Melatonin for rapid eye movement sleep behavior disorder in Parkinson's disease: A randomised controlled trial.

BACKGROUND: Melatonin may reduce REM-sleep behavior disorder (RBD) symptoms in Parkinson's disease (PD), though robust clinical trials are lacking. OBJECTIVE: To assess the efficacy of prolonged-release (PR) melatonin for RBD in PD. METHODS: Randomized, double-blind, placebo-controlled, parallel-group trial with an 8-week intervention and 4-week observation pre- and postintervention (ACTRN12613000648729). Thirty PD patients with rapid eye movement sleep behavior disorder were randomized to 4 mg of prolonged-release melatonin (Circadin) or matched placebo, ingested orally once-daily before bedtime. Primary outcome was the aggregate of rapid eye movement sleep behavior disorder incidents averaged over weeks 5 to 8 of treatment captured by a weekly diary. Data were included in a mixed-model analysis of variance (n = 15 per group). RESULTS: No differences between groups at the primary endpoint (3.4 events/week melatonin vs. 3.6 placebo; difference, 0.2; 95% confidence interval = -3.2 to 3.6; P = 0.92). Adverse events included mild headaches, fatigue, and morning sleepiness (n = 4 melatonin; n = 5 placebo). CONCLUSION: Prolonged-release melatonin 4 mg did not reduce rapid eye movement sleep behavior disorder in PD. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Clinical and radiological outcomes of 5-year drug-free remission-steered treatment in patients with early arthritis: IMPROVED study.

OBJECTIVES: To determine the 5-year outcomes of early remission induction therapy followed by targeted treatment aimed at drug-free remission (DFR) in patients with early arthritis. METHODS: In 12 hospitals, 610 patients with early (<2 years) rheumatoid arthritis (RA) or undifferentiated arthritis (UA) started on methotrexate (MTX) 25 mg/week and prednisone (60 mg/day tapered to 7.5 mg/day). Patients not in early remission (Disease Activity Score <1.6 after 4 months) were randomised (single blind) to arm 1, adding hydroxychloroquine 400 mg/day and sulfasalazine 2000 mg/day, or arm 2, switching to MTX plus adalimumab 40 mg/2 weeks. Treatment adjustments over time aimed at DFR. Outcomes were remission percentages, functional ability, toxicity and radiological damage progression after 5 years. RESULTS: After 4 months, 387 patients were in early remission, 83 were randomised to arm 1 and 78 to arm 2. After 5 years, 295/610 (48%) patients were in remission, 26% in sustained DFR (SDFR) (≥1 year) (220/387 (57%) remission and 135/387 (35%) SDFR in the early remission group, 50% remission, 11% SDFR in the randomisation arms without differences between the arms). More patients with UA (37% vs 23% RA, p=0.001) and more anticitrullinated protein antibody (ACPA)-negative patients (37% vs 18% ACPA-positive, p<0.001) achieved SDFR.Overall, mean Health Assessment Questionnaire was 0.6 (0.5), and median (IQR) damage progression was 0.5 (0-2.7) Sharp/van der Heijde points, with only five patients showing progression >25 points in 5 years. CONCLUSIONS: Five years of DFR-steered treatment in patients with early RA resulted in almost normal functional ability without clinically relevant joint damage across treatment groups. Patients who achieved early remission had the best clinical outcomes. There were no differences between the randomisation arms. SDFR is a realistic treatment goal.

Remission induction therapy with methotrexate and prednisone in patients with early rheumatoid and undifferentiated arthritis (the IMPROVED study).

AIM: Classifying more patients as rheumatoid arthritis (RA) (2010 American College of Rheumatology/European League Against Rheumatism criteria for RA) may improve treatment outcomes but may cause overtreatment in daily practice. The authors determined the efficacy of initial methotrexate (MTX) plus prednisone treatment in patients with 1987 or 2010 classified RA and undifferentiated arthritis (UA). METHOD: 610 recent onset RA or UA patients started with MTX 25 mg/week and prednisone 60 mg/day tapered to 7.5 mg/day in 7 weeks. Percentage remissions after 4 months were compared between RA (1987 or 2010 criteria) and UA. Predictors for remission were identified. RESULTS: With the 2010 criteria, 19% more patients were classified as RA than with the 1987 criteria, but similar remission rates were achieved: 291/479 (61%) 2010 classified RA and 211/264 (58%) 1987 classified RA patients (p=0.52), and 79/122 (65%) UA patients (p=0.46). Anticitrullinated protein antibodies (ACPA) positive RA patients achieved more remission (66%) than ACPA negative RA patients (51%, p=0.001), but also had a lower mean baseline Disease Activity Score (DAS) (3.2 vs 3.6, p<0.001). Independent predictors for remission were male sex, low joint counts, DAS and Health Assessment Questionnaire, low body mass index and ACPA positivity. CONCLUSION: Initial treatment with MTX and a tapered high dose of prednisone results in similarly high remission percentages after 4 months (about 60%) in RA patients, regardless of fulfilling the 1987 or 2010 criteria, and in UA patients. Independent predictors indicate that initiating treatment while disease activity is relatively low results in more remission.

Large-joint damage in patients with early rheumatoid arthritis and its association with treatment strategy and damage of the small joints.

OBJECTIVE: To determine the prevalence of large-joint damage and the association with small-joint damage in patients with RA after 8 years of low DAS (≤2.4)-targeted treatment with different treatment strategies. METHODS: Radiological data of 290 patients participating in the BeSt study, a randomized trial comparing initial monotherapy and initial combination therapy strategies, were used. Radiographs of large joints were scored using the Larsen score and of the small joints using the Sharp-van der Heijde score. With multivariate logistic regression analysis, an association between total damage of the small joints and of the large joints was investigated. RESULTS: After 8 years of treatment, damage was observed in 12% of shoulders, 10% of elbows, 26% of wrists, 13% of hips, 18% of knees and 7% of the ankles. Damage in one or more large joints was found in 64% of patients, with a median score of 1. No difference was found between initial monotherapy or combination therapy strategies. There was a significant association between damage progression in small joints and damage to one or more large joints (OR 1.02; 95% CI 1.00-1.04). CONCLUSION: After 8 years of DAS-targeted treatment in early RA patients, large-joint damage was found in 64% of patients and was associated with small-joint damage. Continued DAS-targeted treatment is probably more important in damage suppression than initial treatment strategy. Patients with more damage to hands and feet also have more damage to the large joints.

Implementing neonatal screening for congenital cytomegalovirus: addressing the deafness of policy makers.

Congenital cytomegalovirus (CMV) infection is an important public health problem with approximately 7 in 1,000 newborns infected and consequently at risk for hearing impairment. Newborn hearing screening will fail to detect this hearing impairment in approximately half of the cases because late onset hearing loss is frequent. Hearing impairment has profound impact on cognitive and social development of children and their families, determining most of the disease burden of congenital CMV infection. The potential value of newborn screening for congenital CMV is increasingly discussed. To date, many experts acknowledge the benefit of antiviral treatment in the prevention of hearing deterioration in newborns with neurological symptoms, and the benefit of early identification of late-onset hearing impairment by means of extensive audiological follow up of infected infants. These opinions imply that the potential of newborn screening for CMV would lie in the identification of the large proportion of asymptomatic congenitally infected newborns at risk for developing late-onset hearing loss. Experience with postnatal antiviral treatment of symptomatic newborns is encouraging, but has not been studied in asymptomatic congenitally infected newborns. A large-scale study on the safety and effectiveness of combined screening and antiviral therapy for congenital CMV infection is the necessary next step to take and should not be delayed.

Development and characterization of 11 novel microsatellite loci for the roundscale spearfish Tetrapturus georgii and their cross-species amplification among other istiophorid species.

Eleven novel polymorphic microsatellite loci were developed and characterized for the recently validated roundscale spearfish Tetrapturus georgii. Characterization of these markers, based on 35 roundscale spearfish from the western North Atlantic, revealed two to 21 alleles per locus with an average expected heterozygosity (H(E) ) of 0·09-0·94, and all loci conformed to Hardy-Weinberg expectations. Cross-amplification of these 11 loci against all other eight known istiophorid species indicates promising prospects for the utility of these markers for istiophorids in general.

Aging and impaired immunity to influenza viruses: implications for vaccine development.

Influenza infections are responsible for significant morbidity and mortality each year, with the highest infection rates found in the elderly population. The main strategy to reduce the impact of influenza infections in the elderly population is vaccination. However, the efficacy of influenza vaccines that are licensed for use in the elderly is relatively low (17-53%). The complex age-related changes that occur in both innate and adaptive immunity are thought to hamper the immune response to influenza immunization and to reduce protection against infection in the elderly. For the development of improved vaccines that overcome the limitations of an aged immune system, it is crucial to understand the mechanisms that lead to immune dysfunction. Here, we review the recent progress in unravelling the mechanisms behind the age-related immune dysfunction in elderly, as well as the recent developments in improving influenza vaccines and identification of new correlates of protection.

Accuracy and repeatability of cone-beam computed tomography (CBCT) measurements used in the determination of facial indices in the laboratory setup.

AIM: To assess the three dimensional (3D) surface accuracy of a phantom's face acquired from a cone-beam computed tomography (CBCT) scan and to determine the reliability of selected cephalometric measurements performed with Maxilim software (Medicim N.V., Mechelen, Belgium). MATERIAL AND METHODS: A mannequin head was imaged with a CBCT (I-CAT, Imaging Sciences International, Inc., Hatfield, USA). The data were used to produce 3D surface meshes (Maxilim and Mimics, Materialise N.V., Leuven, Belgium) which were compared with an optical surface scan of the head using Focus Inspection software (Metris N.V., Leuven, Belgium). The intra- and inter-observer reliability for the measurement of distances between facial landmarks with Maxilim 3D cephalometry were determined by calculating Pearson correlation coefficients and intraclass correlation (ICC). The Dahlberg formula was used to assess the method error (ME). RESULTS: (1) The maximal range of the 3D mesh deviations was 1.9 mm for Maxilim, and 1.8mm for Mimics segmentation. (2) Test-retest and inter-observer reliability were high; Pearson's correlation coefficient was 1.000 and the ICC was 0.9998. The ME of the vertical measurements was a little larger than that calculated for the width measurements. Maximum ME was 1.33 mm. CONCLUSIONS: The 3D surface accuracy of CBCT scans segmented with Maxilim and Mimics software is high. Maxilim also shows satisfactory intra- and inter-assessor reliability for measurement of distances on a rigid facial surface.

Reliability of clinical measurements used in the determination of facial indices.

AIM: The purpose was to investigate the index by which facial height/width ratio is optimally determined and the reliability of anthropometrical measurements. MATERIAL AND METHODS: The following measurements: zygion-zygion, sellion-gnathion, supraorbitale-gnathion, and interpupillary distance (IPD) were performed twice by the senior surgeon, and trainee surgeon, during an average interval of 18.6 days, on 50 patients (23 male and 27 female). The IPD was measured with a digital pupillometer (PM-600 - Nidek Co, Aichi, Japan), while the other parameters were measured with an anthropometrical Tessier Ruler. The Pearson correlation coefficient was determined for the intra-observer reliability (test-retest) and the intra-class co-efficiency was used to determine inter-observer reliability. RESULTS: The mean measurement error for the IPD with the digital pupillometer was less than 1mm. For all other facial measurements with the Tessier Ruler, horizontal and vertical, the error was more than 2mm. The intra- and inter-observer reliabilities (in vertical dimension) were better for the measurements of supraorbitale-gnathion, than those for sellion-gnathion. The Pearson correlation coefficient for the classical facial index was from 0.874 to 0.912 for the IPD/supraorbital-gnathion index. CONCLUSIONS: Measuring these distances with an anthropometrical ruler is not highly reliable, although the distance supraorbitale-gnathion can be measured more precisely than the distance sellion-gnathion. However, IPD measurements with a digital pupillometer are very reliable. These findings, together with the visibility of these parameters in the frontal view, lead to the introduction of a new facial index: IPD/supraorbitale-gnathion.

The 180 splice variant of NCAM-containing exon 18-is specifically expressed in small cell lung cancer cells.

BACKGROUND: The Neural Cell Adhesion Molecule (NCAM) is a glycoprotein expressed as 120, 140 and/or 180 kDa isoforms, all derived through alternative splicing of a single gene. NCAM 120 contains no intracellular domain, whereas NCAM 140 and 180 have different intracellular domains determined by alternative splicing of exon 18. NCAM has been described as a biomarker to discriminate small cell lung cancer (SCLC) from non-SCLC (NSCLC). However, peripheral blood mononuclear cells (PBMC) also express NCAM. We studied the expression of NCAM splice variants in cell lines, tumor tissues and control cells. METHODS: Using reverse transcriptase-PCR we evaluated the expression of NCAM exon 18 splice variants in lung cancers cell lines, control cell lines, PBMC of healthy controls and SCLC tissue. In addition we studied the expression of the NCAM exon 18 encoded protein (E18) in SCLC by immunocytochemistry and flow cytometry using an E18-specific monoclonal antibody obtained by hybridoma fusion of E18-immunized mouse spleen cells. Finally we looked at immune responses to E18 in mice. RESULTS: We found expression of RNA encoding the NCAM 180 variant in all SCLC cell lines. NCAM exon 18 was not expressed in 23/28 (82%) of the other tumor and leukemia cell lines tested and PBMC. Next, we also evaluated the expression of NCAM exon 18 in human SCLC tissue. Expression of NCAM exon 18 in 8 of the 10 (80%) SCLC biopsy samples was found. The newly raised E18-specific antibodies stained NCAM at the adherent junctions between adjacent cells in SCLC cell lines. The data demonstrate the intracellular location of E18 in SCLC. Furthermore, a specific cytotoxic T cell (CTL) response and significant antibody titers were found in mice upon immunization with recombinant E18 and its encoding DNA. CONCLUSIONS: The results of this study can be applied in the diagnosis and immunotherapy of SCLC. A larger study investigating E18 as a marker for SCLC is indicated.

Thymocytes in Thy-1-/- mice show augmented TCR signaling and impaired differentiation.

Thy-1, a single variable-like immunoglobulin superfamily domain anchored in the plasma membrane by a glycosyl phosphaditylinositol tail [1], is a major surface glycoprotein in adult mammalian neurons and rodent thymocytes [2]; the function of Thy-1 has remained enigmatic since its discovery [3]. Studies in vitro have implicated Thy-1 in homotypic and heterotypic cell-cell interactions [2,4]. Ligation of Thy-1 initiates transmembrane signaling pathways that lead to diverse physiological outcomes in different cells [2,5-7]. In rodents, Thy-1 is highly expressed on the surface of CD4+CD8+ double-positive immature thymocytes and downregulated in mature T cells. Here, we report that thymocytes from Thy-1-/- mice [8] had altered cell-cell contacts, and hyperresponsiveness to T-cell receptor (TCR) triggering as demonstrated by the heightened activation of p56lck, phosphorylation of TCR subunits, Ca2+ fluxes and cell proliferation. Thy-1-/- thymocytes exhibited impaired maturation from the double positive to single positive stage of thymocyte development, possibly due to inappropriate negative selection, and were prone to T lymphomas in aged mice. These observations indicate that Thy-1 negatively regulates TCR-mediated signaling and controls activation thresholds during thymocyte differentiation.

Membrane rafts and signaling by the multichain immune recognition receptors.

The recent recognition of the presence of rafts in the plasma membrane and of their involvement in cell signaling has strongly stimulated the search for their function in receptor-mediated signal transduction in lymphocytes. Recent progress suggests that a general feature of membrane rafts is to serve as platforms wherein the signaling cascades triggered through different multichain immune recognition receptors (e.g. the TCR, BCR and FcepsilonRI) are initiated and organized.

Lung permeability, antioxidant status, and NO2 inhalation: a selenium supplementation study in rats.

Little is known about antioxidant status, selenium status in particular, and lung response to NO2, which acts as a proinflammatory air pollutant. The effects of a low selenium diet (1.3 microg Se/d) with or without selenium supplementation were therefore studied in 128 Wistar rats, 2 mo old, male exposed to either acute (50 ppm, 30 min), intermittent subacute (5 ppm, 6 h/d, 5 d), intermittent long-term NO2 (1 ppm, 10 ppm, 6 h/d, 5 d/wk, 28 d), or normal atmospheric air (controls). Following sacrifice, measurements of lipid peroxidation (thiobarbituric acid-reactive substances, chemiluminescence), antioxidative protective enzymes (glutathione peroxidase [GPx], superoxide dismutase [SOD], glutathione S-transferase [GST], ceruloplasmin), lung damage (lactate dehydrogenase, alkaline and acid phosphatases), lung permeability (total protein, albumin), and inflammation (cell populations), along with the determination of new biomarkers such as CC16 (Clara-cell protein), were performed in serum and bronchoalveolar lavage fluid (BALF). While selenium-supplemented animals had increased GPx activity in serum prior to inhalation experiments, they also had decreased BALF CC16, blood SOD, and GST levels. Nevertheless, the protective role of normal selenium status with respect to NO2 lung toxicity was evident both for long-term and acute exposures, as the increase in BALF total proteins and corresponding decrease in serum (indicating increased lung permeability) was significantly more pronounced in selenium-deficient animals. During the various inhalation experiments, serum CC16 demonstrated its key role as an early marker of increased lung permeability. These findings corroborate the important role of selenium status in NO2 oxidative damage modulation, but also indicate, in view of its negative impact on CC16, a natural anti-inflammatory and immunosuppressor, that caution should be used prior to advocating selenium supplementation.

Anterior Lumbar Interbody Fusion in Left-sided Inferior Vena Cava and Right-sided Aortic Arch.

Spinal fusion via anterior lumbar interbody fusion (ALIF) can offer symptomatic relief to patients that suffer severe low back pain, radiculopathy, and claudication. However, a detailed working knowledge of the thoracic, abdominal, and lumbar anatomy, particularly of the vasculature, is vital. We report the case of a 68-year-old man who presented with radiculopathy and progressively worsening low back pain despite 9 months of unsuccessful conservative therapy and pain management. Preoperative computed tomography and magnetic resonance imaging revealed a rare anatomical variation, with an anomalous left-sided inferior vena cava and anomalous aorta. The patient was surgically treated with ALIF at L4,5 and L5 S1 via an altered surgical window. Given the anomalous anatomy of the patient, instead of performing the procedure after mobilizing both of the transposed abdominal great vessels, the inferior vena cava and the abdominal aorta, the ALIF was uneventfully performed in the window between these vessels. There were no perioperative or postoperative complications. At 12-week postoperative follow-up, X-ray imaging demonstrated successful implantation of ALIF cages with no recurrence of symptoms. A detailed working knowledge of anatomy is important, particularly if anatomical variations are present. This has implications for preoperative surgical planning, which is integral to the safety and the success of procedures.

Two-year results of disease activity score (DAS)-remission-steered treatment strategies aiming at drug-free remission in early arthritis patients (the IMPROVED-study).

BACKGROUND: Early suppression of disease activity in (rheumatoid) arthritis (RA) patients may result in drug-free remission and prevent damage. We assessed 2-year clinical and radiological outcomes of two disease activity score (DAS)-remission-steered treatment strategies in early arthritis patients. METHODS: Patients (n = 610) with early RA or undifferentiated arthritis (UA) were treated with methotrexate (MTX) and tapered high dose of prednisone. Patients in early remission (44/53 joints DAS <1.6) after 4 months tapered and stopped medication. Patients who did not achieve early DAS-remission were randomized to either MTX plus hydroxychloroquine plus sulphasalazine plus low dose prednisone (arm 1) or to MTX + adalimumab (arm 2). At four-monthly intervals, medication was tapered and stopped if DAS was <1.6 but restarted, increased or switched if DAS was ≥1.6. Proportions of (drug-free) DAS-remission (DFR) after 2 years and Sharp-van der Heijde scores (SHS) were analyzed separately for the treatment strategies and patients with RA and UA. RESULTS: After 2 years, 301/610 (49 %) patients were in DAS-remission and 131/610 (21 %) in DFR. In the early remission group 241/387 patients (62 %) were in DAS-remission and 111/387 (29 %) DFR. In arm 1 22/83 (27 %) and in arm 2 24/78 (31 %) were in DAS-remission, and 6/83 (7 %) and 7/78 (9 %), respectively, were in DFR. RA and UA patients achieved DAS-remission in comparable percentages (RA: 234/479 (49 %), UA: 64/122 (52 %), p = 0.25). More UA patients achieved DFR (41/122 (34 %)) compared to RA patients (89/479 (19 %), p<0.001). Mean (SD) DAS over time was 1.74 (0.58) across all patients, and median (IQR) SHS progression was 0 (0-0). CONCLUSIONS: After 2 years remission-steered treatment in early RA and UA patients, DAS-remission and DFR percentages were relatively low. Patients who achieved early remission more often achieved (drug-free) remission after 2 years than patients who needed additional treatment steps in the randomization arms, and more UA than RA patients achieved DFR. Overall, disease activity and radiologic damage progression in all patients were well suppressed. TRIAL REGISTRATION: http://www.controlled-trials.com/ISRCTN11916566 Registered 07/11/2006 and EudraCT number 2006-06186-16 Registered 16/07/2007.

Estradiol dependence of the specific mammary tissue targeting of polyoma virus oncogenicity in nude mice.

We have previously reported (Berebbi et al., 1988) that in athymic nude mice, Polyoma virus induces mammary adenocarcinomas (MAC) at high frequency and exclusively in females. In the present study we show that in nude mice: (1) Ovariectomy results in a reduced frequency of MAC and a longer latency period of induction. When testosterone is administered to ovariectomized females, tumor induction is drastically reduced. (2) When estradiol is administered continuously to ovariectomized females the incidence and kinetics of MAC induction are the same as in control females. (3) MAC are induced in castrated males administered with estradiol although only osteosarcomas are observed in control males. (4) The tumor cells are found to harbor functional estradiol and progesterone receptors. (5) MAC can be transplanted from females to males, indicating that tumor growth is estradiol independent. (6) Estradiol is required only between day 10 and day 20 following polyoma injection, whereas the first tumors are detected only around day 60. Our results indicate that MAC induction by Polyoma virus in nude mice is estradiol-dependent during a short initiation period and that tumor progression is estradiol-independent in spite of the fact tumor cells carry functional estradiol and progesterone receptors.

Specific tissue targeting of polyoma virus oncogenicity in athymic nude mice.

Inbred athymic nu/nu mice (BALB/c and C57BL/6) were injected subcutaneously with polyoma virus A2 strain or with polyoma mutants which are able to infect undifferentiated embryonal carcinoma cells and harbor mutations in their enhancer sequences. Mammary adenocarcinomas were induced exclusively in females in which they represent the majority of the tumors. Both males and females developed sarcomas, mostly osteosarcomas, with a similar low frequency. No other type of neoplasm was observed. Mutations affecting the enhancers do not have any effect on the histotype of the tumors. Multiple copies of intact or defective free viral DNA were detected in all tumors. Such a sex-linked specific tissue targeting suggests a hormonal control of tumor initiation and/or promotion. From a pathological point of view, polyoma-induced adenocarcinomas are very similar to human early breast cancers. Tumor induction in nude mice by polyoma virus therefore represents a unique experimental model which differs from the more extensively used newborn immunocompetent mice.

What do internal medicine residents need to enhance their diabetes care?

OBJECTIVE: To identify areas that should be targeted for improvement in care, we examined internal medicine resident practice patterns and beliefs regarding diabetes in a large urban hospital outpatient clinic. RESEARCH DESIGN AND METHODS: Internal medicine residents were surveyed to assess the frequency at which they performed key diabetes quality of care indicators. Responses were compared with recorded performance derived from chart and laboratory database reviews. Resident attitudes about diabetes were determined using the Diabetes Attitude Survey for Practitioners. Finally, an eight-item scale was used to assess barriers to diabetes care. RESULTS: Both self-described and recorded performance of recommended diabetes services short of national recommendations. For yearly eye examinations and lipid screening, recorded performance levels were similar to trainees' reports. However, documented inquiries about patient self-monitoring of blood glucose, performance of foot examinations, and urine protein screening were lower than trainees' reports. Some 49% of the residents selected a target HbA1c of 6.6-7.5% as an attainable goal, yet half of the patients using oral agents or insulin had HbA1c values > 8.0%. No differences in self-described or recorded performance were found by year of training. Most residents did not perceive themselves to need additional training related to diabetes care, and residents were generally neutral about patient autonomy. Patient nonadherence and time constraints within the clinic were most often cited as barriers to care. CONCLUSIONS: The study identifies several areas that require improvement in resident care of diabetes in the ambulatory setting. Because experience during training contributes to future practice patterns, developing a program that teaches trainees how to implement diabetes practice guidelines and methods to achieve optimal glycemic control may be key to future improvements in the quality of diabetes care.

Diabetes in urban African-Americans. IX. Provider adherence to management protocols.

OBJECTIVE: Staged diabetes management should permit glycemic goals to be attained in a timely manner, but the success of such an approach requires conformity by health care providers. To test performance, we analyzed the adherence of practitioners to a protocol for staged management of NIDDM patients. RESEARCH DESIGN AND METHODS: Records of patients treated at the Grady Memorial Hospital Diabetes Clinic were reviewed retrospectively over a 3-year period. For each patient, intensification of therapy was indicated if fasting plasma glucose was > 7.8 mmol/l and a prior HbA1c was > 7.0%. Protocols dictated a progression from dietary therapy alone to increasing dosages of sulfonylureas to increasing dosages of insulin. Patients were seen at bimonthly intervals. RESULTS: During the 3-year period, 1,051 patient visits met protocol criteria for intensification. Adherence to the protocol improved significantly in the 3rd year compared with the first 2 years (30, 31, and 47% adherence in the 1st, 2nd, and 3rd years, respectively). Patients treated with diet alone were significantly less likely to have their therapy intensified than patients on sulfonylureas or insulin (intensification rates 25, 41, and 47%, respectively). In the management of patients treated with diet alone, practitioners were reluctant to intensify therapy at early visits, but were more likely to do so later, 19% of patients beyond goal range at the 2-month visit were started on pharmacological therapy vs. 28% at the 4-month visit, and 39% at the 6-month visit (P < 0.01). In contrast, there was no significant difference in the frequency of therapy intensification between early and late visits for patients on sulfonylureas or insulin. Practitioners appeared to base the decision to intensify on the fasting plasma glucose level more than on the most recent HbA1c. Age did not appear to be a significant factor in the decision to intensify. CONCLUSIONS: Although staged management protocols constitute critical tools to achieve glycemic goals, the adherence of health care providers may be suboptimal. Special efforts may be needed to assure compliance.