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Genetics in Medicine : Official Journal... Feb 2023The U.S. Food and Drug Administration recently approved lonafarnib as the first treatment for Hutchinson-Gilford progeria syndrome (HGPS) and processing-deficient...
The U.S. Food and Drug Administration recently approved lonafarnib as the first treatment for Hutchinson-Gilford progeria syndrome (HGPS) and processing-deficient progeroid laminopathies. This approval was primarily based on a comparison of patients with HGPS treated with lonafarnib in 2 open-label trials with an untreated patient cohort. With up to 11 years of follow-up, it was found that the lonafarnib treated patients with HGPS had a survival benefit of 2.5 years compared with the untreated patients with HGPS. This large treatment effect on the objective endpoint of mortality using a well-matched comparator group mitigated potential sources of bias and together with other evidence, established compelling evidence of a drug effect with benefits that outweighed the risks. This approval is an example of U.S. Food and Drug Administration's regulatory flexibility for a rare disease while ensuring that standards for drug approval are met.
Topics: United States; Humans; Progeria; Lamin Type A; Piperidines; Pyridines
PubMed: 36507973
DOI: 10.1016/j.gim.2022.11.003 -
Journal of the American Heart... Mar 2015Metabolic disease can lead to intrinsic pulmonary hypertension in experimental models. The contributions of metabolic syndrome (MetS) and obesity to pulmonary...
BACKGROUND
Metabolic disease can lead to intrinsic pulmonary hypertension in experimental models. The contributions of metabolic syndrome (MetS) and obesity to pulmonary hypertension and right ventricular dysfunction in humans remain unclear. We investigated the association of MetS and obesity with right ventricular structure and function in patients without cardiovascular disease.
METHODS AND RESULTS
A total of 156 patients with MetS (mean age 44 years, 71% women, mean body mass index 40 kg/m(2)), 45 similarly obese persons without MetS, and 45 nonobese controls underwent echocardiography, including pulsed wave Doppler measurement of pulmonary artery acceleration time (PAAT) and ejection time. Pulmonary artery systolic pressure was estimated from PAAT using validated equations. MetS was associated with lower tricuspid valve e' (right ventricular diastolic function parameter), shorter PAAT, shorter ejection time, and larger pulmonary artery diameter compared with controls (P<0.05 for all). Estimated pulmonary artery systolic pressure based on PAAT was 42±12 mm Hg in participants with MetS compared with 32±9 and 32±10 mm Hg in obese and nonobese controls (P for ANOVA <0.0001). After adjustment for age, sex, hypertension, diabetes, body mass index, and triglycerides, MetS remained associated with a 20-ms-shorter PAAT (β=-20.4, SE=6.5, P=0.002 versus obese). This association persisted after accounting for left ventricular structure and function and after exclusion of participants with obstructive sleep apnea.
CONCLUSIONS
MetS is associated with abnormal right ventricular and pulmonary artery hemodynamics, as shown by shorter PAAT and subclinical right ventricular diastolic dysfunction. Estimated pulmonary artery systolic pressures are higher in MetS and preclinical metabolic heart disease and raise the possibility that pulmonary hypertension contributes to the pathophysiology of metabolic heart disease.
Topics: Adult; Arterial Pressure; Case-Control Studies; Diastole; Echocardiography, Doppler, Pulsed; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Metabolic Syndrome; Middle Aged; Obesity; Predictive Value of Tests; Pulmonary Artery; Risk Factors; Ventricular Dysfunction, Right; Ventricular Function, Left; Ventricular Function, Right
PubMed: 25758604
DOI: 10.1161/JAHA.114.001597 -
American Journal of Physical Medicine &... Mar 2021A 28-yr-old African American man with a history of synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome, tobacco use, and sickle cell trait was referred to a...
A 28-yr-old African American man with a history of synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome, tobacco use, and sickle cell trait was referred to a physiatrist at a multidisciplinary spine center with a 1-yr history of nontraumatic thoracic back pain that had significantly worsened over the previous 4 wks. In the context of recurrent infections requiring hospital admissions and the patient's immunosuppressed status, magnetic resonance imaging of his thoracic spine was obtained, showing an acute or subacute anterior compression deformity of the T7 vertebral body. He was subsequently provided with a hyperextension brace, physical therapy referral, and a trial of intranasal calcitonin. The patient reported significant improvement in pain at his 3-mo follow-up appointment and continued to show pain and functional improvement in physical therapy sessions up to 6 mos later.
Topics: Acquired Hyperostosis Syndrome; Adult; Bone Density Conservation Agents; Braces; Calcitonin; Combined Modality Therapy; Fractures, Compression; Humans; Immunocompromised Host; Male; Pain Measurement; Physical Therapy Modalities; Thoracic Vertebrae
PubMed: 32618750
DOI: 10.1097/PHM.0000000000001513 -
Arthroscopy : the Journal of... May 2018The purpose of this study was to determine whether patients diagnosed with femoroacetabular impingement (FAI) syndrome have prolonged braking times compared with age-...
PURPOSE
The purpose of this study was to determine whether patients diagnosed with femoroacetabular impingement (FAI) syndrome have prolonged braking times compared with age- and gender-matched controls and how long after surgery braking times return to preoperative baseline.
METHODS
Fifty-nine patients undergoing arthroscopic hip surgery for FAI and 59 age- and gender-matched controls without FAI were enrolled in a prospective comparative study between September 2015 and October 2016. Total brake reaction time (BRT) and brake pedal depression (BPD) were measured for study patients preoperatively, and at 2, 4, and 6 weeks postoperatively. BRT and BPD were compared between study and control patients and between preoperative and postoperative time periods, using mixed effects models.
RESULTS
Patients with FAI had significantly prolonged BRT (but not BPD) prior to surgery compared with controls (568 vs 520 msec, P = .002). For study patients undergoing left hip surgery, there was no difference in BRT or BPD between preoperative measurements and any postoperative time point, including the first postoperative appointment at 2 weeks (563 vs 566 msec, P = .89). Patients undergoing right hip surgery had significantly prolonged BRT at 2 weeks postoperatively compared with their preoperative baseline (688 vs 573 msec, P < .001). By 4 weeks postoperatively, study patients undergoing right hip surgery had returned to their preoperative baseline (573 vs 594 msec, P = .28). No significant effect was seen based on visual analog scale pain score, opiate usage, or patient-reported outcome scores.
CONCLUSIONS
Patients undergoing arthroscopic surgery of the right hip show significantly prolonged BRT until 4 weeks after surgery, while patients undergoing surgery of the left hip show no postoperative impairment in either BRT or BPD. The clinical relevance of this measured difference (an increase in 10 feet of stopping distance at 60 miles per hour) remains an open question.
LEVEL OF EVIDENCE
Level II, diagnostic, prospective.
Topics: Adult; Arthroscopy; Automobile Driving; Case-Control Studies; Female; Femoracetabular Impingement; Hip Joint; Humans; Male; Middle Aged; Patient Reported Outcome Measures; Postoperative Period; Prospective Studies; Reaction Time; Treatment Outcome
PubMed: 29625800
DOI: 10.1016/j.arthro.2018.02.030 -
Disability and Health Journal Jun 2024More than seven million people with intellectual and/or developmental disabilities (ID/DD) live in the US and may face an elevated risk for COVID-19.
BACKGROUND
More than seven million people with intellectual and/or developmental disabilities (ID/DD) live in the US and may face an elevated risk for COVID-19.
OBJECTIVE
To identify correlates of COVID-19 and related hospitalizations among people with ID/DD in group homes in Massachusetts.
METHODS
We collected data during March 1, 2020-June 30, 2020 (wave 1) and July 1, 2020-March 31, 2021 (wave 2) from the Massachusetts Department of Public Health and six organizations administering 206 group homes for 1035 residents with ID/DD. The main outcomes were COVID-19 infections and related hospitalizations. We fit multilevel Cox proportional hazards models to estimate associations with observed predictors and assess contextual home- and organizational-level effects.
RESULTS
Compared with Massachusetts residents, group home residents had a higher age-adjusted rate of COVID-19 in wave 1 (incidence rate ratio [IRR], 12.06; 95 % confidence interval [CI], 10.51-13.84) and wave 2 (IRR, 2.47; 95 % CI, 2.12-2.88) and a higher age-adjusted rate of COVID-19 hospitalizations in wave 1 (IRR, 17.64; 95 % CI, 12.59-24.70) and wave 2 (IRR, 4.95; 95 % CI, 3.23-7.60). COVID-19 infections and hospitalizations were more likely among residents aged 65+ and in group homes with 6+ resident beds and recent infection among staff and residents.
CONCLUSIONS
Aggressive efforts to decrease resident density, staff-to-resident ratios, and staff infections through efforts such as vaccination, in addition to ongoing access to personal protective equipment and COVID-19 testing, may reduce COVID-19 and related hospitalizations in people with ID/DD living in group homes.
PubMed: 38879412
DOI: 10.1016/j.dhjo.2024.101645 -
Expert Opinion on Pharmacotherapy 2015Inhaled corticosteroids (ICS) (in fixed combinations with long-acting β2-agonists [LABAs]) are frequently prescribed for patients with chronic obstructive pulmonary... (Review)
Review
INTRODUCTION
Inhaled corticosteroids (ICS) (in fixed combinations with long-acting β2-agonists [LABAs]) are frequently prescribed for patients with chronic obstructive pulmonary disease (COPD), outside their labeled indications and recommended treatment strategies and guidelines, despite having the potential to cause significant side effects.
AREAS COVERED
Although the existence of asthma in patients with asthma-COPD overlap syndrome (ACOS) clearly supports the use of anti-inflammatory treatment (typically an ICS/LABA combination, as ICS monotherapy is usually not indicated for COPD), the current level of ICS/LABA use is not consistent with the prevalence of ACOS in the COPD population. Data have recently become available showing the comparative efficacy of fixed bronchodilator combinations (long-acting muscarinic antagonist [LAMA]/LABA with ICS/LABA combinations). Additionally, new information has emerged on ICS withdrawal without increased risk of exacerbations, under cover of effective bronchodilation.
EXPERT OPINION
For patients with COPD who do not have ACOS, a LAMA/LABA combination may be an appropriate starting therapy, apart from those with mild disease who can be managed with a single long-acting bronchodilator. Patients who remain symptomatic or present with exacerbations despite effectively delivered LAMA/LABA treatment may require additional drug therapy, such as ICS or phosphodiesterase-4 inhibitors. When prescribing an ICS/LABA, the risk:benefit ratio should be considered in individual patients.
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Anti-Inflammatory Agents; Asthma; Bronchodilator Agents; Disease Management; Drug Therapy, Combination; Glucocorticoids; Humans; Muscarinic Antagonists; Phosphodiesterase 4 Inhibitors; Pulmonary Disease, Chronic Obstructive; Syndrome
PubMed: 26194213
DOI: 10.1517/14656566.2015.1067682 -
The American Journal of Cardiology Sep 2014Metabolic syndrome (MS) is commonly associated with left ventricular (LV) diastolic dysfunction and LV hypertrophy. We sought to examine whether preclinical LV diastolic... (Observational Study)
Observational Study
Metabolic syndrome (MS) is commonly associated with left ventricular (LV) diastolic dysfunction and LV hypertrophy. We sought to examine whether preclinical LV diastolic dysfunction can occur independent of LV hypertrophy in MS. We recruited 90 consecutive participants with MS and without cardiovascular disease (mean age 46 years, 78% women) and 26 controls (no risk factors for MS; mean age 43 years, 65% women). Participants underwent echocardiography with tissue Doppler imaging. In age- and gender-adjusted analyses, MS was associated with higher left atrial (LA) diameter, higher LV mass, lower E/A ratio, and lower mean e' (p <0.001 for all). These associations remained significant after further adjusting for blood pressure, antihypertensive medication use, and body mass index. After adjusting for LV mass, MS remained independently associated with higher LA diameter, lower E/A ratio, and lower mean e' (p ≤0.01 for all). Specifically, subjects with MS had a 1.8 cm/s lower mean e' compared with controls (p = 0.01). Notably, differences in mean e' between those with and without MS were more pronounced at younger ages (p for interaction = 0.003). In conclusion, MS was associated with preclinical LV diastolic dysfunction independent of LV mass, as reflected by higher LA diameter, lower E/A ratio, and lower mean e'. This suggests that MS can lead to the development of diastolic dysfunction through mechanisms independent of hypertrophy. Differences in diastolic function were more pronounced at younger ages, highlighting the potential importance of early risk factor modification and preventive strategies in MS.
Topics: Adult; Cross-Sectional Studies; Diastole; Echocardiography, Doppler, Pulsed; Female; Follow-Up Studies; Heart Ventricles; Humans; Incidence; Male; Massachusetts; Metabolic Syndrome; Middle Aged; Prevalence; Ventricular Dysfunction, Left
PubMed: 25084691
DOI: 10.1016/j.amjcard.2014.06.013 -
BioMed Research International 2021Mutations in insulin receptor genes can cause severe insulin resistance syndrome. Compared with Rabson-Mendenhall Syndrome and Donohue's Syndrome, type A insulin...
BACKGROUND
Mutations in insulin receptor genes can cause severe insulin resistance syndrome. Compared with Rabson-Mendenhall Syndrome and Donohue's Syndrome, type A insulin resistance syndrome is generally not serious. The main manifestations in woman with type A insulin resistance syndrome are hyperinsulinemia, insulin resistance, acanthosis nigricans, hyperandrogenism, and polycystic ovary. . A 13-year-old girl (Han nationality) visited the hospital due to hairiness and acanthosis nigricans. Further examination revealed severe hyperinsulinemia, insulin resistance, elevated blood glucose, hyperandrogenism, and polycystic ovary. Analysis of the insulin receptor gene by sequencing showed the presence of a nucleotide change in intron 7 (c. 1610+1G > A). The mutation was a splicing mutation, which can obviously affect the mRNA splicing of the insulin receptor and cause its function loss. The patient was finally diagnosed with type A insulin resistance syndrome. After 2 months of metformin treatment, the patient had spontaneous menstrual cramps and significantly improved acanthosis nigricans and sex hormones.
CONCLUSION
We report for the first time a new splicing mutation on the insulin receptor gene at the 7th intron (c.1610+1G > A), which leads to type A insulin resistance syndrome. In clinically suspected patients with polycystic ovary syndrome, if there are extremely high blood levels of insulin in the blood, genetic testing should be performed to detect insulin receptor gene mutation of type A insulin resistance syndrome.
Topics: Adolescent; Antigens, CD; Female; Humans; Introns; Metabolic Syndrome; Metformin; Point Mutation; RNA Splicing; Receptor, Insulin; Severity of Illness Index
PubMed: 33728347
DOI: 10.1155/2021/8878149 -
Pediatric Cardiology Jan 2016Interstage mortality remains significant for patients undergoing staged palliation for hypoplastic left heart syndrome and other related single right ventricle...
Interstage mortality remains significant for patients undergoing staged palliation for hypoplastic left heart syndrome and other related single right ventricle malformations (HLV). The purpose of this study was to identify factors related to demographics, socioeconomic position, and perioperative course associated with post-Norwood hospital discharge, pre-stage 2, interstage mortality (ISM). Medical record review was conducted for patients with HLV, born from 1/2000 to 7/2009 and discharged alive following the Norwood procedure. Sociodemographic and perioperative factors were reviewed. Patients were determined to have ISM if they died between Norwood procedure hospital discharge and stage 2 palliation. Univariable and multivariable logistic regressions were performed to identify risk factors associated with ISM. A total of 273 patients were included in the analysis; ISM occurred in 32 patients (12%). Multivariable analysis demonstrated that independent risk factors for interstage mortality included teen mothers [adjusted odds ratio (AOR) 6.6, 95% confidence interval (CI) 1.9-22.5], single adult caregivers (AOR 4.1, 95% CI 1.2-14.4), postoperative dysrhythmia (AOR 2.7, 95% CI 1.1-6.4), and longer ICU stay (AOR 2.7, 95% CI 1.2-6.1). Anatomic and surgical course variables were not associated with ISM in multivariable analysis. Patients with HLV are at increased risk of ISM if born to a teen mother, if they lived in a home with only one adult caregiver, suffered a postoperative dysrhythmia, or experienced a prolonged ICU stay. These risk factors are identifiable, and thus these infants may be targeted for interventions to reduce ISM.
Topics: Female; Humans; Hypoplastic Left Heart Syndrome; Infant; Infant, Newborn; Kaplan-Meier Estimate; Logistic Models; Male; Norwood Procedures; Risk Factors; Socioeconomic Factors; Treatment Outcome
PubMed: 26260093
DOI: 10.1007/s00246-015-1241-2 -
Journal of Pediatric Endocrinology &... Jul 2015Donohue syndrome (DS) is a very rare autosomal recessive disease affecting less than one in a million live births. It represents the most severe form of insulin...
Donohue syndrome (DS) is a very rare autosomal recessive disease affecting less than one in a million live births. It represents the most severe form of insulin resistance due to mutations involving the insulin receptor gene. DS is characterized by pre- and postnatal growth retardation with failure to thrive, lipoatrophy, muscle wasting, acanthosis nigricans, hypertrichosis, and dysmorphic features. Glucose homeostasis is affected with hyperinsulinemia, fasting hypoglycemia, and postprandial hyperglycemia. We report a Jordanian patient with genetically proven DS who had the classical physical features, progressive hypertrophic cardiomyopathy, cholestasis, and hyperglycemia, followed by hypoglycemia. In addition, the patient developed polyuria and uremia despite normal creatinine levels, hypernatremia, and hypertension. To our knowledge, these metabolic derangements were not previously reported in patients with DS.
Topics: Cardiomyopathy, Hypertrophic; Donohue Syndrome; Female; Humans; Hyperglycemia; Hyperinsulinism; Hypoglycemia; Infant, Newborn; Insulin Resistance; Polyuria; Prognosis; Uremia
PubMed: 25741786
DOI: 10.1515/jpem-2014-0405