Brief report: Completing a scholarly project during residency training

BACKGROUND: Resident research has potential benefits and scholarly activity is an internal medicine residency training requirement. This study sought to learn about the resources needed and the barriers to performing scholarly work during residency from residents who had been successful. METHODS: A questionnaire was delivered to 138 internal medicine residents presenting their work at the 2002 American College of Physicians-American Society of Internal Medicine annual session. Residents were asked to comment on why they had participated in a scholarly project, the skills and resources needed to complete the project, as well as the barriers. Comparisons were made between residents who presented a research abstract and those who exhibited a clinical vignette. RESULTS: Seventy-three residents (53%) completed the questionnaire. Thirty-nine residents presented a clinical vignette and 34 displayed a research abstract. Residents participated in research for a variety of reasons, including intellectual curiosity (73%), career development (60%), and to fulfill a mandatory scholarly activity requirement at their residency program (32%). The most common barriers were insufficient time (79%), inadequate research skills (45%), and lack of a research curriculum (44%). Residents who had presented research abstracts devoted more time (median, 200 vs 50 hours; P<.05) to their project than those who exhibited clinical vignettes. Sixty-nine percent of residents thought research should be a residency requirement. CONCLUSIONS: The majority of respondents reported that their scholarly project was a worthwhile experience despite considerable barriers. Teaching research skills more explicitly with a focused curriculum and providing adequate protected time may enable residents to be successful.     

Association of unmet need with self-rated health in a community dwelling cohort of disabled seniors 75 years of age and over

Self-rated health (SRH) is a measure of perceived health that has been shown to predict use of community services, functional decline, pain, and mortality. Many factors associated with SRH have been identified, but unmet need for physical assistance with activities of daily living (ADL) has not yet been examined. The objective of this paper is to examine the association between unmet need and SRH while accounting for the effects of other, previously identified, correlates of SRH. We conducted a secondary analysis of a population-based study of 839 residents of Montréal, Québec who were 75 years of age or older, not cognitively impaired, and living in the community. Multivariable logistic regression was used to evaluate the association between met and unmet personal ADL (PADL) and instrumental ADL (IADL) need for physical assistance with SRH. Among 508 disabled community-dwelling elderly, for each additional unmet IADL need, subjects were 1.70 (95% CI: 1.11–2.61) times more likely to report poorer SRH. For each additional unmet PADL need, subjects were 2.26 (95% CI: 1.31–3.91) times more likely to report poorer SRH. Subjects at increased risk of malnutrition, with greater comorbidity and whose income was insufficient to meet their needs were also more likely to report poorer SRH. After adjustment for important correlates, unmet PADL and IADL needs retain a statistically significant association with poorer SRH, with nutritional status, comorbid conditions, and income satisfaction being important confounders of the relationship.     

Insulin levels measured with an insulin-specific assay in patients with fasting hypoglycaemia related to endogenous hyperinsulinism

OBJECTIVE: The finding of insulin levels above a minimum threshold at the time of symptomatic hypoglycaemia is crucial in the diagnosis of endogenous hyperinsulinism. The aim of this study was to evaluate insulin levels at the time of hypoglycaemia with an insulin-specific assay in such patients. DESIGN AND METHODS: We measured insulin levels in 15 patients with fasting hypoglycaemia related to endogenous hyperinsulinism using an insulin-specific immunoradiometric assay (IRMA) without any significant cross-reaction with intact proinsulin. RESULTS: Insulin levels were below 6 mIU/l in all the samples taken at the time of symptomatic hypoglycaemia in 6/15 patients, and in some of the samples in three patients; insulin levels were below 3 mIU/l in samples from 5 patients. C-peptide levels were above 0.6 ng/ml in all these samples. The lowest proinsulin level was 35 pmol/l. Insulin levels were measured with a less specific RIA (40% cross-reaction with proinsulin) in 8/15 patients and were above 6 mIU/l in all samples in seven patients, and all but one sample in the 8th patient. Mean concomitant C-peptide and insulinoma size were lower in those patients with insulin-IRMA levels below 6 mIU/l. CONCLUSION: Symptomatic hypoglycaemia below 0.45 g/l can result from insulin levels below 6 or even 3 mIU/l; lower insulin levels and secretion could be observed preferentially in small insulinomas. If an insulin assay devoid of any significant cross-reaction with intact proinsulin is employed, measuring C-peptide (and/or proinsulin) levels at the time of symptomatic hypoglycaemia is mandatory to make the diagnosis of endogenous hyperinsulinism.     

Lenalidomide maintenance fails to overcome the unfavourable prognosis of low NK-cell counts in rituximab–chemotherapy responsive elderly DLBCL patients: A LYSA group study

Low baseline NK-cell counts (NKCCs) in patients with diffuse large B-cell lymphoma (DLBCL) are associated with a poor prognosis. The REMARC phase III trial (NCT01122472) showed that lenalidomide maintenance prolonged PFS in rituximab–chemotherapy responders. We conducted a REMARC ancillary study analysing the impact of lenalidomide maintenance on the prognostic value of low NKCCs. Blood samples from 335 elderly French patients enrolled in the REMARC trial were analysed by flow cytometry to obtain NKCCs at diagnosis (n = 220), at randomization (n = 186) and/or six months after randomization (n = 184). Baseline NKCCs < 100 cells/μl were associated with shorter PFS and OS (HRs = [2.2 (1.4, 3.3), p < 0.001] and [2.8 (1.7, 4.5), p < 0.001], respectively), independently of aaIPI. In a competing risk analysis, low NKCCs at baseline were associated with a higher risk of relapse/progression (p = 0.0025), but not of death without progression (p = 0.33). Lenalidomide did not affect the prognosis value of low baseline NKCCs (p  = 0.6349). Similar results were obtained for low NKCCs at randomization. Our results demonstrate that low NKCCs at baseline and post rituximab–chemotherapy are robust prognostic factors in DLBCL and reveal that lenalidomide has no impact on this parameter. Other therapeutic strategies aiming at improving NK-cell function could improve outcomes in DLBCL.     

Complications of apheresis in children

BACKGROUND: Although the frequency of complications in adults undergoing therapeutic apheresis is low, there are little data in children. STUDY DESIGN AND METHODS: A retrospective study of 186 children who had undergone a total of 1632 apheresis procedures between 1994 and 2002 was conducted. Adverse reactions were prospectively documented. The procedures were plasma exchange (67%), hematopoietic progenitor cell collection (18%), red blood cell exchange (6.9%), leukodepletion (0.7%), and plasma exchange with immunoadsorption (6.7%). RESULTS: Adverse reactions, most minor, were reported in 55 percent of procedures in 82 percent of patients. The most frequent complications, per procedure and per patient during an entire course of therapy, were hypotension (14 and 48.4%), hypotension requiring fluid bolus (4.8 and 26.9%), symptomatic hypocalcemia (9.7 and 28.5%), allergic reactions (4.4 and 5.9%), catheter-related thrombosis (1.7 and 12.4%), catheter-related infection (2.1 and 16.1%), and severe anemia (hemoglobin [Hb] level, <7 g/dL; 2.5 and 17.2%). There were two deaths (1% of patients). Risk factors for complications by multivariate analysis were lower body weight, lower preapheresis Hb level, apheresis in a critical care unit, and number of procedures per patient. The 55 percent incidence of complications per procedure in our pediatric cohort is much higher than the 4.3 to 28 percent incidence reported in adults. The excess of adverse reactions in children are mostly related to citrate toxicity, higher relative vascular volume shifts, and the need for vascular access. CONCLUSION: Pediatric apheresis presents unique challenges and is associated with higher complication rate compared to adults. It is recommended that this procedure be performed in specialized centers.     

TLR4 activation mediates kidney ischemia/reperfusion injury

Ischemia/reperfusion injury (IRI) may activate innate immunity through the engagement of TLRs by endogenous ligands. TLR4 expressed within the kidney is a potential mediator of innate activation and inflammation. Using a mouse model of kidney IRI, we demonstrated a significant increase in TLR4 expression by tubular epithelial cells (TECs) and infiltrating leukocytes within the kidney following ischemia. TLR4 signaling through the MyD88-dependent pathway was required for the full development of kidney IRI, as both TLR4(-/-) and MyD88(-/-) mice were protected against kidney dysfunction, tubular damage, neutrophil and macrophage accumulation, and expression of proinflammatory cytokines and chemokines. In vitro, WT kidney TECs produced proinflammatory cytokines and chemokines and underwent apoptosis after ischemia. These effects were attenuated in TLR4(-/-) and MyD88(-/-) TECs. In addition, we demonstrated upregulation of the endogenous ligands high-mobility group box 1 (HMGB1), hyaluronan, and biglycan, providing circumstantial evidence that one or more of these ligands may be the source of TLR4 activation. To determine the relative contribution of TLR4 expression by parenchymal cells or leukocytes to kidney damage during IRI, we generated chimeric mice. TLR4(-/-) mice engrafted with WT hematopoietic cells had significantly lower serum creatinine and less tubular damage than WT mice reconstituted with TLR4(-/-) BM, suggesting that TLR4 signaling in intrinsic kidney cells plays the dominant role in mediating kidney damage.     

Role of EP3 and EP4 prostaglandin receptors in reorganization of the cytoskeleton in mature human osteoclasts

OBJECTIVE: Osteoclasts are central to the pathophysiology of several bone diseases. Prostaglandin E2 (PGE2) is well known to influence osteoclasts indirectly, but its direct action on osteoclasts is still controversial and the relevant receptors are unknown. We investigated the distribution and function of EP receptors in human mature osteoclasts. METHODS: Osteoclasts were extracted from femurs and tibias of human fetuses obtained from legal abortions. In situ hybridization and immunohistochemistry were used to detect the presence of EP1, EP2, EP3, and EP4 receptors on these cells. Actin staining and fluorescent microscopy were used to detect the effects of receptor activation on the cytoskeleton. RESULTS: Only EP3 and EP4 receptors were detected at the RNA and protein level in osteoclasts. These receptors were functional: PGE2 decreased the number of osteoclasts presenting an actin ring; 11-deoxy-PGE1, an EP2 and EP4 agonist, also decreased the number of tartrate-resistant acid phosphatase-positive cells with an actin ring; sulprostone, an EP3-specific agonist, had no effect on this variable but increased the number of cells with lamellipodia. CONCLUSION: Mature human osteoclasts present 2 subtypes of EP receptors, namely EP3 and EP4, that mediate different actions of PGE2 on these cells: activation of the EP4 receptors inhibits actin ring formation and activation of the EP3 receptors increases the number of lamellipodia. Activation or inhibition of these receptors by specific agents could be used to study and influence osteoclast function.     

At the tipping point: predicting severe mobility difficulty in vulnerable older women

OBJECTIVES: To identify clinical measures that aid detection of impending severe mobility difficulty in older women. DESIGN: Cross‐sectional and longitudinal cohort study. SETTING: Urban community in Baltimore, Maryland. PARTICIPANTS: One thousand two community‐dwelling, moderate to severely disabled women aged 65 and older in the Women's Health and Aging Study I. MEASUREMENTS: Self‐report and performance measures representing six domains necessary for mobility: central and peripheral nervous systems, muscles, bones and joints, perception, and energy. Severe mobility difficulty was defined as usual gait of 0.5 m/s or less, any reported difficulty walking across a small room, or dependence on a walking aid during a 4‐m walking test. RESULTS: Four hundred sixty‐seven out of 984 (47%) had severe mobility difficulty at baseline, and 104/474 (22%) developed it within 12 months. Baseline mobility difficulty was correlated with poor vision, knee pain, feelings of helplessness, inability to stand with feet side by side for 10 seconds, difficulty keeping balance while dressing or walking, inability to rise from a chair five times, and cognitive impairment. Of these, knee pain (odds ratio (OR)=1.74, 95% confidence interval (CI)=1.05–2.89), helplessness (OR=1.87, 95% CI=1.10–3.24), poor vision (OR=2.03, 95% CI=1.06–3.89), inability to rise from a chair five times (OR=2.50, 95% CI=1.15–5.41), and cognitive impairment (OR=4.75, 95% CI=1.67–13.48) predicted incident severe mobility difficulty within 12 months, independent of age. CONCLUSION: Five simple measures may aid identification of disabled older women at high risk of severe mobility difficulty. Further studies should determine generalizability to men and higher‐functioning individuals.     

Antimicrobial and physicochemical characterization of endodontic sealers after exposure to chlorhexidine digluconate

ObjectivesAssess the antibacterial, physical and chemical properties of AH Plus, BioRoot RCS and Pulp Canal Sealer (PCS) in contact with 2% chlorhexidine digluconate (CHX) used as final irrigant prior to root canal obturation.MethodsThe antimicrobial properties were investigated by direct contact tests for planktonic and biofilm growth of E. faecalis, S. mutans, S.epidermidis and S.aureus in vitro. The setting time, wettability, microhardness and surface roughness were also assessed. The sealers were studied in no contact, 1-minute (short-term) and continuous contact (long-term) with CHX. Chemical characterization of sealers was performed by scanning electron microscopy, X-ray diffraction analysis and Fourier-transform infrared spectroscopy after CHX or saline used as the last irrigant in an ex vivo tooth model and in endo training blocks.ResultsCHX increased the antibacterial activity of all the sealers investigated against planktonic bacteria and biofilms with PCS exerting the highest antimicrobial activity with and without the presence of CHX. The setting of AH Plus and BioRoot RCS was retarded, while for PCS accelerated in the presence of CHX. AH Plus and PCS were more hydrophilic after contact with CHX, whilst BioRoot RCS was hydrophobic in a time-dependent manner. The microhardness of sealers was compromised and the surface roughness increased after CHX exposure for AH Plus and BioRoot RCS, and decreased for PCS. CHX did not affect the sealers’ chemistry, but PCS that exhibited two extra phases.SignificanceCHX improved the antibacterial efficacy of endodontic sealers but further evidence is needed to confirm its suitability as a final irrigant prior to root canal obturation.     

Therapy-related classical Hodgkin lymphoma after a primary haematological malignancy: a report on 13 cases

The risk of developing Hodgkin lymphoma (HL) is increased in immunodeficiencies or during the treatment of some autoimmune diseases. The development of new therapeutic agents has highlighted the risk of unusual lymphoid proliferations, particularly classical HL (cHL). We report the clinicopathological findings of 13 cHL arising in patients treated for a primary haematological malignancy. Eight patients had received an immunomodulator, protein tyrosine-kinase inhibitor or monoclonal antibody, which may have contributed to the cHL development. Most patients had disseminated disease with poor prognostic factors at cHL diagnosis. Despite the initial presentation, good outcomes were achieved with standard cHL chemotherapy.