Music perception and speech intelligibility in noise performance by Italian-speaking cochlear implant users.

OBJECTIVE: The goal of this study was to investigate the performance correlations between music perception and speech intelligibility in noise by Italian-speaking cochlear implant (CI) users. MATERIALS AND METHODS: Twenty postlingually deafened adults with unilateral CIs (mean age 65 years, range 46-92 years) were tested with a music quality questionnaire using three passages of music from Classical Music, Jazz, and Soul. Speech recognition in noise was assessed using two newly developed adaptive tests in Italian: The Sentence Test with Adaptive Randomized Roving levels (STARR) and Matrix tests. RESULTS: Median quality ratings for Classical, Jazz and Soul music were 63%, 58% and 58%, respectively. Median SRTs for the STARR and Matrix tests were 14.3 dB and 7.6 dB, respectively. STARR performance was significantly correlated with Classical music ratings (rs = - 0.49, p = 0.029), whereas Matrix performance was significantly correlated with both Classical (rs = - 0.48, p = 0.031) and Jazz music ratings (rs = - 0.56, p = 0.011). CONCLUSION: Speech with competitive noise and music are naturally present in everyday listening environments. Recent speech perception tests based on an adaptive paradigm and sentence materials in relation with music quality measures might be representative of everyday performance in CI users. The present data contribute to cross-language studies and suggest that improving music perception in CI users may yield everyday benefit in speech perception in noise and may hence enhance the quality of listening for CI users.

Clinical outcomes for pediatric patients receiving radiotherapy for solid tumor central nervous system metastases.

Central nervous system (CNS) metastases are rare, but devastating complications of pediatric solid tumors. Radiotherapy alone or postresection serves as an important treatment; however, data on the use of whole-brain radiotherapy (WBRT) versus focal radiotherapy, including stereotactic radiosurgery or stereotactic radiotherapy, for these indications are limited. We report a single institution experience of 26 pediatric patients treated with radiotherapy for solid tumor CNS metastases without leptomeningeal disease. Focal radiotherapy (n = 10) was well tolerated and survival outcomes did not differ between patients treated with WBRT (n = 16) versus focal radiation, suggesting that focal radiotherapy may be considered for patients with limited CNS metastases.

Palliative radiotherapy for pediatric patients: Parental perceptions of indication, intent, and outcomes.

OBJECTIVES: Palliative radiation therapy (pRT) is often used to improve quality of life for pediatric patients. Though palliative doses are generally lower than those for cure, pRT may still introduce undesirable effects. The decision to pursue additional therapy for a child may be challenging and depends on parents' knowledge and expectations. The goal of this study was to explore parental perceptions of pRT. METHODS: Twenty-eight children referred for pRT were enrolled in our prospective study. Parents were counseled regarding the indication and expected outcomes. They then completed a series of questionnaires to assess their understanding of pRT, side effects that their child experienced, and how the outcomes compared to their expectations. RESULTS: The majority of parents listed pain relief and addressing new disease as the main indication for pRT. When asked about expectations, the majority chose improvement in quality of life and prolongation of their child's life. Interestingly, 32% of parents expected pRT to cure their child's disease. Most patients undergoing pRT did not experience any adverse symptoms. The outcomes of pRT in the majority of cases exceeded parental expectations. CONCLUSION: Improved quality of life with pRT sometimes blurs the distinction between palliation and cure. We found that most parents understand the aim to improve quality of life, although a proportion of parents perceived pRT as a cure to their child's disease. Despite this, the majority of parents reported that the outcome of the pRT course exceeded their expectations. We postulate that parents derive comfort from pursuing active treatment.

A systematic review of the impact of adjusting input dynamic range (IDR), electrical threshold (T) level and rate of stimulation on speech perception ability in cochlear implant users.

OBJECTIVE: To systematically review the evidence of how adjustments of the electrical threshold (T) level, input dynamic range (IDR) and electrical stimulation rate impact on speech perception for cochlear implant (CI) users. DESIGN: Systematic review. STUDY SAMPLE: A search of two electronic data sources yielded 32 studies, which met the inclusion criteria. A quality assessment and two evidence-based practice (EBP) review rating schemes were used to grade studies. RESULTS: Due to the heterogeneity of speech perception measures, CI device type and study design, comparisons were made by structured review. CONCLUSION: The quality of studies was found to be moderate to poor. Increasing T levels above behavioural threshold, or as a proportion of electrical dynamic range (EDR), has been demonstrated to improve perception of monosyllables in quiet and sentences in both quiet and in noise. Specific IIDR and IDR setting may improve perception of monosyllables in quiet and sentences in noise. However, no recommendation could be determined for setting rate of stimulation as speech perception varied significantly across rates examined. To optimise speech perception, a bespoke approach to parameter setting providing an individualised CI fitting is recommended; however, detail of how to optimise settings and the interactions between parameters is as yet unknown.

RNAi-independent role for Argonaute2 in CTCF/CP190 chromatin insulator function.

A major role of the RNAi pathway in Schizosaccharomyces pombe is to nucleate heterochromatin, but it remains unclear whether this mechanism is conserved. To address this question in Drosophila, we performed genome-wide localization of Argonaute2 (AGO2) by chromatin immunoprecipitation (ChIP)-seq in two different embryonic cell lines and found that AGO2 localizes to euchromatin but not heterochromatin. This localization pattern is further supported by immunofluorescence staining of polytene chromosomes and cell lines, and these studies also indicate that a substantial fraction of AGO2 resides in the nucleus. Intriguingly, AGO2 colocalizes extensively with CTCF/CP190 chromatin insulators but not with genomic regions corresponding to endogenous siRNA production. Moreover, AGO2, but not its catalytic activity or Dicer-2, is required for CTCF/CP190-dependent Fab-8 insulator function. AGO2 interacts physically with CTCF and CP190, and depletion of either CTCF or CP190 results in genome-wide loss of AGO2 chromatin association. Finally, mutation of CTCF, CP190, or AGO2 leads to reduction of chromosomal looping interactions, thereby altering gene expression. We propose that RNAi-independent recruitment of AGO2 to chromatin by insulator proteins promotes the definition of transcriptional domains throughout the genome.

Temporal Fine Structure Processing, Pitch, and Speech Perception in Adult Cochlear Implant Recipients.

OBJECTIVES: The aim of the study was to investigate the link between temporal fine structure (TFS) processing, pitch, and speech perception performance in adult cochlear implant (CI) recipients, including bimodal listeners who may benefit better low-frequency (LF) temporal coding in the contralateral ear. DESIGN: The study participants were 43 adult CI recipients (23 unilateral, 6 bilateral, and 14 bimodal listeners). Two new LF pitch perception tests-harmonic intonation (HI) and disharmonic intonation (DI)-were used to evaluate TFS sensitivity. HI and DI were designed to estimate a difference limen for discrimination of tone changes based on harmonic or inharmonic pitch glides. Speech perception was assessed using the newly developed Italian Sentence Test with Adaptive Randomized Roving level (STARR) test where sentences relevant to everyday contexts were presented at low, medium, and high levels in a fluctuating background noise to estimate a speech reception threshold (SRT). RESULTS: Although TFS and STARR performances in the majority of CI recipients were much poorer than those of hearing people reported in the literature, a considerable intersubject variability was observed. For CI listeners, median just noticeable differences were 27.0 and 147.0 Hz for HI and DI, respectively. HI outcomes were significantly better than those for DI. Median STARR score was 14.8 dB. Better performers with speech reception thresholds less than 20 dB had a median score of 8.6 dB. A significant effect of age was observed for both HI/DI tests, suggesting that TFS sensitivity tended to worsen with increasing age. CI pure-tone thresholds and duration of profound deafness were significantly correlated with STARR performance. Bimodal users showed significantly better TFS and STARR performance for bimodal listening than for their CI-only condition. Median bimodal gains were 33.0 Hz for the HI test and 95.0 Hz for the DI test. DI outcomes in bimodal users revealed a significant correlation with unaided hearing thresholds for octave frequencies lower than 1000 Hz. Median STARR scores were 17.3 versus 8.1 dB for CI only and bimodal listening, respectively. STARR performance was significantly correlated with HI findings for CI listeners and with those of DI for bimodal listeners. CONCLUSIONS: LF pitch perception was found to be abnormal in the majority of adult CI recipients, confirming poor TFS processing of CIs. Similarly, the STARR findings reflected a common performance deterioration with the HI/DI tests, suggesting the cause probably being a lack of access to TFS information. Contralateral hearing aid users obtained a remarkable bimodal benefit for all tests. Such results highlighted the importance of TFS cues for challenging speech perception and the relevance to everyday listening conditions. HI/DI and STARR tests show promise for gaining insights into how TFS and speech perception are being limited and may guide the customization of CI program parameters and support the fine tuning of bimodal listening.

The role of speech rate for Italian-speaking cochlear implant users: insights for everyday speech perception.

This study investigated the effect of speech rate for Italian-speaking cochlear implant (CI) users with the aim of gaining insight into everyday listening situations where speaker's rate may vary considerably together with speech level in fluctuating background noise. The test material was prepared by processing the Italian STARR test with temporal compression of sentence material. Twelve adult CI users were divided into two subgroups based on their STARR performance: good and poor performers. The effect of varying speech rate was remarkable for both subgroups. Good performers showed significant performance deterioration for the faster speech rate, whereas outcomes for poor performers improved significantly for the slower speech rate. Background noise is inevitable during daily life and CI users face a variety of speakers, so must cope with changes in both speech level and rate. Traditional tests with a single talker speaking very clearly while using a moderate to low speech rate may overestimate everyday speech perception for CI users. The use of tests that mimic everyday perception is of great importance and should become a routine part of audiometric measures for hearing impaired people.

Genome-wide localization of exosome components to active promoters and chromatin insulators in Drosophila.

Chromatin insulators are functionally conserved DNA-protein complexes situated throughout the genome that organize independent transcriptional domains. Previous work implicated RNA as an important cofactor in chromatin insulator activity, although the precise mechanisms are not yet understood. Here we identify the exosome, the highly conserved major cellular 3' to 5' RNA degradation machinery, as a physical interactor of CP190-dependent chromatin insulator complexes in Drosophila. Genome-wide profiling of exosome by ChIP-seq in two different embryonic cell lines reveals extensive and specific overlap with the CP190, BEAF-32 and CTCF insulator proteins. Colocalization occurs mainly at promoters but also boundary elements such as Mcp, Fab-8, scs and scs', which overlaps with a promoter. Surprisingly, exosome associates primarily with promoters but not gene bodies of active genes, arguing against simple cotranscriptional recruitment to RNA substrates. Similar to insulator proteins, exosome is also significantly enriched at divergently transcribed promoters. Directed ChIP of exosome in cell lines depleted of insulator proteins shows that CTCF is required specifically for exosome association at Mcp and Fab-8 but not other sites, suggesting that alternate mechanisms must also contribute to exosome chromatin recruitment. Taken together, our results reveal a novel positive relationship between exosome and chromatin insulators throughout the genome.

The perception of complex pitch in cochlear implants: A comparison of monopolar and tripolar stimulation.

Cochlear implant listeners typically perform poorly in tasks of complex pitch perception (e.g., musical pitch and voice pitch). One explanation is that wide current spread during implant activation creates channel interactions that may interfere with perception of temporal fundamental frequency information contained in the amplitude modulations within channels. Current focusing using a tripolar mode of stimulation has been proposed as a way of reducing channel interactions, minimising spread of excitation and potentially improving place and temporal pitch cues. The present study evaluated the effect of mode in a group of cochlear implant listeners on a pitch ranking task using male and female singing voices separated by either a half or a quarter octave. Results were variable across participants, but on average, pitch ranking was at chance level when the pitches were a quarter octave apart and improved when the difference was a half octave. No advantage was observed for tripolar over monopolar mode at either pitch interval, suggesting that previously published psychophysical advantages for focused modes may not translate into improvements in complex pitch ranking. Evaluation of the spectral centroid of the stimulation pattern, plus a lack of significant difference between male and female voices, suggested that participants may have had difficulty in accessing temporal pitch cues in either mode.

Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project.

We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.

STARR: a speech test for evaluation of the effectiveness of auditory prostheses under realistic conditions.

OBJECTIVES: The objective was to develop and evaluate a new sentence test, the Sentence Test with Adaptive Randomized Roving levels, intended to emulate everyday listening experience, using both normal-hearing (NH) and cochlear implant (CI) groups, examining practicality, learning, test-retest variability, and interlist variability. DESIGN: In experiment 1, each of 25 NH adults was tested using five lists, each comprising 30 sentences. One male and one female speaker each spoke 15 sentences. Ten sentences were presented at each of three presentation levels: 50, 65, and 80 dB SPL. The relative level of a speech-shaped noise was varied adaptively to estimate the speech reception threshold (SRT). Counterbalance for list order was achieved by staggering the allocation of lists to participants. To allow assessment of learning effects, no practice was given. The variability of mean SRTs across lists was small, but correction factors were derived for each list so that, after correction, all lists gave the same mean SRT. Test-retest variability was estimated by examining the corrected SRTs for each subject's five lists. In experiment 2, 25 CI users each received one test list after a small amount of practice. Experiment 3 examined the effect of speech rate using time-compressed speech, for age-matched NH and CI users. RESULTS: The mean SRT for the NH participants was approximately -6 dB and was similar for the male and female speakers. There was a small but significant improvement in SRTs between the first and later lists administered, but no further improvement for subsequent lists. On the basis of the variability of the corrected SRTs within each participant, a 2.2 dB difference in SRT is meaningful for comparisons using one test list per condition, for a single participant. The percentage of key words correct varied with presentation level over a 13% range, being best at 65 dB SPL. Only 40% of the CI group achieved an SRT lower than 20 dB for both speakers. There was large individual variability in the SRTs, and SRTs were higher for the female than for the male speaker. For the CI participants, the percentage of key words correct varied markedly with level, from 19% at the lowest level to 57% at the medium level. Time compression had a small effect for NH participants but a very large effect for CI participants. CONCLUSIONS: The Sentence Test with Adaptive Randomized Roving levels seems practical to administer and is reasonably sensitive. For NH participants, a 2.2 dB difference in SRT is meaningful for a single list per condition and a single participant. Although learning effects were small for NH participants, it seems prudent to provide some practice sentences when testing hearing-impaired or CI participants. The very large effect of time compression for the CI group has implications for live voice testing of children, because speech rate is only poorly controlled in such testing.

Clinical Characteristics, Experiences, and Outcomes of Transgender Patients With Cancer.

IMPORTANCE: More than 1 million people in the US identify as transgender; however, few studies have examined the experiences and outcomes of transgender patients with cancer. OBJECTIVE: To examine clinical characteristics, experiences, and outcomes of transgender patients with cancer. DESIGN, SETTING, AND PARTICIPANTS: This retrospective case series assessed transgender patients with at least 1 cancer diagnosis who were evaluated at Dana-Farber Cancer Institute or Brigham and Women's Hospital in Boston, Massachusetts, between January 1, 2005, and December 31, 2019. MAIN OUTCOMES AND MEASURES: Demographic, clinical, and treatment characteristics for all patients and documentation by oncologic practitioners of important aspects of providing gender-affirming care, including pronouns used by the patient, were recorded. RESULTS: A total of 37 transgender patients with cancer were assessed (mean [SD] age, 38.9 [21.8] years at first cancer diagnosis). Fifteen patients (40.5%) had hematologic malignant cancers, and 25 patients (67.6%) had solid malignant tumors. Sixteen patients (43.2%) initiated gender-affirming hormone therapy or surgery after their cancer diagnosis. Cancer treatment was frequently multimodal, with 24 patients (64.9%) receiving systemic therapy, 24 (64.9%) receiving surgery, and 20 (54.1%) receiving radiation therapy along with other cancer-directed treatment, such as cryoablation. Five patients (13.5%) had documentation from an oncologic practitioner that addressed a potential interaction between their gender-affirming care and their cancer treatment. Thirty-three patients had follow-up visits with oncologic practitioners after starting their transition. Of those patients, pronouns used were documented by a member of the oncologic team for 4 patients (12.1%). However, for 3 of the 4 patients, documentation did not consistently use patient-reported information. At the last follow-up, 5 patients (13.5%) had died of their disease, and 26 (70.3%) were living without disease. CONCLUSIONS AND RELEVANCE: This case series study found that transgender patients were diagnosed with diverse cancers, and many initiated gender-affirming hormone therapy or surgery after their diagnosis. Documentation by oncologic practitioners infrequently included pronouns used by the patient or discussion surrounding the interactions between cancer treatment and gender-affirming care, signifying that urgent improvements are needed in cancer care for transgender patients.

Florid Foreign Body-type Giant Cell Response to Keratin Is Associated With Improved Overall Survival in Patients Receiving Preoperative Therapy for Esophageal Squamous Cell Carcinoma.

While most resection specimens from patients with neoadjuvantly treated esophageal squamous cell carcinoma show therapy-related changes in the form of inflammation and fibrosis, others harbor a florid foreign body-type giant cell response to keratin debris. The purpose of our study was to perform a detailed clinicopathologic analysis of these histologic types of treatment responses and correlate these findings with patient outcome. Clinical and pathologic parameters from 110 esophagogastrectomies were recorded and analyzed. Two main types of histologic responses were observed: inflammatory-predominant response (59%) and florid foreign body-type giant cell response to keratin (41%). Irrespective of cG, cTNM, and amount of residual cancer, florid foreign body-type giant cell reaction was predominantly noted deep within the esophageal wall, while the inflammatory response was restricted to the mucosa, submucosa, and inner half of muscularis propria. Patients with foreign body-type giant cell response showed significantly better overall survival compared with the inflammatory response group (log-rank test P=0.015). Florid foreign body-type giant cell response was the only factor associated with improved survival in a multivariable analysis for overall survival (hazard ratio=0.5; 95% confidence interval=0.3-1.0; P=0.038), but not in the model for disease-specific survival, whereas ypTNM stage II was the only significant risk factor for disease-specific survival in multivariable analysis (hazard ratio=3.4; 95% confidence interval=1.0-11.2; P=0.047). Our results suggest that in addition to the College of American Pathologists Tumor Regression Score and ypTNM stage, subtype of histologic response to therapy may represent another prognostic marker for neoadjuvantly treated esophageal squamous cell carcinoma.

Use of a healthy volunteer imaging program to optimize clinical implementation of stereotactic MR-guided adaptive radiotherapy.

PURPOSE: MR-linacs (MRLs) have enabled the use of stereotactic magnetic resonance (MR) guided online adaptive radiotherapy (SMART) across many cancers. As data emerges to support SMART, uncertainty remains regarding optimal technical parameters, such as optimal patient positioning, immobilization, image quality, and contouring protocols. Prior to clinical implementation of SMART, we conducted a prospective study in healthy volunteers (HVs) to determine optimal technical parameters and to develop and practice a multidisciplinary SMART workflow. METHODS: HVs 18 years or older were eligible to participate in this IRB-approved study. Using a 0.35 T MRL, simulated adaptive treatments were performed by a multi-disciplinary treatment team in HVs. For each scan, image quality parameters were assessed on a 5-point scale (5 = extremely high, 1 = extremely poor). Adaptive recontouring times were compared between HVs and subsequent clinical cases with a t-test. RESULTS: 18 simulated treatments were performed in HVs on MRL. Mean parameters for visibility of target, visibility of nearby organs, and overall image quality were 4.58, 4.62, and 4.62, respectively (range of 4-5 for all measures). In HVs, mean ART was 15.7 min (range 4-35), comparable to mean of 16.1 (range 7-33) in the clinical cases (p = 0.8963). Using HV cases, optimal simulation and contouring guidelines were developed across a range of disease sites and have since been implemented clinically. CONCLUSIONS: Prior to clinical implementation of SMART, scans of HVs on an MRL resulted in acceptable image quality and target visibility across a range of organs with similar ARTs to clinical SMART. We continue to utilize HV scans prior to clinical implementation of SMART in new disease sites and to further optimize target tracking and immobilization. Further study is needed to determine the optimal duration of HV scanning prior to clinical implementation.

Phase I/II Study of Stereotactic Body Radiation Therapy for Pulmonary Metastases in Pediatric Patients.

PURPOSE: Pulmonary metastases are common in many pediatric solid tumors; however, little is known about safety and efficacy of lung stereotactic body radiation therapy (SBRT) for pediatric patients. We conducted a phase I/II study to investigate the minimum effective dose level of SBRT with an acceptable safety profile in pediatric patients. METHODS AND MATERIALS: Patients with sarcoma and metastatic pulmonary lesions ≤3 cm in diameter and ≤21 years of age were enrolled. Dose levels 1, 2, and 3 were 24, 30, and 36 Gy in 3 fractions, respectively. Enrolled patients with metastases from primary renal tumors and sarcoma histologies were to begin at dose level 1 and 2, respectively. Exclusion criteria included receipt of whole-lung/hemi-thorax irradiation >12 Gy within 6 months of consent. Primary endpoints were tolerability and safety per Common Terminology Criteria for Adverse Events grading and disease response at 6 weeks post-SBRT per response evaluation criteria in solid tumors (RECIST) 1.1 criteria. Secondary endpoints included rates of local control and distant failure within the lung, but outside of the treatment volume. RESULTS: Five patients with median age of 13 years (range, 7-21) received SBRT at dose level 2. Primary tumor histologies included Ewing sarcoma (n = 3), anaplastic chordoma (n = 1), and osteosarcoma (n = 1). No grade ≥3 adverse events were observed. At 6 weeks after SBRT, 7/8 (87.5%) lesions achieved partial response. With median follow-up of 2.1 years (range, 1.4-2.5), 2-year local control and distant failure-free survival were 60% (n = 8) and 40% (n = 5), respectively. One patient developed widespread metastases and succumbed to disease 1.4 years after SBRT. CONCLUSIONS: SBRT for pulmonary metastases produces responses in pediatric patients with sarcoma at 6 weeks with acceptable toxicity; however, patients remain at risk of local and distant failure within the lung. Future prospective studies are needed to investigate whether higher doses of SBRT, possibly in combination with other therapies, are safe and provide more durable response.

Comparison of dual-time-constant and fast-acting automatic gain control (AGC) systems in cochlear implants.

Cochlear implants usually employ an automatic gain control (AGC) system as a first stage of processing. AGC1 was a fast-acting (syllabic) compressor. AGC2 was a dual-time-constant system; it usually performed as a slow-acting compressor, but incorporated an additional fast-acting system to provide protection from sudden increases in sound level. Six experienced cochlear-implant users were tested in a counterbalanced order, receiving one-month of experience with a given AGC type before switching to the other type. Performance was evaluated shortly after provision of a given AGC type and after one-month of experience with that AGC type. Questionnaires, mainly relating to listening in quiet situations, did not reveal significant differences between the two AGC types. However, fixed-level and roving-level tests of sentence identification in noise both revealed significantly better performance for AGC2. It is suggested that the poorer performance for AGC1 occurred because AGC1 introduced cross-modulation between the target speech and background noise, which made perceptual separation of the target and background more difficult.

Managing type 2 diabetes: going beyond glycemic control.

BACKGROUND: Aggressive management of type 2 diabetes is necessary to achieve glycemic and nonglycemic treatment goals. Attainment of treatment goals is associated with a decreased risk of diabetes-related complications, costs, and health care utilization. OBJECTIVE: To review the advantages and disadvantages of different glucose-lowering agents, with an emphasis on the role of thiazolidinediones (TZDs). SUMMARY: Diabetes has become increasingly prevalent, particularly among younger age groups in the United States, accounting for approximately 15% of health care expenditures by managed care organizations. Reducing a patient's glycated hemoglobin (A1C) has been shown to decrease the risk of diabetes-related complications, as well as reduce medical costs and health care utilization. Despite this knowledge, achievement of the American Diabetes Association (ADA) goal A1C of < 7% is suboptimal, and < 1 in 10 patients also reach the ADA targets for cholesterol (low-density lipoprotein < 100 mg per dL) and blood pressure (< 130/80 mm Hg). To ensure that all ADA treatment goals are met, clinicians need to closely monitor patients and adjust therapy as needed, taking into consideration both a drug's glycemic and nonglycemic effects when selecting medication therapy. Four basic defects contribute to type 2 diabetes: insulin resistance, decreased insulin secretion, increased hepatic glucose production, and reduced glucagon-like peptide-1 levels. Unlike metformin, sulfonylureas, and insulin that address only 1 or 2 physiologic defects, TZDs uniquely address 3 of these defects at the adipocyte. Metformin is recommended for initial drug therapy; TZDs, sulfonylureas, and insulin are useful options as add-on therapy for patients whose A1C levels remain >or= 7% despite treatment with metformin and lifestyle interventions. It has been suggested that TZDs, when used either as add-on therapy or when appropriate as monotherapy, may conserve pancreatic beta-cell function over an observed 3- to 5-year period of time and sustain a decrease in A1C ranging from 0.5%-1.5%. Although rarely associated with hypoglycemia, TZDs may cause total body weight gain that is most commonly caused by volume expansion, which may manifest as new or worsened heart failure in susceptible individuals. Pioglitazone and rosiglitazone, the 2 TZDs available in the United States, contain black box label warnings about their potential to cause or exacerbate congestive heart failure; additional data have suggested a link to ischemic cardiac events. Recent data also suggest that TZDs may reduce bone density. Conversely, pioglitazone may have some vasculoprotective effect related to elevation of high-density lipoprotein and lessened progression of carotid intima-media thickness; however, any effect on macrovascular clinical outcomes is unknown. Other drug options are available for the treatment of type 2 diabetes, such as incretin-based therapies. Yet despite their favorable effects on glycemia, they have not been included to date in the ADA treatment algorithm. CONCLUSIONS: Proper glycemic control and attainment of other nonglycemic management targets (e.g., blood pressure, lipids, body weight) are essential to the prevention of long-term complications of diabetes and to reduction of overall disease management costs. Therefore, patients with diabetes should be followed closely to ensure that they achieve and maintain both glycemic and nonglycemic treatment goals. Most patients will not sustain an adequate level of control using nondrug or single-drug therapeutic approaches. When choosing among treatment options, consideration should be given to the nonglycemic as well as glycemic effects of various glucose-lowering agents.

Effects of pioglitazone and rosiglitazone on blood lipid levels and glycemic control in patients with type 2 diabetes mellitus: a retrospective review of randomly selected medical records.

BACKGROUND: The antihyperglycemic effects of pioglitazone hydrochloride and rosiglitazone maleate are well documented. The results of clinical trials and observational studies have suggested, however, that there are individual differences in the effects of these drugs on blood lipid levels. OBJECTIVE: The present study evaluated the effects of pioglitazone and rosiglitazone on blood lipid levels and glycemic control in patients with type 2 diabetes mellitus. METHODS: This was a retrospective review of randomly selected medical records from 605 primary care practices in the United States in which adults with type 2 diabetes received pioglitazone or rosiglitazone between August 1, 1999, and August 31, 2000. The outcome measures were mean changes in serum concentrations of triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and glycosylated hemoglobin (HbA1c) values. RESULTS: Treatment with pioglitazone was associated with a reduction in mean TG of 55.17 mg/dL, a reduction in TC of 8.45 mg/dL, an increase in HDL-C of 2.65 mg/dL, and a reduction in LDL-C of 5.05 mg/dL. Treatment with rosiglitazone was associated with a reduction in mean TG of 13.34 mg/dL, an increase in TC of 4.81 mg/dL, a reduction in HDL-C of 0.12 mg/dL, and an increase in LDL-C of 3.56 mg/dL. With the exception of HDL-C, the differences in mean changes in lipid parameters between treatment groups were statistically significant (P < 0.001, pioglitazone vs rosiglitazone). Reductions in HbA1c were statistically equivalent between treatments (1.04% pioglitazone, 1.18% rosiglitazone). CONCLUSIONS: Treatment with pioglitazone was associated with greater beneficial effects on blood lipid levels than treatment with rosiglitazone, whereas glycemic control was equivalent between the 2 treatments.