Search

Purpose Possible dulaglutide-induced cholecystitis, with successful resumption of dulaglutide after cholecystectomy, is discussed. Summary A 72-year-old White man was started on dulaglutide for outpatient management of type 2 diabetes, in addition to his existing antihyperglycemic regimen of metformin, glipizide, pioglitazone, and insulin glargine. His glycated hemoglobin (HbA1c) concentration improved from 8.2% to 7.2% with the addition of dulaglutide. Furthermore, the use of dulaglutide did not lead to weight loss. After 16 months of treatment with dulaglutide, he presented to the emergency room with nausea, loss of appetite, and progressive sharp, nonradiating right upper quadrant pain. Based on symptom presentation, laboratory workup, and computed tomography scan results, acute cholecystitis was diagnosed. He underwent a cholecystectomy to remove what was found to be a gangrenous gallbladder. Per documented surgical dictation from the cholecystectomy, the gallbladder was removed, but portions of the biliary tree were left intact. The patient was continued on dulaglutide postoperatively without recurrence of bile stones, biliary tree disease, or abdominal symptoms at 8 months after initial cholecystitis incident. Conclusion A male patient with possible dulaglutide-induced cholecystitis was successfully continued on dulaglutide therapy post cholecystectomy without recurrent complications within the biliary tract.

ImportanceOlder adults with insomnia have a high risk of incident and recurrent depression. Depression prevention is urgently needed, and such efforts have been neglected for older adults.ObjectiveTo examine whether treatment of insomnia disorder with cognitive behavioral therapy for insomnia (CBT-I) compared with an active comparator condition, sleep education therapy (SET), prevents major depressive disorder in older adults.Design, setting, and participantsThis assessor-blinded, parallel-group, single-site randomized clinical trial assessed a community-based sample of 431 people and enrolled 291 adults 60 years or older with insomnia disorder who had no major depression or major health events in past year. Study recruitment was performed from July 1, 2012, to April 30, 2015. The trial protocol was modified to extend follow-up from 24 to 36 months, with follow-up completion in July 2018. Data analysis was performed from March 1, 2019, to March 30, 2020.InterventionsParticipants were randomized to 2 months of CBT-I (n = 156) or SET (n = 135).Main outcomes and measuresThe primary outcome was time to incident major depressive disorder as diagnosed by interview and Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria. Secondary outcome was sustained remission of insomnia disorder before depression event or duration of follow-up.ResultsAmong 291 randomized participants (mean [SD] age, 70.1 [6.7] years; 168 [57.7%] female; 7 [2.4%] Asian, 32 [11.0%] Black, 3 [1.0%] Pacific Islander, 241 [82.8%] White, 6 [2.1%] multiracial, and 2 [0.7%] unknown), 156 were randomized to CBT-I and 135 to SET. A total of 140 participants (89.7%) completed CBT-I and 130 (96.3%) participants completed SET (χ2 = 4.9, P = .03), with 114 (73.1%) completing 24 months of follow-up in the CBT-I group and 117 (86.7%) in the SET group (χ2 = 8.4, P = .004). After protocol modification, 92 (59.0%) of the CBT-I participants and 86 (63.7%) of the SET participants agreed to extended follow-up (χ2 = 0.7, P = .41), with 81 (51.9%) of the CBT-I participants and 77 (57.0%) of the SET group completing 36 months of follow-up (χ2 = 0.8; P = .39). Incident or recurrent major depression occurred in 19 participants (12.2%) in the CBT-I group and in 35 participants (25.9%) in the SET group, with an overall benefit (hazard ratio, 0.51; 95%, CI 0.29-0.88; P = .02) consistent across subgroups. Remission of insomnia disorder continuously sustained before depression event or during follow-up was more likely in CBT-I participants (41 [26.3%]) compared with the SET participants (26 [19.3%], P = .03). Those in the CBT-I group with sustained remission of insomnia disorder had an 82.6% decreased likelihood of depression (hazard ratio, 0.17; 95%, CI 0.04-0.73; P = .02) compared with those in the SET group without sustained remission of insomnia disorder.Conclusions and relevanceThe findings of this randomized clinical trial indicate that treatment of insomnia with CBT-I has an overall benefit in the prevention of incident and recurrent major depression in older adults with insomnia disorder. Community-level screening for insomnia concerns in older adults and wide delivery of CBT-I-based treatment for insomnia could substantially advance public health efforts to treat insomnia and prevent depression in this vulnerable older adult population.Trial registrationClinicalTrials.gov Identifier: NCT01641263.

An early-stage decision clinicians often make in the management of complex wounds is which method of wound preparation will be appropriate for the patient. This decision can be affected by numerous wound and patient risk factors that present challenges and may make surgical debridement difficult in patients with complex wounds. Recently, negative pressure wound therapy with instillation and dwell time (NPWTi-d) using a novel reticulated open-cell foam dressing with through holes (ROCF-CC) was shown to aid in the loosening and removal of thick exudate and nonviable tissue from wounds.The authors present their experiences of using NPWTi-d with ROCF-CC, along with rationales for wound care decisions.Patients received antibiotics and surgical debridement when appropriate. Therapy selection and parameters were based on a decision-tree model for wound care management that takes into consideration patient and wound information. Most patients received NPWTi-d with ROCF-CC for a duration of 5 to 8 days; however, 1 patient received NPWTi-d with ROCF-CC for more than 30 days due to the wound extent and severity. Therapy consisted of instilling saline or quarter-strength sodium hypochlorite solution with dwell times of 3 to 10 minutes, followed by 2 hours or 3.5 hours of NPWT either at -100 mm Hg or -125 mm Hg.There were 6 patients (3 men, 3 women; average age, 58.5 years) treated. Wound types included 3 pressure ulcers, 1 necrotizing soft tissue infection, 1 perianal abscess, and 1 large abdominal wound. Patient comorbidities included obesity, type 2 diabetes, and radiation therapy. In all cases, progression of wound healing was observed with no complications. This method produced viable granulation tissue and wound bed preparation; however, patients were not followed to closure or grafting.These cases help support the use of NPWTi-d with ROCF-CC as a viable option for wound care providers in the early-stage management of complex wounds.

Background and aimsSleep disturbance is a prominent complaint in cocaine and alcohol dependence. This controlled study evaluated differences of polysomnographic (PSG) sleep in cocaine- and alcohol-dependent subjects, and examined whether substance dependence interacts with age to alter slow wave sleep and rapid eye movement (REM) sleep.DesignCross-sectional comparison.SettingLos Angeles and San Diego, CA, USA.ParticipantsAbstinent cocaine-dependent subjects (n=32), abstinent alcohol-dependent subjects (n=73) and controls (n=108); mean age 40.3years recruited 2005-12.MeasurementsPSG measures of sleep continuity and sleep architecture primary outcomes of Stage 3 sleep and REM sleep. Covariates included age, ethnicity, education, smoking, body mass index and depressive symptoms.FindingsCompared with controls, both groups of substance dependent subjects showed loss of Stage 3 sleep (P&nbsp

Importance: A major challenge for drug development in neurodegenerative diseases is that adequately powered efficacy studies with meaningful end points typically require several hundred participants and long durations. Prion diseases represent the archetype of brain diseases caused by protein misfolding, the most common subtype being sporadic Creutzfeldt-Jakob disease (sCJD), a rapidly progressive dementia. There is no well-established trial method in prion disease. Objective: To establish a more powerful and meaningful clinical trial method in sCJD. Design, Setting, and Participants: A stratified medicine and simulation approach based on a prospective interval-cohort study conducted from October 2008 to June 2014. This study involved 598 participants with probable or definite sCJD followed up over 470 patient-years at a specialist national referral service in the United Kingdom with domiciliary, care home, and hospital patient visits. We fitted linear mixed models to the outcome measurements, and simulated clinical trials involving 10 to 120 patients (no dropouts) with early to moderately advanced prion disease using model parameters to compare the power of various designs. Main Outcomes and Measures: A total of 2681 assessments were done using a functionally orientated composite end point (Medical Research Council Scale) and associated with clinical investigations (brain magnetic resonance imaging, electroencephalography, and cerebrospinal fluid analysis) and molecular data (prion protein [PrP] gene sequencing, PrPSc type). Results: Of the 598 participants, 273 were men. The PrP gene sequence was significantly associated with decline relative to any other demographic or investigation factors. Patients with sCJD and polymorphic codon 129 genotypes MM, VV, and MV lost 10% of their function in 5.3 (95% CI, 4.2-6.9), 13.2 (95% CI, 10.9-16.6), and 27.8 (95% CI, 21.9-37.8) days, respectively (P

Cases of iatrogenic CJD still occur in the UK 30 years after administration of human pituitary-derived growth hormone ceased. Rudge et al. report a change over time in genotype profile at polymorphic codon 129 of the human prion protein gene in UK patients, distinct from that seen in other countries., Patients with iatrogenic Creutzfeldt-Jakob disease due to administration of cadaver-sourced growth hormone during childhood are still being seen in the UK 30 years after cessation of this treatment. Of the 77 patients who have developed iatrogenic Creutzfeldt-Jakob disease, 56 have been genotyped. There has been a marked change in genotype profile at polymorphic codon 129 of the prion protein gene (PRNP) from predominantly valine homozygous to a mixed picture of methionine homozygous and methionine-valine heterozygous over time. The incubation period of iatrogenic Creutzfeldt-Jakob disease is significantly different between all three genotypes. This experience is a striking contrast with that in France and the USA, which may relate to contamination of different growth hormone batches with different strains of human prions. We describe the clinical, imaging, molecular and autopsy features in 22 of 24 patients who have developed iatrogenic Creutzfeldt-Jakob disease in the UK since 2003. Mean age at onset of symptoms was 42.7 years. Gait ataxia and lower limb dysaesthesiae were the most frequent presenting symptoms. All had cerebellar signs, and the majority had myoclonus and lower limb pyramidal signs, with relatively preserved cognitive function, when first seen. There was a progressive decline in neurological and cognitive function leading to death after 5–32 (mean 14) months. Despite incubation periods approaching 40 years, the clinical duration in methionine homozygote patients appeared to be shorter than that seen in heterozygote patients. MRI showed restricted diffusion in the basal ganglia, thalamus, hippocampus, frontal and the paracentral motor cortex and cerebellar vermis. The electroencephalogram was abnormal in 15 patients and cerebrospinal fluid 14-3-3 protein was positive in half the patients. Neuropathological examination was conducted in nine patients. All but one showed synaptic prion deposition with numerous kuru type plaques in the basal ganglia, anterior frontal and parietal cortex, thalamus, basal ganglia and cerebellum. The patient with the shortest clinical duration had an atypical synaptic deposition of abnormal prion protein and no kuru plaques. Taken together, these data provide a remarkable example of the interplay between the strain of the pathogen and host prion protein genotype. Based on extensive modelling of human prion transmission barriers in transgenic mice expressing human prion protein on a mouse prion protein null background, the temporal distribution of codon 129 genotypes within the cohort of patients with iatrogenic Creutzfeldt-Jakob disease in the UK suggests that there was a point source of infecting prion contamination of growth hormone derived from a patient with Creutzfeldt-Jakob disease expressing prion protein valine 129.

PURPOSE: To explore the use of SD/01 (a polyethylene glycol–conjugated filgrastim shown in preclinical studies to have a prolonged half-life) in patients with chemotherapy-induced neutropenia. PATIENTS AND METHODS: Thirteen patients with non–small-cell lung cancer were randomized to receive daily filgrastim (5 μg/kg/d) or a single injection of SD/01 (30, 100, or 300 μg/kg) 2 weeks before chemotherapy and again 24 hours after administration of carboplatin and paclitaxel. Pharmacodynamic, pharmacokinetic, and safety analyses were performed. RESULTS: Peak serum concentrations of SD/01 and the duration of increased serum concentrations were dependent on the SD/01 dose. SD/01 concentrations remained increased longer in patients with chemotherapy-induced neutropenia. Prechemotherapy median absolute neutrophil counts (ANCs) in patients receiving SD/01 were increased in a dose-dependent fashion, with the duration of this effect also being dose dependent. After chemotherapy, median ANC nadirs were similar in the filgrastim cohort and the cohort receiving SD/01 30 μg/kg, with higher nadirs seen in the cohorts receiving SD/01 100 or 300 μg/kg. Dose-limiting toxicities were not noted. CD34+ cells were mobilized in all cohorts. CONCLUSION: A single dose of SD/01 increases the serum concentration of SD/01 for several days in a dose-dependent fashion and is not associated with significant toxicity. The effects of SD/01 on ANC and CD34+ cell mobilization are comparable or greater than those achieved with daily filgrastim. The self-regulation of this molecule provides a potential therapeutic advantage in a variety of clinical settings associated with neutropenia.

Objective: To determine the feasibility and maximum tolerated dose of dose-dense topotecan as induction chemotherapy before standard therapy (carboplatin plus etoposide alone or in combination with radiotherapy) in patients with small cell lung cancer (SCLC). Patients and methods: Chemotherapy-naive patients with SCLC and good performance status were eligible. Three 2-week cycles of dose-dense topotecan administered on days 1–3 with granulocyte colony-stimulating factor support were followed by four cycles of standard carboplatin plus etoposide therapy alone (extensive-stage SCLC) or with radiotherapy (limited-stage SCLC). The dose of topotecan was escalated from 1.5 mg/m2/day to 2.5 mg/m2/day in increments of 0.25 mg/m2/day within cohorts of 3–5 patients each. Dose-limiting toxicity was defined as any grade 3 or 4 toxicity resulting in a treatment reduction or a delay of >3 days. Results: Twenty-two patients with SCLC (5 limited-stage, 17 extensive-stage) were enrolled. Treatment was well tolerated. The dose-limiting toxicities were thrombocytopenia and neutropenia, and the maximum tolerated dose of dose-dense topotecan induction therapy was 2.25 mg/m2/day. Overall, topotecan-related grade 3/4 haematological toxicities included neutropenia (n = 4), thrombocytopenia (n = 3) and febrile neutropenia (n = 1). No grade 4 non-haematological toxicities occurred. Grade 3 adverse events included nausea (n = 2), renal toxicity (n = 1) and anorexia (n = 1). Toxicity during the carboplatin plus etoposide ± radiotherapy phase of therapy was consistent with that reported in previous trials. The overall response rate was 80% for limited-stage and 76% for extensive-stage SCLC. Median survival was 8 months in patients with limited-stage SCLC and 13.5 months for patients with extensive-stage SCLC. Conclusion: The results of this phase I study suggest that a regimen of sequential dose-dense topotecan and carboplatin plus etoposide is feasible, and the preliminary activity observed in patients with SCLC warrants further investigation at a starting dose of topotecan 2.25 mg/m2/day.

The effect of a typical 5-day chemotherapy treatment with cisplatin (20-40 mg/m2 per day) and 5-fluorouracil (5-FU, 1 gm/m2 per day) on the pharmacokinetics of ondansetron was investigated. Twenty cancer patients received 8 mg of ondansetron in three periods, including an oral tablet on day 1, an intravenous infusion on day 4, and an oral tablet on day 5. Absolute bioavailability after the oral dosing on day 1 was 87.5 +/- 31.3%, and on day 5 was 85.2 +/- 22.1% (P > .05). Mean values of AUC, Cmax, Tmax, and half life on days 1 and 5 were 399 +/- 275 and 381 +/- 222 ng.hour/mL, 53.3 +/- 26.8 and 43.6 +/- 21.7 ng/mL, 1.9 +/- 1.4 and 2 +/- 1.4 hours, and 5.21 +/- 1.78 and 6.19 +/- 1.99 hours, respectively. These values were not significantly different (P > .05). In summary, this study showed that cisplatin and 5-FU did not significantly alter the pharmacokinetics of oral ondansetron in cancer patients during the 5 days of chemotherapy. Oral bioavailability of ondansetron appeared to be greater in cancer patients than in healthy subjects.

We report a method for controlling and adjusting plasma opioid concentration to preselected target values in individual human subjects in order to study analgesic and other effects of opioids at steady state. The method employs a computer-controlled infusion pump and an algorithm that utilizes individual subject pharmacokinetic parameters predetermined with tailoring bolus opioid doses. We used this approach to produce 3-step increases in plasma concentrations of alfentanil, fentanyl and morphine in each of 15 subjects. We maintained each plasma concentration plateau for 70 min, measured plasma opioid concentrations achieved during the infusions and analyzed the results for bias and precision of the individually tailored infusions. Our results show that pharmacokinetically tailored opioid infusions produce stable plasma opioid concentrations within 10 min for alfentanil and morphine; with each drug overall prediction error was 20% or less. Fentanyl was somewhat more difficult to control by this method than were the other 2 opioids. We conclude that individual tailoring of opioid infusions minimizes the impact of individual pharmacokinetic differences on achieving preselected plasma opioid concentrations and provides an accurate means of controlling steady-state drug concentrations for studies of concentration-effect relationships and comparisons of side-effect intensities produced by equianalgesic plasma opioid concentrations.

We used computer-controlled individually tailored infusions to study relationships between plasma drug concentration and opioid effects, and to evaluate the therapeutic margins of alfentanil, fentanyl and morphine in human subjects. In order to compare the 3 drugs, we infused each opioid to 3 different steady-state target plasma concentrations during separate 8 h test periods so that concentration-effect curves could be defined for each opioid and subject. Dental electrical stimulation produced a consistent degree of baseline experimental pain, and we measured the influence of increasing plasma opioid concentrations on pain intensity and the magnitude of pain-related evoked potentials. We also quantified ventilatory function and subjective side-effects during baseline (no drug), at the 3 target plasma concentrations with each drug. Finally, we measured actual plasma opioid concentrations during each phase of the infusion period. This procedure allowed us to calculate for each opioid the plasma concentration required to produce a 50% decrease in reported pain intensity and evoked potential amplitude (IC50). Subsequent calculation of side-effect magnitudes at the analgesic IC50s permitted direct comparisons of therapeutic margins between alfentanil, fentanyl and morphine. We found a robust relationship between plasma drug concentration and analgesic, ventilatory, and subjective-effect magnitudes for each opioid in this study. We conclude that the magnitudes of individual side-effects associated with equianalgesic, steady-state plasma concentrations of these 3 mu receptor-selective opioids do not differ across drugs.

The five-year experience involving over 800 employees has effected reduced coronary risk factors, improved physical work capacity and maximal oxygen uptake and reduced employee absenteeism from personal sick leave. As in all instances where the self-selection process confounds the nature of the results, the extent of extrapolation from these data must be guarded. Nevertheless, the results support and further extend previous studies suggesting a reduction of CVD following formal behavior and life-style modification. It is the opinion of the authors that similar programs can be implemented where health services, flexible hours, agency cooperation and salaried coordinators can be assembled.

Fifteen crossbred pigs of Swedish Landrace and Yorkshire, about 6 months of age and susceptible to develop malignant hyperthermia (MH) when exposed to halothane, were subjected to stress provoked by the myorelaxant succinylcholine. The results were compared with those of 12 normal pigs. During the stress the halothane-sensitive (HS) pigs showed much higher levels of plasma noradrenaline and adrenaline and more severe ventricular arrhythmias than the controls. The degree of myocardial degeneration and necrosis being similar to catecholamine induced myocardial damage was significantly higher in the HS pigs than in the controls. The ultrastructural examination revealed three main types of changes in affected myocardial cells. One type of myocardial cell damage was characterized by various degree of hypercontraction, enlarged mitochondria with dense bodies and dilated sarcoplasmic reticulum. The other type showed mitochondria with tubular configuration whereas the third type of cell damage was characterized by almost normal mitochondria combined with a severe damage of the myofilaments. Three HS pigs which died within 30 min after stress showed signs of malignant hyperthermia. No signs of the disease were observed in the other 12 HS pigs.

We have determined that the mixed agonist-antagonist narcotic, butorphanol, improves CO2 response and ventilation after fentanyl anesthesia. A tentative dosage range has been established. Twenty-two patients were anesthetized with isoflurane, nitrous oxide, and fentanyl, which was continuously infused throughout the study. Postoperatively three 1-mg doses of butorphanol were administered IV. Blood pressure, heart rate, plasma epinephrine and norepinephrine concentrations, and pain intensity were essentially unchanged after butorphanol. Most of the improvement in breathing occurred after the first 1-mg dose. Mean respiratory rate increased from 7.8 +/- 5.0 to 11.0 +/- 4.8 min-1 (P less than or equal to 0.005), tidal volume increased from 469 +/- 302 to 844 +/- 390 ml (P less than or equal to 0.005), minute ventilation increased from 4.32 +/- 2.97 to 8.51 +/- 3.14 L/min (P less than or equal to 0.005), and the slope of the ventilatory response to CO2 increased from 0.36 +/- 0.37 to 0.90 +/- 0.80 L X min-1 X mm Hg-1 (P less than or equal to 0.05). Resting PaCO2 decreased from a baseline of 57.8 +/- 11.1 to 51.7 +/- 5.12 mm Hg (P less than or equal to 0.05) after the third dose.

Lower intercostal and abdominal muscles interact with other respiratory muscles to produce inspiration as well as expiration. Intercostal nerve blockade from T6-T12 was produced in seven healthy males to study its effect on: 1) supine pulmonary function, 2) inspiratory effort, 3) hypercapnic ventilatory response, including mouth occlusion pressures with and without an expiratory load, and 4) ventilation during progressive exercise on a cycle ergometer. Studies during control and blocked states were performed on different days. Lower chest and abdominal wall paralysis was documented with electromyography. Findings include a minimal decrease in peak expiratory flows with intercostal blockade (P = 0.02), but no other changes in supine resting pulmonary function tests, inspiratory effort, or hypercapnic ventilatory response slopes. Minute ventilation, respiratory rate, and VT/TI during exercise were also minimally increased, indicating an increase in the drive to breathe, which was unrelated to a change in metabolic rate. During exercise, total time to exhaustion was decreased following intercostal nerve blockade. Bilateral intercostal nerve blockade produced minimal decreases in peak expiratory flow at rest in supine subjects. During seated exercise, there was a slight increase in respiratory drive, probably due to minor alterations in the mechanics of breathing induced by intercostal blockade. The authors conclude that, in healthy young subjects, intercostal nerve blockade does not exert a clinically significant adverse affect on pulmonary mechanics and that ventilatory function is well-maintained even at extremes of ventilatory demand.