Time of day does not impact spinal serotonin levels in humans.

Spinal serotonin enables neuro-motor recovery (i.e., plasticity) in patients with debilitating paralysis. While there exists time of day fluctuations in serotonin-dependent spinal plasticity, it is unknown, in humans, whether this is due to dynamic changes in spinal serotonin levels or downstream signaling processes. The primary objective of this study was to determine if time of day variations in spinal serotonin levels exists in humans. To assess this, intrathecal drains were placed in seven adults with cerebrospinal fluid (CSF) collected at diurnal (05:00 to 07:00) and nocturnal (17:00 to 19:00) intervals. High performance liquid chromatography with mass spectrometry was used to quantify CSF serotonin levels with comparisons being made using univariate analysis. From the 7 adult patients, 21 distinct CSF samples were collected: 9 during the diurnal interval and 12 during nocturnal. Diurnal CSF samples demonstrated an average serotonin level of 216.6 ± $ \pm $ 67.7 nM. Nocturnal CSF samples demonstrated an average serotonin level of 206.7 ± $ \pm $ 75.8 nM. There was no significant difference between diurnal and nocturnal CSF serotonin levels (p = .762). Within this small cohort of spine healthy adults, there were no differences in diurnal versus nocturnal spinal serotonin levels. These observations exclude spinal serotonin levels as the etiology for time of day fluctuations in serotonin-dependent spinal plasticity expression.

Buy or Build: Challenges Developing Consumer Digital Health Interventions.

BACKGROUND: Digital health interventions offer opportunities to improve collaborative care between clinicians and patients. Designing and implementing digital health interventions requires decisions about buying or building each technology-related component, all of which can lead to unanticipated issues. OBJECTIVES: This study aimed to describe issues encountered from our "buy or build" decisions developing two digital health interventions over different timeframes, designed to use patient-generated health data to: (1) improve hypertension control and (2) measure and improve adherence to HIV-related medications. METHODS: CONDUIT-HID (CONtrolling Disease Using Information Technology-Hypertension In Diabetes) was developed during 2010 to 2015 to allow patients receiving care from a multispecialty group practice to easily upload home blood pressure readings into their electronic health record and trigger clinician action if mean blood pressure values indicated inadequate control. USE-MI (Unobtrusive SEnsing of Medication Intake) was developed from 2016 to 2022 to allow entry of patients' HIV-related medication regimens, send reminders if patients had not taken their medications by the scheduled time(s), attempt to detect medication ingestion through machine learning analysis of smartwatch motion data, and present graphical adherence summaries to patients and clinicians. RESULTS: Both projects required multiple "buy or build" decisions across all system components, including data collection, transfer, analysis, and display. We used commercial, off-the-shelf technology where possible, but virtually all of these components still required substantial custom development. We found that, even though our projects spanned years, issues related to our "buy or build" decisions stemmed from several common themes, including mismatches between existing and new technologies, our use case being new or unanticipated, technology stability, technology longevity, and resource limitations. CONCLUSION: Those designing and implementing digital health interventions need to make numerous "buy or build" decisions as they create the technologies that underpin their intervention. These "buy or build" decisions, and the ensuing issues that will arise because of them, require careful planning, particularly if they represent an "edge case" use of existing commercial systems.

Synchronous Type 3 EVAR Endoleaks at Multiple Sites Following Transfemoral Transcatheter Aortic Valve Replacement.

We describe a complication following transfemoral transcatheter aortic valve replacement in a patient who underwent remote endovascular abdominal aortic aneurysm repair. This report highlights technical complications to be vigilant of when using intravascular catheterization in patients with previous aneurysm repair while also showcasing synchronous type 3 endoleaks at multiple sites. (Level of Difficulty: Advanced.).

Timing and durability of response to erenumab in patients with episodic migraine.

OBJECTIVE: We sought to evaluate temporal response patterns to erenumab treatment in patients with episodic migraine. BACKGROUND: Although many patients treated with erenumab experience onset of efficacy as early as 1 week, clinical benefits of migraine preventive therapies may accrue with continued treatment. Furthermore, details about the maintenance of clinical responses have not been reported. METHODS: This was a post hoc analysis of a 6-month, randomized, double-blind, placebo-controlled, phase 3 study of erenumab for the prevention of episodic migraine. We analyzed temporal responses to erenumab using a threshold of ≥50% reduction from baseline in monthly migraine days (MMDs). RESULTS: During the 6-month treatment period, 73.7% (230/312) and 79.6% (253/318) of patients in the erenumab 70 mg (n = 312) and 140 mg (n = 318) groups, respectively, achieved a response in at least 1 month. In this group of responders, at least half reached first monthly response (first month with ≥50% reduction from baseline in MMDs) by month 2 and at least 75% of them by month 3. The remainder responded in months 4-6. Of patients in the erenumab 70 and 140 mg groups, 35.3% (110/312) and 41.8% (133/318), respectively, responded over months 1-3 (mean response over first 3 months). Of these patients, 81.8% (90/110) and 81.9% (109/133) maintained this response over months 4-6 (mean response over last 3 months) in the 70 and 140 mg groups, respectively. Many patients who did not achieve an initial response (≥50% reduction from baseline in MMDs during month 1) responded later with continued treatment, with approximately one-half or more of initial nonresponders responding by months 4-6. CONCLUSIONS: These results support guidelines recommending at least 3 months following the initiation of erenumab for migraine prevention before the assessment of response.

Timing and durability of response to erenumab in patients with chronic migraine.

BACKGROUND: Erenumab is a human anti-calcitonin gene-related peptide receptor monoclonal antibody approved for migraine prevention. We sought to further assess the temporal patterns of response to erenumab in patients with chronic migraine (CM), specifically the onset and sustainability of monthly migraine day (MMD) response. METHODS: This is a post hoc analysis of a 12-week, randomized, double-blind, placebo-controlled study of erenumab for migraine prevention in patients with CM (≥15 headache days/month, including ≥8 migraine days/month). Onset and sustainability were assessed according to MMD reduction from baseline, with the following response categories: responders (≥50% reduction), partial responders (≥30% and <50%), or nonresponders (<30%). RESULTS: Among the erenumab 140 mg group (n = 187), 54.0% (101/187) achieved a response at any month during the study with a median time to onset of monthly response of 1 month. This improvement was maintained in most patients with continued treatment. An initial response was achieved at Month 1 by 28.3% (53/187) of patients; 69.8% (37/53) of whom maintained a response at Months 2 and 3. Although many patients responded early, some patients required longer treatment to achieve a response; 79.4% (27/34) of initial partial responders and 21.0% (21/100) of initial nonresponders subsequently achieved a response. Similar findings were observed for the erenumab 70mg group (n = 188). CONCLUSION: A majority of erenumab-treated patients with CM who achieved an initial response at Month 1 sustained this benefit. Many patients responded later with continued treatment. Our data support recommendations to assess outcomes after ≥3 months of preventive treatment with erenumab in CM.

Unearthing novel thiazolidinone building blocks as carboxylic acid bioisosteres.

Aim: Thiazolidinones were prepared as building blocks for the replacement of carboxylic acids. Materials & methods: Chemical syntheses of thiazolidinones were developed. In addition, the drug-likeness of the target compounds was evaluated in silico. Results: The prepared compounds included the novel structure 4; 5-(3-Iodophenylmethylene)-2,4-thiazolidinedione. Conclusion: Exploration of the methods required to synthesize thiazolidinone building blocks was completed. This work allows future generation of bioisosteric analogs of drugs.

Risk of natalizumab-associated progressive multifocal leukoencephalopathy.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is associated with natalizumab treatment. We quantified the risk of PML in patients with multiple sclerosis, according to the presence or absence of three risk factors: positive status with respect to anti-JC virus antibodies, prior use of immunosuppressants, and increasing duration of natalizumab treatment. METHODS: We used data from postmarketing sources, clinical studies, and an independent Swedish registry to estimate the incidence of PML among natalizumab-treated patients with multiple sclerosis, according to positive or negative status with respect to anti-JC virus antibodies, prior or no prior use of immunosuppressants, and duration of treatment (1 to 24 months vs. 25 to 48 months). Blood samples were available for anti-JC virus antibody testing from 5896 patients with multiple sclerosis and from 54 patients with multiple sclerosis who were treated with natalizumab and in whom PML later developed. RESULTS: As of February 29, 2012, there were 212 confirmed cases of PML among 99,571 patients treated with natalizumab (2.1 cases per 1000 patients). All 54 patients with PML for whom samples were available before the diagnosis were positive for anti-JC virus antibodies. When the risk of PML was stratified according to three risk factors, the risk of PML was lowest among the patients who were negative for anti-JC virus antibodies, with the incidence estimated to be 0.09 cases or less per 1000 patients (95% confidence interval [CI], 0 to 0.48). Patients who were positive for anti-JC virus antibodies, had taken immunosuppressants before the initiation of natalizumab therapy, and had received 25 to 48 months of natalizumab treatment had the highest estimated risk (incidence, 11.1 cases per 1000 patients [95% CI, 8.3 to 14.5]). CONCLUSIONS: Positive status with respect to anti-JC virus antibodies, prior use of immunosuppressants, and increased duration of natalizumab treatment, alone or in combination, were associated with distinct levels of PML risk in natalizumab-treated patients with multiple sclerosis. (Funded by Biogen Idec and Elan Pharmaceuticals.).

Low-contrast acuity measures visual improvement in phase 3 trial of natalizumab in relapsing MS.

OBJECTIVE: Low-contrast letter acuity has demonstrated treatment effects for sustained visual loss in trials of natalizumab for relapsing multiple sclerosis (MS). To test new therapies that may involve neuroprotection and repair, it will be essential for outcome measures to detect improvement as well as loss of visual function. We determined the effects of natalizumab on the frequency and cumulative probability of visual improvement using low-contrast letter acuity a prespecified tertiary outcome measure in AFFIRM. METHODS: AFFIRM was a randomized, double-blind, placebo-controlled, phase 3 trial that evaluated efficacy and safety of natalizumab (n=627) vs. placebo (n=315) in relapsing-remitting MS. Binocular acuities were measured at low-contrast (1.25%, 2.5%) and high-contrast visual acuity (VA). Improvement was defined as 12-week sustained increases from baseline. Clinically meaningful change for primary analyses was pre-defined as 7-letter improvement for low-contrast acuity and 5-letter improvement for VA based upon previous studies. RESULTS: Compared to placebo, cumulative probabilities of sustained visual improvement were greater in the natalizumab group by 57% for 2.5% contrast (21.7% vs. 14.0%; HR=1.57; 95% CI: 1.11-2.22; P=0.012) and 39% for 1.25% contrast (32.5% vs. 25.0%; HR=1.39; 95% CI: 1.07-1.82; P=0.014). The 5- and 10-letter low-contrast assessments did not show treatment differences. High-contrast VA was insensitive to changes over time and treatment effects. CONCLUSION: Low-contrast letter acuity detected treatment effects on sustained visual improvement in patients with relapsing MS. The ability to detect visual improvement and loss makes low-contrast acuity an important measure for future trials assessing the impact of therapy on this outcome and the potential of a therapy for neuroprotection and repair.

Anti-John Cunnigham virus antibody prevalence in multiple sclerosis patients: baseline results of STRATIFY-1.

OBJECTIVE: A study was undertaken to define the prevalence of anti-JC virus (JCV) antibodies in multiple sclerosis (MS) patients and to evaluate the analytical false-negative rate of a 2-step anti-JC virus antibody assay. METHODS: STRATIFY-1 is an ongoing, longitudinal, observational study of relapsing MS patients in the United States who are being treated or considering treatment with natalizumab. Baseline serum and plasma samples were collected for anti-JC virus antibody detection using an analytically validated, 2-step, virus-like particle-based enzyme-linked immunosorbent assay. Urine was collected for JC virus DNA detection. RESULTS: At baseline (n = 1,096), overall anti-JC virus antibody prevalence was 56.0% (95% confidence interval [CI], 53.0-59.0) in STRATIFY-1 patients, with an assay false-negative rate of 2.7% (95% CI, 0.9-6.2). Prevalence was significantly lower in females (53.4%; 95% CI, 49.9-56.8) than males (64.3%; 95% CI, 58.2-70.0) and increased with age, p = 0.0019 and p = 0.0001, respectively. Prevalence was similar in patients regardless of natalizumab exposure or prior immunosuppressant use, p = 0.9709 and p = 0.6632, respectively. STRATIFY-1 results were generally consistent with those observed in another large North American cohort, TYGRIS-US (n = 1,480). INTERPRETATION: Baseline results from STRATIFY-1 are consistent with other studies utilizing this assay that demonstrate a 50 to 60% prevalence of anti-JC virus antibodies, a low false-negative rate, and an association of increasing age and male gender with increasing anti-JC virus antibody prevalence. Neither natalizumab exposure nor prior immunosuppressant use appear to affect prevalence. Longitudinal data from STRATIFY-1 will confirm the stability of anti-JC virus antibody prevalence over time.

Rivaroxaban for thromboprophylaxis in patients undergoing major orthopedic surgery.

OBJECTIVE: To review the pharmacology, pharmacokinetics, and clinical efficacy/safety profile of rivaroxaban to inform health-care professionals of this new agent for the prevention of venous thromboembolism (VTE) in patients undergoing major orthopedic surgery. DATA SOURCES: A literature search was performed in PubMed/MEDLINE (1966-March 2010), International Pharmaceutical Abstracts (1970-March 2010), and EMBASE (1990-March 2010), limited to publications in English, using the search terms BAY 59-7939, rivaroxaban, factor Xa inhibitor, hip replacement, and/or knee replacement to identify literature sources. References from retrieved articles were evaluated to identify relevant literature. Unpublished Phase 3 clinical trials in progress (using www.clinicaltrials.gov) were also reviewed. The Food and Drug Administration, European Medicines Agency, and Health Canada Web sites were used to retrieve product monographs, regulatory guidance, and advisory committee briefing packets. STUDY SELECTION AND DATA EXTRACTION: All available studies relevant to the pharmacology, pharmacokinetics, and clinical safety/efficacy of rivaroxaban for the prevention of VTE in patients undergoing major orthopedic surgery were included, with preference for clinical data. DATA SYNTHESIS: Rivaroxaban use was significantly more effective for thromboprophylaxis in patients undergoing total knee replacement (TKR) or total hip replacement (THR), compared to enoxaparin for the composite incidence of deep vein thrombosis, nonfatal pulmonary embolism, all-cause mortality, and the rate of major VTE; bleeding events occurred at statistically similar rates. In Phase 3 studies, rivaroxaban 10 mg was administered orally 6-8 hours post-surgery and post-hemostasis. Thereafter, administration was once daily for 35 days in THR and 10-14 days in TKR. CONCLUSIONS: Rivaroxaban has demonstrated comparable safety and superior efficacy to the commonly used low-molecular-weight heparin, enoxaparin. Ongoing and future clinical trials will allow clinicians to further assess the efficacy, safety, and pharmacoeconomics of rivaroxaban.

Impact of obesity on outcomes after open surgical and endovascular abdominal aortic aneurysm repair.

BACKGROUND: This study examined impact of obesity on outcomes after abdominal aortic aneurysm repair. STUDY DESIGN: Data were obtained from the Veterans Affairs National Surgical Quality Improvement Program. Body mass index (BMI) was categorized according to National Institutes of Health guidelines. Multivariate regression adjusted for 40 other risk factors to analyze trends in complications and death within 30 days. RESULTS: We identified 2,201 patients undergoing 1,185 open and 1,016 endovascular aneurysm repairs (EVAR) for abdominal aortic aneurysms from January 2004 through December 2005. BMI distribution was identical in both groups and reflected national population statistics: approximately 30% were normal (BMI 18.5 to 24.9), 40% were overweight (25.0 to 29.9), and 30% were obese class I (30.0 to 34.9), II (35.0 to 39.9), or III (>/=40.0). After open repair, obesity of any class was independently predictive of wound complications (adjusted odds ratio = 2.4; 95% CI, 1.5 to 5.3; p = 0.002). Class III obesity was also an independent predictor or renal complications (adjusted odds rato = 6.3; 95% CI, 2.2 to 18.0; p < 0.0001) and cardiac complications (adjusted odds ratio = 4.5; 95% CI, 1.1 to 22.9; p = 0.045. After EVAR, obesity (any class) was predictive of wound complications (adjusted odds ratio = 3.1; 95% CI, 1.1 to 8.1; p = 0.026), but not predictive of other complications or death. Between the two types of operation, there were fewer complications and deaths after EVAR compared with open repair across all BMI categories, but outcomes were most disparate among the obese. CONCLUSIONS: Obesity is an independent risk factor that surgeons should consider during patient selection and operative planning for abdominal aortic aneurysm repair. Obese patients appear to particularly benefit from successful EVAR over open repair, but if open repair is required, special attention should be paid to cardiac risk, perioperative renal protection, and aggresive wound infection prevention measures.

Ustekinumab: treatment of adult moderate-to-severe chronic plaque psoriasis.

OBJECTIVE: To systematically review the pharmacology, pharmacokinetics, clinical efficacy, and safety profile of ustekinumab to inform pharmacists and other healthcare professionals of this new biologic therapy for psoriasis. DATA SOURCES: A search of PubMed/MEDLINE, EMBASE, and International Pharmaceutical Abstracts was performed through July 2009, limited to publications in English, using the search terms CNTO-1275, ustekinumab, interleukin-12, interleukin-23, and/or psoriasis to identify literature sources. References from the retrieved articles were also evaluated to identify relevant literature. An abstract from a Congress of the European Academy of Dermatology and Venereology and unpublished Phase 3 clinical trials in progress (using www.clinicaltrials.gov) were also reviewed. The Food and Drug Administration, European Medicines Agency, and Health Canada Web sites were used to retrieve product monographs, regulatory guidances, and advisory committee briefing packets. STUDY SELECTION AND DATA EXTRACTION: All available studies relevant to the pharmacology, pharmacokinetics, and clinical safety/efficacy of ustekinumab for the treatment of psoriasis were included, with preference for human data. DATA SYNTHESIS: Ustekinumab, an anti-interleukin-12/23 monoclonal antibody, achieved the primary endpoint of 75% reduction in the Psoriasis Area and Severity Index score in a large proportion of patients in the Phase 3 PHOENIX trials. Commensurate improvements were also seen in the Physician's Global Assessment and Dermatology Life Quality Index scores. These efficacy results were reproduced in the ACCEPT trial, demonstrating superiority of ustekinumab to etanercept. The frequency of adverse events was similar between ustekinumab and placebo; common adverse events reported included nasopharyngitis, upper respiratory tract infection, headache, arthralgia, cough, and injection site reactions. Phase 3 studies indicate that the optimal dosing appears to be 45 mg for patients weighing less than 100 kg or 90 mg for patients weighing more than 100 kg, with both doses administered subcutaneously. In these studies, the second dose was given 4 weeks after the first and then every 8-12 weeks thereafter, based upon response. CONCLUSIONS: Ustekinumab, a promising new therapy, reduces the extent and severity of psoriasis and was well tolerated in clinical trials. Ongoing clinical trials will allow clinicians to further assess the efficacy/safety profile of this novel biologic.

Hypoglycemia and clinical outcomes in patients with diabetes hospitalized in the general ward.

OBJECTIVE: Hypoglycemia is associated with adverse outcomes in mixed populations of patients in intensive care units. It is not known whether the same risks exist for diabetic patients who are less severely ill. In this study, we aimed to determine whether hypoglycemic episodes are associated with higher mortality in diabetic patients hospitalized in the general ward. RESEARCH DESIGN AND METHODS: This retrospective cohort study analyzed 4,368 admissions of 2,582 patients with diabetes hospitalized in the general ward of a teaching hospital between January 2003 and August 2004. The associations between the number and severity of hypoglycemic (

Successful devascularization of carotid body tumors by covered stent placement in the external carotid artery.

Management of highly vascular carotid body tumors can involve pre-operative percutaneous embolization before definitive surgical resection. This step reduces tumor size, reduces operative blood loss, and makes for a less hazardous dissection with the goal of reducing morbidity and mortality. The effectiveness of a recently described technique of interrupting vascular supply via covered stent placement in the external carotid artery is further described in a series of three recent cases. This technique may be useful for large tumors with a primary blood supply from the external carotid since it avoids the intracranial embolic risk of coils used for this purpose.

Prehospital rapid sequence intubation for head trauma: conditions for a successful program.

BACKGROUND: Recent reports have questioned the safety and efficacy of prehospital rapid sequence intubation (RSI) for patients with head trauma. The purpose of this study is to determine the rate of successful prehospital RSI, associated complications, and delays in transport of critically injured trauma patients treated by a select, well-trained group of paramedics with frequent exposure to this procedure and a rigorous quality control system. METHODS: A helicopter paramedic group's database of patient flight records (1999 to 2003) was merged with registry data of a suburban Level I trauma center. Both databases included comprehensive performance improvement data. After Institutional Review Board approval, data were analyzed to determine RSI success rate, impact on oxygenation, delays in transport and complications associated with attempted RSI. Attempted RSI was defined as any insertion of the laryngoscope into the oropharynx. RESULTS: In all, 1,117 trauma patients were transported. One hundred and seventy-five had attempted RSI (74% male, mean age 31.1 +/- 19.2 years, 91% blunt trauma, 88% with Head/Neck AIS >or=2, mean Injury Severity Score 25.6, mean scene Glasgow Coma Scale score 4.8 +/- 2.4). One hundred and sixty-nine patients (96.6%) had successful scene RSI. Seventy percent were intubated on the first attempt, 89% by the second attempt, and 96% by the third attempt. Of the six patients (3.4% overall) who failed RSI, (2.3% overall) had scene cricothyroidotomy and two (1.1% overall) were managed by bag-valve mask. Complications included five (2.9%) right mainstem intubations and 2 (1.2%) endotracheal tube dislodgments en route. There were no esophageal intubations. Four patients in extremis (2.3%) had arterial desaturations associated with RSI. Arterial blood gas analyzed upon arrival revealed (mean pCO2 36.6 +/- 8, median 37). Attempted RSI was associated with a mean of 6 minutes of added scene time. CONCLUSION: Prehospital RSI for trauma patients can be safely and effectively performed with low rates of complication and without significant delay in transport. This study suggests that resources for prehospital airway management should be focused on training, regular experience, and close monitoring of a limited group of providers, thereby maximizing their exposure and experience with this procedure. This is particularly important given the high rates of traumatic brain injury encountered.