Abstract Background Recent descriptions of the clinical and laboratory features of subjects with acute porphyrias in the US are lacking. Our aim was to describe clinical, biochemical, and genetic ...features of 108 subjects. Methods Between September 2010 and December 2012, 108 subjects with acute porphyrias (90 acute intermittent porphyrias, 9 hereditary coproporphyrias, 9 variegate porphyrias) were enrolled into an observational study. Genetic testing was performed at a central genetic testing laboratory and clinical information entered into a central database. Selected features were compared with data for adults in the US. Results Most subjects (88/108, 81%) were female, with self-reported onset of symptoms in the second through fourth decades of life. The most common symptom was abdominal pain. Appendectomies and cholecystectomies were common before a diagnosis of porphyria. The diagnosis was delayed by a mean of 15 years. Anxiety and depression were common, and 18% complained of chronic symptoms, especially neuropathic and other pains. The incidences of systemic arterial hypertension, chronic kidney disease, seizure disorders, and psychiatric conditions were markedly increased. Mutations of the known causative genes were found in 102/105 of those tested, with novel mutations being found in 37, including in 7/8 subjects with hereditary coproporphyria. Therapy with intravenous hematin was the most effective therapy both for treatment of acute attacks and for prevention of recurrent attacks. Conclusions Acute porphyrias often remain undiagnosed for more than a decade after first symptoms develop. Intravenous hematin is the treatment of choice, both for treatment of acute attacks and for prevention of recurrent attacks.
Background: Spitzoid morphology in familial melanoma has been associated with germline variants in POT1, a telomere maintenance gene (TMG), suggesting a link between telomere biology and spitzoid ...differentiation. Objective: To assess if familial melanoma cases associated with germline variants in TMG (POT1, ACD, TERF2IP, and TERT) commonly exhibit spitzoid morphology. Methods: In this case series, melanomas were classified as having spitzoid morphology if at least 3 of 4 dermatopathologists reported this finding in ≥25% of tumor cells. Logistic regression was used to calculate odds ratios (OR) of spitzoid morphology compared to familial melanomas from unmatched noncarriers that were previously reviewed by a National Cancer Institute dermatopathologist. Results: Spitzoid morphology was observed in 77% (23 of 30), 75% (3 of 4), 50% (2 of 4), and 50% (1 of 2) of melanomas from individuals with germline variants in POT1, TERF2IP, ACD, and TERT, respectively. Compared to noncarriers (n = 139 melanomas), POT1 carriers (OR = 225.1, 95% confidence interval: 51.7-980.5; P < .001) and individuals with TERF2IP, ACD, and TERT variants (OR = 82.4, 95% confidence interval: 21.3-494.6; P < .001) had increased odds of spitzoid morphology. Limitations: Findings may not be generalizable to nonfamilial melanoma cases. Conclusion: Spitzoid morphology in familial melanoma could suggest germline alteration of TMG.
Summary Background Neuroprotection with NA-1 (Tat-NR2B9c), an inhibitor of postsynaptic density-95 protein, has been shown in a primate model of stroke. We assessed whether NA-1 could reduce ...ischaemic brain damage in human beings. Methods For this double-blind, randomised, controlled study, we enrolled patients aged 18 years or older who had a ruptured or unruptured intracranial aneurysm amenable to endovascular repair from 14 hospitals in Canada and the USA. We used a computer-generated randomisation sequence to allocate patients to receive an intravenous infusion of either NA-1 or saline control at the end of their endovascular procedure (1:1; stratified by site, age, and aneurysm status). Both patients and investigators were masked to treatment allocation. The primary outcome was safety and primary clinical outcomes were the number and volume of new ischaemic strokes defined by MRI at 12–95 h after infusion. We used a modified intention-to-treat (mITT) analysis. This trial is registered with ClinicalTrials.gov , number NCT00728182. Findings Between Sept 16, 2008, and March 30, 2011, we randomly allocated 197 patients to treatment—12 individuals did not receive treatment because they were found to be ineligible after randomisation, so the mITT population consisted of 185 individuals, 92 in the NA-1 group and 93 in the placebo group. Two minor adverse events were adjudged to be associated with NA-1; no serious adverse events were attributable to NA-1. We recorded no difference between groups in the volume of lesions by either diffusion-weighted MRI (adjusted p value=0·120) or fluid-attenuated inversion recovery MRI (adjusted p value=0·236). Patients in the NA-1 group sustained fewer ischaemic infarcts than did patients in the placebo group, as gauged by diffusion-weighted MRI (adjusted incidence rate ratio 0·53, 95% CI 0·38–0·74) and fluid-attenuated inversion recovery MRI (0·59, 0·42–0·83). Interpretation Our findings suggest that neuroprotection in human ischaemic stroke is possible and that it should be investigated in larger trials. Funding NoNO Inc and Arbor Vita Corp.
Abstract Objective To determine whether the combination of Constraint-Induced Movement Therapy (CIMT) and conventional rehabilitation techniques can produce meaningful motor improvement in chronic ...stroke patients with initially fisted hands. Design Case series. Setting University hospital outpatient laboratory. Participants Consecutive sample (N=6) >1 year poststroke with plegic hands. Interventions Treatment consisted of an initial period of 3 weeks (phase A) when adaptive equipment in the home, orthotics, and splints were employed to improve ability to engage in activities of daily living. This was continued in phase B, when CIMT and selected neurodevelopmental treatment techniques were added. Main Outcome Measures Motor Activity Log (MAL), accelerometry, Fugl-Meyer Motor Assessment (F-M). Results Patients exhibited a large improvement in spontaneous real-world use of the more-affected arm (mean lower-functioning MAL change=1.3±0.4 points; P <.001; d ′ =3.0) and a similar pattern of increase in an objective measure of real-world more-affected arm movement (mean change in ratio of more- to less-affected arm accelerometer recordings=0.12±0.1 points; P =.016; d ′ =1.2). A large improvement in motor status was also recorded (mean F-M change=5.3±3.3 points; P =.005; d ′ =1.6). Conclusions The findings of this pilot study suggest that stroke patients with plegic hands can benefit from CIMT combined with some conventional rehabilitation techniques, even long after brain injury. More research is warranted.
Background Alcohol screening scores ≥5 on the Alcohol Use Disorders Identification Test–Consumption (AUDIT-C) up to a year before surgery have been associated with postoperative complications, but ...the association with postoperative health care use is unknown. This study evaluated whether AUDIT-C scores in the year before surgery were associated with postoperative hospital length of stay, total ICU days, return to the operating room, and hospital readmission. Study Design This cohort study included male Veterans Affairs patients who completed the AUDIT-C on mailed surveys (October 2003 through September 2006) and were hospitalized for nonemergent noncardiac major operations in the following year. Postoperative health care use was evaluated across 4 AUDIT-C risk groups (scores 0, 1 to 4, 5 to 8, and 9 to 12) using linear or logistic regression models adjusted for sociodemographics, smoking status, surgical category, relative value unit, and time from AUDIT-C to surgery. Patients with AUDIT-C scores indicating low-risk drinking (scores 1 to 4) were the referent group. Results Adjusted analyses revealed that among eligible surgical patients (n = 5,171), those with the highest AUDIT-C scores (ie, 9 to 12) had longer postoperative hospital length of stay (5.8 95% CI, 5.0−6.7 vs 5.0 95% CI, 4.7−5.3 days), more ICU days (4.5 95% CI, 3.2−5.8 vs 2.8 95% CI, 2.6−3.1 days), and increased probability of return to the operating room (10% 95% CI, 6−13% vs 5% 95% CI, 4−6%) in the 30 days after surgery, but not increased hospital readmission within 30 days postdischarge, relative to the low-risk group. Conclusions AUDIT-C screening results could be used to identify patients at risk for increased postoperative health care use who might benefit from preoperative alcohol interventions.
We compared proton beam therapy (PBT) with intensity modulated radiation therapy (IMRT) for pediatric craniopharyngioma in terms of disease control, cyst dynamics, and toxicity.
We reviewed records ...from 52 children treated with PBT (n=21) or IMRT (n=31) at 2 institutions from 1996-2012. Endpoints were overall survival (OS), disease control, cyst dynamics, and toxicity.
At 59.6 months' median follow-up (PBT 33 mo vs IMRT 106 mo; P<.001), the 3-year outcomes were 96% for OS, 95% for nodular failure-free survival and 76% for cystic failure-free survival. Neither OS nor disease control differed between treatment groups (OS P=.742; nodular failure-free survival P=.546; cystic failure-free survival P=.994). During therapy, 40% of patients had cyst growth (20% requiring intervention); immediately after therapy, 17 patients (33%) had cyst growth (transient in 14), more commonly in the IMRT group (42% vs 19% PBT; P=.082); and 27% experienced late cyst growth (32% IMRT, 19% PBT; P=.353), with intervention required in 40%. Toxicity did not differ between groups. On multivariate analysis, cyst growth was related to visual and hypothalamic toxicity (P=.009 and .04, respectively). Patients given radiation as salvage therapy (for recurrence) rather than adjuvant therapy had higher rates of visual and endocrine (P=.017 and .024, respectively) dysfunction.
Survival and disease-control outcomes were equivalent for PBT and IMRT. Cyst growth is common, unpredictable, and should be followed during and after therapy, because it contributes to late toxicity. Delaying radiation therapy until recurrence may result in worse visual and endocrine function.
Abstract We estimated the inpatient resource use for a Fontan patient from birth to adulthood and explored factors that might induce cost differences (2014 US dollar). Inpatient costing records from ...four hospitals with greatest numbers of Fontan patients in Australia and New Zealand were linked with the Fontan registry database. Inpatient records between July 1995 and September 2014 for 420 Fontan patients were linked, and the most frequent primary diagnoses were hypoplastic left heart syndrome (HLHS) (20.7%), tricuspid atresia (19.7%), and double inlet left ventricle (17.1%). The mean hospital cost for a Fontan patient from birth to 18 years of age was estimated to be $390,601 (95% confidence interval CI $264,703 to $516,499), corresponding to 164 (95% CI 98 to 231) inpatient days. The cost incurred from birth through to Fontan completion (the staged procedures period) was $219,482 (95% CI $202,410 to $236,553) and the cost thereafter over 15 years was $146,820 (95% CI $44,409 to $249,231), corresponding to 82 (95% CI 72 to 92) and 65 (95% CI 18 to 112) inpatient days respectively. Costs were higher in male and HLHS patients in the staged procedures period (P<0.001). Having fenestration was associated with higher costs in the staged procedures period (P<0.001) and lower cost post Fontan over 15 years (P=0.66). In conclusion, patients with single-ventricle congenital heart disease continue to demand considerable inpatient resources after the staged procedures period. Over 40% of the pediatric hospital costs for Fontan patients were estimated to occur after the last planned surgery.
Cancer treatment evolves through oncology clinical trials. Cancer trials are multimodal and complex. Assuring high-quality data are available to answer not only study objectives but also questions ...not anticipated at study initiation is the role of quality assurance. The National Cancer Institute reorganized its cancer clinical trials program in 2014. The National Clinical Trials Network (NCTN) was formed and within it was established a Diagnostic Imaging and Radiation Therapy Quality Assurance Organization. This organization is Imaging and Radiation Oncology Core, the Imaging and Radiation Oncology Core Group, consisting of 6 quality assurance centers that provide imaging and radiation therapy quality assurance for the NCTN. Sophisticated imaging is used for cancer diagnosis, treatment, and management as well as for image-driven technologies to plan and execute radiation treatment. Integration of imaging and radiation oncology data acquisition, review, management, and archive strategies are essential for trial compliance and future research. Lessons learned from previous trials are and provide evidence to support diagnostic imaging and radiation therapy data acquisition in NCTN trials.
Background Patients who screen positive for alcohol misuse on the Alcohol Use Disorder Identification Test Consumption Questionnaire (AUDIT-C ≥5 points) have significantly increased postoperative ...complications. Severe alcohol misuse (AUDIT-C ≥9 points) is associated with increased postoperative health care use; however, little is known about the prevalence of alcohol misuse in demographic and clinical subgroups of surgical patients. Methods The prevalence of alcohol misuse was evaluated among 10,284 patients (9,771 men and 513 women) who underwent major noncardiac surgery in Veterans Affairs (VA) hospitals during the fiscal years 2004 to 2006 and completed the AUDIT-C. Sex-stratified analyses evaluated prevalence rates of alcohol misuse (AUDIT-C ≥5) and severe misuse (AUDIT-C ≥9) across demographic and clinical subgroups. Results Overall, 1,607 (16%) men and 24 (5%) women screened positive for alcohol misuse (AUDIT-C ≥5) in the year before operation, with 4% and 2% screening positive for severe misuse (AUDIT-C ≥9), respectively. Alcohol misuse was more common among men who were <60 years of age, divorced or separated, current smokers, or American Stoke Association class 1 or 2, and those with cirrhosis/hepatitis or substance use disorders. Among patients with alcohol misuse, 36% of men and 58% of women were American Society of Anesthesiologists class 1 or 2, and most did not have diagnoses that were commonly associated with alcohol misuse. Conclusion Alcohol misuse is relatively common in male surgical patients. Moreover, surgical patients undergoing operation who screen positive for alcohol misuse are often relatively healthy, without health problems that might alert providers to their alcohol misuse in the absence of screening.
There is ongoing debate on the clinical benefits of antibiotic prophylaxis for reducing pelvic infection after miscarriage surgery. We aimed to study the cost-effectiveness of antibiotic prophylaxis ...in the surgical management of miscarriage in low-income countries.
We did an incremental cost-effectiveness analysis using data from 3412 women recruited to the AIMS trial, a randomised, double-blind, placebo-controlled trial designed to evaluate the effectiveness of antibiotic prophylaxis in the surgical management of miscarriage in Malawi, Pakistan, Tanzania, and Uganda. Economic evaluation was done from a health-care-provider perspective on the basis of the outcome of cost per pelvic infection avoided within 2 weeks of surgery. Pelvic infection was broadly defined by the presence of clinical features or the clinically identified need to administer antibiotics. We used non-parametric bootstrapping and multilevel random effects models to estimate incremental mean costs and outcomes. Decision uncertainty was shown via cost-effectiveness acceptability frontiers. The AIMS trial is registered with the ISRCTN registry, number ISRCTN97143849.
Between June 2, 2014, and April 26, 2017, 3412 women were assigned to receive either antibiotic prophylaxis (1705 50% of 3412) or placebo (1707 50% of 3412) in the AIMS trial. 158 (5%) of 3412 women developed pelvic infection within 2 weeks of surgery, of whom 68 (43%) were in the antibiotic prophylaxis group and 90 (57%) in the placebo group. There is 97–98% probability that antibiotic prophylaxis is a cost-effective intervention at expected thresholds of willingness-to-pay per additional pelvic infection avoided. In terms of post-surgery antibiotics, the antibiotic prophylaxis group was US$0·27 (95% CI −0·49 to −0·05) less expensive per woman than the placebo group. A secondary analysis, a sensitivity analysis, and all subgroup analyses supported these findings. Antibiotic prophylaxis, if implemented routinely before miscarriage surgery, could translate to an annual total cost saving of up to $1·4 million across the four participating countries and up to $8·5 million across the two regions of sub-Saharan Africa and south Asia.
Antibiotic prophylaxis is more effective and less expensive than no antibiotic prophylaxis. Policy makers in various settings should be confident that antibiotic prophylaxis in miscarriage surgery is cost-effective.
UK Medical Research Council, Wellcome Trust, and the UK Department for International Development.
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