Risk of Gastrointestinal Bleeding With Extended Use of Nonsteroidal Anti-Inflammatory Drug Analgesia After Joint Arthroplasty

BackgroundChronic nonsteroidal anti-inflammatory drug (NSAID) use is associated with gastrointestinal bleeding via inhibition of endogenous mucosal protection and platelet aggregation. This study aimed to determine whether extended NSAIDs after joint arthroplasty is associated with increased risk of gastrointestinal bleeding.MethodsThis was a retrospective study examining 28,794 adults who underwent joint arthroplasty by one of 50 surgeons from 2016 to 2018. Episodes of gastrointestinal bleeding within 90 days postoperatively were identified prospectively. Postoperative medications were reported directly by patients with electronic questionnaires. The primary analysis was performed using binary logistic regression.ResultsA total of 74 (0.26%) episodes of gastrointestinal bleeding occurred within 90 days (median 8 days) postoperatively. Of 5086 patients with complete data included in the primary analysis, 59.6% had used NSAIDs with median duration of 2 weeks (interquartile range, 0-6 weeks). Patients with gastrointestinal bleeding were significantly older (71.3 vs 67.0 years), required longer hospitalizations (2.1 vs 1.5 days), and more commonly had a history of peptic ulcers (10.8% vs 0.9%). However, there was no positive association between NSAID use and gastrointestinal bleeding. In fact, the odds of gastrointestinal bleeding were lower in patients taking NSAIDs. Gastrointestinal bleeding was associated with anticoagulants, antiplatelet agents, and, to a lesser extent, aspirin.ConclusionNSAIDs were not associated with gastrointestinal bleeding and may be prescribed safely for a majority of patients after joint arthroplasty. The greatest odds of gastrointestinal bleeding occurred in patients with peptic ulcer disease and those who received antiplatelet and anticoagulation agents. Increasing age and bilateral surgery were also associated with gastrointestinal bleeding.Level of EvidenceLevel III.     

Tezacaftor/ivacaftor in people with cystic fibrosis who stopped lumacaftor/ivacaftor due to respiratory adverse events

BackgroundIncreased rates of respiratory adverse events have been observed in people ≥12 years of age with cystic fibrosis homozygous for the Phe508del-CFTR mutation treated with lumacaftor/ivacaftor, particularly in those with percent predicted forced expiratory volume in 1 s (ppFEV₁) of <40%. We evaluated the safety, tolerability, and efficacy of tezacaftor/ivacaftor in people with cystic fibrosis homozygous for Phe508del-CFTR who discontinued lumacaftor/ivacaftor due to treatment-related respiratory signs or symptoms.MethodsParticipants ≥12 years of age with cystic fibrosis homozygous for Phe508del-CFTR with ppFEV₁ of ≥25% and ≤90% were randomized 1:1 and treated with tezacaftor/ivacaftor or placebo for 56 days.ResultsOf 97 participants, 94 (96.9%) completed the study. The primary endpoint was incidence of predefined respiratory adverse events of special interest (chest discomfort, dyspnea, respiration abnormal, asthma, bronchial hyperreactivity, bronchospasm, and wheezing): tezacaftor/ivacaftor, 14.0%; placebo, 21.3%. The adverse events were mild or moderate in severity. None were serious or led to treatment interruption or discontinuation. Overall, the discontinuation rate was similar between groups. The mean (SD) ppFEV₁ at baseline was 44.6% (16.1%) with tezacaftor/ivacaftor and 48.0% (18.1%) with placebo. The posterior mean difference in absolute change in ppFEV₁ from baseline to the average value of days 28 and 56 was 2.7 percentage points with tezacaftor/ivacaftor vs placebo.ConclusionsTezacaftor/ivacaftor was generally safe, well tolerated, and efficacious in people ≥12 years of age with cystic fibrosis homozygous for Phe508del-CFTR with ppFEV₁ of ≥25% and ≤90% who previously discontinued lumacaftor/ivacaftor due to treatment-related respiratory signs or symptoms.     

Discontinuation of Phenytoin, Carbamazepine, and Valproate in Patients with Active Epilepsy

The effects of discontinuing individual antiepileptic drugs (AEDs) in patients with active epilepsy who are receiving combination therapy have not been studied systematically. We report a double-blind, prospective study of discontinuation of phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA) in 70 patients with chronic active epilepsy. Each drug discontinuation was randomized to one of two relatively fast rates of reduction, and a control group of 25 patients continued with stable therapy. Patients who had CBZ removed had a significant increase in seizures that was maintained for 4 weeks after the end of drug reduction, and 10 of these 23 patients had to restart therapy with CBZ. There was no significant change in seizure numbers in the other groups. Two patients discontinued from VPA had to restart the drug; none had to restart PHT. The optimal rates of reduction of CBZ remain uncertain. There was no evidence for a clinically or temporally distinct burst of "discontinuation seizures" in any group. Any marked increase in seizures always resolved on reintroduction of the discontinued drug.     

Case-mix measurements for understanding and managing healthcare institutions

This article will characterize the clinical classification systems which may be utilized in healthcare institutions by illustrating their use in data analysis and management, demonstrating current examples of reimbursement, and detailing recent research trends in clinical classification systems. The systems discussed are diagnosis related groups (DRGs), DRG systems adjusted for patient severity, and ambulatory patient groups (APGs).     

Plant foods and colon cancer: an assessment of specific foods and their related nutrients (United States)

Plant foods have been associated inversely with colon cancer. Since amajor focus of this study was to identify components of plant foods whichmay account for their association with colon cancer, nutrients which arecommonly found in plant foods also were evaluated. A population-basedcase-control study was conducted in Northern California, Utah, and the TwinCities area of Minnesota (United States). Complete data were available frominterviewer-administered questionnaires on 1,993 cases and 2,410 controls.Higher intakes of vegetables (for highest relative to lowest quintile ofintake) were associated inversely with colon cancer risk: the odds ratio(OR) was 0.7 for both men (95 percent [CI] confidence interval = 0.5-0.9)and women (CI = 0.5-1.0). Associations were stronger among those withproximal tumors. Total fruit intake was not associated with colon cancerrisk although, among men, higher levels of whole grain intake wereassociated with a decreased risk (OR = 0.6, CI = 0.4-0.9 for older men);high intakes of refined grains were associated with an increased risk (OR =1.5, CI = 1.1-2.1). Dietary fiber intake was associated with a decreasedrisk of colon cancer: OR = 0.5 (CI = 0.3-0.9) for older men; OR = 0.7 (CI =0.4-1.2) for older women; OR = 0.6 (CI = 0.4-1.0) for men with proximaltumors; OR = 0.5 (CI = 0.3-0.9) for women with proximal tumors. Othernutrients, for which plant foods were the major contributor - such asvitamin B6, thiamin, and niacin (women only) - also were associatedinversely with colon cancer. Neither beta-carotene nor vitamin C wasprotective for colon cancer. Adjustment of plant foods for nutrients foundin plant foods or for supplement use did not appreciably alter the observedassociations between plant foods and colon cancer.     

Attenuation of the cutaneous blood flow response during combined exercise and heat stress

Skin blood flow (SkBF) was measured in six male subjects using laser-Doppler velocimetry, with zero-gradient auditory canal temperature (T_ac) used as an index of body core temperature (T_c). Subjects performed incremental, upright cycling commencing at 40% peak power ( _peak: 10 min), increasing every 4 min by 5 % _peak thereafter. Trials were conducted in hot (ambient temperature (T_a) 36.7 ±0.2°C, relative humidity (rh) 46.1 ±3.2%; _peak ±S.D.), and neutral environments (T_a 19.6 ±0.3°C, rh 50.2 ±1.4%). SkBF increased with T_ac in all subjects. Attenuation of SkBF occurred at the same T_ac, relative SkBF and cardiac frequency (f _c) between environments, but at a lower exercise intensity (40.8 ±0.8% versus 55.8 ±3.0% _peak) in the hot environment (p<0.05). Data indicate that T_c thresholds for SkBF attenuation may exist. However, it is suggested that attenuation thresholds coincided with a reduced central blood volume, which may occur at a critical level of cutaneous blood pooling.     

Persistent psychosis after reduction in pre- and post-synaptic dopaminergic function

Summary The purpose of this study was to evaluate the hypothesis that neuroleptic non-response in the face of adequate DA post-synaptic receptor blockade reflects failure of regulatory mechanisms to decrease DA pre-synaptic activity. Eight chronic schizophrenics, meeting rigorous criteria for neuroleptic non-response, were treated for four weeks with alpha-methylparatyrosine as an adjunct to their previously stable neuroleptic dose. Treatment with AMPT produced a prompt decrease in plasma HVA that was, on average, 72% lower at the end of the study. While there was also strong clinical evidence of reduction in central dopaminergic activity (both a significant reduction in dyskinetic movements and increase in extrapyramidal symptoms), there was virtually no change in severity of psychotic symptoms. Thus, in this group of non-responders, psychotic symptoms persisted despite both extensive dopamine post-synaptic receptor blockade and marked reduction of presynaptic activity. These symptoms may not be directly DA dependent.     

Temporary antibiotic loaded acrylic hip replacement: a novel method for management of the infected THA

Postoperative infection after hip joint replacement is an uncommon but potentially devastating complication in contemporary orthopaedics. Management in two stages is the more favored approach in North America. This introduces difficulty with patient management in the interval between stages, delays rehabilitation, and introduces technical difficulty during the second stage. A method has been developed whereby a temporary antibiotic-loaded facsimile of the hip is introduced at the first stage, designed to maintain stability of the joint, length of the limb, and mobility of the patient. It has been used in a total of 86 cases to date. The results in 46 cases with a minimum follow-up of 2 years are reviewed in this article. The infection was controlled in 93.5% of cases.     

Phase I and pharmacokinetics studies of prochlorperazine 2-h i.v. infusion as a doxorubicin-efflux blocker

In an earlier phase I study, we reported that the maximal tolerated dose (MTD) of prochlorperazine (PCZ) given as a 15-min i.v. infusion was 75 mg/m². The highest peak plasma PCZ concentration achieved was 1100 ng/ml. The present study was conducted to determine if PCZ levels high enough to block doxorubicin (DOX) efflux in vitro could be achieved and sustained in vivo by increasing the duration of i.v. infusion from 15 min to 2 h. The treatment schedule consisted of i.v. prehydration with at least 500 ml normal saline (NS) and administration of a fixed standard dose of 60 mg/m² DOX as an i.v. bolus over 15 min followed by i.v. doses of 75, 105, 135, or 180 mg/m² PCZ in 250 ml NS over 2 h. The hematologic toxicities attributable to DOX were as expected and independent of the PCZ dose. Toxicities attributable to PCZ were sedation, dryness of mouth, anxiety, akathisia, hypotension, cramps, and confusion. The MTD of PCZ was 180 mg/m². Large interpatient variation in peak PCZ plasma levels (91–3215 ng/ml) was seen, with the plasma half-life (t1/2) being approximately 57 min in patients given 135–180 mg/m² PCZ. The volume of distribution (V_d), total clearance (Cl_T), and area under the curve (AUC) were 350.1±183.8 l/m², 260.7±142.7 l m² h^–1 and 1539±922 ng ml h^–1, respectively, in patients given 180 mg/m² PCZ and the respective values for patients receiving 135 mg/m² were 48.9±23.76 l/m², 33.2±2.62 l m² h^–1, and 4117±302 ng ml h^–1. High PCZ plasma levels (>600 ng/ml) were sustained in all patients treated with 135 mg/m² PCZ for up to 24 h. DOX plasma elimination was biphasic at 135 and 180 mg/m² PCZ, and a>10-ng/ml DOX plasma level was maintained for 24 h. Partial responses were seen in three of six patients with malignant mesothelioma, in two of ten patients with non-small-cell lung carcinoma, and in the single patient with hepatoma. Our data show that PCZ can be safely given as a 2-h infusion at 135 mg/m² with clinically manageable toxicities. The antitumor activity of the combination of DOX and PCZ needs to be confirmed in phase II trials.This work was supported by NIH grant R01 CA-29360 and S1488, CRC grant M01 RR-05280, and the Joan Levy Cancer Foundation. This paper was presented at the meeting of the American Association for Cancer Research, Orlando, Florida, May 19–22, 1993