31%). Of 144 patients evaluated for genetic predisposition for phaeochromocytoma, 95 (66%) were positive. Unrecognised PPGL during pregnancy (odds ratio 27·0; 95% CI 3·5-3473·1), abdominal or pelvic tumour location (11·3; 1·5-1440·5), and catecholamine excess at least ten-times the upper limit of the normal range (4·7; 1·8-13·8) were associated with adverse outcomes. For patients diagnosed during pregnancy, α-adrenergic blockade therapy was associated with fewer adverse outcomes (3·6; 1·1-13·2 for no α-adrenergic blockade vs α-adrenergic blockade), whereas surgery during pregnancy was not associated with better outcomes (0·9; 0·3-3·9 for no surgery vs surgery). INTERPRETATION: Unrecognised and untreated PPGL was associated with a substantially higher risk of either maternal or fetal complications. Appropriate case detection and counselling for premenopausal women at risk for PPGL could prevent adverse pregnancy-related outcomes. FUNDING: US National Institutes of Health.

Purpose: The current standard-of-care for front-line therapy for acute myeloid leukaemia (AML) results in short-term and long-term toxicity, but still approximately 40% of children relapse. Therefore, there is a major need to accelerate the evaluation of innovative medicines, yet drug development continues to be adult-focused. Furthermore, the large number of competing agents in rare patient populations requires coordinated prioritisation, within the global regulatory framework and cooperative group initiatives. Methods: The fourth multi-stakeholder Paediatric Strategy Forum focused on AML in children and adolescents. Results: CD123 is a high priority target and the paediatric development should be accelerated as a proof-of-concept. Efforts must be coordinated, however, as there are a limited number of studies that can be delivered. Studies of FLT3 inhibitors in agreed paediatric investigation plans present challenges to be completed because they require enrolment of a larger number of patients than actually exist. A consensus was developed by industry and academia of optimised clinical trials. For AML with rare mutations that are more frequent in adolescents than in children, adult trials should enrol adolescents and when scientifically justified, efficacy data could be extrapolated. Methodologies and definitions of minimal residual disease need to be standardised internationally and validated as a new response criterion. Industry supported, academic sponsored platform trials could identify products to be further developed. The Leukaemia and Lymphoma Society PedAL/EUpAL initiative has the potential to be a major advance in the field. Conclusion: These initiatives continue to accelerate drug development for children with AML and ultimately improve clinical outcomes.

Background Chronic low back pain (cLBP) results in significant physical, psycho-social and socioeconomic burden. Identifying efficient and reliable patient reported outcome measures is critical for research and clinical purposes. The NIH’s Patient Reported Outcomes Measurement Information System (PROMIS) instruments have not been compared to validated “legacy” instruments in older adults with cLBP. This study evaluates construct (convergent and discriminant) validity and time to complete (TTC) PROMIS as compared to legacy instruments. Methods We enrolled older Veterans (age 60+) with cLBP with/without leg pain scheduled for lumbar epidural steroid injections. Subjects completed PROMIS computer adaptive test item banks and corresponding legacy instruments in the following domains: pain intensity, interference, and behavior; functional status; depression and anxiety; fatigue; sleep and social functioning. Convergent and discriminant validity between PROMIS and legacy instruments was evaluated using Spearman rank order correlations; Mann-Whitney U tests compared TTC. Results Of the 71 Veterans recruited, the median (IQR) age was 67 (63–71) years old, 94% were men, 76% were White, 17% Black, and 96% were Non-Hispanic. Spearman correlations between PROMIS and legacy instruments showed moderate to very strong convergent validity in all domains (r = 0.4–1.0), except for social functioning and pain behavior (PROMIS Pain Behavior with Fear Avoidance Belief Questionnaire). The total median TTC for all PROMIS items was significantly shorter than legacy items, 8 min 50 s vs 29 min 14 s respectively, p Conclusions Given time efficiency of using PROMIS, along with strong construct validity, PROMIS instruments are a practical choice for measuring multidimensional PROs in older Veterans with cLBP for both research and clinical purposes.

Purpose: To assess the morphological and functional outcome of oral eplerenone for treatment of patients with chronic central serous chorioretinopathy (CSC) in a real life experience. Patients and methods: In this retrospective study, we reviewed the clinical files of 30 patients with chronic CSC. All patients were treated with eplerenone for a period of 6 weeks or 3 months depending on the clinical response. Main outcome measures included: best corrected visual acuity (BCVA), central macular thickness (CMT) and height of the subretinal fluid (SRF). Comparisons between responders and non-responders were performed to identify factors that were predictive of the treatment response. Results: All patients were treated with eplerenone 18 ± 20 weeks after onset of the first symptoms. BCVA (LogMAR) improved from 0.2 ± 0.2 to 0.13 ± 0.18 at 6 weeks ( p = 0.01) and to 0.09 ± 0.15 at 3 months ( p = 0.01). Mean CMT decreased from 409 ± 136 to 323 ± 87 µm at 6 weeks ( p = 0.001) and to 298 ± 98 µm at 3 months ( p = 0.01). Mean height of SRF decreased from 153 ± 126 to 73 ± 79 µm at 6 weeks ( p = 0.001) and to 49 ± 88 µm at 3 months ( p = 0.005). Complete resolution of SRF was achieved in 20 patients after 3 months (67%). Reported stress in the medical history was the only statistical significant predictive factor associated with a positive treatment response. Conclusion: This study showed a statistically significant improvement of the best corrected visual acuity and a significant reduction of macular thickness and subretinal fluid in patients with chronic CSC treated with oral eplerenone, especially in patients under stress.

Objective Among older adult women with early-stage breast cancer who undergo lumpectomy, the benefits of radiotherapy vary according to tumor characteristics and life expectancy. We aimed to develop a risk calculator to predict individualized probability of long-term survival and local recurrence, accounting for these factors. Methods We developed a simulation model to estimate an individual patient's risk of local recurrence and all-cause mortality according to age, comorbidities, functional status, tumor characteristics, and radiotherapy status. We integrated two existing prediction models, the Early Breast Cancer Trialist's Collaborative Group prediction model for breast cancer specific outcomes and ePrognosis for life expectancy. An online risk calculator “Radiotherapy for Older Women (ROW)” was developed through an iterative multi-stage process, that included individual consultation and group meetings with an advisory committee (AC) comprised of patients, advocates, clinicians, and researchers. Results We developed the tool over 40 months and had 15 group meetings. The risk calculator developed as a simulation model with 16 factors (5 tumor-related, 3 demographic, 4 comorbidities, and 4 functional statuses). Across 56,700 simulated scenarios, the benefit of RT in terms of absolute 10-year local recurrence reduction, ranged from 0% to 34%, depending on individual characteristics. Based on feedback from the AC, overall survival and local recurrence were chosen as the output for ROW, with these outcomes displayed numerically (percentages and natural frequencies) and graphically (pictographs). Conclusions This tool “ROW” could facilitate shared decision making regarding receipt of radiotherapy for older women with early breast cancer. Additional studies to examine usability testing are underway.

ObjectiveTo determine whether groups of surrogates for patients with severe acute brain injury (SABI) with poor prognosis can be identified based on their prioritization of goals-of-care (GOC) decisional concerns, an online survey of 1,588 adults recruited via a probability-based panel representative of the US population was conducted.MethodsParticipants acted as a surrogate for a GOC decision for a hypothetical patient with SABI and were randomized to 1 of 2 prognostic scenarios: the patient likely being left with a range of severe functional disability (SD) or remaining in a vegetative state (VS). Participants prioritized a list of 12 decisional concerns via best-worst scaling. Latent class analysis (LCA) was used to discover decisional groups.ResultsThe completion rate was 44.6%; data weighting was conducted to mitigate nonresponse bias. For 792 SD respondents, LCA revealed 4 groups. All groups shared concerns regarding respecting patient wishes and minimizing suffering. The 4 groups were otherwise distinguished by unique concerns that their members highlighted: an older adult remaining severely disabled (34.4%), family consensus (26.4%), doubt regarding prognostic accuracy (20.7%), and cost of long-term care (18.6%). For the 796 VS respondents, LCA revealed 5 groups. Four of the 5 groups had similar concern profiles to the 4 SD groups. The largest (29.0%) expressed the most prognostic doubt. An additional group (15.8%) prioritized religious concerns.ConclusionsAlthough surrogate decision makers for patients with SABI are concerned with respecting patient wishes and minimizing suffering, certain groups highly prioritize other specific decisional factors. These data can help inform future interventions for supporting decision makers.

OBJECTIVES Decisions about the management of febrile infants ≤60 days old may be well suited for shared decision making (SDM). Our objectives were to learn about parents' experiences with receiving and understanding information in the emergency department (ED) and their perspectives on SDM, including for decisions about lumbar puncture (LP). METHODS We conducted semistructured interviews with 23 parents of febrile infants ≤60 days old evaluated in the pediatric ED at an urban, academic medical center. Interviews assessed parents' experiences in the ED and their perspectives on communication and SDM. Two investigators coded the interview transcripts, refined codes, and identified themes using the constant comparative method. RESULTS Parents' unmet need for information negatively impacted parents' understanding, stress, and trust in the physician. Themes for parents' perspectives on SDM included the following: (1) giving parents the opportunity to express their opinions and concerns builds confidence in the decision making process, (2) parents' preferences for participation in decision making vary considerably, and (3) different perceptions about risks influence parents' preferences about having their infant undergo an LP. Although some parents would defer decision making to the physician, they still wanted to be able to express their opinions. Other parents wanted to have the final say in decision making. Parents valued risks and benefits of having their child undergo an LP differently, which influenced their preferences. CONCLUSIONS Physicians need to adequately inform parents to facilitate parents' understanding of information and gain their trust. Shared decision making may be warranted for decisions about whether to perform an LP, although parents' preferences for participating in decision making vary.

Background Despite high risk for cardiovascular disease (CVD) mortality, screening and treatment of hyperlipidemia in patients with rheumatoid arthritis (RA) is suboptimal. We asked primary care physicians (PCPs) and rheumatologists to identify barriers to screening and treatment for hyperlipidemia among patients with RA. Methods We recruited rheumatologists and PCPs nationally to participate in separate moderated structured group teleconference discussions using the nominal group technique. Participants in each group generated lists of barriers to screening and treatment for hyperlipidemia in patients with RA, then each selected the three most important barriers from this list. The resulting barriers were organized into physician-, patient- and system-level barriers, informed by the socioecological framework. Results Twenty-seven rheumatologists participated in a total of 3 groups (group size ranged from 7 to 11) and twenty PCPs participated in a total of 3 groups (group size ranged from 4 to 9). Rheumatologists prioritized physician level barriers (e.g. ‘ownership’ of hyperlipidemia screening and treatment), whereas PCPs prioritized patient-level barriers (e.g. complexity of RA and its treatments). Conclusion Rheumatologists were conflicted about whether treatment of CVD risk among patients with RA should fall within the role of the rheumatologist or the PCP. All participating PCPs agreed that CVD risk reduction was within their role. Factors that influenced PCPs’ decisions for screening and treatment for CVD risk in patients with RA were mainly related to their concern about how treatment for CVD risk could influence RA symptomatology (myalgia from statins) or how inflammation from RA and RA medications influences lipid profiles.

The ε4 allele of apolipoprotein E (APOE) is the dominant genetic risk factor for late-onset Alzheimer’s disease (AD). However, the reason for the association between APOE4 and AD remains unclear. While much of the research has focused on the ability of the apoE4 protein to increase the aggregation and decrease the clearance of Aβ, there is also an abundance of data showing that APOE4 negatively impacts many additional processes in the brain, including bioenergetics. In order to gain a more comprehensive understanding of APOE4′s role in AD pathogenesis, we performed a transcriptomics analysis of APOE4 vs. APOE3 expression in the entorhinal cortex (EC) and primary visual cortex (PVC) of aged APOE mice. This study revealed EC-specific upregulation of genes related to oxidative phosphorylation (OxPhos). Follow-up analysis utilizing the Seahorse platform showed decreased mitochondrial respiration with age in the hippocampus and cortex of APOE4 vs. APOE3 mice, but not in the EC of these mice. Additional studies, as well as the original transcriptomics data, suggest that multiple bioenergetic pathways are differentially regulated by APOE4 expression in the EC of aged APOE mice in order to increase the mitochondrial coupling efficiency in this region. Given the importance of the EC as one of the first regions to be affected by AD pathology in humans, the observation that the EC is susceptible to differential bioenergetic regulation in response to a metabolic stressor such as APOE4 may point to a causative factor in the pathogenesis of AD.

to determine the frequency of major somatic mutations in the JAK2, MPL and CALR genes in the genomeof patients with Ph-negative myeloproliferative neoplasms that occur in individuals who have been exposed to ionizing radiation as a result of the Chornobyl accident.Molecular genetic analysis of genomic DNA samples isolated from blood was performed in90 patients with Ph-negative myeloproliferative neoplasia (MPN) with a history of radiation exposure and 191patients with spontaneous MPN utilizing allele-specific polymerase chain reaction (PCR).The presence of major mutations in the genes JAK2, CALR and MPL was revealed in patients with MPN witha history of radiation exposure with a frequency 58.9 % (53 of 90), 12.2 % (11 of 90), and 0 % respectively, and without exposure with frequency 75.4 % (144 of 191), 3.1 % (6 out of 191) and 1.6 % (3 out of 191) respectively.Mutations JAK2 V617F in patients with spontaneous MPN were observed in each clinical form: polycythemia vera (PV),essential thrombocythemia (ET) and primary myelofibrosis (PMF). CALR mutations were detected exclusively inpatients with PMF and ET, significantly more often in groups with a radiation exposure history (18.9 % and 33.3 %,vs. 4.2 % and 6.5 %) than without one. At the same time, the occurence of MPL mutations was determined only inpatients with spontaneous MPN in 1.6 % of casees. Triple negative mutation status of genes JAK2, MPL and CALR prevailed in the group of patients with MPN with a history of radiation exposure and was 27.8 %, against 16.2 % inpatients without radiation exposure (p = 0.05).Genomic research of patients with Ph-negative MPN revealed features of molecular genetic damage inthose patients who were exposed to IR as a result of the Chornobyl accident and those with spontaneous MPN. Thedata obtained by determining of JAK2, MPL and CALR genes mutational status in the genome of patients with MPN isnecessary to expand the understanding of the mechanism of leukogenesis, especially caused by radiation.Meta: vyznachyty chastotu osnovnykh somatychnykh mutatsiĭ geniv JAK2, MPL ta CALR u genomi khvorykh na Ph-negatyvnimiieloproliferatyvni neoplaziï, shcho vynykaiut' v osib, iaki zaznaly diï ionizuiuchoï radiatsiï vnaslidok avariï na ChAES.Materialy i metody. Provedeno molekuliarno-genetychnyĭ analiz zrazkiv genomnoï DNK, vydilenykh z krovi 90khvorykh na Ph-negatyvni miieloproliferatyvni neoplaziï (MPN) z radiatsiieiu v anamnezi i 191 khvorogo na spontanniMPN metodom alel'-spetsyfichnoï polimeraznoï lantsiugovoï reaktsiï.Rezul'taty. Vyiavleno naiavnist' osnovnykh mutatsiĭ v genakh JAK2, MPL i CALR u khvorykh na MPN z radiatsiĭnym anamnezom z chastotoiu 58,9 % (53 iz 90), 12,2 % (11 z 90), ta 0 % vidpovidno, ta bez takogo – 75,4 % (144 zi 191), 3,1%(6 zi 191) ta 1,6% (3 zi 191) vidpovidno. Mutatsiï JAK2 V617F u khvorykh na spontanni MPN sposterigalysia v kozhniĭnozologichniĭ formi: spravzhniĭ politsytemiï (SP), esentsial'niĭ trombotsytemiï (ET) i pervynnomu miielofibrozi(PMF). Mutatsiï CALR vyiavlialysia vykliuchno u khvorykh na PMF ta ET, dostovirno chastishe u grupakh z radiatsiĭnymanamnezom (18,9 %, ta 33,3 %, proty 4,2 % ta 6,5 %), nizh bez takogo. Vodnochas chastota mutatsiĭ MPL vyznachenatil'ky u khvorykh na spontanni MPN – u 1,6 %. Potriĭno negatyvnyĭ mutatsiĭnyĭ status geniv JAK2, MPL ta CALR prevaliuvav u grupi khvorykh na MPN z radiatsiĭnym anamnezom i skladav 27,8 %, proty 16,2 %, bez takogo (r = 0,05).Vysnovky. Doslidzhennia genomu khvorykh na Ph-negatyvni MPN vyiavyly osoblyvosti molekuliarno-genetychnykhposhkodzhen' u tykh khvorykh, iaki zaznaly vplyvu ionizuiuchoï radiatsiï vnaslidok avariï na ChAES i tykh, khto zakhvorivspontanno. Otrymani dani mutatsiĭnogo statusu geniv JAK2, MPL ta CALR v genomi khvorykh na MPN ie neobkhidnymy dliarozshyrennia uiavlen' shchodo mekhanizmu leĭkogenezu, osoblyvo sprychynenogo radiatsiieiu.

Objective: To understand prevalence and factors associated with opioid dispensation among systemic lupus erythematosus (SLE) patients who persistently frequent the emergency department (ED) to improve quality of care.Methods: In this retrospective observational cohort study, the authors identified SLE patients who persistently frequented the ED, defined as having three or more ED visits over 12 months, for at least 2 out of 4 years between 2013 and 2016. The authors collected patient-level variables including demographics and long-term opioid therapy (LTOT). Each encounter was categorized as: SLE-, infection-, pain-related, or “other.” Additional encounter-level variables such as healthcare resource utilization and disposition were recorded. The authors used mixed effects multivariate logistic regression to analyze factors associated with (1) opioid administration in the ED and (2) opioid prescription upon discharge from the ED. Results: Seventy-seven SLE patients having 1,143 encounters were identified as persistently frequent ED users. Opioids were administered in the ED for 38 percent of all encounters. Medicaid, LTOT, physician as the ED provider versus advanced-practice providers, more imaging tests, and rheumatology specialty consultation were associated with increased odds of opioid administration in the ED. Opioids were prescribed on discharge for 17 percent of encounters discharged from the ED. African American patients, those on Medicaid, and patients utilizing the ED for SLE-related activity/complications compared to “other” reasons were more likely to receive opioid prescription upon discharge from the ED than their respective counterparts.Conclusion: Opioids are commonly dispensed in the ED for SLE patients. This is true even for patients utilizing the ED for SLE-related disease activity/complications.

BACKGROUND: Patient care ownership improves accountability, clinical skills, and quality of patient care among resident physicians, but appears to be gradually eroding. Research is limited by the lack of a reliable, objective measure of ownership. OBJECTIVE: To validate the Patient Care Ownership Scale, an instrument that measures decision ownership among internal medicine residents. DESIGN: Multi-institutional, cross-sectional study using a 66-item, online survey that queried residents on ownership’s key constructs (advocacy, responsibility, accountability, follow-through, knowledge, communication, initiative, continuity of care, autonomy, self-efficacy, and perceived ownership) as well as mood and burnout. PARTICIPANTS: Internal medicine residents in five geographically diverse residency programs completing an inpatient rotation. MAIN MEASURES: We performed exploratory and confirmatory factor analysis in two randomly split groups to evaluate for subscales and inform item reduction. We conducted reliability testing with Cronbach’s α. We performed bivariate analyses to examine construct validity and identify correlates of ownership. KEY RESULTS: Of the 785 eligible residents, 625 completed the survey (80% response rate); we included responses from 563 in the analysis. We identified three factors corresponding to assertiveness, conscientiousness, and confidence or perceived competence. After iterative item reduction, the 13-item ownership scale demonstrated good reliability (Cronbach’s α = 0.82). Convergent validity was supported by a significant association with perceived ownership (eliminated from the final scale) (r = 0.67, p < 0.001). There was a positive association between ownership and training level (p < 0.01) and prior experience in the intensive care unit (p < 0.001). There were significant, inverse relationships between ownership and self-defined burnout (r = − 0.24, p < 0.001), depression (r = − 0.22, p < 0.001), detachment (r = − 0.26, p < 0.001), and frustration (r = − 0.15, p = 0.02), and significant positive associations between ownership and feeling energetic (r = 0.29, p < 0.001), happy (r = 0.33, p < 0.001), and fulfilled (r = 0.34, p < 0.001). CONCLUSIONS: The Patient Care Ownership Scale is valid in diverse residency program settings. Medical educators and investigators can use our scale to assess interventions aimed at fostering ownership. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11606-021-06703-x.

Background The public health crises that emerged in the COVID-19 pandemic significantly impacted the provision of medical care and placed sudden restrictions on ongoing clinical research. Patient-facing clinical research confronted unique challenges in which recruitment and study protocols were halted and then adapted to meet safety procedures during the pandemic. Our study protocol included the use of a Lung Cancer Screening Decision Tool (LCSDecTool) in the context of a primary care visit and was considerably impacted by the pandemic. We describe our experience adapting a multi-site clinical trial of the LCSDecTool within the Department of Veterans Affairs Health Care System. We conducted a randomized controlled trial (RCT) comparing the LCSDecTool to a control intervention. Outcomes included lung cancer screening (LCS) knowledge, shared decision-making, and uptake and adherence to LCS protocol. We identified three strategies that led to the successful adaptation of the study design during the pandemic: (1) multi-level coordination and communication across the organization and study sites, (2) flexibility and adaptability in research during a time of uncertainty and changes in regulation, and (3) leveraging technology to deliver the intervention and conduct study visits, which raised issues concerning equity and internal and external validity. Conclusion Our experience highlights strategies successfully employed to adapt an intervention and behavioral research study protocol during the COVID-19 pandemic. This experience will inform clinical research moving forward both during and subsequent to the constraints placed on research and clinical care during the COVID-19 pandemic.

BACKGROUND: For many older women with early-stage breast cancer, radiotherapy (RT) reduces local recurrence but does not improve overall survival. Risk calculators provide individualized risk estimation; however, there is a paucity of risk calculators specific to the elderly, in whom competing mortality is an important consideration. This study aimed to develop and validate a risk calculator to provide older patients with accurate, personalized risk estimates for local recurrence and mortality. METHODS: We used two existing prediction models, the Early Breast Cancer Trialist Collaboration Group prediction model for breast cancer specific outcomes and ePrognosis for life expectancy, to construct a simulation model to predict individual patient risk. This new model was used to create the “Radiotherapy for Older Women (ROW)” risk calculator. ROW predicts 5-year and 10-year risks of local recurrence and mortality, according to age, comorbidities, functional status, tumor characteristics, and RT receipt. To validate the risk calculator, we collected clinical data from all women older than 65, with newly diagnosed stage I/II breast cancer between 2001 and 2010 at our institution. Discrimination was assessed using c-statistics. Calibration was examined graphically by plotting observed versus predicted probabilities and Hosmer-Lemeshow tests (H-L tests; a p-value RESULTS: Based on our simulation, the 5-year all-cause mortality estimated by ROW ranged from 2% to 79%. ROW also projected the 5-year local recurrence, from 1% to 57% for patients not undergoing RT, and from 0% to 26% for patients undergoing RT. Among the 487 patients we identified in the validation study, the predicted 5-year mortality was 20%, compared to observed 5-year mortality of 16%. The predicted 5-year local recurrence rate was 3.9%, compared to observed 5-year local recurrence rate of 3.1%. The c-statistics were 0.761 for 5-year mortality and 0.775 for 5-year local recurrence. The calibration plot for 5-year local recurrence reflected good agreement between the observed outcomes and predictions; however, the model seemed to over-estimate 5-year all cause-mortality (H-L test; p=0.01). The performance for 10-year outcomes was similar (Table). A beta-version of this risk calculator can be accessed online at https://rtbreastcancer.org. CONCLUSIONS: Based on simulation modeling without cohort data collection, the authors developed an online individualized risk calculator. The outcome estimates projected by the tool were compatible with the observed estimates from real-world data. Such individualized risk provision could facilitate shared decision-making between provider and patient. Future research collecting prospective data to validate our estimates is needed. MortalityLocal recurrencec-statistics95% CIc-statistics95% CI5-year0.761(0.700, 0.822)0.775(0.664, 0.887)10-year0.769(0.722, 0.817)0.721(0.594, 0.849)CI: Confidence interval Citation Format: Shi-Yi Wang, Sarah Mougalian, Brigid Killelea, Jeph Herrin, Liana Fraenkel, Cary Gross, Suzanne Evans. Development and validation of the “radiotherapy for older women” risk calculator [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-07-08.

Objective To review the effect of patient decision aids for adults making treatment decisions regarding the management of chronic musculoskeletal pain. Methods We performed a systematic review of randomized controlled trials of adults using patient decision aids to make treatment decisions for chronic musculoskeletal pain in the outpatient setting. Results Of 477 records screened, 17 met the inclusion criteria. Chronic musculoskeletal pain conditions included osteoarthritis of the hip, knee, or trapeziometacarpal joint and back pain. Thirteen studies evaluated the use of a decision aid for deciding between surgical and nonsurgical management. The remaining four studies evaluated decision aids for nonsurgical treatment options. Outcomes included decision quality, pain, function, and surgery utilization. The effects of decision aids on decision-making outcomes were mixed. Comparing decision aids with usual care, all five studies that examined knowledge scores found improvement in patient knowledge. None of the four studies that evaluated satisfaction with the decision-making process found a difference with use of a decision aid. There was limited and inconsistent data on other decision-related outcomes. Of the eight studies that evaluated surgery utilization, seven found no difference in surgery rates with use of a decision aid. Five studies made comparisons between different types of decision aids, and there was no clearly superior format. Conclusions Decision aids may improve patients’ knowledge about treatment options for chronic musculoskeletal pain but largely did not impact other outcomes. Future efforts should focus on improving the effectiveness of decision aids and incorporating nonpharmacologic and nonsurgical management options.

Objective Treat-to-target implementation in rheumatoid arthritis (RA) requires a shared decision-making (SDM) process. However, ability to pay is a major determinant of patient choice, but how this factor affects SDM is under-explored. Methods Visits at 4 RA clinics during which patients faced a decision to change their treatment were audiotaped between May 2016 and June 2017. Audiotapes were transcribed verbatim and analyzed using qualitative framework analysis. Results A total of 156 visits were analyzed. Most patients with RA, except those with effective insurance coverage, had deliberations disrupted or sidelined by third-party insurance providers having power to authorize the preferred disease-modifying antirheumatic drug choice. This triangulated SDM complicated efficiency in deliberations and timely treatment and was a barrier to shared engagement about health risks and symptom improvement typically found in patient-provider dyads. Conclusion Rheumatology care providers should aim to incorporate treatment costs and ability to pay into their deliberations so that individualized out-of-pocket estimates can be considered during triangulated SDM at the point-of-care.

Despite its effectiveness, bisphosphonate use for osteoporosis is low. We assessed bisphosphonate information on the internet and found the most commonly listed benefits/risks were bone density loss, gastrointestinal issues, and jaw necrosis, that risk quantification was rare, and information quality varied. Findings underscore the importance of clinical communication about bisphosphonates. The US Preventative Services Task Force recommends osteoporosis screening and treatment with bisphosphonates in high-risk populations. However, bisphosphonate use among individuals with osteoporosis remains low. The content and quality of information from outside sources may influence individuals’ bisphosphonate decisions. Therefore, we sought to assess the content and quality of osteoporosis treatment information available to the public by conducting an internet search and coding available bisphosphonate information. Eleven search terms about osteoporosis and bisphosphonates were entered into four search engines. Two raters assessed websites for information about bisphosphonates, whether and how benefits and side effects were described and quantified, contraindications, and dosing instructions. Coders also assessed website interface and slant/balance of information. One thousand four hundred seventy-three websites were identified. Two hundred twenty-seven websites met inclusion criteria and were coded. The most common bisphosphonate benefit described was prevention of bone density loss (77.1% of websites). The most common side effects described were gastrointestinal problems (66.1%) and jaw osteonecrosis (58.6%). Most websites did not quantify bisphosphonate benefits (78.0%) or side effects (82.4%). Complementary/integrative health websites (p

BACKGROUND: Patient care ownership is essential to delivering high-quality medical care but appears to be eroding among trainees. The lack of an objective measure has limited the study of ownership in physicians. OBJECTIVE: To develop an instrument to measure psychological ownership of patient care. DESIGN: Cross-sectional study. PARTICIPANTS: Internal medicine trainees in a large, academic hospital completing an inpatient rotation. MAIN MEASURES: Our scale prototype adapted an existing ownership scale (developed in the non-medical setting) based on themes identified in qualitative studies of patient care ownership. We conducted cognitive interviews to determine face validity of the scale items. Our finalized scale measures ownership’s key constructs: advocacy, responsibility, accountability, follow-through, knowledge, communication, initiative, continuity of care, autonomy, and perceived ownership. We distributed an online, anonymous, 46-question survey to 219 residents; 192 residents completed the survey; and 166 responses were included in the analysis. We calculated Cronbach’s α to determine the scale’s internal consistency. Exploratory factor analysis was used to explore possible subscales. We examined construct validity using bivariate and correlational analysis. KEY RESULTS: The 15-item ownership scale demonstrated good internal consistency (Cronbach’s α = 0.89). We identified three possible subscales corresponding to assertiveness, being the “go-to” person, and diligence. Training level and prior intensive care unit experience significantly predicted ownership (p

To characterize a cohort of elderly men with prolactinomas and their response to treatment. We have identified 28 elderly men diagnosed after the age of 65 with prolactinomas at seven different endocrine clinics in Israel. A retrospective electronic chart review identified a control group of 76 younger men with macroprolactinomas treated in one of the centers. Mean age at diagnosis was 71.3 ± 5.6 (range 65–86) years, and current age 76.6 ± 7.5 years. Initial complaints leading to diagnosis included sexual dysfunction in 17 males (61%), headaches in two patients (7%), and visual abnormalities in two (7%). Three men presented with osteoporosis. Ten patients (36%) were diagnosed incidentally following brain imaging for unrelated reasons. Seventeen patients (61%) had macroadenoma, while eleven (39%) presented with a microadenoma or no visible adenoma. Mean prolactin (PRL) at presentation was 1594 (median 382; range 50–18,329) ng/ml. Testosterone was low in 21 men. Patients were treated with cabergoline (max dose, 1.1 ± 0.5 mg/week), except for one given bromocriptine; none required pituitary surgery or radiotherapy. Treatment normalized PRL in 24 patients, and in three men PRL suppressed to

The ATP/GTP-Binding Protein 1 (AGTPBP1) gene (OMIM *606830) catalyzes deglutamylation of polyglutamylated proteins, and its deficiency manifests by cerebellar ataxia and peripheral neuropathy in mice and lower motor neuron-like disease in sheep. In the mutant mice, cerebellar atrophy due to Purkinje cell degeneration is observed, likely due to increased tubulin polyglutamylation in affected brain areas. We report two unrelated individuals who presented with early onset cerebellar atrophy, developmental arrest with progressive muscle weakness, and feeding and respiratory difficulties, accompanied by severe motor neuronopathy. Whole exome sequencing followed by segregation analysis in the families and cDNA studies revealed deleterious biallelic variants in the AGTPBP1 gene. We conclude that complete loss-of-function of AGTPBP1 in humans, just like in mice and sheep, is associated with cerebellar and motor neuron disease, reminiscent of Pontocerebellar Hypoplasia Type 1 (PCH1).

Summary A previously healthy 24-year-old female underwent an emergent caesarean section without a major bleeding described. During the first post-operative days (POD) she complained of fatigue, headache and a failure to lactate with no specific and conclusive findings on head CT. On the following days, fever rose with a suspicion of an obstetric surgery-related infection, again with no evidence to support the diagnosis. On POD5 a new-onset hyponatremia was documented. The urine analysis suggested SIADH, and following a treatment failure, further investigation was performed and demonstrated both central hypothyroidism and adrenal insufficiency. The patient was immediately treated with hydrocortisone followed by levothyroxine with a rapid resolution of symptoms and hyponatremia. Further laboratory investigation demonstrated anterior hypopituitarism. The main differential diagnosis was Sheehan’s syndrome vs lymphocytic hypophysitis. Brain MRI was performed as soon as it was available and findings consistent with Sheehan’s syndrome confirmed the diagnosis. Lifelong hormonal replacement therapy was initiated. Further complaints on polyuria and polydipsia have led to a water deprivation testing and the diagnosis of partial central insipidus and appropriate treatment with DDAVP. Learning points: Sheehan’s syndrome can occur, though rarely, without an obvious major post-partum hemorrhage. The syndrome may resemble lymphocytic hypophysitis clinically and imaging studies may be crucial in order to differentiate both conditions. Hypopituitarism presentation may be variable and depends on the specific hormone deficit. Euvolemic hyponatremia workup must include thyroid function test and 08:00 AM cortisol levels.

OBJECTIVE Patients have a poor understanding of outcomes related to total knee replacement (TKR) surgery, with most patients underestimating the potential benefits and overestimating the risk of complications. In this study, we sought to compare the impacts of descriptive information alone or in combination with an icon array, experience condition (images), or spinner on participants' preference for TKR. METHODS A total of 648 members of an online arthritis network were randomized to 1 of 4 outcome presentation formats: numeric only, numeric with an icon array, numeric with a set of 50 images, or numeric with a functional spinner. Preferences for TKR were measured before and immediately after viewing the outcome information using an 11-point numeric rating scale. Knowledge was assessed by asking participants to report the frequency of each outcome. RESULTS Participants randomized to the icon array, images, and spinner had stronger preferences for TKR (after controlling for baseline preferences) compared to those viewing the numeric only format (P < 0.05 for all mean differences). Knowledge scores were highest in participants randomized to the icon array; however, knowledge did not mediate the association between format and change in preference for TKR. CONCLUSION Decision support at the point-of-care is being increasingly recognized as a vital component of care. Our findings suggest that adding graphic information to descriptive statistics strengthens preferences for TKR. Although experience formats using images may be too complex to use in clinical practice, icon arrays and spinners may be a viable and easily adaptable decision aid to support communication of probabilistic information.

BACKGROUND: Environmental contamination of norovirus (NoV) is believed to be a significant source for further transmission in hospitals.AIM: To investigate the risk of acquiring NoV in a cleaned room previously occupied by a patient with NoV infection. The risk of having a roommate with recent NoV infection was also assessed.METHODS: In a retrospective cohort, comprising 33,788 room stays at five infectious Disease wards in southern Sweden from 2013 to 2018, the risk of acquiring NoV infection after admission to an exposed or non-exposed room was analysed with uni- and multivariable statistical analysis, controlling for age, colonization pressure and any roommate. RNA sequencing of the NoV strains involved in suspected room transmission was also performed.RESULTS: Five of the 1106 patients exposed to a room with a prior occupant with NoV infection and 49 in the non-exposed group acquired NoV infection. An association between NoV acquisition was found in the univariable analysis (odds ratio (OR) 3.3, P=0.01), but not when adjusting for potential confounders (OR 1.9, P=0.2). Sequencing of the NoV samples showed that only two of the five exposed patients with acquired NoV infection were infected by identical strains to the prior room occupant, inferring a room transmission risk of 0.2% (95% confidence interval 0.05-0.78%). None of the 52 patients who shared room with a roommate with NoV symptoms resolved for ≥48 h acquired NoV infection.CONCLUSIONS: In absolute terms, the risk of room transmission of NoV is low. Discontinuation of isolation ≥48 h after resolution of symptoms seems adequate. (Less)

Guidelines and recommendations developed and/or endorsed by the American College of Rheumatology (ACR) are intended to provide general guidance for commonly encountered clinical scenarios. The recommendations do not dictate the care for an individual patient. The ACR considers adherence to the recommendations described in this guideline to be voluntary, with the ultimate determination regarding their application to be made by the clinicians in light of each patient’s individual circumstances. Guidelines and recommendations are intended to promote beneficial or desirable outcomes but cannot guarantee any specific outcome. Guidelines and recommendations developed and endorsed by the ACR are subject to periodic revision as warranted by the evolution of medical knowledge, technology, and practice. ACR recommendations are not intended to dictate payment or insurance decisions, or drug formularies or other third-party analyses. Third parties that cite ACR guidelines should state that these recommendations are not meant for this purpose. These recommendations cannot adequately convey all uncertainties and nuances of patient care. The American College of Rheumatology is an independent, professional, medical and scientific society that does not guarantee, warrant, or endorse any commercial product or service. OBJECTIVE. To develop updated guidelines for the pharmacologic management of rheumatoid arthritis. METHODS. We developed clinically relevant population, intervention, comparator, and outcomes (PICO) questions. After conducting a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to rate the certainty of evidence. A voting panel comprising clinicians and patients achieved consensus on the direction (for or against) and strength (strong or conditional) of recommendations. RESULTS. The guideline addresses treatment with disease-modifying antirheumatic drugs (DMARDs), including conventional synthetic DMARDs, biologic DMARDs, and targeted synthetic DMARDs, use of glucocorticoids, and use of DMARDs in certain high-risk populations (i.e., those with liver disease, heart failure, lymphoproliferative disorders, previous serious infections, and nontuberculous mycobacterial lung disease). The guideline includes 44 recommendations (7 strong and 37 conditional). CONCLUSION. This clinical practice guideline is intended to serve as a tool to support clinician and patient decision-making. Recommendations are not prescriptive, and individual treatment decisions should be made through a shared decision-making process based on patients’ values, goals, preferences, and comorbidities.

Bisphosphonates are common treatment for osteoporosis. Among patients admitted with hip fracture, atypical femoral fractures (AFF) were more prevalent in those who were treated with Bisphosphonates for five or more years. Five years of Bisphosphonates treatment may signify an increased risk for AFF, though the absolute risk remains very low. Atypical femoral fractures (AFF) are a rare complication of bisphosphonate (BP) treatment. We evaluated the correlation between BP exposure and AFF risk among hip fracture patients. This retrospective nested case–control study included patients over age 50 years, operated for osteoporotic hip fracture between July 2014 and November 2018, who attended our Fracture Liaison Service. We classified fracture radiographs and compared demographic, clinical, biochemical, and drug purchase data between patients with AFF and those with typical osteoporotic hip fracture (controls). To correct for the younger age of patients with AFF, we matched each case (AFF) with three controls according to age ( $$\pm$$ 1 year) and sex and performed a conditional logistic regression model. Of 989 patients, 31 (3%) had AFF. Patients with AFF were younger than those with inter-trochanteric fractures (mean ± SD: 72.3 ± 10.3 vs. 80.2 ± 9.6 years, p

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that is complex in its onset, pattern of spread, and disease progression. The heterogeneity of ALS makes it extremely challenging to determine if a disease modifying therapy is effectively slowing progression. While accurately modeling ALS progression is critical to developing therapeutics, current computational methods fail to capture the complexity of disease progression. We aimed to robustly characterize disease progression patterns in ALS.We obtained data from four clinical cohorts that cover more than 3,500 patients and include both observational and clinical trial studies. To determine whether there were common patterns of disease progression, we developed an approach based on a Mixture of Gaussian Processes (MoGP) to model longitudinal clinical data. Our approach automatically identifies clusters of patients who show similar disease progression patterns, modeling their average trajectory and the spread of the distribution in each cluster. Importantly, the method does not require any prior knowledge of the expected number of clusters.The MoGP approach revealed that ALS progression, as measured using the ALS functional rating scale (ALSFRS-R) or forced vital capacity, is often non-linear with periods of stable disease preceded or followed by rapid decline. Patterns of progression in ALSFRS-R were robust to sparse data. When at least one year of longitudinal data were available, MoGP predictions were significantly more accurate than linear models, which are commonly used in clinical trials. Progression patterns were consistent across different cohorts despite differences in the frequency of data collection and the lengths of follow-up periods. We further showed that clusters identified from one large, publicly available study population could be used to stratify unseen participants in other studies. We also showed that these progression trajectories correspond with survival outcomes.This work highlights the importance of modeling nonlinear disease progression for developing more advanced clinical trial endpoint analysis models. In ALS, sporadic, rapid decline (“functional cliffs”) and sigmoidal patterns in disease progression in untreated patients may obscure detection of therapeutic efficacy if linear models are used. We provide a pre-trained computational model of observed clinical patterns that can be used by others to analyze new ALS patient cohorts. We expect that the MoGP approach can also be applied to additional ALS outcome measures and to other progressive diseases. Our results provide a critical advance in characterizing the complex disease progression patterns of ALS.

Nosocomial outbreaks of coronavirus disease 2019 (COVID-19) can have devastating consequences from both a resource cost and patient healthcare perspective. Relying on reverse transcription-polymerase chain reaction (RT-PCR) for identifying infected individuals may result in missed cases. Screening for antibodies after an outbreak can help to find missed cases and better illuminate routes of transmission.In this study, we present the results of a serological screening of the healthcare workers (HCWs) on a ward for infectious diseases in Sweden with a point-of-care antibody test 8 weeks after an outbreak of COVID-19. In all, 107/123 (87%) of HCWs who were tested with RT-PCR in the outbreak investigation participated in this study on seroprevalence. Participants were also asked to fill out a questionnaire entailing epidemiological data. The cohort was stratified by RT-PCR result and the resulting groups were compared to each other.Six (8%) HCWs who were tested RT-PCR negative during the outbreak investigation had developed specific IgG antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). These HCWs had all worked shifts with colleagues who later were tested RT-PCR positive during the outbreak.Our results indicate that a serological follow-up screening after an outbreak may be used as a complement to virus detection in an outbreak situation. However, immunoglobulin (Ig) G-detection should also be performed at the start of an outbreak, to facilitate interpretation of the results.

Objective We aim to describe an evidence synthesis approach using parallel streams of evidence that informed the development of the 2021 American College of Rheumatology (ACR) guideline for the management of rheumatoid arthritis (RA). Methods We developed the evidence synthesis approach using parallel streams of evidence in multiple rounds of discussion, piloting, feedback, and revisions. A number of working groups involving ACR staff, content experts, and methodologists coordinated to develop and implement the approach. Results We used a major stream of evidence that identified evidence specific to the clinical questions being addressed in the guideline (ie, we were able to match relevant articles to specific questions). We also used additional streams that identified data that applied across multiple questions. We describe in this article the different steps of the major stream, ie, screening and tagging, matching articles to question clusters, matching articles to individual questions, data abstraction and analysis, and Grading of Recommendations Assessment, Development and Evaluation (GRADEing). We then describe how we packaged the parallel streams of evidence into standardized structured tables to facilitate formulating the recommendations. These tables included information for the following factors: desirable effects, undesirable effects, certainty of evidence, valuation of outcomes, cost of interventions, and cost-effectiveness of interventions. The approach allowed us to match eligible articles for 47 of 81 clinical questions. We identified no eligible articles that addressed the remaining 34 questions. Conclusion We were successful in using parallel streams of evidence to inform the development of the 2021 ACR guideline for the management of RA.

OBJECTIVE To assess the incidence, presentation, and management of rheumatoid arthritis (RA) in patients with HIV, including the use of disease-modifying antirheumatic drugs (DMARDs) in this immunosuppressed population. METHODS Patients included in this study were from the Veterans Aging Cohort Study, a longitudinal cohort of veterans with HIV and age-, race-, and site-matched uninfected veterans. We identified all patients who had ≥1 rheumatologist-generated International Classification of Diseases, Ninth Revision (ICD-9) or Tenth Revision (ICD-10) code for RA and whose serum samples were tested for rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies. To further confirm the diagnosis of RA, medical charts were reviewed to verify whether patients met the American College of Rheumatology/European Alliance of Associations for Rheumatology 2010 criteria for RA. We recorded DMARD use and adverse effects during the first contiguous course of treatment (i.e., >6 months of no interruption in DMARD treatment). RESULTS This study included 56,250 patients with HIV and 116,944 uninfected individuals over 2,384,541 person-years. Of the 2,748 individuals in this cohort who were reviewed for a diagnosis of RA based on ICD-9 or ICD-10 codes, incident RA was identified in 215 individuals, including 21 patients with HIV. The incidence rate ratio of RA for patients with HIV compared to uninfected individuals was 0.29 (95% confidence interval 0.19-0.48). Most of the patients diagnosed as having RA (88%) were seropositive for RA-associated autoantibodies (RF and/or anti-CCP). However, high autoantibody titers were less frequent in RA patients with HIV compared to RA patients without HIV. In total, 5% of RA patients with HIV (1 of 21) had both high titers of anti-CCP and high titers of RF, compared to 41% of uninfected individuals (81 of 194). DMARDs were prescribed in 71% of RA patients with HIV (15 of 21) compared to 94% of RA patients without HIV (183 of 194). There was no indication that the DMARD safety profile was worse among RA patients with HIV who were prescribed DMARDs (n = 10 assessed) compared to RA patients without HIV who were prescribed DMARDs (n = 158 assessed). CONCLUSION In this cohort, incident RA was less common in patients with HIV compared to uninfected individuals. Moreover, compared to RA patients without HIV, the seropositivity rate and titers of RA-specific autoantibodies were lower among RA patients with HIV, and those with HIV were prescribed DMARDs less frequently than those without HIV.

NFPAs are clinically silent tumors that develop from different pituitary lineages. Their classification landscape has changed with the recognition that even in the absence of evidence of hormone production based on immunohistochemistry, they can be assigned to specific lineages based on staining for transcription factors. Early evidence suggests that the clinical behavior of transcription factor positive/hormone negative tumors is similar to that of transcription factor positive/hormone positive tumors. Whether these findings, if confirmed, will have significant implications on the clinical management of NFPA remains to be established. There is consensus regarding surgery as the first-line treatment of these often large tumors, which present with clinical signs and symptoms of mass effect. However, the optimal postsurgical management is still a matter of debate. The selection of tumors that need adjuvant treatment, as well as the timing and type of medical and/or radiation therapy, remains to be established.

Myeloproliferative neoplasms (MPNs) driver mutations are usually found in JAK2, MPL, and CALR genes; however, 10%-15% of cases are triple negative (TN). A previous study showed lower rate of JAK2 V617F in primary myelofibrosis patients exposed to low doses of ionizing radiation (IR) from Chernobyl accident. To examine distinct driver mutations, we enrolled 281 Ukrainian IR-exposed and unexposed MPN patients. Genomic DNA was obtained from peripheral blood leukocytes. JAK2 V617F, MPL W515, types 1- and 2-like CALR mutations were identified by Sanger Sequencing and real time polymerase chain reaction. Chromosomal alterations were assessed by oligo-SNP microarray platform. Additional genetic variants were identified by whole exome and targeted sequencing. Statistical significance was evaluated by Fisher's exact test and Wilcoxon's rank sum test (R, version 3.4.2). IR-exposed MPN patients exhibited a different genetic profile vs unexposed: lower rate of JAK2 V617F (58.4% vs 75.4%, P =.0077), higher rate of type 1-like CALR mutation (12.2% vs 3.1%, P =.0056), higher rate of TN cases (27.8% vs 16.2%, P =.0366), higher rate of potentially pathogenic sequence variants (mean numbers: 4.8 vs 3.1, P =.0242). Furthermore, we identified several potential drivers specific to IR-exposed TN MPN patients: ATM p.S1691R with copy-neutral loss of heterozygosity at 11q; EZH2 p.D659G at 7q and SUZ12 p.V71 M at 17q with copy number loss. Thus, IR-exposed MPN patients represent a group with distinct genomic characteristics worthy of further study., United States. Army Research Office. Institute for Collaborative Biotechnologies (Grant W9111NF-09–001)

Key Points Question Is cortical-sparing adrenalectomy associated with increased pheochromocytoma-specific morbidity and mortality for patients with bilateral pheochromocytomas compared with total adrenalectomy? Findings In this cohort study of 625 patients with bilateral pheochromocytomas, most had hereditary syndromes, but 36% initially presented with unilateral pheochromocytoma. Bilateral total adrenalectomy resulted in a high rate of adverse effects from glucocorticoid replacement therapy, whereas cortical-sparing surgery was not associated with a worse outcome. Meaning These findings suggest that cortical-sparing surgery may be the preferred approach for patients at risk for, or diagnosed with, bilateral pheochromocytomas, especially those harboring a germline mutation in one of the known predisposition genes., This cohort study compares outcomes associated with cortical-sparing adrenalectomy vs total adrenalectomy for patients with bilateral pheochromocytomas., Importance Large studies investigating long-term outcomes of patients with bilateral pheochromocytomas treated with either total or cortical-sparing adrenalectomies are needed to inform clinical management. Objective To determine the association of total vs cortical-sparing adrenalectomy with pheochromocytoma-specific mortality, the burden of primary adrenal insufficiency after bilateral adrenalectomy, and the risk of pheochromocytoma recurrence. Design, Setting, and Participants This cohort study used data from a multicenter consortium-based registry for 625 patients treated for bilateral pheochromocytomas between 1950 and 2018. Data were analyzed from September 1, 2018, to June 1, 2019. Exposures Total or cortical-sparing adrenalectomy. Main Outcomes and Measures Primary adrenal insufficiency, recurrent pheochromocytoma, and mortality. Results Of 625 patients (300 [48%] female) with a median (interquartile range [IQR]) age of 30 (22-40) years at diagnosis, 401 (64%) were diagnosed with synchronous bilateral pheochromocytomas and 224 (36%) were diagnosed with metachronous pheochromocytomas (median [IQR] interval to second adrenalectomy, 6 [1-13] years). In 505 of 526 tested patients (96%), germline mutations were detected in the genes RET (282 patients [54%]), VHL (184 patients [35%]), and other genes (39 patients [7%]). Of 849 adrenalectomies performed in 625 patients, 324 (52%) were planned as cortical sparing and were successful in 248 of 324 patients (76.5%). Primary adrenal insufficiency occurred in all patients treated with total adrenalectomy but only in 23.5% of patients treated with attempted cortical-sparing adrenalectomy. A third of patients with adrenal insufficiency developed complications, such as adrenal crisis or iatrogenic Cushing syndrome. Of 377 patients who became steroid dependent, 67 (18%) developed at least 1 adrenal crisis and 50 (13%) developed iatrogenic Cushing syndrome during median (IQR) follow-up of 8 (3-25) years. Two patients developed recurrent pheochromocytoma in the adrenal bed despite total adrenalectomy. In contrast, 33 patients (13%) treated with successful cortical-sparing adrenalectomy developed another pheochromocytoma within the remnant adrenal after a median (IQR) of 8 (4-13) years, all of which were successfully treated with another surgery. Cortical-sparing surgery was not associated with survival. Overall survival was associated with comorbidities unrelated to pheochromocytoma: of 63 patients who died, only 3 (5%) died of metastatic pheochromocytoma. Conclusions and Relevance Patients undergoing cortical-sparing adrenalectomy did not demonstrate decreased survival, despite development of recurrent pheochromocytoma in 13%. Cortical-sparing adrenalectomy should be considered in all patients with hereditary pheochromocytoma.

Background Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes.Methods We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18-85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR) 25-75 mL/min per 1.73 m(2) of body surface area, and a urine albumin-to-creatinine ratio (UACR) of 300-5000 mg/g who had received maximum labelled or tolerated renin-angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0.75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders) were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0.75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for >= 30 days) or end-stage kidney disease (eGFR = 90 days, chronic dialysis for >= 90 days, kidney transplantation, or death from kidney failure) in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials. gov, number NCT01858532.Findings Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325) or placebo group (n=1323). Median follow-up was 2.2 years (IQR 1.4-2.9). 79 (6.0%) of 1325 patients in the atrasentan group and 105 (7.9%) of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR] 0.65 [95% CI 0.49-0.88]; p=0.0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3.5%) of 1325 patients in the atrasentan group and 34 (2.6%) of 1323 patients in the placebo group (HR 1.33 [95% CI 0.85-2.07]; p=0.208). 58 (4.4%) patients in the atrasentan group and 52 (3.9%) in the placebo group died (HR 1.09 [95% CI 0.75-1.59]; p=0.65).Interpretation Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

Hannu Laaksovirta konsortion jäsenenä. The Genomics England Research Consortium, The International ALS/FTD Genomics Consortium (iAFGC), The International FTD Genetics Consortium (IFGC), The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium, The PROSPECT Consortium,17 James B. Rowe,17 Luisa Benussi,18 Giuliano Binetti,18,19 Roberta Ghidoni,18 Edwin Jabbari,20,21 Coralie Viollet,22 Jonathan D. Glass,23 Andrew B. Singleton,24 Vincenzo Silani,25,26 Owen A. Ross,27 Mina Ryten,8,28,29 Ali Torkamani,30 Toshiko Tanaka,31 Luigi Ferrucci,31 Susan M. Resnick,32 We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered. We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.

The goal of this study was to develop and evaluate psychometric properties of the PrEP Sexual Expectancies Scale (PSEXS). The PSEXS represents a range of expectations for how PrEP use will affect one’s sexual experience. The scale was developed to understand perceived reinforcements of PrEP use among men who have sex with men (MSM), including sexual risk-taking. The study builds upon Expectancy Theory to develop a measure of sex-related PrEP expectancies with a representative sample of 1155 MSM participants from Ukraine and 408 MSM participants from the U.S. Expectancy items represented two domains: increased sexual risk-taking and enhancement of sexual experience. Confirmatory analyses showed that a two-factor model provided a good fit to the data. The PSEXS scale had a high internal reliability in both samples (Ukraine α = 0.88, U.S. α = 0.83), and the identified fafctor structure explains a large amount of variance in both samples. Recent studies suggest that expectations of intimacy and better sexual experience can be a significant deciding factor for PrEP uptake. The PSEXS provides researchers with a useful measure for examining MSM’s expectancy beliefs about the impact of PrEP use on their sexual life.

Patients with a severe acute brain injury admitted to the intensive care unit often have a poor neurological prognosis. In these situations, a clinician is responsible for conducting a goals-of-care conversation with the patient’s surrogate decision makers. The diversity in thought and background of surrogate decision makers can present challenges during these conversations. For this reason, our study aimed to identify predictive characteristics of US surrogate decision makers’ favoring life-sustaining treatment (LST) over comfort measures only for patients with severe acute brain injury. We analyzed data from a cross-sectional survey study that had recruited 1588 subjects from an online probability-based US population sample. Seven hundred and ninety-two subjects had randomly received a hypothetical scenario regarding a relative intubated with severe acute brain injury with a prognosis of severe disability but with the potential to regain some consciousness. Seven hundred and ninety-six subjects had been randomized to a similar scenario in which the relative was projected to remain vegetative. For each scenario, we conducted univariate analyses and binary logistic regressions to determine predictors of LST selection among available respondent characteristics. 15.0% of subjects selected LST for the severe disability scenario compared to 11.4% for the vegetative state scenario (p = 0.07), with those selecting LST in both groups expressing less decisional certainty. For the severe disability scenario, independent predictors of LST included having less than a high school education (adjusted OR = 2.87, 95% CI = 1.23–6.76), concern regarding prognostic accuracy (7.64, 3.61–16.15), and concern regarding the cost of care (4.07, 1.80–9.18). For the vegetative scenario, predictors included the youngest age group (30–44 years, 3.33, 1.02–10.86), male gender (3.26, 1.75–6.06), English as a second language (2.94, 1.09–7.89), Evangelical Protestant (3.72, 1.28–10.84) and Catholic (4.01, 1.72–9.36) affiliations, and low income (

Importance Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed for knee osteoarthritis. However, they are associated with uncertain long-term clinical benefit and significant toxic effects. Objective To evaluate whether discontinuing NSAIDs and engaging in a telephone-based cognitive behavioral therapy (CBT) program is noninferior to continuing NSAIDs for patients with knee osteoarthritis. Design, Setting, and Participants The Stopping NSAIDs for Arthritis Pain multicenter randomized withdrawal trial was conducted for 364 patients taking NSAIDs for knee osteoarthritis pain on most days of the week for at least 3 months between September 1, 2013, and September 30, 2018. Analysis was performed on an intent-to-treat basis. Interventions Participants discontinued their current NSAID and took 15 mg per day of meloxicam daily during a 2-week run-in period. Those who remained eligible were randomized in a 1:1 ratio to receive meloxicam or placebo for 4 weeks (blinded phase 1). Participants receiving meloxicam then continued this medication for 10 weeks, while those receiving placebo participated in a 10-week CBT program (unblinded phase 2). Main Outcomes and Measures The primary outcome measure was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score at 4 weeks with the noninferiority margin set at 1. Secondary outcomes included the area under the curve of the pain score after 4 weeks as well as the WOMAC pain score, area under the curve of the pain score, WOMAC disability score, and global impression of change after treatment at 14 weeks. Results A total of 180 participants (161 men; mean [SD] age, 58. 2 [11.8] years) were randomized to receive placebo followed by CBT, and a total of 184 participants (154 men; mean [SD] age, 58.5 [10.0] years) were randomized to receive meloxicam. After adjustment for baseline pain and study site, the estimated mean difference in WOMAC pain score between the placebo and meloxicam groups after 4 weeks was 1.4 (95% CI, 0.8-2.0; noninferiority testP = .92). At week 14, the adjusted mean difference in WOMAC pain score between the placebo (followed by CBT) and meloxicam groups was 0.8 (95% CI, 0.2-1.4; noninferiorityP = .28). There was no statistically significant difference in the global impression of change (mean difference in scores, –0.2; 95% CI, –0.4 to 0.1;P = .15) or lower extremity disability (mean difference in scores, 0.9; 95% CI, –1.4 to 3.2;P = .45) between the 2 groups after 14 weeks. Conclusions and Relevance Among patients with knee osteoarthritis, placebo and CBT (after placebo) are inferior to meloxicam. However, the WOMAC pain score differences between the 2 groups were small, and there were no statistically significant differences in participants’ global impression of change or function after 14 weeks. Trial Registration ClinicalTrials.gov Identifier:NCT01799213

Since the discovery of the novel coronavirus (SARS-Co-V-2) in December 2019, multiple characteristics have been reported, as our understanding of this new disease unfolds. One such association is its tendency to cause thromboembolic events, particularly venous thromboembolism1,2. In a four-week period during the initial spread of COVID-19 at a 300 bed community hospital in western Massachusetts, 23 patients who were PCR positive for SARS-CoV-2 RNA required treatment in either the intensive care unit (ICU) or intermediate/step-down unit (SDU). All patients were treated with standard DVT prophylaxis from the time of admission, except for two patients who were on full anticoagulation for chronic atrial fibrillation. Of the 23 patients, 7 (30%) were diagnosed with acute, clinically significant, pulmonary embolism (PE). Four of the 7 manifested evidence of acute cor pulmonale, one of whom succumbed as a direct consequence of a massive PE. Other markers were reviewed in the 7 patients to identify trends that could allow for early suspicion of PE in COVID-19 patients. Although D-dimer tended to rise during the hospitalization relative to the control group, the results were inconsistent, and there were no other meaningful distinguishing features between the groups at the time of admission.

Background Case reports describe incident sarcoidosis in persons with HIV (PWH). The association between HIV and risk of sarcoidosis, and differences in presentation in PWH, have not been systematically assessed. Methods Subjects were selected from the Veterans Aging Cohort Study (VACS), a longitudinal cohort study including veterans with HIV and matched uninfected veterans. This was a prospective observational analysis in which we evaluated both the incidence (via incidence rate ratio) and presentation and treatment (by comparison of rates of organ involvement and use of medications) of sarcoidosis in PWH compared with HIV-negative controls. We also assessed risk factors (via Cox regression) associated with the development of sarcoidosis including CD4 count and viral load trajectory. Results Of 1614 patients evaluated via chart review, 875 (54%) had prevalent sarcoidosis and 325 (20%) had confirmed incident sarcoidosis. Incident sarcoidosis occurred in 59 PWH and 266 uninfected. The incidence of sarcoidosis was lower in PWH than uninfected (incidence rate ratio [IRR], 0.61; 95% CI, 0.46–0.81) and especially low in patients with unsuppressed viremia (IRR, 0.04; 95% CI, 0.02–0.08) compared with uninfected). At diagnosis of sarcoidosis, the median CD4 count among PWH was 409 cells/mm3; 77% had HIV-1 RNA Conclusions HIV, particularly with persistent viremia, was associated with decreased risk of incident sarcoidosis; severity and treatment were similar between PWH and uninfected.

Background Studies have shown that hypothyroid patients treated with Levothyroxine replacement therapy often experience fluctuations in TSH levels, while others remain well controlled over time. Aim To assess the association between pre-treatment TSH and other biochemical and clinical characteristics and long-term maintenance of normal TSH under Levothyroxine treatment. Methods This is a retrospective nested case-control study. Study population included patients above age 18 insured by Clalit Health Service (CHS) in the South of Israel between the years 2002-2017, diagnosed with hypothyroidism (ICD 9 code 244.9) and who had at least one TSH measurement before initiating levothyroxine therapy, purchased this medication for at least 5 consecutive years with one annual TSH measurement while on treatment. Patients with surgical, post iodine ablation or congenital hypothyroidism were excluded. Patients with a TSH level within the normal range for 5 consecutive years were defined as cases while the others served as controls. Demographic, laboratory, pregnancy status and pharmacy purchase were extracted from the computerized medical records of CHS and compared between the groups. Results Out of 5472 patients included in the study, 644 had a normal TSH for 5 consecutive years (11.8%, cases). Mean age at first levothyroxine purchase was 55.8±13.7 in cases and 54.10±16.2 in controls (p=0.003) and females comprised 84.8% and 81.4% respectively (p=0.035). Mean pretreatment TSH was 5.15±9.6 in cases and 10.02±29 in controls (p Conclusions In our study population of adults with hypothyroidism treated with levothyroxine, only 11.8% were controlled for at least 5 consecutive years. Positive thyroid autoantibodies, pretreatment subclinical hypothyroidism and use of iron supplements lowered probability of long term TSH normalization, while age was associated with the increased rate. Further research should test whether TSH control for 5 consecutive years signals simply “good contol”, or perhaps the possibility of transient forms of hypothyroidism for which treatment discontinuation is recommended.

OBJECTIVE: To provide guidance to rheumatology providers on the management of adult rheumatic disease in the context of the coronavirus disease 2019 (COVID-19) pandemic. METHODS: A task force, including 10 rheumatologists and 4 infectious disease specialists from North America, was convened. Clinical questions were collated, and an evidence report was rapidly generated and disseminated. Questions and drafted statements were reviewed and assessed using a modified Delphi process. This included 2 rounds of asynchronous anonymous voting by e-mail and 3 webinars with the entire panel. Task force members voted on agreement with draft statements using a 1-9-point numerical scoring system, and consensus was determined to be low, moderate, or high based on the dispersion of votes. For approval, median votes were required to meet predefined levels of agreement (median values of 7-9, 4-6, and 1-3 defined as agreement, uncertainty, or disagreement, respectively) with either moderate or high levels of consensus. RESULTS: The task force approved 77 initial guidance statements: 36 with moderate and 41 with high consensus. These were combined, resulting in 25 final guidance statements. CONCLUSION: These guidance statements are provided to promote optimal care during the current pandemic. However, given the low level of available evidence and the rapidly evolving literature, this guidance is presented as a "living document," and future updates are anticipated.

Objective To provide guidance to rheumatology providers on the management of adult rheumatic disease in the context of the coronavirus disease 2019 (COVID-19) pandemic. Methods A task force, including 10 rheumatologists and 4 infectious disease specialists from North America, was convened. Clinical questions were collated, and an evidence report was rapidly generated and disseminated. Questions and drafted statements were reviewed and assessed using a modified Delphi process. This included asynchronous anonymous voting by email and webinars with the entire panel. Task force members voted on agreement with draft statements using a 1-9-point numerical scoring system, and consensus was determined to be low, moderate, or high based on the dispersion of votes. For approval, median votes were required to meet predefined levels of agreement (median values of 7-9, 4-6, and 1-3 defined as agreement, uncertainty, or disagreement, respectively) with either moderate or high levels of consensus. Results Draft guidance statements approved by the task force have been combined to form final guidance. Conclusion These guidance statements are provided to promote optimal care during the current pandemic. However, given the low level of available evidence and the rapidly evolving literature, this guidance is presented as a "living document," and future updates are anticipated.

The R6/2 transgenic mouse model of Huntington's disease (HD) shows a disintegration of circadian rhythms that can be delayed by pharmacological and non-pharmacological means. Since the molecular machinery underlying the circadian clocks is intact, albeit progressively dysfunctional, we wondered if light phase shifts could modulate the deterioration in daily rhythms in R6/2 mice. Mice were subjected to four x 4 hour advances in light onset. R6/2 mice adapted to phase advances, although angles of entrainment increased with age. A second cohort was subjected to a jet-lag paradigm (6 hour delay or advance in light onset, then reversal after 2 weeks). R6/2 mice adapted to the original shift, but could not adjust accurately to the reversal. Interestingly, phase shifts ameliorated the circadian rhythm breakdown seen in R6/2 mice under normal LD conditions. Our previous finding that the circadian period (tau) of 16 week old R6/2 mice shortens to approximately 23 hours may explain how they adapt to phase advances and maintain regular circadian rhythms. We tested this using a 23 hour period light/dark cycle. R6/2 mice entrained to this cycle, but onsets of activity continued to advance, and circadian rhythms still disintegrated. Therefore, the beneficial effects of phase-shifting are not due solely to the light cycle being closer to the tau of the mice. Our data show that R6/2 mice can adapt to changes in the LD schedule, even beyond the age when their circadian rhythms would normally disintegrate. Nevertheless, they show abnormal responses to changes in light cycles. These might be caused by a shortened tau, impaired photic re-synchronization, impaired light detection and/or reduced masking by evening light. If similar abnormalities are present in HD patients, they may suffer exaggerated jet-lag. Since the underlying molecular clock mechanism remains intact, light may be a useful treatment for circadian dysfunction in HD.