scholarly journals Deep phenotyping classical galactosemia: clinical outcomes and biochemical markers

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Mendy M Welsink-Karssies ◽  
Sacha Ferdinandusse ◽  
Gert J Geurtsen ◽  
Carla E M Hollak ◽  
Hidde H Huidekoper ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Newborn Screening ◽  
Clinical Outcomes ◽  
Movement Disorders ◽  
Brain Mri ◽  
Primary Ovarian Insufficiency ◽  
Ovarian Insufficiency ◽  
Classical Galactosemia ◽  
Intellectual Outcome

Abstract Early diagnosis and dietary treatment do not prevent long-term complications, which mostly affect the central nervous system in classical galactosemia patients. The clinical outcome of patients is highly variable, and there is an urgent need for prognostic biomarkers. The aim of this study was first to increase knowledge on the natural history of classical galactosemia by studying a cohort of patients with varying geno- and phenotypes and second to study the association between clinical outcomes and two possible prognostic biomarkers. In addition, the association between abnormalities on brain MRI and clinical outcomes was investigated. Classical galactosemia patients visiting the galactosemia expertise outpatient clinic of the Amsterdam University Medical Centre were evaluated according to the International Classical Galactosemia guideline with the addition of an examination by a neurologist, serum immunoglobulin G N-glycan profiling and a brain MRI. The biomarkers of interest were galactose-1-phosphate levels and N-glycan profiles, and the clinical outcomes studied were intellectual outcome and the presence or absence of movement disorders and/or primary ovarian insufficiency. Data of 56 classical galactosemia patients are reported. The intellectual outcome ranged from 45 to 103 (mean 77 ± 14) and was <85 in 62%. Movement disorders were found in 17 (47%) of the 36 tested patients. In females aged 12 years and older, primary ovarian insufficiency was diagnosed in 12 (71%) of the 17 patients. Significant differences in N-glycan peaks were found between controls and patients. However, no significant differences in either N-glycans or galactose-1-phosphate levels were found between patients with a poor (intellectual outcome < 85) and normal intellectual outcome (intellectual outcome ≥ 85), and with or without movement disorders or primary ovarian insufficiency. The variant patients detected by newborn screening, with previously unknown geno- and phenotypes and currently no long-term complications, demonstrated significantly lower galactose-1-phospate levels than classical patients (P < 0.0005). Qualitative analysis of the MRI’s demonstrated brain abnormalities in 18 of the 21 patients, more severely in patients with a lower intellectual outcome and/or with movement disorders. This study demonstrates a large variability in clinical outcome, which varies from a below average intelligence, movement disorders and in females primary ovarian insufficiency to a normal clinical outcome. In our cohort of classical galactosemia patients, galactose-1-phosphate levels and N-glycan variations were not associated with clinical outcomes, but galactose-1-phosphate levels did differentiate between classical and variant patients detected by newborn screening. The correlation between brain abnormalities and clinical outcome should be further investigated by quantitative analysis of the MR images. The variability in clinical outcome necessitates individual and standardized evaluation of all classical galactosemia patients.

Clinical Outcomes, Structure, and Function Improve With Both Heavy and Moderate Loads in the Treatment of Patellar Tendinopathy: A Randomized Clinical Trial

2021 ◽  
Vol 49 (4) ◽  
pp. 982-993
Author(s):  
Anne-Sofie Agergaard ◽  
Rene B. Svensson ◽  
Nikolaj M. Malmgaard-Clausen ◽  
Christian Couppé ◽  
Mikkel H. Hjortshoej ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Outcome ◽  
Randomized Clinical Trial ◽  
Clinical Outcomes ◽  
Rating Scale ◽  
Power Doppler ◽  
Patellar Tendinopathy ◽  
Short Term ◽  
Level Of Evidence

Background: Loading interventions have become a predominant treatment strategy for tendinopathy, and positive clinical outcomes and tendon tissue responses may depend on the exercise dose and load magnitude. Purpose/Hypothesis: The purpose was to investigate if the load magnitude influenced the effect of a 12-week loading intervention for patellar tendinopathy in the short term (12 weeks) and long term (52 weeks). We hypothesized that a greater load magnitude of 90% of 1 repetition maximum (RM) would yield a more positive clinical outcome, tendon structure, and tendon function compared with a lower load magnitude of 55% of 1 RM when the total exercise volume was kept equal in both groups. Study Design: Randomized clinical trial; Level of evidence, 1. Methods: A total of 44 adult participants with chronic patellar tendinopathy were included and randomized to undergo moderate slow resistance (MSR group; 55% of 1 RM) or heavy slow resistance (HSR group; 90% of 1 RM). Function and symptoms (Victorian Institute of Sport Assessment–Patella questionnaire [VISA-P]), tendon pain during activity (numeric rating scale [NRS]), and ultrasound findings (tendon vascularization and swelling) were assessed before the intervention, at 6 and 12 weeks during the intervention, and at 52 weeks from baseline. Tendon function (functional tests) and tendon structure (ultrasound and magnetic resonance imaging) were investigated before and after the intervention period. Results: The HSR and MSR interventions both yielded significant clinical improvements in the VISA-P score (mean ± SEM) (HSR: 0 weeks, 58.8 ± 4.3; 12 weeks, 70.5 ± 4.4; 52 weeks, 79.7 ± 4.6) (MSR: 0 weeks, 59.9 ± 2.5; 12 weeks, 72.5 ± 2.9; 52 weeks, 82.6 ± 2.5), NRS score for running, NRS score for squats, NRS score for preferred sport, single-leg decline squat, and patient satisfaction after 12 weeks, and these were maintained after 52 weeks. HSR loading was not superior to MSR loading for any of the measured clinical outcomes. Similarly, there were no differences in functional (strength and jumping ability) or structural (tendon thickness, power Doppler area, and cross-sectional area) improvements between the groups undergoing HSR and MSR loading. Conclusion: There was no superior effect of exercising with a high load magnitude (HSR) compared with a moderate load magnitude (MSR) for the clinical outcome, tendon structure, or tendon function in the treatment of patellar tendinopathy in the short term. Both HSR and MSR showed equally good, continued improvements in outcomes in the long term but did not reach normal values for healthy tendons. Registration: NCT03096067 (ClinicalTrials.gov identifier)

scholarly journals Rationale and design of a cohort study on primary ovarian insufficiency in female survivors of Hodgkin’s lymphoma: influence on long-term adverse effects (SOPHIA)

BMJ Open ◽  
2018 ◽  
Vol 8 (9) ◽  
pp. e018120
Author(s):  
Inge M Krul ◽  
Annemieke W J Opstal-van Winden ◽  
Josée M Zijlstra ◽  
Yolande Appelman ◽  
Sanne B Schagen ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Hodgkin’S Lymphoma ◽  
Primary Ovarian Insufficiency ◽  
Hodgkin's Lymphoma ◽  
Reverse Causality ◽  
Mineral Density ◽  
Cvd Risk ◽  
Ovarian Insufficiency

IntroductionHodgkin’s lymphoma (HL) has become the prototype of a curable disease. However, many young survivors suffer from late adverse effects of treatment. Both chemotherapy (CT) and radiotherapy (RT) may induce primary ovarian insufficiency (POI), which has been associated with reduced bone mineral density (BMD), neurocognitive dysfunction and possibly cardiovascular disease (CVD). While the general assumption is that POI increases CVD risk, other hypotheses postulate reverse causality, suggesting that cardiovascular risk factors determine menopausal age or that biological ageing underlies both POI and CVD risk. None of these hypotheses are supported by convincing evidence. Furthermore, most studies on POI-associated conditions have been conducted in women with early natural or surgery-induced menopause with short follow-up times. In this study, we will examine the long-term effects of CT-induced and/or RT-induced POI on BMD, cardiovascular status, neurocognitive function and quality of life in female HL survivors.Methods and analysisThis study will be performed within an existing Dutch cohort of HL survivors. Eligible women were treated for HL at ages 15–39 years in three large hospitals since 1965 and survived for ≥8 years after their diagnosis. Women visiting a survivorship care outpatient clinic will be invited for a neurocognitive, cardiovascular and BMD assessment, and asked to complete several questionnaires and to provide a blood sample. Using multivariable regression analyses, we will compare the outcomes of HL survivors who developed POI with those who did not. Cardiovascular status will also be compared with women with natural POI.Ethics and disseminationThis study has been approved by the Institutional Review Board of the Netherlands Cancer Institute and has been registered at ‘Toetsingonline’ from the Dutch Central Committee on Research involving Human Subjects (file no. NL44714.031.13). Results will be disseminated through peer-reviewed publications and will be incorporated in follow-up guidelines for HL survivors.

scholarly journals Insights into the Pathophysiology of Infertility in Females with Classical Galactosaemia

2019 ◽  
Vol 20 (20) ◽  
pp. 5236 ◽  
Author(s):  
Zaza Abidin ◽  
Eileen P. Treacy
Keyword(s):  
Inborn Error ◽  
Primary Ovarian Insufficiency ◽  
Future Prospects ◽  
Ovarian Dysfunction ◽  
Galactose Metabolism ◽  
Ovarian Insufficiency ◽  
New Horizons ◽  
Classical Galactosaemia ◽  
Rare Inborn Error

Classical galactosaemia (CG) (OMIM 230400) is a rare inborn error of galactose metabolism caused by the deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT, EC 2.7.7.12). Primary ovarian insufficiency (POI) is the most common long-term complication experienced by females with CG, presenting with hypergonadotrophic hypoestrogenic infertility affecting at least 80% of females despite new-born screening and lifelong galactose dietary restriction. In this review, we describe the hypothesized pathophysiology of POI from CG, implications of timing of the ovarian dysfunction, and the new horizons and future prospects for treatments and fertility preservation.

Impact of perioperative complications on clinical outcome scores in lumbar fusion surgery

2013 ◽  
Vol 18 (3) ◽  
pp. 265-268 ◽  
Author(s):  
Manish P. Lambat ◽  
Steven D. Glassman ◽  
Leah Y. Carreon
Keyword(s):  
Clinical Outcome ◽  
Clinical Outcomes ◽  
Lumbar Fusion ◽  
Perioperative Complications ◽  
Major Complication ◽  
Postoperative Outcome ◽  
Minor Complication ◽  
Sf 36 ◽  
Outcome Scores

Object Although lumbar fusion is effective in well-selected patients, it is not without complications associated with short-term morbidity. There is a paucity of literature on the effect of these complications on long-term clinical outcomes. The purpose of this study was to determine whether perioperative complications—that is, those occurring within 30 days after surgery—alter the long-term clinical outcomes after lumbar fusion. Methods The authors retrospectively reviewed surgical and clinical databases for the period from 2001 to 2008 to identify patients who had undergone instrumented lumbar spinal fusion and had complete preoperative and 2-year postoperative outcome measures data. Outcome measures included the 36-Item Short-Form Health Survey (SF-36) Physical Component Summary, SF-36 Mental Component Summary, Oswestry Disability Index (ODI), and Numeric Rating Scales (0–10) for back and leg pain. Three patient groups were created for comparison—one with major complications, one with only minor complications, and another with no complications—using propensity matching techniques based on demographics, baseline clinical outcome scores, and surgical characteristics. Preoperative and 2-year postoperative outcome scores in the groups were compared. One-way ANOVA was used to compare continuous variables, and the Fisher exact test was used to compare categorical variables between the groups. Significance was set at p < 0.001. Results In the database with 1144 patients, 81 had a major complication. Of these 81 patients, 78 were propensity matched to a similar group of patients with minor complications and another group with no complications. Comparison of the 3 groups revealed that 2-year postoperative outcomes were not statistically different for any of the measures. Overall ODI at 2 years was better in patients having no complications (39.6) or only minor complications (37.0) than in those having major complications (44.5), but this difference was not statistically significant (p = 0.074). The proportion of patients reaching a minimum clinically important difference (MCID) for ODI was statistically significantly smaller in the major complication group (31%) than in the minor complication (51%) and no complication groups (65%; p < 0.001). Conclusions A smaller proportion of patients achieved MCID for ODI 2 years after a major perioperative complication following lumbar fusion than after a minor complication or no complications.

scholarly journals Poor clinical outcomes associated with suboptimal antibiotic treatment among older long-term care facility residents with urinary tract infection: a retrospective cohort study

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Haley J. Appaneal ◽  
Theresa I. Shireman ◽  
Vrishali V. Lopes ◽  
Vincent Mor ◽  
David M. Dosa ◽  
...  
Keyword(s):  
Cohort Study ◽  
Clinical Outcome ◽  
Clinical Outcomes ◽  
Antibiotic Treatment ◽  
Antibiotic Use ◽  
Poor Clinical Outcome ◽  
Dose Frequency ◽  
Term Care ◽  
Increased Risk

Abstract Background Antibiotic use is associated with several antibiotic-related harms in vulnerable, older long-term care (LTC) residents. Suboptimal antibiotic use may also be associated with harms but has not yet been investigated. The aim of this work was to compare rates of poor clinical outcomes among LTC residents with UTI receiving suboptimal versus optimal antibiotic treatment. Methods We conducted a retrospective cohort study among residents with an incident urinary tract infection (UTI) treated in Veterans Affairs LTC units (2013–2018). Potentially suboptimal antibiotic treatment was defined as use of a suboptimal initial antibiotic drug choice, dose frequency, and/or excessive treatment duration. The primary outcome was time to a composite measure of poor clinical outcome, defined as UTI recurrence, acute care hospitalization/emergency department visit, adverse drug event, Clostridioides difficile infection (CDI), or death within 30 days of antibiotic discontinuation. Shared frailty Cox proportional hazard regression models were used to compare the time-to-event between suboptimal and optimal treatment. Results Among 19,701 LTC residents with an incident UTI, 64.6% received potentially suboptimal antibiotic treatment and 35.4% experienced a poor clinical outcome. In adjusted analyses, potentially suboptimal antibiotic treatment was associated with a small increased hazard of poor clinical outcome (aHR 1.06, 95% CI 1.01–1.11) as compared with optimal treatment, driven by an increased hazard of CDI (aHR 1.94, 95% CI 1.54–2.44). Conclusion In this national cohort study, suboptimal antibiotic treatment was associated with a 6% increased risk of the composite measure of poor clinical outcomes, in particular, a 94% increased risk of CDI. Beyond the decision to use antibiotics, clinicians should also consider the potential harms of suboptimal treatment choices with regards to drug type, dose frequency, and duration used.

Galactosaemia occurring in association with primary ovarian insufficiency, Addison’s disease and chronic myeloid leukaemia

2021 ◽  
Vol 14 (8) ◽  
pp. e244788
Author(s):  
Brandon Khoury ◽  
Mohamed KM Shakir ◽  
Thanh Duc Hoang
Keyword(s):  
Chronic Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Failure To Thrive ◽  
Primary Ovarian Insufficiency ◽  
Nutritional Deficiencies ◽  
Ovarian Insufficiency ◽  
Gonadal Dysfunction ◽  
Increased Risk ◽  
Severe Type

Classic galactosaemia is the most severe type, inherited in an autosomal recessive fashion and normally detected on newborn screening. It is caused by an inability to digest galactose due to a deficiency of galactose-1-phosphate uridyltransferase (GALT), resulting in an intolerance of feeds in the neonatal period, failure to thrive, hypoglycaemia, jaundice, cataracts, hepatomegaly, vomiting, diarrhoea, developmental delay and an increased risk of Escherichia coli sepsis. The long-term sequelae of this disorder include cognitive impairment, neurological symptoms, such as ataxia, nutritional deficiencies, such as calcium and vitamin D, and gonadal dysfunction. We report here a case of a 34-year-old woman with classic galactosaemia diagnosed in adulthood, developing primary ovarian insufficiency and osteoporosis as well as primary adrenal insufficiency and chronic myeloid leukaemia, which are two associations not seen in current literature. Further studies are needed to determine if an association exists between these diseases.

Contribution of endovascular therapy to the management of poor-grade aneurysmal subarachnoid hemorrhage: clinical and angiographic outcomes

2006 ◽  
Vol 105 (5) ◽  
pp. 664-670 ◽  
Author(s):  
Shuichi Suzuki ◽  
Reza Jahan ◽  
Gary R. Duckwiler ◽  
John Frazee ◽  
Neil Martin ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Mortality Rate ◽  
Clinical Outcome ◽  
Clinical Outcomes ◽  
Endovascular Therapy ◽  
Endovascular Embolization ◽  
Poor Grade ◽  
Surgical Clip

Object Treatment of patients presenting with poor-grade (Hunt and Hess Grade IV or V) subarachnoid hemorrhage (SAH) is controversial. Endovascular coil embolization has been considered a valuable therapeutic alternative to surgical clip placement for this kind of patient. The aim of the present study was to evaluate immediate and long-term angiographic and clinical outcomes in patients with poor-grade SAH treated by endovascular embolization. Methods One hundred eleven patients with Hunt and Hess Grade IV or V SAH were treated with endovascular embolization at the University of California at Los Angeles Medical Center between October 1990 and December 2004. Eighty patients harbored Grade IV hemorrhages and 31 patients had Grade V ones. Immediate and long-term anatomical and clinical outcomes were evaluated in all patients. Long-term clinical outcome assessments were based on follow-up data obtained over an average of 32 months posttherapy. Technical complications occurred in 15 patients (13.5%). Immediate complete aneurysm occlusion was observed in 51.4% of aneurysms. Angiographic, long-term follow-up review revealed aneurysm recanalization in 16.2% of cases. Thirty-nine patients (35.1%) demonstrated a favorable long-term clinical outcome. The overall mortality rate in this patient series was 32.4%. The mortality rate associated with vasospasm was significantly higher in patients with Grade IV SAHs than in those with Grade V hemorrhages. Conclusions The results of this study demonstrate a valuable contribution of endovascular therapy of ruptured intracranial aneurysms in patients with Hunt and Hess Grade IV or V SAH. This technique was successful in decreasing repeated aneurysm rupture and in enabling aggressive medical management during the acute phase of SAH. This is particularly important in patients with Grade IV SAH because of their potential for obtaining higher physical and functional recoveries.

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