Follow-up of patients with urinary tract infections discharged from the emergency department: a mixed methods study.

OBJECTIVES: To evaluate the quality of culture follow-up after emergency department (ED) discharge in patients with urinary tract infections (UTIs). METHODS: This convergent mixed methods study included an observational cohort study and a qualitative interview study in UTI patients discharged from the ED of a Dutch university hospital. The primary outcomes of the observational study were the proportion of patients requiring adjustment of antibiotic therapy after culture review, and the proportion of patients in whom these adjustments were made. Logistic regression identified factors associated with these outcomes. Interviews assessed patient experiences and transcripts were analysed using inductive thematic content analysis. Integration of the results informed recommendations for high-quality follow-up. RESULTS: Out of 455 patients, 285 (63%) required culture-based treatment adjustments. In most patients, no adjustments were made (239/285, 84%). De-escalation was most frequently omitted (98%), followed by discontinuation of antibiotics (92%). A mean of 7.1 (SD  3.8) antibiotic days per patient could have been avoided in 103 patients. Patients with diabetes were less likely to require adjustments (aOR   0.50, 95%-CI  0.29-0.85). Patients with moderate or severe renal impairment (aOR  4.1, 95%-CI  1.45-11.33; aOR  4.2, 95%-CI   1.50-11.94) or recurrent UTIs (aOR  5.0, 95%-CI  2.27-11.18) were more likely to have received necessary adjustments. Twelve interviews also revealed varying degrees of follow-up. Three themes were identified: 'information and communication', 'coordination and accessibility of care' and 'individual needs and preferences'. Recommendations for high-quality follow-up advocate a person centred approach. CONCLUSIONS: This study highlights the importance of urine culture follow-up after ED discharge, mainly to reduce unnecessary antibiotic treatment, promote de-escalation and improve patient experience.

Spontaneous speech: a robust measurement before, during and after awake brain surgery in patients with glioma.

BACKGROUND: Patients with glioma often report language complaints with devastating effect on daily life. Analysing spontaneous speech can help to understand underlying language problems. Spontaneous speech monitoring is also of importance during awake brain surgery: it can guide tumour resection and contributes to maintaining language function. We aimed to investigate the spontaneous speech of patients with glioma in the perioperative period and the additional value of spontaneous speech analyses compared to standardised language testing. METHODS: We elicited and transcribed spontaneous speech of eight patients with glioma elected for awake brain surgery preoperatively, intraoperatively and 2.0-3.5 months postoperatively. Linguistic errors were coded. Type Token Ratio, Mean Length of Utterance of words, minimal utterances, and errors were extracted from the transcriptions. Patients were categorised based on total error patterns: stable, decrease or increase during surgery. Reliable Change Index scores were calculated for all spontaneous speech variables to objectify changes between time points. Language performance on language tests was compared to spontaneous speech variables. RESULTS: Most errors occurred in lexico-syntax, followed by phonology/articulation, syntax, and semantics. The predominant errors were Repetitions, Self-corrections, and Incomplete sentences. Most patients remained stable over time in almost all spontaneous speech variables, except in Incomplete sentences, which deteriorated in most patients postoperatively compared to intraoperatively. Some spontaneous speech variables (total errors, MLUw, TTR) gave more information on language change than a standard language test. CONCLUSIONS: While the course of spontaneous speech over time remained relatively stable in most patients, Incomplete sentences seems to be a robust marker of language difficulties patients with glioma. These errors can be prioritised in spontaneous speech analysis to save time, especially to determine intra- to postoperative deterioration. Importantly, spontaneous speech analyses can give more information on language change than standardised language testing and should therefore be used in addition to standardised language tests.

Human brain mapping using co-registered fUS, fMRI and ESM during awake brain surgeries: A proof-of-concept study.

Accurate, depth-resolved functional imaging is key in both understanding and treatment of the human brain. A new sonography-based imaging technique named functional Ultrasound (fUS) uniquely combines high sensitivity with submillimeter-subsecond spatiotemporal resolution available in large fields-of-view. In this proof-of-concept study we show that: (A) fUS reveals the same eloquent regions as found by fMRI while concomitantly visualizing in-vivo microvascular morphology underlying these functional hemodynamics and (B) fUS-based functional maps are confirmed by Electrocortical Stimulation Mapping (ESM), the current gold-standard in awake neurosurgical practice. This unique cross-modality experiment was performed using motor, visual and language-related functional tasks in patients undergoing awake brain tumor resection. The current work serves as an important milestone towards further maturity of fUS as well as a novel avenue to increase our understanding of hemodynamics-based functional brain imaging.

Characteristics of mpox positive, versus mpox negative, and mpox unsuspected clients from the Centre of Sexual Health, Public Health Service of Amsterdam, 20 May to 15 September 2022.

BACKGROUND: In May 2022, an outbreak of mpox (monkeypox) in men-who-have-sex-with-men (MSM) emerged and quickly affected over 100 countries. In the early stages of the outbreak, overlap in symptoms with sexually transmitted infections (STI) made triage for mpox testing challenging. More information was needed on whom to screen and the main route of transmission. OBJECTIVES: We aimed to identify characteristics of mpox cases to further strengthen case definitions. We also compared Cycle threshold (Ct) values of the DNA positive mpox samples as a proxy for viral load by body location. METHODS: From 20 May 2022 to 15 September 2022, we tested all MSM who presented with malaise, and/or ulcerative lesions, and/or proctitis and/or a papular-vesicular-pustular eruption attending the Centre of Sexual Health in Amsterdam, the Netherlands, for mpox, with a PCR test. In the same period, 6932 MSM mpox unsuspected clients were not tested. We compared those tested positive for mpox with those tested negative and those unsuspected for mpox. RESULTS: Of the 374 MSM tested, 135 (36%) were positive for mpox. The mpox-positive MSM were older (median age, respectively, 36, 34 and 34 years, p = 0.019) and more often lived with HIV (30% vs. 16% and 7%, p < 0.001). Furthermore, mpox-positive patients more often reported receptive anal sex without a condom, sexualized drug use, more sex partners, and were more often diagnosed with bacterial STI (p < 0.001). Systemic symptoms and anogenital lesions were associated with mpox infection. For mpox-positive patients, anal samples (p = 0.009) and lesional samples (p = 0.006) showed significantly lower median mpox Ct values compared to throat samples. CONCLUSIONS: Mpox-positive patients more often reported receptive anal sex without a condom, had more sex partners and more often lived with HIV. Our results suggest that in the current mpox outbreak among MSM, sexual transmission is the main route.

Current clinical practice in antibiotic treatment of Staphylococcus aureus bacteraemia: results from a survey in five European countries.

OBJECTIVES: To determine clinical practice variation and identify knowledge gaps in antibiotic treatment of Staphylococcus aureus bacteraemia (SAB). METHODS: A web-based survey with questions addressing antibiotic treatment of SAB was distributed through the ESGAP network among infectious disease specialists, clinical microbiologists and internists in Croatia, France, Greece, the Netherlands and the UK between July 2021 and November 2021. RESULTS: A total number of 1687 respondents opened the survey link, of whom 677 (40%) answered at least one question. For MSSA and MRSA bacteraemia, 98% and 94% preferred initial monotherapy, respectively. In patients with SAB and non-removable infected prosthetic material, between 80% and 90% would use rifampicin as part of the treatment. For bone and joint infections, 65%-77% of respondents would consider oral step-down therapy, but for endovascular infections only 12%-32% would. Respondents recommended widely varying treatment durations for SAB with different foci of infection. Overall, 48% stated they used 18F-fluorodeoxyglucose positron emission tomography/CT (18F-FDG-PET/CT) to guide antibiotic treatment duration. Persistent bacteraemia was the only risk factor for complicated SAB that would prompt a majority to extend treatment from 2 to 4-6 weeks. CONCLUSIONS: This survey in five European countries shows considerable clinical practice variation between and within countries in the antibiotic management of SAB, in particular regarding oral step-down therapy, choice of oral antibiotic agents, treatment duration and use of 18F-FDG-PET/CT. Physicians use varying criteria for treatment decisions, as evidence from clinical trials is often lacking. These areas of practice variation could be used to prioritize future studies for further improvement of SAB care.

Nephrotoxicity of concomitant piperacillin/tazobactam and teicoplanin compared with monotherapy.

OBJECTIVES: Piperacillin/tazobactam combined with vancomycin has been associated with a decline in renal function when compared with monotherapy. Teicoplanin is a glycopeptide similar to vancomycin. We investigated whether piperacillin/tazobactam combined with teicoplanin is associated with a decline in renal function as well. METHODS: We conducted a single-centre retrospective cohort study with data from our electronic health records from 9 August 2013 to 15 November 2019, including all adult patients that received either piperacillin/tazobactam, teicoplanin or piperacillin/tazobactam + teicoplanin. The incidence of acute kidney injury (AKI) at 48-72 h served as the primary outcome, whereas change in serum creatinine served as a secondary outcome. RESULTS: Of the 4202 included patients, 3188 (75.9%) received piperacillin/tazobactam, 791 (18.8%) received teicoplanin and 223 (5.3%) received piperacillin/tazobactam + teicoplanin. The incidence of AKI at 48-72 h after commencement of antibiotic therapy was 5.4% for piperacillin/tazobactam, 3.4% for teicoplanin and 11.7% for piperacillin/tazobactam + teicoplanin (P < 0.001). However, mean serum creatinine at 48-72 h was slightly higher in the piperacillin/tazobactam + teicoplanin group therapy compared with baseline [+1.61% (95% CI -2.25 to 5.70)], indicating a slight decrease in renal function, and decreased for piperacillin/tazobactam [-1.98% (95% CI -2.73 to -1.22)] and teicoplanin [-8.01% (95% CI -9.54 to -6.45)]. After correcting for significant confounders in a multivariate linear regression analysis, these patterns remained. CONCLUSIONS: Our study suggests that piperacillin/tazobactam + teicoplanin is associated with a higher prevalence of AKI compared with monotherapy. However, as the overall decline in renal function with piperacillin/tazobactam + teicoplanin is very small, its clinical relevance is likely limited. Therefore, piperacillin/tazobactam + teicoplanin can probably be safely combined.

How to measure quantitative antibiotic use in order to support antimicrobial stewardship in acute care hospitals: a retrospective observational study.

A cornerstone of antimicrobial stewardship programs (ASPs) is monitoring quantitative antibiotic use. Frequently used metrics are defined daily dose (DDD) and days of therapy (DOT). The purpose of this study was (1) to explore for the hospital setting the possibilities of quantitative data retrieval on the level of medical specialty and (2) to describe factors affecting the usability and interpretation of these quantitative metrics. We performed a retrospective observational study, measuring overall systemic antibiotic use at specialty level over a 1-year period, from December 1st 2014 to December 1st 2015, in one university and 13 non-university hospitals in the Netherlands. We distinguished surgical and non-surgical adult specialties. The association between DDDs, calculated from aggregated dispensing data, and DOTs, calculated from patient-level prescription data, was explored descriptively and related to organizational factors, data sources (prescription versus dispensing data), data registration, and data extraction. Twelve hospitals were able to extract dispensing data (DDD), three of which on the level of medical specialty; 13 hospitals were able to extract prescription data (DOT), 11 of which by medical specialty. A large variation in quantitative antibiotic use was found between hospitals and the correlation between DDDs and DOTs at specialty level was low. Differences between hospitals related to organizational factors, data sources, data registration, and data extraction procedures likely contributed to the variation in quantitative use and the low correlation between DDDs and DOTs. The differences in healthcare organization, data sources, data registration, and data extraction procedures contributed to the variation in reported quantitative use between hospitals. Uniform registration and extraction procedures are necessary for appropriate measurement and interpretation and benchmarking of quantitative antibiotic use.

A survey on antimicrobial stewardship prerequisites, objectives and improvement strategies: systematic development and nationwide assessment in Dutch acute care hospitals.

Background: Stewardship guidelines define three essential building blocks for successful hospital antimicrobial stewardship programmes (ASPs): stewardship prerequisites, stewardship objectives and improvement strategies. Objectives: We systematically developed a survey, based on these building blocks, to evaluate the current state of antimicrobial stewardship in hospitals. We tested this survey in 64 Dutch acute care hospitals. Methods: We performed a literature review on surveys of antimicrobial stewardship. After extraction and categorization of survey questions, five experts merged and rephrased questions during a consensus meeting. After a pilot study, the survey was sent to 80 Dutch hospitals. Results: The final survey consisted of 46 questions, categorized into hospital characteristics, stewardship prerequisites, stewardship objectives and stewardship strategies. The response rate was 80% (n = 64). Ninety-four percent of hospitals had established an antimicrobial stewardship team, consisting of at least one hospital pharmacist and one clinical microbiologist. An infectious diseases specialist was present in 68% of the teams. Nine percent had dedicated IT support. Forty-one percent of the teams were financially supported, with a median of 0.6 full-time equivalents (FTE; 0.1-1.8). The majority of hospitals performed monitoring of restricted antibiotic agents (91%), dose optimization (65%), bedside consultation (56%) and intravenous-to-oral switch (53%). Fifty-eight percent of the hospitals provided education to residents and 28% to specialists. Conclusions: The survey provides information on the progress that is being made in hospitals regarding the three building blocks of a successful ASP, and provides clear aims to strengthen ASPs. Ultimately, these data will be related to national data on antibiotic consumption and resistance.

The association between diabetes status, HbA1c, diabetes duration, microvascular disease, and bone quality of the distal radius and tibia as measured with high-resolution peripheral quantitative computed tomography-The Maastricht Study.

In this small cross-sectional study of predominantly well-treated participants with relatively short-term type 2 diabetes duration, HbA1c > 7% (53 mmol/mol) was associated with lower cortical density and thickness and higher cortical porosity at the distal radius, lower trabecular thickness at the distal tibia, and higher trabecular number at both sites. INTRODUCTION: To examine the association between diabetes status and volumetric bone mineral density (vBMD), bone microarchitecture and strength of the distal radius and tibia as assessed with HR-pQCT. Additionally-in participants with type 2 diabetes (T2DM), to examine the association between HbA1c, diabetes duration, and microvascular disease (MVD) and bone parameters. METHODS: Cross-sectional data from 410 (radius) and 198 (tibia) participants of The Maastricht Study (mean age 58 year, 51% female). Diabetes status (normal glucose metabolism, prediabetes, or T2DM) was based on an oral glucose tolerance test and medication history. RESULTS: After full adjustment, prediabetes and T2DM were not associated with vBMD, bone microarchitecture, and strength of the radius and tibia, except for lower trabecular number (Tb.N) of the tibia (- 4%) in prediabetes and smaller cross-sectional area of the tibia (- 7%) in T2DM. In T2DM, HbA1c > 7% was associated with lower cortical vBMD (- 5%), cortical thickness (- 16%), higher cortical porosity (+ 20%) and Tb.N (+ 9%) of the radius, and higher Tb.N (+ 9%) and lower trabecular thickness (- 13%) of the tibia. Diabetes duration > 5 years was associated with higher Tb.N (+ 6%) of the radius. The presence of MVD was not associated with any bone parameters. CONCLUSIONS: In this study with predominantly well-treated T2DM participants with relatively short-term diabetes duration, inadequate blood glucose control was negatively associated with cortical bone measures of the radius. In contrast, trabecular number was increased at both sites. Studies of larger sample size are warranted for more detailed investigations of bone density and bone quality in patients with T2DM.

International neurocognitive normative study: neurocognitive comparison data in diverse resource-limited settings: AIDS Clinical Trials Group A5271.

Infrastructure for conducting neurological research in resource-limited settings (RLS) is limited. The lack of neurological and neuropsychological (NP) assessment and normative data needed for clinical interpretation impedes research and clinical care. Here, we report on ACTG 5271, which provided neurological training of clinical site personnel and collected neurocognitive normative comparison data in diverse settings. At ten sites in seven RLS countries, we provided training for NP assessments. We collected normative comparison data on HIV- participants from Brazil (n = 240), India (n = 480), Malawi (n = 481), Peru (n = 239), South Africa (480), Thailand (n = 240), and Zimbabwe (n = 240). Participants had a negative HIV test within 30 days before standardized NP exams were administered at baseline and 770 at 6 months. Participants were enrolled in eight strata, gender (female and male), education (<10 and ≥10 years), and age (<35 and ≥35 years). Of 2400 enrolled, 770 completed the 6-month follow-up. As expected, significant between-country differences were evident in all the neurocognitive test scores (p < 0.0001). There was variation between the age, gender, and education strata on the neurocognitive tests. Age and education were important variables for all tests; older participants had poorer performance, and those with higher education had better performance. Women had better performance on verbal learning/memory and speed of processing tests, while men performed better on motor tests. This study provides the necessary neurocognitive normative data needed to build infrastructure for future neurological and neurocognitive studies in diverse RLS. These normative data are a much-needed resource for both clinicians and researchers.

Pharmacokinetics of caspofungin in ICU patients.

OBJECTIVES: Caspofungin is used for treatment of invasive fungal infections. As the pharmacokinetics (PK) of antimicrobial agents in critically ill patients can be highly variable, we set out to explore caspofungin PK in ICU patients. METHODS: ICU patients receiving caspofungin were eligible. Patients received a loading dose of 70 mg followed by 50 mg daily (70 mg if body weight >80 kg); they were evaluable upon completion of the first PK curve at day 3. Additionally, daily trough samples were taken and a second PK curve was recorded at day 7. PK analysis was performed using a standard two-stage approach. RESULTS: Twenty-one patients were evaluable. Median (range) age and body weight were 71 (45-80) years and 75 (50-99) kg. PK sampling on day 3 (n = 21) resulted in the following median (IQR) parameters: AUC0-24 88.7 (72.2-97.5) mg·h/L; Cmin 2.15 (1.40-2.48) mg/L; Cmax 7.51 (6.05-8.17) mg/L; V 7.72 (6.12-9.01) L; and CL 0.57 (0.54-0.77) L/h. PK sampling on day 7 (n = 13) resulted in AUC0-24 107.2 (90.4-125.3) mg·h/L, Cmin 2.55 (1.82-3.08) mg/L, Cmax 8.65 (7.16-9.34) mg/L, V 7.03 (5.51-7.73) L and CL 0.54 (0.44-0.60) L/h. We did not identify any covariates significantly affecting caspofungin PK in ICU patients (e.g. body weight, albumin, liver function). Caspofungin was well tolerated and no unexpected side effects were observed. CONCLUSIONS: Caspofungin PK in ICU patients showed limited intraindividual and moderate interindividual variability, and caspofungin was well tolerated. A standard two-stage approach did not reveal significant covariates. Our study showed similar caspofungin PK parameters in ICU patients compared with non-critically ill patients.

Nerve entry points in the mimic musculature of the horse head.

Facial expressions are important in pain recognition in horses, but current observation-based pain scales remain subjective. A promising technique to quantitatively measure subtle changes in expression patterns, including changes invisible to the human eye, is surface electromyography (sEMG). To achieve high-quality and reliable sEMG signals, unilateral placement of bipolar electrodes is required in relation to the motor endplates (MEP). We aimed to localize the nerve entry points (NEPs; where the nerve branch first pierced the muscle belly) and the direction of the terminal nerve endings to estimate MEP locations of the innervating nerves in five equine facial muscles involved in pain expression. Three cadaveric Dutch Warmblood horse heads were dissected to identify the NEPs in the musculi caninus, levator anguli oculi medialis, nasolabialis, masseter and zygomaticus. These points were marked with pins and measured in relation to a reference line between two anatomical landmarks near the origin and insertion of the respective muscle. Relative distances were calculated from the most caudally situated landmark. NEPs were located at 33%-38% (caninus), 69%-86% (levator anguli oculi medialis) and 0%-18% (zygomaticus) from the caudal landmark. The nasolabialis showed two innervations zones. Its NEPs were located at 47%-72% (dorsal muscle branch) and 52%-91% (ventral branch). All terminal nerve endings were found to run in rostral direction. The masseter showed numerous NEPs diffusely spread within the muscle belly. Therefore, calculation of relative positions was not performed. These results could form the basis for feasibility studies and standardization of bipolar electrode positioning in vivo to measure facial muscle activity patterns in horses.

Acute grade IV toxic hepatitis due to the e-cigarette.

A 46-year-old woman presented at the emergency department because of acute hepatitis with jaundice. After hepatological work-up including liver biopsy, drug induced liver disease (DILI) was suspected. Patient recovered completely within a few months. One year later she presented again with jaundice due to acute hepatitis. Vaping was the only agent that could be identified as causative agent for DILI. After VAPING cessation, the hepatitis resolved completely. Calculated RUCAM score was 10, making the diagnosis of toxic hepatitis very likely. During follow-up liver tests remained normal. This is the first report of severe DILI secondary to the use of e-cigarettes. In future vaping can be included in the differential diagnosis of DILI.

Trauma-related preventable death; data analysis and panel review at a level 1 trauma centre in Amsterdam, the Netherlands.

PURPOSE: Trauma-related death is used as a parameter to evaluate the quality of trauma care and identify cases in which mortality could have been prevented under optimal trauma care conditions. The aim of this study was to identify trauma-related preventable death (TRPD) within our institute by an external expert panel and to evaluate inter-panel reliability. METHODS: Trauma-related deaths between the 1st of January 2020 and the 1st of February 2022 at the Amsterdam University Medical Centre were identified. The severely injured patients (injury severity score ≥ 16) were enrolled for preventability analysis by an external multidisciplinary panel, consisting of a trauma surgeon, anaesthesiologist, emergency physician, neurosurgeon, and forensic physician. Case descriptions were provided, and panellists were asked to classify deaths as non-preventable, potentially preventable, and preventable. Agreements between the five observers were assessed by Fleiss kappa statistics. RESULTS: In total 95 trauma-related deaths were identified. Of which 36 fatalities were included for analysis, the mean age was 55.3 years (± 24.5), 69.4% were male and 88.9% suffered blunt trauma. The mean injury severity score was 35.3 (± 15.3). Interobserver agreement within the external panel was moderate for survivability (Fleiss kappa 0.474) but low for categorical preventable death classification (Fleiss kappa 0.298). Most of the disagreements were between non-preventable or potentially preventable with care that could have been improved. CONCLUSION: Multidisciplinary panel review has a moderate inter-observer agreement regarding survivability and low agreement regarding categorical preventable death classification. A valid definition and classification of TRPD is required to improve inter-observer agreement and quality of trauma care.

Hyperferritinemia and non-HFE hemochromatosis: differential diagnosis and workup.

Hyperferritinemia is a common reason for referral to a hepatogastroenterologist. The most frequent causes are not associated with iron overload (e.g. inflammatory diseases, alcohol abuse, metabolic syndrome, etc.). However, hyperferritinemia can also be caused by a genetic variant in one of the iron regulatory genes, called hereditary hemochromatosis, often but not always associated with iron overload. A variation in the human Hemostatic Iron Regulator protein (HFE) gene is the most common genotype, but many other variants have been described. In this paper we discuss two cases of rare hyperferritinemia associated disorders, ferroportin disease and hyperferritinemia-cataract syndrome. We also propose an algorithm for evaluating hyperferritinemia, facilitating a correct diagnosis and preventing potentially unnecessary examinations and therapeutic actions.

The influence of laboratory-induced MELD score differences on liver allocation: more reality than myth.

BACKGROUND: Liver allocation in Eurotransplant (ET) is based on the MELD score. Interlaboratory MELD score differences in INR and creatinine determination have been reported. The clinical implication of this observation has not been demonstrated. METHODS: MELD scores were calculated in 66 patients with liver cirrhosis using bilirubin, creatinine, and INR analyzed in six liver transplant centers. Based on allocation results of ET, patients transplanted from December 2006 to June 2007 were divided according to MELD score in four groups. For each group, the influence of the match MELD on the probability of receiving a transplant was studied (Cox proportional hazards model). RESULTS: Laboratory-dependent significant differences in MELD score were demonstrated. Cox proportional hazards model showed a significant association between MELD score and the probability of organ allocation. The unadjusted hazard ratio for receiving a liver transplant was significantly different between group 2 and group 4 (group 2: MELD 19-24; group 4: MELD > 30). CONCLUSION: Laboratory-dependent significant differences in MELD score were observed between the six transplant centers. We demonstrated a significant association between the MELD score and the probability of organ allocation. The observed interlaboratory variation might yield a significant difference in organ allocation in patients with high MELD scores.

Suppressors of interictal discharges in idiopathic childhood occipital epilepsy of Gastaut.

Idiopathic childhood occipital epilepsy of Gastaut (ICOE-G) is a rare form of epilepsy, characterized by visual hallucinations, periods of blindness, motor seizures, and migraine-like symptoms. A characteristic EEG feature is fixation-off sensitivity: epileptiform discharges are suppressed by visual input. Here, we present an 11-year-old girl suffering from ICOE-G, who was studied to identify potential additional suppressors of the epileptiform discharges.

Adalimumab successful in sarcoidosis patients with refractory chronic non-infectious uveitis.

INTRODUCTION: Adalimumab, a humanized monoclonal antibody targeted against TNF-α, has proved to be successful in the treatment of uveitis. Another anti-TNF-α agent, i.e., infliximab, has been reported of benefit in the treatment of refractory sarcoidosis. The aim of this prospective case series was to evaluate the effect of adalimumab on intraocular inflammatory signs and other relevant clinical manifestations (lung function, serological inflammatory parameters, and fatigue) of sarcoidosis. METHODS: Sarcoidosis patients with refractory posterior uveitis (n = 26, 17 females, 41 eyes in total) were systematically followed for 12 months after initiation of adalimumab 40 mg sc once a week. Inclusion criteria were non-responsiveness to prednisone and methotrexate (MTX) or intolerance to these drugs. Adjunctive therapy with prednisone and MTX was tapered during treatment with adalimumab. Localization and improvement, stabilization or deterioration of intraocular inflammatory signs was scored. Pulmonary function- and laboratory testing were performed and Fatigue Assessment Scale was completed. Results at baseline, 6 months, and 12 months were compared. RESULTS: Choroidal involvement resolved in 10/15 patients, five had partial improvement; vasculitis resolved in 1/1 patient; papillitis resolved in 7/8 patients, one had partial response; macular edema resolved in 5/8 patients, three had partial response; vitreous cleared completely in 5/5 patients. Overall outcome regarding intraocular inflammatory signs showed improvement in 22 patients (85%) and stabilization in four patients (15%). At 12 months, no recurrences were reported in those successfully treated. Laboratory parameters of inflammatory activity (C-reactive protein; serum angiotensin-converting enzyme and soluble interleukin-2 Receptor) improved (p < 0.01). Moreover, fatigue improved in 14/21 (67%) of the patients suffering from fatigue and the diffusion capacity for carbon monoxide (DLCO) improved in 7/8 (88%) of patients with a decreased DLCO (p < 0.01). The dosage of both prednisone and MTX could be tapered down significantly (p < 0.01 and p < 0.05, respectively). CONCLUSIONS: Adalimumab appeared successful in sarcoidosis patients with refractory chronic non-infectious uveitis showing improvement in intraocular inflammatory signs as well as in other relevant clinical indicators of disease activity. Future randomized studies are needed to determine the optimal dosage, dose interval and duration of therapy in refractory multisystemic sarcoidosis.

The impact of HIV/HCV co-infection on health care utilization and disability: results of the ACTG Longitudinal Linked Randomized Trials (ALLRT) Cohort.

HIV/hepatitis C virus (HCV) co-infection places a growing burden on the HIV/AIDS care delivery system. Evidence-based estimates of health services utilization among HIV/HCV co-infected patients can inform efficient planning. We analyzed data from the ACTG Longitudinal Linked Randomized Trials (ALLRT) cohort to estimate resource utilization and disability among HIV/HCV co-infected patients and compare them to rates seen in HIV mono-infected patients. The analysis included HIV-infected subjects enrolled in the ALLRT cohort between 2000 and 2007 who had at least one CD4 count measured and completed at least one resource utilization data collection form (N = 3143). Primary outcomes included the relative risk of hospital nights, emergency department (ED) visits, and disability days for HIV/HCV co-infected vs HIV mono-infected subjects. When controlling for age, sex, race, history of AIDS-defining events, current CD4 count and current HIV RNA, the relative risk of hospitalization, ED visits, and disability days for subjects with HIV/HCV co-infection compared to those with HIV mono-infection were 1.8 (95% CI: 1.3-2.5), 1.7 (95% CI: 1.4-2.1), and 1.6 (95% CI: 1.3-1.9) respectively. Programs serving HIV/HCV co-infected patients can expect approximately 70% higher rates of utilization than expected from a similar cohort of HIV mono-infected patients.

Evaluation of multiplex ligation-dependent probe amplification as a method for the detection of copy number abnormalities in B-cell precursor acute lymphoblastic leukemia.

Recent genomic studies have shown that copy number abnormalities (CNA) of genes involved in lymphoid differentiation and cell cycle control are common in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). We have evaluated Multiplex Ligation-dependent Probe Amplification (MLPA) on 43 BCP-ALL patients for the detection of the most common deletions among these genes and compared the results to those obtained by fluorescence in situ hybridization (FISH) and genomic quantitative PCR (qPCR). There was good correlation between methods for CDKN2A/B, IKZF1, and PAX5 deletions in the majority of cases and MLPA confirmed the presence of deletions within the PAR1 region in two of three cases identified by FISH. Small intragenic aberrations detected by MLPA, which were below the resolution of FISH for CDKN2A/B (n = 7), IKZF1 (n = 3), and PAX5 (n = 3) were confirmed by qPCR. MLPA and qPCR were unable to detect populations present at a low level (<20%) by FISH. In addition, although MLPA identified the presence of a deletion, it was unable to discern the presence of mixed cell populations which had been identified by FISH: CDKN2A/B (n = 3), IKZF1 (n = 1), PAX5 (n = 2), and PAR1 deletion (n = 1). Nevertheless, this study has demonstrated that MLPA is a robust technique for the reliable detection of CNA involving multiple targets in a single test and thus is ideal for rapid high throughput testing of large cohorts with a view to establishing incidence and prognostic significance.