Long-term Suppressive Therapy Research Articles

Low trabecular bone score in postmenopausal women with differentiated thyroid carcinoma after long-term TSH suppressive therapy.

We carried out a study in 61 premenopausal and 84 postmenopausal Caucasian women with DTC. Serum biochemistry, bone markers, TBS, BMD, and bone fractures were evaluated 1-3 months post surgery and after a median follow-up of 10 years. In the final study, patients belonged to Group I Premenopausal (n = 14) who remained in this status; Group II Premenopausal who became postmenopausal (n = 47); Group III patients who were and continued as postmenopausal (n = 84). Baseline premenopausal patients had a normal TBS mean value of 1.39 ± 0.14 significantly higher than that found in postmenopausal 1.31 ± 0.12 (p = 001). In the final study, premenopausal patients continued to have a normal TBS of 1.46 ± 0.08 compared to the significantly lower value of postmenopausal patients 1.25 ± 0.11 (p = 0.0009). Lumbar BMD (L-BMD) loss after the long-term study was significant in Group II (0.99 g/cm2 ± 0.13 vs. 0.91 ± 0.12 g/cm2, p < 0.0001) and there was a slight, but not significant, bone loss in Group I (1.00 ± 0.12 vs. 0.98 ± 0.11, p = 0.1936) and in Group III (0.86 ± 0.12 vs. 0.84 ± 0.15, p = 0.1924) compared with baseline values. Longer-term suppression therapy in female patients with DTC did not increase significantly the risk of bone loss, although we found in postmenopausal patients deterioration of bone microarchitecture. TBS study should be considered in the evaluation of postmenopausal DTC patients on long-term DTC for the evaluation of the risk of fractures.

Differentiated Human SH-SY5Y Cells Provide a Reductionist Model of Herpes Simplex Virus 1 Neurotropism

Neuron-virus interactions that occur during herpes simplex virus (HSV) infection are not fully understood. Neurons are the site of lifelong latency and are a crucial target for long-term suppressive therapy or viral clearance. A reproducible neuronal model of human origin would facilitate studies of HSV and other neurotropic viruses. Current neuronal models in the herpesvirus field vary widely and have caveats, including incomplete differentiation, nonhuman origins, or the use of dividing cells that have neuropotential but lack neuronal morphology. In this study, we used a robust approach to differentiate human SH-SY5Y neuroblastoma cells over 2.5 weeks, producing a uniform population of mature human neuronal cells. We demonstrate that terminally differentiated SH-SY5Y cells have neuronal morphology and express proteins with subcellular localization indicative of mature neurons. These neuronal cells are able to support a productive HSV-1 infection, with kinetics and overall titers similar to those seen in undifferentiated SH-SY5Y cells and the related SK-N-SH cell line. However, terminally differentiated, neuronal SH-SY5Y cells release significantly less extracellular HSV-1 by 24 h postinfection (hpi), suggesting a unique neuronal response to viral infection. With this model, we are able to distinguish differences in neuronal spread between two strains of HSV-1. We also show expression of the antiviral protein cyclic GMP-AMP synthase (cGAS) in neuronal SH-SY5Y cells, which is the first demonstration of the presence of this protein in nonepithelial cells. These data provide a model for studying neuron-virus interactions at the single-cell level as well as via bulk biochemistry and will be advantageous for the study of neurotropic viruses in vitroIMPORTANCE Herpes simplex virus (HSV) affects millions of people worldwide, causing painful oral and genital lesions, in addition to a multitude of more severe symptoms such as eye disease, neonatal infection, and, in rare cases, encephalitis. Presently, there is no cure available to treat those infected or prevent future transmission. Due to the ability of HSV to cause a persistent, lifelong infection in the peripheral nervous system, the virus remains within the host for life. To better understand the basis of virus-neuron interactions that allow HSV to persist within the host peripheral nervous system, improved neuronal models are required. Here we describe a cost-effective and scalable human neuronal model system that can be used to study many neurotropic viruses, such as HSV, Zika virus, dengue virus, and rabies virus.

The effect of long-term thyroid-stimulating hormone suppressive therapy on the gonadal steroid hormones of patients with thyroid carcinoma after surgery.

To analyze the effect of long-term thyroid-stimulating hormone (TSH) suppressive therapy on the gonadal hormones and related symptoms in patients after surgery. From 2008 to 2011, totally 238 patients were recruited, who underwent thyroid surgery and subsequent TSH suppression treatment in Department of thyroid Surgery, China-Japan Union hospital, Jilin University. Then their postoperative follow-up data (3-8 years) were collected, including operational method, pathological diagnosis, whether processed radioiodine therapy and the period/dose of TSH suppression treatment. In addition, the menstrual cycle, menstruation quantity, whether accompanied with dysmenorrheal and menstrual disorder or not, date of last menstrual period, ages of menopause and so on were also collected. (I) Neither the level nor the duration of TSH treatment had any function on estradiol (E2) and testosterone (T) in male patients; (II) in the subgroup of patients with TSH treatment for 3-5 years, patients who took high dose of TSH (TSH ≥0.5 U/L) obtained the lower T level compared with the group of medium dose (1.08±0.34 vs. 1.36±0.46 nmol/L, P=0.001); (III) in the medium dose (0.1 IU/L ≤ TSH <0.5 IU/L) of TSH treatment, patients in luteal phase showed significant difference between two separate durations as the E2 level was 196.0 pmol/L in 3-5 years group vs. 442.5 pmol/L in 6-8 years group, P=0.018; (IV) the level of follicle-stimulating hormone (FSH) did not show any change in terms of the dose and the duration of TSH treatment; (V) the menstrual volume, dysmenorrhea condition, menstrual cycle and menopause related indicators did not show any difference in terms of doses and duration of TSH treatment (P=0.701, 0.412 and 0.507 respectively). The long term of TSH repressive therapy after surgery did not affect T and E2 level in male patients. As for female patients, the impact was mainly reflected in the T and E2 levels especially in female sexual maturity but not FSH level. In addition, TSH treatment did not play any role on menstruation or menopause.

Efficacy and safety of clindamycin-based treatment for bone and joint infections: a cohort study.

Clindamycin has high bioavailability together with good diffusion in bone tissue and could represent an alternative antibiotic compound for the treatment of bone and joint infections (BJIs). However, data regarding the efficacy and safety of clindamycin for BJIs are limited. A monocentric cohort study based on our medical dashboard, which prospectively recorded 28 characteristics for all hospitalized patients since July 2005, was performed. BJIs were selected, and then, all mono-microbial BJI managed with clindamycin-based therapy were included. Remission was defined as the absence of clinical and/or microbiological relapse after treatment. The duration of follow-up without relapse was determined retrospectively using computerized medical records. For 10years, 196 BJIs, of which 80 (41%) were device-associated infections, were treated with clindamycin-based therapy. The bacterial causative agent was Staphylococcus aureus in 130 cases (66%), coagulase-negative staphylococci in 29 cases (15%), streptococci in 31 cases (16%) and other bacteria in 6 cases (3%). When used in combination therapy, clindamycin was mainly paired with fluoroquinolones (31%) or rifampin (27%). The mean duration of clindamycin treatment was 7.4±3.2weeks (range, 1-24). An AE was recorded for 9 (4.5%) patients. Remission was recorded for 111 (57%) patients, with a mean duration of clinical follow-up of 28±24months. Treatment failure occurred in 22 (11%) patients, 50 patients (25%) were lost to follow-up, and 8 (4%) required long-term suppressive therapy. Among the assessable patients, clindamycin-based therapy was efficient in 111/133 cases (83%) and thus represents a reliable and safe alternative treatment option.

Hepatic, Renal, Hematologic, and Inflammatory Markers in HIV-Infected Children on Long-term Suppressive Antiretroviral Therapy.

Data on long-term toxicity of antiretroviral therapy (ART) in HIV-infected children are sparse. PENPACT-1 was an open-label trial in which HIV-infected children were assigned randomly to receive protease inhibitor (PI)- or nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based ART. We examined changes in clinical, immunologic, and inflammatory markers from baseline to year 4 in the subset of children in the PENPACT-1 study who experienced viral suppression between week 24 and year 4 of ART. Liver enzyme, creatinine, and cholesterol levels and hematologic parameters were assessed during the trial. Cystatin C, high-sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), d-dimer, and soluble CD14 (sCD14) were assayed from cryopreserved specimens. Ninety-nine children (52 on PI-based and 47 on NNRTI-based ART) met inclusion criteria. The median age at initiation of ART was 6.5 years (interquartile range [IQR], 3.7-13.4 years), and 22% were aged <3 years at ART initiation; 56% of the PI-treated children received lopinavir/ritonavir, and 70% of NNRTI-treated children received efavirenz initially. We found no evidence of significant clinical toxicity in either group; growth, liver, kidney, and hematologic parameters either remained unchanged or improved between baseline and year 4. Total cholesterol levels increased modestly, but no difference between the groups was found. IL-6 and hs-CRP levels decreased more after 4 years in the NNRTI-based ART group. The median change in IL-6 level was -0.35 pg/ml in the PI-based ART group and -1.0 in the NNRTI-based ART group (P = .05), and the median change in hs-CRP level was 0.25 µg/ml in the PI-based ART group and -0.95 µg/ml in the NNRTI-based ART group (P = .005). These results support the safety of prolonged ART use in HIV-infected children and suggest that suppressive NNRTI-based regimens can be associated with lower levels of systemic inflammation.

Impact of Different Antiretroviral Strategies on Total HIV-DNA Level in Virologically Suppressed HIV-1 Infected Patients.

Background: Total HIV-DNA load in peripheral blood cell (PBMCs) reflects the global viral reservoir that seems not to be affected by antiretroviral treatment. However, some studies report-ed a different permeability of different drugs in cellular compartments.Objective: To investigate the relation between the amount of total HIV-1 DNA and different treatment strategies.Methods: Total HIV-1 DNA was quantified by real time PCR in PBMCs collected from 161 patients with long-term undetectable HIV-RNA receiving different therapy schedules (3-drug regimens or 2-drug regimen containing Raltegravir as integrase inhibitor).Results: Overall, HIV patients who started therapy with a median pre-ART CD4+ cell count >400 cells/mm3 and HIV viral load of 3 log10 copies/ml, achieved a lower amount of HIV total DNA. No significant correlation was found in DNA size when patients were stratified on the basis of different therapeutic protocols. However, HIV DNA load analysis, when only performed in HIV patients with a median pre-ART CD4+ cell count >200 cells/mm3 and HIV viral load < 3 log10 copies/ml, showed a significative DNA decrease in Raltegravir treated group with respect to the NNRTIs-treated group.Conclusion: The data emphasize that HIV-DNA level represents a predictive factor in long-term sup-pressive therapy patients. In addition, the diminished reservoir, only observed in patients treated with the NRTI-sparing regimen RAL plus PI/r before immunological and virological derangement, sug-gests that latest generation drugs, such as integrase inhibitors, might represent an optimal chance in the management of HIV infection.

Relationship between sarcopenia and dose-limiting toxicity (DLT) of sorafenib (SOR) in patients (pts) with advanced radioactive iodine-refractory differentiated thyroid cancer (RAI-R DTC) in the phase III DECISION trial.

e17594 Background: In the phase III DECISION trial comparing SOR with placebo, pts with advanced RAI-R DTC treated with SOR experienced higher rates of adverse events (AEs) than pts with renal cell carcinoma and hepatocellular carcinoma treated with SOR (Brose et al. Lancet 2014). We hypothesized that long-term thyroxine suppressive therapy might result in a high prevalence of sarcopenia, which is known to be associated with increased toxicity of SOR (Antoun et al. Ann Oncol 2010), and we investigated whether sarcopenia at baseline correlated with DLT. Methods: In DECISION, pts with an analyzable baseline lumbar CT scan were eligible. Skeletal muscle cross-sectional area at the third lumbar vertebra was measured, and the median value for each sex defined the cut-off points for sarcopenia. DLT was defined as any AE leading to dose modification; early toxicities occurred ≤30 days after treatment initiation. Results: Of 365 eligible pts, 199 (55%) were sarcopenic (SOR n = 100, placebo n = 99) with large geographic differences: 65/91 Asians (71%), 29/62 North Americans (47%), and 105/212 Europeans (50%). Sarcopenia was 3-fold more frequent than non-sarcopenia in pts ≥75 years of age (19% vs 6%) and was associated with lower body weight (mean [standard deviation]: 71.3 [16.8] vs 80.8 [19.5]; P &lt; 0.0001). Among SOR pts, 76/180 (42%) experienced early DLT of which 44/76 (58%) occurred in sarcopenic pts (P = 0.6497). Among the 90 males, 61 (68%) were sarcopenic and of the 35 males with early DLT, 27 (77%) were sarcopenic. Median time to DLT in sarcopenic vs non-sarcopenic pts who received SOR was 63 vs 95 days, respectively (log-rank P = 0.5328). Conclusions: In this exploratory analysis from DECISION, approximately half of the pts were sarcopenic. In the overall population, no association between sarcopenia and early DLT or DLT were found. Clinical trial information: NCT00984282.

Pre-ART Immune Abnormalities Persist After ART Initiation

The mechanism of persistent immune activation despite long-term suppressive antiretroviral therapy (ART) for HIV infection remains unclear. To better

Long-term treatment-related morbidity in differentiated thyroid cancer: a systematic review of the literature.

BackgroundDifferentiated thyroid cancer (DTC) occurs in relatively young patients and is associated with a good prognosis and long survival. The management of this disease involves thyroidectomy, radioiodine therapy, and long-term thyroid-stimulating hormone suppression therapy (THST). The long-term effects of the treatment and the interaction between subclinical hyperthyroidism and long-term hypoparathyroidism are poorly understood. This review sought to examine the available evidence.MethodsA PubMed search was carried out using the search terms “Thyroid Neoplasms” AND (“Thyroxine” OR “Hypocalcemia” OR “Thyrotropin”). Original English language articles published in the last 30 years studying the morbidity from thyroid-stimulating hormone (TSH) suppression and hypoparathyroidism following a surgery for DTC were retrieved and reviewed by 2 authors.ResultsOf the 3,000 results, 66 papers including 4,517 patients were selected for the present study. Studies reported on a range of skeletal (included in 34 studies, 1,647 patients), cardiovascular (17 studies, 957 patients), psychological (10 studies, 663 patients), and other outcomes (10 studies, 1,348 patients). Nine of 26 studies on patients who underwent THST showed a reduction in bone density, and 13 of 23 studies showed an increase in bone turnover markers. Skeletal effects were more marked in postmenopausal women. There was no evidence of increased fracture risk, and only little data were available on hypoparathyroidism. Four of five studies showed an increased left ventricular mass index on echocardiography, and one study showed a higher prevalence of atrial fibrillation (AF). There was little difference in basic physiological parameters and limited literature regarding symptoms or significant events. Six studies showed associations between long-term TSH suppression and impaired quality of life. Impaired glucose metabolism and prothrombotic states were also found in DTC patients.ConclusionThere is limited literature regarding long-term DTC treatment-related morbidity, particularly regarding the effects of long-term hypocalcemia. Most studies have focused on surrogate markers and not on clinical outcomes. A large prospective study on defined clinical outcomes would help characterize the morbidity of treatment and stimulate research on tailoring treatment strategies.

Single-cell analysis of HIV-1 transcriptional activity reveals expression of proviruses in expanded clones during ART

Little is known about the fraction of human immunodeficiency virus type 1 (HIV-1) proviruses that express unspliced viral RNA in vivo or about the levels of HIV RNA expression within single infected cells. We developed a sensitive cell-associated HIV RNA and DNA single-genome sequencing (CARD-SGS) method to investigate fractional proviral expression of HIV RNA (1.3-kb fragment of p6, protease, and reverse transcriptase) and the levels of HIV RNA in single HIV-infected cells from blood samples obtained from individuals with viremia or individuals on long-term suppressive antiretroviral therapy (ART). Spiking experiments show that the CARD-SGS method can detect a single cell expressing HIV RNA. Applying CARD-SGS to blood mononuclear cells in six samples from four HIV-infected donors (one with viremia and not on ART and three with viremia suppressed on ART) revealed that an average of 7% of proviruses (range: 2-18%) expressed HIV RNA. Levels of expression varied from one to 62 HIV RNA molecules per cell (median of 1). CARD-SGS also revealed the frequent expression of identical HIV RNA sequences across multiple single cells and across multiple time points in donors on suppressive ART consistent with constitutive expression of HIV RNA in infected cell clones. Defective proviruses were found to express HIV RNA at levels similar to those proviruses that had no obvious defects. CARD-SGS is a useful tool to characterize fractional proviral expression in single infected cells that persist despite ART and to assess the impact of experimental interventions on proviral populations and their expression.

Increased cell-free mitochondrial DNA is a marker of ongoing inflammation and better neurocognitive function in virologically suppressed HIV-infected individuals.

Cell-free mitochondrial DNA (mtDNA) is a highly immunogenic molecule that is associated with several inflammatory conditions and with neurocognitive impairment during untreated HIV infection. Here, we investigate how cell-free mtDNA in cerebrospinal fluid (CSF) is associated with inflammation, neuronal damage, and neurocognitive functioning in the context of long-term suppressive antiretroviral therapy (ART). We quantified the levels of cell-free mtDNA in the CSF from 41 HIV-infected individuals with completely suppressed HIV RNA levels in blood plasma (<50 copies/mL) by droplet digital PCR. We measured soluble CD14, soluble CD163, interferon γ-induced protein 10 (IP-10), monocyte chemoattractant protein-1 (MCP-1), interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor-α (TNF-α), neopterin, and neurofilament light chain (NFL) by immunoassays in CSF supernatant or blood plasma. Higher levels of mtDNA in CSF were associated with higher levels of MCP-1 (r=0.56, p<0.01) in CSF and TNF-α (r=0.43, p<0.01) and IL-8 (r=0.44, p<0.01) in blood plasma. Subjects with a previous diagnosis of AIDS showed significantly higher levels of mtDNA (p<0.01) than subjects without AIDS. The associations between mtDNA and MCP-1 in CSF and TNF-α in blood remained significant after adjusting for previous diagnosis of AIDS (p<0.01). Additionally, higher levels of mtDNA were associated with a lower CD4 nadir (r=-0.41, p<0.01) and lower current CD4% (r=-0.34, p=0.03). Paradoxically, higher levels of mtDNA in CSF were significantly associated with better neurocognitive performance (r=0.43, p=0.02) and with less neuronal damage (i.e. lower NFL). Higher cell-free mtDNA is associated with inflammation during treated HIV infection, but the impact on neurocognitive functioning and neuronal damage remains unclear and may differ in the setting of suppressive ART.

The Effect of TSH Suppression on Vertebral Trabecular Bone Scores in Patients With Differentiated Thyroid Carcinoma.

The effect of thyrotropin (TSH) suppressive therapy on trabecular bone scores (TBSs) is unclear. The aim of this study was to investigate the effect of TSH suppression on vertebral TBSs of postmenopausal women with differentiated thyroid carcinoma (DTC). We conducted a retrospective cohort study including 273 postmenopausal women with DTC who had received TSH suppressive therapy. Bone mineral density (BMD) and TBSs at the lumbar spine were analyzed using dual-energy X-ray absorptiometry (DXA). The association between the parameters of TSH suppressive therapy and bone parameters was investigated. Study subjects showed upper-normal free thyroxine levels and suppressed TSH at DXA evaluation. The mean duration of TSH suppression was 4.4 ± 2.9 years. Serum free T4 and TSH were not independently associated with lumbar spine BMD or TBS levels. Duration of TSH suppression was negatively correlated with lumbar spine TBS levels, but not with BMD. Longer duration of TSH suppression was independently associated with lower lumbar spine TBSs after adjusting for age, body mass index (BMI), and BMD. Lumbar spine TBSs were significantly lower in patients whose duration of TSH suppression was ≥5 years compared with those whose duration was <3 years after adjusting for age, BMI, and BMD. Longer duration of TSH suppression in postmenopausal DTC patients was associated with decreased vertebral bone strength by altering TBSs rather than BMD. TBSs should be considered when estimating vertebral bone fragility in postmenopausal DTC patients receiving long-term TSH suppressive therapy.

Vascular Graft Infections, Mycotic Aneurysms, and Endovascular Infections: A Scientific Statement From the American Heart Association.

### Background The use of synthetic material for reconstructive vascular surgery was first reported during the early 1950s. Infection involving vascular graft prostheses is an infrequent but devastating complication of reconstructive vascular graft surgery and is associated with a high morbidity and, in some situations, mortality. Improvements in surgical techniques and graft design, including the use of native venous or arterial tissue, have reduced the frequency of infection and severity of complications from vascular graft infection (VGI). However, these advances have also led to more frequent vascular graft procedures occurring in a patient population with multiple underlying comorbidities that would have previously disqualified them as candidates for vascular reconstructive surgery. Underlying comorbidities, such as diabetes mellitus or immune compromise, increase the risk of infection and serious infection-related complications. The major complications of VGI include sepsis, amputation, disruption of infected anastomotic suture line with rupture or pseudoaneurysm formation, embolization of infected thrombi, reinfection of reconstructed vascular grafts, enteric fistulae to the small or large bowel, bacteremic spread of infection to other sites, and death. VGIs can be categorized broadly into those that occur in an extracavitary location, primarily in the groin or lower extremities, or in an intracavitary location, primarily within the abdomen or less commonly within the thorax. ### Frequency The frequency of VGI depends on the anatomic location of the graft. The infection rate is 1.5% to 2% for most extracavitary grafts and as high as 6% with vascular grafts in the groin.1–9 For intracavitary grafts, the infection rate is ≈1% to 5%.1–6 Graft infection is most common after emergency procedures and after reoperation.1–4,10 Aortic graft erosion or fistulous communication into the duodenum or other areas of the bowel reportedly occurs in 1% to 2% of patients after aortic reconstruction.11, …

Appropriateness of Acid Suppression Therapy.

The inappropriate startup of long-term acid suppressive therapy (AST) can have clinical and pharmacoeconomic impacts on ambulatory care. To assess the proportion of patients with appropriate initiation of long-term AST in non-critically ill patients. To describe possible risk factors for nonappropriate AST. To calculate the potential savings when eliminating the nonappropriate startup of AST. This observational, retrospective study evaluated the appropriateness of startup of long-term AST in medical records using a broad variety of international criteria and guidelines and using a validated screening instrument. A sample of 597 patients was included in the analysis. In 57% of them, AST was appropriately initiated. No specific risk profile could be defined. There was some indication that the availability of a clinical pharmacist and the use of standing orders were correlated to the outcome. Extrapolation to the total population (ie, 2836 patients) led to a total cost of €8880 during hospital stay plus an extra €40 391 per month after discharge. Avoiding inappropriate initiation of AST could lead to a saving of €3805 plus €17 441 per month. In all, 43% of initiation of long-term AST in the hospital was inappropriate. The potential savings from avoiding this could be substantial from a health care payer perspective. No patient characteristics that could predict for inappropriate initiation of AST were identified. A correlation between inappropriate initiation and medical disciplines using standing orders that include AST was seen.

Scimitar Syndrome Repair in Adults: Intermediate-Term Results Using an Extracardiac Conduit

Scimitar syndrome may be corrected using different techniques. Repair using an extracardiac conduit has rarely been performed. This study assessed the intermediate-term outcomes of this technique in adults. From January 2000 to June 2011, 7 adult patients underwent correction with a ringed polytetrafluoroethylene conduit used to connect the scimitar vein (SV) to the left atrium, posterior to the inferior vena cava (IVC). Preoperative and perioperative data were reviewed retrospectively. All patients (32 ± 10.6 years old) were symptomatic (3 patients were New York Heart Association [NYHA] functional class II, 4 had recurrent pneumonia), with a ratio of pulmonary to systemic blood flow greater than 2, without significant pulmonary hypertension. In all patients, the SV drained the entire right lung venous return to the IVC below the diaphragm. Surgical repair was performed by sternotomy, normothermic cardiopulmonary bypass, and aortic cross-clamping. Four patients required additional closure of an atrial septal defect. Mean conduit diameter was 14 mm (range, 12 to 16 mm). Patients received long-term platelet suppression therapy with aspirin. There were no deaths and no reoperations. Mean follow-up time was 9.1 ± 3.6 years. Postoperative morbidity was nil. No evidence of subclinical stroke orembolization was found in postoperative magnetic resonance imaging of the brain. No thrombi on the prosthesis or in the left atria were detected at the latestechocardiogram, with laminar flow from the SV to the left atrium. At last follow-up, all patients were in NYHA class I. Correction of scimitar syndrome with anextracardiac conduit can be easily and safely performed in adults, with excellent intermediate-term durability, without graft thrombi or stenosis. This technique avoidsdeep hypothermic circulatory arrest when the SV is short or enters the IVC in an unusually caudad location.

Interferon-γ Autoantibodies as Predisposing Factor for Nontuberculous Mycobacterial Infection

Interferon-γ Autoantibodies as Predisposing Factor for Nontuberculous Mycobacterial Infection

Should Asymptomatic Bacteriuria Be Systematically Treated in Kidney Transplant Recipients? Results From a Randomized Controlled Trial.

The indication for antimicrobial treatment of asymptomatic bacteriuria (AB) after kidney transplantation (KT) remains controversial. Between January 2011 and December 2013, 112 KT recipients that developed one episode or more of AB beyond the second month after transplantation were included in this open-label trial. Participants were randomized (1:1 ratio) to the treatment group (systematic antimicrobial therapy for all episodes of AB occurring ≤24 mo after transplantation [53 patients]) or control group (no antimicrobial therapy [59 patients]). Systematic screening for AB was performed similarly in both groups. The primary outcome was the occurrence of acute pyelonephritis at 24-mo follow-up. Secondary outcomes included lower urinary tract infection, acute rejection, Clostridium difficile infection, colonization or infection by multidrug-resistant bacteria, graft function and all-cause mortality. There were no differences in the primary outcome in the intention-to-treat population (7.5% [4 of 53] in the treatment group vs. 8.4% [5 of 59] in the control group; odds ratio [OR] 0.88, 95% confidence interval [CI] 0.22-3.47) or the per-protocol population (3.8% [1 of 26] in the treatment group vs. 8.0% [4 of 50] in the control group; OR 0.46, 95% CI 0.05-4.34). Moreover, we found no differences in any of the secondary outcomes. In conclusion, systematic screening and treatment of AB beyond the second month after transplantation provided no apparent benefit among KT recipients (NCT02373085).

An unusual pathogen for prosthetic joint infection

In 2012, an 84-year-old Chinese man presented with progressive, chronic left atraumatic knee pain and swelling. His medical history was notable for pulmonary tuberculosis treated in China in 1951 and rheumatoid arthritis diagnosed in 2006. His joint pain progressed despite use of disease modifying drugs and steroid injections. Antitumor necrosis factor inhibitors were not used because of concerns of tuberculosis reactivation. Clinical examination showed he had antalgic gait, knee eff usion, stiff ness, and joint-line tenderness. Laboratory results included erythrocyte sedimentation rate of 88 mm/h and C-reactive protein of 205 mg/L. Radiographs showed severe tri-compartmental degenerative arthritis (fi gure A). The patient underwent total knee arthroplasty in August, 2012 (fi gure B). Extensive synovitis was noted and pathological examination showed granulomatous infl ammation (fi gure C). Staining of synovial tissue for acid-fast bacilli and tuberculosis PCR were negative. The patient’s knee symptoms initially improved, but 5 months after total knee arthroplasty he developed a draining sinus from the knee incision. He underwent irrigation and debridement of the knee with exchange of the polyethylene tibial insert. Initial synovial tissue fl uid cultures were negative, but subsequent acid-fast bacilli cultures from synovial tissue and joint fl uid grew Mycobacterium tuberculosis. Sputum cultures were negative for pulmonary tuberculosis. He started a course of antituberculosis therapy including rifampicin, isoniazid, pyrazinamide, and ethambutol for treatment of tuberculosis prosthetic joint infection in February, 2013. He was advised to undergo a two-stage resection-revision arthroplasty but declined further surgery and thus an implant retention strategy was pursued. The patient completed 12 months of antituberculosis therapy in February, 2014. He has since continued rifampicin and isoniazid treatment with a plan for long-term suppressive therapy in the setting of retained prosthesis. At his latest follow-up, 2 years after initial diagnosis of tuberculous prosthetic joint infection, the incision had healed without clinical sign of infection and his knee has a pain-free range of motion from 0–95°. Tuberculous arthritis accounts for 1–5% of people with tuberculosis. Scarce data are available for optimum management of tuberculous prosthetic joint infection. This case illustrates an unusual reactivation of tuberculosis in an isolated extra-pulmonary site after joint replacement surgery. Prompt initiation of antituberculosis therapy might enable implant retention, although continuation of suppressive therapy might be needed. In the setting of globalisation and the increasing use of immunomodulatory therapies and joint replacement surgeries, this case illustrates the need for tuberculosis to be thought about early in the diff erential diagnosis for culture-negative prosthetic joint infection in patients with previous exposures or epidemiological risk factors.

Cardiac Effects of Thyrotropin Oversuppression with Levothyroxine in Young Women with Differentiated Thyroid Cancer.

Background. We investigated the cardiac effects of TSH (thyroid-stimulating hormone) oversuppression in women with thyroidectomized differentiated thyroid cancer (DTC) during levothyroxine suppression therapy. Methods. Fourteen young female patients with DTC were enrolled. The duration of TSH-suppressive therapy was 5 to 9 years. They satisfied the following criteria: (1) a serum level of TSH < 0.1 mU/L in the intermediate-risk or TSH < 0.3 mU/L in the low-recurrence-risk group and (2) having been receiving a fixed dose of LT4 before the study. Controls matched for age, sex, and body mass index (BMI) were compared in terms of the levels of serum free T4, free T3, TSH, plasma N-terminal pro-brain natriuretic peptide (NT-pro-BNP), and cardiac functions and structures. Results. DTC patients and control subjects were well matched in heart rate and blood pressure. There were marked differences in serum TSH (P = 0.001) and free T4 (P = 0.002). However, there were no differences between the groups in serum free T3 and plasma NT-pro-BNP. Furthermore, there were nonsignificant differences in cardiac functions and structures between the groups. Conclusions. This study shows that TSH suppression therapy in women with DTC may be safe with respect to cardiac functions and structures despite intermittent oversuppression of TSH during long-term suppressive therapy. Trial Registration. This trial is registered with clinicaltrials.gov identifier NCT02645786.

CCR5-Δ32 Heterozygosity, HIV-1 Reservoir Size, and Lymphocyte Activation in Individuals Receiving Long-term Suppressive Antiretroviral Therapy.

We conducted a case-controlled study of the associations of CCR5-Δ32 heterozygosity with human immunodeficiency virus type 1 (HIV-1) reservoir size, lymphocyte activation, and CCR5 expression in 114 CCR5(Δ32/WT) and 177 wild-type CCR5 AIDS Clinical Trials Group participants receiving suppressive antiretroviral therapy. Overall, no significant differences were found between groups for any of these parameters. However, higher levels of CCR5 expression correlated with lower amounts of cell-associated HIV-1 RNA. The relationship between CCR5-Δ32 heterozygosity, CCR5 expression, and markers of HIV-1 persistence is likely to be complex and may be influenced by factors such as the duration of ART.