The utility of ChatGPT as a generative medical translator.

PURPOSE: Large language models continue to dramatically change the medical landscape. We aimed to explore the utility of ChatGPT in providing accurate, actionable, and understandable generative medical translations in English, Spanish, and Mandarin pertaining to Otolaryngology. METHODS: Responses of GPT-4 to commonly asked patient questions listed on official otolaryngology clinical practice guidelines (CPG) were evaluated with the Patient Education materials Assessment Tool-printable (PEMAT-P.) Additional critical elements were identified a priori to evaluate ChatGPT's accuracy and thoroughness in its responses. Multiple fluent speakers of English, Mandarin, and Spanish evaluated each response generated by ChatGPT. RESULTS: Total PEMAT-P scores differed between English, Mandarin, and Spanish GPT-4 generated responses depicting a moderate effect size of language, Eta-Square 0.07 with scores ranging from 73 to 77 (P-value = 0.03). Overall understandability scores did not differ between English, Mandarin, and Spanish depicting a small effect size of language, Eta-Square 0.02 scores ranging from 76 to 79 (P-value = 0.17), nor did overall actionability scores Eta-Square 0 score ranging 66-73 (P-value = 0.44). Overall a priori procedure-specific responses similarly did not differ between English, Spanish, and Mandarin Eta-Square 0.02 scores ranging 61-78 (P-value = 0.22). CONCLUSION: GPT-4 produces accurate, understandable, and actionable outputs in English, Spanish, and Mandarin. Responses generated by GPT-4 in Spanish and Mandarin are comparable to English counterparts indicating a novel use for these models within Otolaryngology, and implications for bridging healthcare access and literacy gaps. LEVEL OF EVIDENCE: IV.

Clinicodemographic Predictors of Tracheotomy Tube Size and Decannulation: A Multiinstitutional Retrospective Cohort Study on Tracheotomy.

OBJECTIVE: We aimed to discern clinico-demographic predictors of large (≥8) tracheostomy tube size placement, and, secondarily, to assess the effect of large tracheostomy tube size and other parameters on odds of decannulation before hospital discharge. SUMMARY OF BACKGROUND DATA: Factors determining choice of tracheostomy tube size are not well-characterized in the current literature, despite evidence linking large tracheostomy tube size with posttracheotomy tracheal stenosis. The effect of tracheostomy tube size on timing of decannulation is also unknown, an important consideration given reported associations between endotracheal tube size and probability of failed extubation. METHODS: We collected information pertaining to patients who underwent tracheotomy at 1 of 10 U.S. health care institutions between 2010 and 2019. Tracheostomy tube size was dichotomized (≥8 and <8). Multivariable logistic regression models were fit to identify predictors of (1) large tracheostomy tube size, and (2) decannulation before hospital discharge. RESULTS: The study included 5307 patients, including 2797 (52.7%) in the large tracheostomy cohort. Patient height (odds ratio [OR] = 1.060 per inch; 95% confidence interval [CI] 1.041-1.070) and obesity (1.37; 95% CI 1.1891.579) were associated with greater odds of large tracheostomy tube; otolaryngology performing the tracheotomy was associated with significantly lower odds of large tracheostomy tube (OR = 0.155; 95% CI 0.131-0.184). Large tracheostomy tube size (OR = 1.036; 95% CI 0.885-1.213) did not affect odds of decannulation. CONCLUSIONS: Obesity was linked with increased likelihood of large tracheostomy tube size, independent of patient height. Probability of decannulation before hospital discharge is influenced by multiple patient-centric factors, but not by size of tracheostomy tube.

Complications Associated with AMBU™ Scope Use: An FDA MAUDE Analysis.

Ambu® aScope™ is a disposable flexible videoscope used for a wide range of medical procedures. However, adverse events associated with this device can occur. The Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database was explored for patient-related adverse events associated with Ambu® aScope™ use between January 1, 2000 and December 15, 2023. Search terms included "Ambu" and "Ascope." Thirty unique adverse events were identified. Twenty-one of the events were associated with patient injury, and 9 with device malfunction. Eight patient-reported problems were documented as foreign bodies, 3 events as airway obstruction, desaturation, or hypoxic events, and 1 event as anxiety/cardiac arrest. The remaining 18 reported insufficient information other than associated with patient injury. We found that Ambu® aScope™ flexible nasolaryngoscopes and bronchoscopes are a common and effective tool for airway evaluations that may infrequently serve as a rare form of foreign body with potentially life-threatening consequences.

Impact of Obesity on Timing of Tracheotomy: A Multi-institutional Retrospective Study.

OBJECTIVE: To examine the impact of increased body mass index (BMI) on (1) tracheotomy timing and (2) short-term surgical complications requiring a return to the operating room and 30-day mortality utilizing data from the Multi-Institutional Study on Tracheotomy (MIST). METHODS: A retrospective analysis of patients from the MIST database who underwent surgical or percutaneous tracheotomy between 2013 and 2016 at eight institutions was completed. Unadjusted and adjusted logistic regression analyses were used to assess the impact of obesity on tracheotomy timing and complications. RESULTS: Among the 3369 patients who underwent tracheotomy, 41.0% were obese and 21.6% were morbidly obese. BMI was associated with higher rates of prolonged intubation prior to tracheotomy accounting for comorbidities, indication for tracheotomy, institution, and type of tracheostomy (p = 0.001). Morbidly obese patients (BMI ≥35 kg/m2) experienced a longer duration of intubation compared with patients with a normal BMI (median days intubated [IQR 25%-75%]: 11.0 days [7-17 days] versus 9.0 days [5-14 days]; p < 0.001) but did not have statistically higher rates of return to the operating room within 30 days (p = 0.12) or mortality (p = 0.90) on multivariable analysis. This same finding of prolonged intubation was not seen in overweight, nonobese patients when compared with normal BMI patients (median days intubated [IQR 25%-75%]: 10.0 days [6-15 days] versus 10.0 days [6-15 days]; p = 0.36). CONCLUSION: BMI was associated with increased duration of intubation prior to tracheotomy. Although morbidly obese patients had a longer duration of intubation, there were no differences in return to the operating room or mortality within 30 days. LEVEL OF EVIDENCE: III Laryngoscope, 2024.

SNOT-22 subdomain outcomes following treatment for sinonasal malignancy: A prospective, multicenter study.

BACKGROUND: Patients with sinonasal malignancy (SNM) present with significant sinonasal quality of life (QOL) impairment. Global sinonasal QOL as measured by the 22-item Sinonasal Outcomes Test (SNOT-22) has been shown to improve with treatment. This study aims to characterize SNOT-22 subdomain outcomes in SNM. METHODS: Patients diagnosed with SNM were prospectively enrolled in a multi-center patient registry. SNOT-22 scores were collected at the time of diagnosis and through the post-treatment period for up to 5 years. Multivariable regression analysis was used to identify drivers of variation in SNOT-22 subdomains. RESULTS: Note that 234 patients were reviewed, with a mean follow-up of 22 months (3 months-64 months). Rhinologic, psychological, and sleep subdomains significantly improved versus baseline (all p < 0.05). Subanalysis of 40 patients with follow-up at all timepoints showed statistically significant improvement in rhinologic, extra-nasal, psychological, and sleep subdomains, with minimal clinically important difference met between 2 and 5 years in sleep and psychological subdomains. Adjuvant chemoradiation was associated with worse outcomes in rhinologic (adjusted odds ratio (5.22 [1.69-8.66])), extra-nasal (2.21 [0.22-4.17]) and ear/facial (5.53 [2.10-8.91]) subdomains. Pterygopalatine fossa involvement was associated with worse outcomes in rhinologic (3.22 [0.54-5.93]) and ear/facial (2.97 [0.32-5.65]) subdomains. Positive margins (5.74 [2.17-9.29]) and surgical approach-combined versus endoscopic (3.41 [0.78-6.05])-were associated with worse psychological outcomes. Adjuvant radiation (2.28 [0.18-4.40]) was associated with worse sleep outcomes. CONCLUSIONS: Sinonasal QOL improvements associated with treatment of SNM are driven by rhinologic, extra-nasal, psychological, and sleep subdomains.

Factors Associated With Otolaryngologists Performing Tracheotomy.

Importance: Tracheotomies are frequently performed by nonotolaryngology services. The factors that determine which specialty performs the procedure are not defined in the literature but may be influenced by tracheotomy approach (open vs percutaneous) and other clinicodemographic factors. Objective: To evaluate demographic and clinical characteristics associated with tracheotomies performed by otolaryngologists compared with other specialists and to differentiate those factors from factors associated with use of open vs percutaneous tracheotomy. Design, Setting, and Participants: This multicenter, retrospective cohort study included patients aged 18 years or older who underwent a tracheotomy for cardiopulmonary failure at 1 of 8 US academic institutions between January 1, 2013, and December 31, 2016. Data were analyzed from September 2022 to July 2023. Exposure: Tracheotomy. Main Outcomes and Measures: The primary outcome was factors associated with an otolaryngologist performing tracheotomy. The secondary outcome was factors associated with use of the open tracheotomy technique. Results: A total of 2929 patients (mean [SD] age, 57.2 [17.2] years; 1751 [59.8%] male) who received a tracheotomy for cardiopulmonary failure (652 [22.3%] performed by otolaryngologists and 2277 [77.7%] by another service) were analyzed. Although 1664 of all tracheotomies (56.8%) were performed by an open approach, only 602 open tracheotomies (36.2%) were performed by otolaryngologists. Most tracheotomies performed by otolaryngologists (602 of 652 [92.3%]) used the open technique. Multivariable regression analysis revealed that self-reported Black race (odds ratio [OR], 1.89; 95% CI, 1.52-2.35), history of neck surgery (OR, 2.71; 95% CI, 2.06-3.57), antiplatelet and/or anticoagulation therapy (OR, 1.74; 95% CI, 1.29-2.36), and morbid obesity (OR, 1.54; 95% CI, 1.24-1.92) were associated with greater odds of an otolaryngologist performing tracheotomy. In contrast, history of neck surgery (OR, 1.36; 95% CI, 0.96-1.92), antiplatelet and/or anticoagulation therapy (OR, 0.80; 95% CI, 0.56-1.14), and morbid obesity (OR, 0.94; 95% CI, 0.74-1.19) were not associated with undergoing open tracheotomy when performed by any service, and Black race (OR, 0.56; 95% CI, 0.44-0.71) was associated with lesser odds of an open approach being used. Age-adjusted Charlson Comorbidity Index score greater than 4 was associated with greater odds of both an otolaryngologist performing tracheotomy (OR, 1.26; 95% CI, 1.03-1.53) and use of the open tracheotomy technique (OR, 1.48, 95% CI, 1.21-1.82). Conclusions and Relevance: In this study, otolaryngologists were significantly more likely than other specialists to perform a tracheotomy for patients with history of neck surgery, morbid obesity, and ongoing anticoagulation therapy. These findings suggest that patients undergoing tracheotomy performed by an otolaryngologist are more likely to present with complex and challenging clinical characteristics.

Cochlear Implantation and Risk of Falls in Older Adults.

OBJECTIVE: To examine whether cochlear implantation (CI) increases the risk of clinically significant falls in older adults. STUDY DESIGN: Retrospective analysis of deidentified administrative claims from a US commercial insurance database. SETTING: Nationwide deidentified private insurance claims database (Clinformatics Data Mart; Optum). METHODS: Patients undergoing CI were identified through Current Procedural Terminology codes. Number of days with falls resulting in health care expenditure were counted 1 year pre- and post-CI. Generalized estimating equation Poisson regression was used to determine medical and sociodemographic predictors for fall days, including age, sex, race, and income, with pre- vs post-CI status. RESULTS: Between 2003 and 2019, 3773 patients aged >50 years underwent CI. An overall 139 (3.68%) patients recorded at least 1 fall diagnosis a year pre-CI, and 142 (3.76%) recorded at least 1 fall diagnosis post-CI. The average number of days with fall diagnoses per patient with a recorded fall was 3.12 pre-CI and 2.04 post-CI. In bivariate analysis, age (P < .0001) and Charlson Comorbidity Index (P < .0001) were predictive of falls, but sex (P < .10), race (P < .72), and income (P < .51) were not. Poisson regression demonstrated a statistically significant association between Charlson Comorbidity Index and days with fall diagnoses (risk ratio, 1.39 [95% CI, 1.30-1.49]; P < .0001]). No statistically significant difference in falls was seen pre- vs post-CI (risk ratio, 0.67 [95% CI, 0.34-1.33]; P < .25]). Age also was not predictive of falls in multivariate analysis. CONCLUSIONS: CI does not appear to increase the risk of falls in older adults. Patient comorbidities correlate most strongly with fall risk and should be considered in patient selection for CI.

Virgin ß-Cells at the Neogenic Niche Proliferate Normally and Mature Slowly.

Proliferation of pancreatic ß-cells has long been known to reach its peak in the neonatal stages and decline during adulthood. However, ß-cell proliferation has been studied under the assumption that all ß-cells constitute a single, homogenous population. It is unknown whether a subpopulation of ß-cells retains the capacity to proliferate at a higher rate and thus contributes disproportionately to the maintenance of mature ß-cell mass in adults. We therefore assessed the proliferative capacity and turnover potential of virgin ß-cells, a novel population of immature ß-cells found at the islet periphery. We demonstrate that virgin ß-cells can proliferate but do so at rates similar to those of mature ß-cells from the same islet under normal and challenged conditions. Virgin ß-cell proliferation rates also conform to the age-dependent decline previously reported for ß-cells at large. We further show that virgin ß-cells represent a long-lived, stable subpopulation of ß-cells with low turnover into mature ß-cells under healthy conditions. Our observations indicate that virgin ß-cells at the islet periphery can divide but do not contribute disproportionately to the maintenance of adult ß-cell mass.

Functional Outcomes of Septal Extension Grafting in Aesthetic Rhinoplasty: A Cohort Analysis.

Background: Septal extension grafts (SEGs) are used widely in rhinoplasty as a means of controlling tip position. Grafts positioned in a side-to-side configuration may cause nasal airway obstruction. Methods: Retrospective cohort analysis of patients undergoing cosmetic rhinoplasty. Patients undergoing SEG placement were grouped according to completion of the Nasal Obstruction Symptom Evaluation (NOSE) or Standardized Cosmesis and Health Nasal Outcomes Survey (SCHNOS). The latter has a cosmetic (C) and functional (O) domain. Each group was matched to a cohort that did not undergo SEG placement using criteria: preoperative NOSE or SCHNOS-O score, age, and gender. Patient demographics and outcomes, including NOSE, SCHNOS, and visual analog scale (VAS) scores, were compared between SEG and no-SEG groups using univariate and multivariate analyses. If patients underwent placement of an SEG and complained of obstruction, the laterality of the graft in relation to the complaint was examined. Results: SEGs were placed in 79 patients, of whom 77 completed the NOSE survey and 37 completed the SCHNOS-O both pre- and postoperatively. These patients were matched to patients without SEGs. For both the SCHNOS and NOSE-matched cohorts, functional outcomes (NOSE, SCHNOS-O, and VAS-F) did not significantly differ between SEG and no-SEG groups. These findings were also observed when patients were stratified by cosmetic surgery alone versus combined functional and cosmetic surgery. On multivariate linear regression analysis, when accounting for intraoperative techniques, there was no difference in postoperative NOSE or SCHNOS-O outcomes between the SEG and no-SEG cohorts. Side of postoperative nasal obstruction did not correlate with side of SEG placement. Conclusion: SEGs, when used in a unilateral side-to-side configuration, yield excellent aesthetic results without compromising functional outcomes.

ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models.

PURPOSE: To evaluate the preclinical pharmacokinetics and antitumor efficacy of a novel orally bioavailable poly(ADP-ribose) polymerase (PARP) inhibitor, ABT-888. EXPERIMENTAL DESIGN: In vitro potency was determined in a PARP-1 and PARP-2 enzyme assay. In vivo efficacy was evaluated in syngeneic and xenograft models in combination with temozolomide, platinums, cyclophosphamide, and ionizing radiation. RESULTS: ABT-888 is a potent inhibitor of both PARP-1 and PARP-2 with K(i)s of 5.2 and 2.9 nmol/L, respectively. The compound has good oral bioavailability and crosses the blood-brain barrier. ABT-888 strongly potentiated temozolomide in the B16F10 s.c. murine melanoma model. PARP inhibition dramatically increased the efficacy of temozolomide at ABT-888 doses as low as 3.1 mg/kg/d and a maximal efficacy achieved at 25 mg/kg/d. In the 9L orthotopic rat glioma model, temozolomide alone exhibited minimal efficacy, whereas ABT-888, when combined with temozolomide, significantly slowed tumor progression. In the MX-1 breast xenograft model (BRCA1 deletion and BRCA2 mutation), ABT-888 potentiated cisplatin, carboplatin, and cyclophosphamide, causing regression of established tumors, whereas with comparable doses of cytotoxic agents alone, only modest tumor inhibition was exhibited. Finally, ABT-888 potentiated radiation (2 Gy/d x 10) in an HCT-116 colon carcinoma model. In each model, ABT-888 did not display single-agent activity. CONCLUSIONS: ABT-888 is a potent inhibitor of PARP, has good oral bioavailability, can cross the blood-brain barrier, and potentiates temozolomide, platinums, cyclophosphamide, and radiation in syngeneic and xenograft tumor models. This broad spectrum of chemopotentiation and radiopotentiation makes this compound an attractive candidate for clinical evaluation.

Organic anion transporting polypeptide 1B1 activity classified by SLCO1B1 genotype influences atrasentan pharmacokinetics.

OBJECTIVE: Our objective was to learn whether genetic polymorphisms of metabolic enzymes or transport proteins provide a mechanistic understanding of the in vivo disposition of atrasentan, a selective endothelin A receptor antagonist. METHODS: Atrasentan uptake was measured in HeLa cells transfected to express major alleles of organic anion transporting polypeptide 1B1 (OATP1B1). The results were used to classify individuals as extensive, intermediate, or poor OATP1B1 transporters according to their SLCO1B1 genotypes. Analysis of covariance including genotype, study, age, weight, sex, and ethnicity was used to identify factors influencing atrasentan single-dose (n = 44) and steady-state (n = 38) pharmacokinetic parameters. Genotypes for cytochrome P450 3A5, uridine diphosphate-glucuronosyltransferase (UGT) 1A1, UGT2B4, UGT2B15, adenosine triphosphate-binding cassette subfamily B (ABCB) 1, solute carrier organic anion transporter (SLCO) 1B1, and solute carrier family 22 (SLC22) A2 were each assessed. RESULTS: Single-dose atrasentan exposure (P = .0244), steady-state atrasentan exposure (P = .0108), and maximum postdose plasma concentration (P = .0002) were associated with OATP1B1 activity classified by SLCO1B1 genotype. No other tested genotypes were observed to be associated with both single-dose and steady-state atrasentan pharmacokinetics. CONCLUSIONS: OATP1B1 is a meaningful factor for atrasentan disposition. Individuals may be classified as having extensive, intermediate, or poor OATP1B1 transport phenotypes according to SLCO1B1 genotypes. Increased exposures of OATP1B1 substrates might be expected in individuals who have the poor transporter phenotype or are treated with an OATP1B1 inhibitor.

Phase 1 study of ABT-751, a novel microtubule inhibitor, in patients with refractory hematologic malignancies.

PURPOSE: ABT-751 is an oral antimitotic agent that binds to the colchicine site on beta-tubulin. A phase 1 study was conducted to determine the maximum tolerated dose and toxicities of ABT-751 in patients with advanced myelodysplastic syndrome and relapsed or refractory acute leukemias. STUDY DESIGN: Thirty-two patients were treated: nine with 100 (n = 3), 125 (n = 3), or 150 mg/m(2) (n = 3) of ABT-751 given orally once daily for 7 days every 3 weeks and 23 with 75 (n = 3), 100 (n = 3), 125 (n = 5), 150 (n = 5), 175 (n = 3), or 200 mg/m(2) (n = 4) of ABT-751 given orally once daily for 21 days every 4 weeks. Consenting patients had pharmacogenetic sampling and enumeration of circulating endothelial cells (CEC). RESULTS: Dose-limiting toxicity consisted of ileus in one patient at 200 mg/m(2), with a subsequent patient developing grade 2 constipation at the same dose level. One patient with relapsed acute myelogenous leukemia achieved a complete remission that was sustained for 2 months. Four other patients had transient hematologic improvements, consisting of a decrease in peripheral blood blasts and improvements in platelet counts. CEC number was reduced in three patients with a concomitant reduction in peripheral blasts. A previously undescribed nonsynonymous single nucleotide polymorphism, encoding Ala(185)Thr, was identified in exon 4 of the beta-tubulin gene, TUBB, in three other patients. The recommended phase 2 dose in hematologic malignancies is 175 mg/m(2) daily orally for 21 days every 4 weeks. CONCLUSION: Further assessment of ABT-751, especially in combination with other agents, in patients with acute leukemias is warranted.

Psychological and autonomic effects of art making in college-aged students.

BACKGROUND AND OBJECTIVES: Anxiety disorders comprise the most common category of mental illness among US young adults. Art making might be one method to help reduce anxiety, but the few studies investigating this have used only subjective measures of anxiety. DESIGN: This study employed both subjective (self-reported state anxiety from the State-Trait Anxiety Inventory) and objective (heart rate variability) measures to assess whether 30-minute periods of art making reduced anxiety in 47 first-year college students prior to their final examinations. METHODS: Students participated in free-form painting, mandala coloring, clay modeling, and control sessions. RESULTS: Repeated-measures ANOVA with post hoc analysis revealed significantly greater pre- to post-session reductions in anxiety for all three types of art-making sessions than for the control session, as measured objectively. Measured subjectively, only free-form painting yielded a significant decrease in anxiety compared to the control session. CONCLUSIONS: Given the health benefits of anxiety reduction, further study is warranted to determine the duration of art making's anxiety-reducing effect.

Assessment of airway caliber and bronchodilator responsiveness in subjects with spinal cord injury.

STUDY OBJECTIVES: Previous spirometric findings among subjects with chronic tetraplegia that reduction in FEV1 and maximal forced expiratory flow, mid-expiratory phase (FEF(25-75%)) correlated with airway hyperresponsiveness to histamine, and that many of these subjects exhibited significant bronchodilator responsiveness, suggested that baseline airway caliber was low in this population. To better evaluate airway dynamics in patients with spinal cord injury, we used body plethysmography to determine specific airway conductance (sGaw), a less effort-dependent and more reflective surrogate marker of airway caliber. DESIGN: Cohort study. SETTING: Veterans Affairs medical center. PARTICIPANTS: Thirty clinically stable subjects with chronic spinal cord injury, including 15 subjects with tetraplegia (injury at C4-C7) and 15 subjects with low paraplegia (injury below T7), participated in the study. Fifteen able-bodied individuals served as a control group. INTERVENTIONS: Subjects underwent baseline assessment of spirometric and body plethysmographic parameters. Repeat measurements were performed among subjects with tetraplegia and paraplegia before and 30 min after receiving aerosolized ipratropium bromide (2.5 mL 0.02% solution; 12 subjects) or normal saline solution (2.5 mL; 6 subjects). MEASUREMENTS AND RESULTS: We found that subjects with tetraplegia had significantly reduced mean values for sGaw (0.16 cm H2O/s), total lung capacity, FVC, FEV1, and FEF(25-75%) compared to subjects in the other two groups. Subjects with tetraplegia who received ipratropium bromide experienced significant increases in sGaw (135%), FEV1 (12%; 260 mL), and FEF(25-75%) (27%). Significant, though far smaller, increases in sGaw (19%) were found among subjects with paraplegia. No discernable change in any pulmonary function parameter was found following the administration of normal saline solution. CONCLUSIONS: Subjects with tetraplegia, as opposed to those with low paraplegia, have reduced baseline airway caliber due to heightened vagomotor airway tone, which we hypothesize is the result of the interruption of sympathetic innervation to the lungs, and/or from low circulating epinephrine levels.

Autonomic nervous system function among individuals with acute musculoskeletal injury.

OBJECTIVE: To determine differences in peripheral and cardiovascular autonomic function between individuals with acute musculoskeletal injury (<1 week) and healthy controls. METHODS: Autonomic cardiovascular modulation, baroreceptor sensitivity, skin conductance, and peripheral skin temperature were obtained in 6 subjects with acute musculoskeletal injury and 6 age- and sex-matched controls. Power spectral analysis was performed on both beat-to-beat R-R intervals and continuous systolic blood pressure (SBP) peaks. Baroreceptor sensitivity was derived using both heart rate and blood pressure spectral analysis components. RESULTS: The SD of R-R intervals was significantly different for the acute injury group relative to controls (49.8 +/- 10.5 vs 76.8 +/- 12.7 ms; P < .01). Continuous SBP peaks and skin conductance (sympathetic vasomotor and sudomotor indices, respectively) were significantly higher (59.6 +/- 6.7 vs 23.8 +/- 6.4 mm Hg2 /Hz, and 3.87 +/- 1.04 vs 2.19 +/- 0.3 mhos; P < .01, respectively) and baroreceptor sensitivity lower (0.97 +/- 0.07 vs 1.10 +/- 0.08 mm Hg; P < .02) in the acute injury group compared with controls. Regression analysis revealed a significant relationship between skin conductance and continuous SBP peaks (r = 0.75; P < .01). CONCLUSIONS: These findings suggest that interaction between cutaneous and vasomotor sympathetic neurons in response to acute musculoskeletal injury, reflected as increased afferent input from sensitized nociceptors and other sensory neurons, results in alterations in autonomic function.

Impact of CYP2D6 intermediate metabolizer alleles on single-dose desipramine pharmacokinetics.

This study utilized cytochrome P450 2D6 (CYP2D6) genotypes to explain variability of desipramine pharmacokinetics in a cohort of non-poor metabolizer individuals. In an interaction study utilizing desipramine as a probe, genotyping for the CYP2D6*3, *4, *5 and *6 alleles was used to screen out CYP2D6 poor metabolizers. Individuals were categorized according to these and additional alleles (CYP2D6*2, *9, *10, *17, *41 and x2). Genotypes of individuals heterozygous for two or three of *2, *17 and *41 alleles were confirmed by molecular haplotyping. Pharmacokinetic parameters of desipramine were analysed according to CYP2D6 category. Molecular haplotyping was necessary to definitively categorize four of 16 individuals. A subject who had unusually high plasma elimination half-time, exposure and metabolic ratios carried an intermediate metabolizer (IM) *9 allele in combination with a non-functional allele. This combination has a population frequency of less than 1 : 200. Individuals with *1/*1, *1/*2 and *2/*2 genotypes had lower than average plasma elimination half-time, exposure and metabolic ratios. For desipramine, additional genotyping of CYP2D6 IM alleles helped define subgroups of the CYP2D6-positive cohort. This suggests that genotyping for IM alleles will aid in interpretation of clinical trials involving CYP2D6 substrates. Due to the diversity of IM alleles, molecular haplotyping may be necessary to fully characterize CYP2D6 genotype-phenotype relationships.

CYP3A5 genotype has a dose-dependent effect on ABT-773 plasma levels.

BACKGROUND: The metabolizing enzyme cytochrome P450 (CYP) 3A5 is polymorphically expressed as a result of genetic variants that do not encode functional protein. Because of overlapping substrate specificity with CYP3A4 and the multidrug efflux pump P-glycoprotein, the importance of CYP3A5 genetic polymorphism for pharmacokinetics is controversial. OBJECTIVE: Our objective was to determine whether genetic polymorphisms in CYP3A5 or MDR-1 (which encodes P-glycoprotein) influence the drug levels of ABT-773, a ketolide antibiotic that is a substrate for both CYP3A and P-glycoprotein. METHODS: Healthy volunteers given 3 different oral dose levels of ABT-773 were genotyped at 2 common CYP3A5 and 7 common MDR-1 polymorphisms. Individuals were categorized as CYP3A5-positive if they carried at least 1 functional CYP3A5*1 allele and as CYP3A5-negative if they did not. Area under the plasma concentration-time curves (AUCs) from 0 to 6 hours (AUC(t)) and maximum postdose plasma concentration (C(max)) after a single dose and on day 5 of a twice-daily regimen were calculated and correlated with genotypes. RESULTS: ABT-773 AUC(t) and C(max) were, on average, higher in CYP3A5-negative subjects given 450 mg ABT-773 (n = 9) than in CYP3A5-positive subjects with identical doses (n = 8). The relationship for AUC(t) was statistically significant both after a single dose (geometric mean and 95% confidence interval [CI], 5.0 microg.h/mL [3.9-6.4 microg.h/mL] versus 2.8 microg.h/mL [1.8-4.3 microg.h/mL]; P =.03) and on the fifth day of twice-daily dosing (12.4 microg.h/mL [8.7-17.6 microg.h/mL] versus 7.4 microg.h/mL [5.5-9.8 microg.h/mL], P =.04). The relationship for C(max) was statistically significant after a single dose (1220 microg/mL [867-1167 microg/mL] versus 727 microg/mL [506-1044 microg/mL], P =.04) and showed a trend in the same direction on the fifth day of twice-daily dosing (2566 microg/mL [1813-3631 microg/mL] versus 1621 microg/mL [1122-2343 microg/mL], P =.07). In contrast, AUC(t) and C(max) were not significantly different between CYP3A5-positive and CYP3A5-negative individuals given 150 mg or 300 mg ABT-773. ABT-773 plasma levels did not trend with MDR-1 genotypes. CONCLUSIONS: These results suggest that CYP3A5 genotype may be an important determinant of in vivo drug disposition and that this effect may be dose-dependent.

Relationship of respiratory symptoms with smoking status and pulmonary function in chronic spinal cord injury.

OBJECTIVE: The relationship of respiratory symptoms to pulmonary function parameters and smoking status was assessed in subjects with chronic (>1 year) spinal cord injury (SCI). METHODS AND PARTICIPANTS: As part of their annual physical examination, subjects were queried regarding respiratory symptoms and underwent pulmonary function studies. The 180 patients who successfully completed pulmonary function testing were evaluated, including 79 subjects with tetraplegia (56 nonsmokers and 23 smokers) and 101 subjects with paraplegia (78 nonsmokers and 23 smokers). FINDINGS: Logistic-regression analysis revealed the following independent predictors of breathlessness: level of injury (tetraplegia, paraplegia, odds ratio = 3.5, P < 0.0015), cough combined with phlegm and/or wheeze (CPWZ, odds ratio = 3.1, P < 0.015), total lung capacity percentage predicted (TLC <60%, odds ratio = 3.9, P < 0.02), and expiratory reserve volume (ERV < 0.6 L, odds ratio = 2.5, P < 0.05). Independent predictors of CPWZ were current smoking (odds ratio = 3.3, P < 0.004), breathlessness (odds ratio = 2.9, P < 0.03), and forced expiratory volume in 1 second (FEV1 <60%, odds ratio = 3.2, P < 0.01). CONCLUSION: Altered respiratory mechanics associated with tetraplegia contribute to breathlessness, restrictive ventilatory impairment (low TLC%), and reduced expiratory muscle strength (low ERV). These factors apparently overshadow adverse effects caused by smoking. Conversely, smoking and reduction of airflow (low FEV1%) were predictive of CPWZ, symptoms commonly associated with cigarette use.

Frequency of the frame-shifting CYP2D7 138delT polymorphism in a large, ethnically diverse sample population.

Cytochrome P450 2D7 (CYP2D7) has long been considered a pseudogene. A recent report described an indel polymorphism (CYP2D7 138delT) that causes a frameshift generating an open reading frame and functional protein. This polymorphism was observed in 6 of 12 samples from an Indian population. Individuals with the 138delT polymorphism expressed CYP2D7 protein from a brain-specific, alternatively spliced transcript (J Biol Chem 279:27383-27389, 2004). The unexpectedly high frequency of the variant allele and resulting CYP2D7 expression could have important implications for brain-specific metabolism of CYP2D substrates including many psychoactive drugs. However, the 138delT variant has not been detected in other studies (Pharmacogenetics 11:45-55, 2001; Biochem Biophys Res Commun 336:1241-1250, 2005). Our goal was to determine the frequency of this variant in a larger, ethnically diverse population. CYP2D7 138delT genotypes for 163 Caucasians, 95 East Asians, 50 Indians, 68 Hispanic Latinos, and 68 African Americans were determined by Pyrosequencing. The 138delT allele was observed at a frequency of 1.0% in East Asians and 0.74% in Hispanic Latinos. The deletion was not observed in Indians or the other ethnic populations. In addition, in each of the three samples with 138delT, the putative brain-specific transcript contains a premature stop codon that would preclude protein expression. The low frequency of the CYP2D7 138delT polymorphism in our ethnically diverse sample, and particularly the absence from 50 Indian samples, is in contrast to the high frequency previously reported. Our results suggest that CYP2D7 138delT is unlikely to be highly relevant for population variation of pharmacokinetics or drug response.