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Background: Total hip arthroplasty (THA) is a proven and effective treatment for end-stage osteoarthritis. The success of THA is due in part to highly crosslinked polyethylene (XL) implants. In 2007, a new generation of polyethylene liners entered clinical use. The new liners infused polyethylene with vitamin E and became vitamin E infused polyethylene (EP). The EP liner was hypothesized to prevent the loss of mechanical properties caused by oxidation, extending the lifetime of the implant. This international prospective study aimed to quantify the clinical outcomes of a 977 patient cohort receiving EP and XL liners 10 years after surgery., Methods: The prospective cohort study began in 2007, including eight countries and 17 centers. The final cohort included 977 patients (EP liner: n = 520; XL liner: n = 457). Patients were followed preoperatively, postoperatively, and at 1, 3, 5, 7, and 10 years. Each follow-up visit involved clinical evaluation, radiography, and survey collection. The demographics and revisions were also recorded. Mann-Whitney U tests were used to evaluate statistical differences., Results: At 10 years following surgery, 534 patients were eligible for follow-up. Of those eligible, 352 patients returned for clinical evaluation (65.9% eligible; 36.0% overall). No statistical differences were found (P > 0.05) in the demographics of the followed-up cohort. The linear wear rates were 0.00338 mm/year for EP liners and 0.0236 mm/year for XL liners using individual regression (P < 0.0001). No significant difference was observed in wear rates using cohort regression. Similarly, surveys suggested no significant outcomes between the EP and XL liner cohorts. The overall incidence of revision was 2.3% for EP and 2.0% for XL liners., Conclusions: The EP liner demonstrated significantly lower wear than its XL counterparts at 10 years after implantation. Results are promising, as vitamin E polyethylene may improve the lifetime performance of THA implants and ensure that arthroplasty innovations reflect the changing patient population., (Copyright © 2024. Published by Elsevier Inc.)

Listeriosis is rare after hematopoietic stem cell transplantation (HCT). Little is known about listeriosis in this population. In this retrospective international case-control study, we evaluated 41 listeriosis episodes occurring between 2000 and 2021 in HCT recipients (111 transplant centers in 30 countries) and assessed risk factors for listeriosis by comparisons with matched controls. The 41 listeriosis episodes (all due to Listeria monocytogenes [LM]) occurred in 30 allogeneic (allo)-HCT recipients and 11 autologous (auto)-HCT recipients at a median of 6.2 months (interquartile range [IQR], 1.6 to 19.3 months) post-HCT. The estimated incidence was 49.8/100,000 allo-HCT recipients and 13.7/100,000 auto-HCT recipients. The most common manifestations in our cohort were fever (n = 39; 95%), headache (n = 9; 22%), diarrhea, and impaired consciousness (n = 8 each; 20%). Four patients (10%) presented with septic shock, and 19 of 38 (50%) were severely lymphocytopenic. Thirty-seven patients (90%) had LM bacteremia. Eleven patients (27%) had neurolisteriosis, of whom 4 presented with nonspecific signs and 5 had normal brain imaging findings. Cerebrospinal fluid analysis revealed high protein and pleocytosis (mainly neutrophilic). Three-month mortality was 17% overall (n = 7), including 27% (n = 3 of 11) in patients with neurolisteriosis and 13% (n = 4 of 30) in those without neurolisteriosis. In the multivariate analysis comparing cases with 74 controls, non-first HCT (odds ratio [OR], 5.84; 95% confidence interval [CI], 1.10 to 30.82; P = .038); and lymphocytopenia <500 cells/mm 3 (OR, 7.54; 95% CI, 1.50 to 37.83; P = .014) were significantly associated with listeriosis. There were no statistically significant differences in background characteristics, immunosuppression, and cotrimoxazole prophylaxis between cases and controls. HCT recipients are at increased risk for listeriosis compared to the general population. Listeriosis cause severe disease with septic shock and mortality. Neurolisteriosis can present with nonspecific signs and normal imaging. Lymphocytopenia and non-first HCT are associated with an increased risk of listeriosis, and cotrimoxazole was not protective., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Helicobacter cinaedi is known to cause invasive infections in immunocompromised adults. Here we report the first case of H. cinaedi bacteremia in a child with nephrotic syndrome. The patient presented with a mild transient febrile illness that resolved spontaneously. We discuss the diagnostic challenges associated with this case and the microbiologic approach, including genomic analysis. Furthermore, we review the current case together with all previous pediatric cases (n = 6). Notably, all cases involved neonates or otherwise immunocompromised individuals and were characterized by severe disease with complicated infections (eg, meningitis, cholangitis and arthritis). H. cinaedi bacteremia in children is associated with a wide spectrum of clinical presentations ranging from mild to life-threatening conditions. This bacterium may be difficult to diagnose and require specialized methods., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Vitamin E-diffused highly cross-linked polyethylene (VEPE) acetabular liners for total hip arthroplasty (THA) have shown favorable results in small cohort studies. However, larger studies are warranted to compare its performance to highly cross-linked polyethylene (XLPE) and demonstrate clinical significance in 10-year arthroplasty outcomes. This study compared acetabular liner wear and patient-reported outcome measures (PROMs) between patients treated with VEPE and XLPE liners in a prospective, international, multicenter study with minimum 7-year follow-up., Methods: A total of 977 patients (17 centers; 8 countries) were enrolled from 2007 to 2012. The centers were randomly assigned to implants. At 1-year, 3-year, 5-year, and 7-year postoperative visits, radiographs, PROMs, and incidence of revision were collected. Acetabular liner wear was calculated using computer-assisted vector analysis of serial radiographs. General health, disease progression, and treatment satisfaction reported by patients were scored using 5 validated surveys and compared using Mann-Whitney U tests. At 7 years, 75.4% of eligible patients submitted data., Results: The mean acetabular liner wear rate was -0.009 mm/y and 0.024 mm/y for the VEPE and XLPE group, respectively (P = .01). There were no statistically significant differences in PROMs. The overall revision incidence was 1.8% (n = 18). The revision incidence in VEPE and XLPE cohorts were 1.92% (n = 10) versus 1.75% (n = 8), respectively., Conclusion: We found that VEPE acetabular liners in total hip arthroplasty led to no significant clinical difference in 7-year outcomes as measured by acetabular liner wear rate, PROMs, and revision rate. While VEPE liners showed less wear, the wear rate for both the VEPE and XLPE liners was below the threshold for osteolysis. Therefore, the difference in liner wear may indicate comparative clinical performance at 7 years, as further indicated by the lack of difference in PROMs and the low revision incidence., (Copyright © 2023. Published by Elsevier Inc.)

Background: Fosmanogepix is a first-in-class antifungal targeting the fungal enzyme Gwt1, with broad-spectrum activity against yeasts and moulds, including multidrug-resistant fungi, formulated for intravenous (IV) and oral administration., Methods: This global, multicenter, non-comparative study evaluated the safety and efficacy of fosmanogepix for first-line treatment of candidaemia in non-neutropenic adults. Participants with candidaemia, defined as a positive blood culture for Candida spp. within 96 h prior to study entry, with ≤2 days of prior systemic antifungals, were eligible. Participants received fosmanogepix for 14 days: 1000 mg IV twice daily on Day 1, followed by maintenance 600 mg IV once daily, and optional switch to 700 mg orally once daily from Day 4. Eligible participants who received at least one dose of fosmanogepix and had confirmed diagnosis of candidaemia (<96 h of treatment start) composed the modified intent-to-treat (mITT) population. Primary efficacy endpoint was treatment success at the end of study treatment (EOST) as determined by the Data Review Committee. Success was defined as clearance of Candida from blood cultures with no additional antifungal treatment and survival at the EOST., Results: Treatment success was 80% (16/20, mITT; EOST) and Day 30 survival was 85% (17/20; 3 deaths unrelated to fosmanogepix). Ten of 21 (48%) were switched to oral fosmanogepix. Fosmanogepix was well tolerated with no treatment-related serious adverse events/discontinuations. Fosmanogepix had potent in vitro activity against baseline isolates of Candida spp. (MICrange: CLSI, 0.002-0.03 mg/L)., Conclusions: Results from this single-arm Phase 2 trial suggest that fosmanogepix may be a safe, well-tolerated, and efficacious treatment for non-neutropenic patients with candidaemia, including those with renal impairment., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Objective: Ophthalmological pathologies such as glaucoma, diabetic retinopathy and age-related macular degeneration are major causes of blindness and vision impairment. There is a need for novel decision support tools that can simplify and speed up the diagnosis of these pathologies. A key step in this process is to automatically estimate the quality of the fundus images to make sure these are interpretable by a human operator or a machine learning model. We present a novel fundus image quality scale and deep learning (DL) model that can estimate fundus image quality relative to this new scale., Methods: A total of 1245 images were graded for quality by two ophthalmologists within the range 1-10, with a resolution of 0.5. A DL regression model was trained for fundus image quality assessment. The architecture used was Inception-V3. The model was developed using a total of 89,947 images from 6 databases, of which 1245 were labeled by the specialists and the remaining 88,702 images were used for pre-training and semi-supervised learning. The final DL model was evaluated on an internal test set (n=209) as well as an external test set (n=194)., Results: The final DL model, denoted FundusQ-Net, achieved a mean absolute error of 0.61 (0.54-0.68) on the internal test set. When evaluated as a binary classification model on the public DRIMDB database as an external test set the model obtained an accuracy of 99%., Significance: the proposed algorithm provides a new robust tool for automated quality grading of fundus images., Competing Interests: Declaration of Competing Interest Prof. Ingeborg Stalmans holds equities in MONA a spin off from the Catholic University of Leuven and the Belgian research institute VITO. MONA develops a solution to diagnose eye diseases from retinal pictures with artificial intelligence. The other authors have no conflicts of interests to declare., (Copyright © 2023. Published by Elsevier B.V.)

In order to characterize pneumococcal endovascular infection in the post-vaccination era, a retrospective nationwide study based on the Israeli Adult IPD database was conducted. Between 2010 and 2019, 0.6% (23 cases) of IPD cases were of endovascular type, occurring mainly in males (72.3%) with underlying medical conditions (78.2%). Additional pneumococcal source (10 patients) and concomitant infections were not uncommon. Penicillin and ceftriaxone susceptibility rates were 65.2% and 91.3%, respectively; 60.9% of the isolates were not covered by the pneumococcal conjugate vaccine. 21.7% of patients died during hospitalization. In conclusion, pneumococcal endovascular infections still carry significant morbidity and mortality., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

A significant amount of the carbon (C) assimilated in photosynthesis by trees is re-emitted to the atmosphere via the respiratory CO2 flux of roots. Because of technical constraints, we have little understanding of the extent and dynamics of the respiratory CO2 flux of roots at the total root system scale (RCF). This study aimed to fill this gap and to quantify the daily C budget of entire trees. We used aeroponics as a novel approach to measure directly and simultaneously RCF and the net CO2 flux of the entire shoot (SCF), to estimate their night- and day-time contributions to daily tree CO2 budget and to estimate the relative contribution of different root categories to RCF in large saplings of the tropical tree species Ceiba pentandra (L.) Gaertn. By maintaining root temperature within a narrow range (24-27.5 °C), we controlled for its effect on RCF, thus allowing the potential relationship between RCF and SCF to be tested. The carbon gain of the fast-growing saplings was 0.79 ± 0.10 g C sapling-1 day-1, with day-time shoot CO2 uptake outweighing night-time shoot and day- and night-time root CO2 losses by a factor of two. Other than a slight rise in the morning hours, RCF was relatively stable and not coupled to the daily dynamics of SCF. Albeit having lower specific respiration rates compared with fine-roots, the relative contributions of coarse-roots (diameter >2 mm) to RCF were substantial because of their large biomass and were estimated to range from 43 to 63% of RCF at midday of different days during the growing season. The results of this study suggest that (i) the entire root system needs to be monitored for its impact on the tree CO2 budget, (ii) RCF cannot be derived from SCF and (iii) the importance of coarse-root respiration to RCF may be greater than appreciated., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Immune reconstitution inflammatory syndrome (IRIS) is increasingly reported in various HIV negative patients with immunosuppression, but the relationship with hematopoietic cell transplantation (HCT) is not well defined. We report a case of IRIS in a patient infected with pulmonary and CNS Nocardiosis following HCT due to primary myelofibrosis., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Advances in treatment for multiple myeloma (MM) patients entail a high risk for opportunistic infections such as invasive pulmonary aspergillosis (IPA)., Objectives: This study was conducted to describe the patient's profile, clinical manifestations, diagnosis and outcome of MM patients with IPA, in our large haemato-oncology centre., Patients/methods: We retrospectively analysed patients with MM who underwent Broncho alveolar lavage for pneumonia at Rambam Hospital during a 13-year period from July 2005 to February 2018. We focused on those with Aspergillus pneumonia., Results: Of the 669 patients with multiple myeloma, mean age 62.6 (±7.6) years, forty-two patients (6.2%) were diagnosed with IPA. Among them, 60% had a probable diagnosis and 40% possible. Clinical presentation was similar for IPA and other pulmonary infections. Compared to those with other pulmonary infections, IPA was more commonly diagnosed in patients with long-standing disease (p = .00012) and among patients receiving 3 or more lines of myeloma therapies (p = .04). Thirty-day mortality rates following diagnostic bronchoscopy did not differ between IPA and non-IPA patients. (p = .85)., Conclusions: Multiple myeloma patients had an increased risk for IPA, most notably in patients with 3 or more lines of anti-myeloma treatment and more advanced disease. This clearly emphasises the vigilance needed for IPA in these patients., (© 2021 Wiley-VCH GmbH.)

Background: Vancomycin is often used as antimicrobial prophylaxis in patients undergoing total hip or knee arthroplasty. Vancomycin requires longer infusion times to avoid associated side effects. We hypothesized that vancomycin infusion is often started too late and that delayed infusion may predispose patients to increased rates of surgical site infections and prosthetic joint infections., Methods: We reviewed clinical data for all primary total hip arthroplasty (THA) and total knee arthroplasty (TKA) patients at our institution between 2013 and 2020 who received intravenous vancomycin as primary perioperative gram-positive antibiotic prophylaxis. We calculated duration of infusion before incision or tourniquet inflation, with a cutoff of 30 minutes defining adequate administration. Patients were divided into two groups: 1) appropriate administration and 2) incomplete administration. Surgical factors and quality outcomes were compared between groups., Results: We reviewed 1047 primary THA and TKA patients (524 THAs and 523 TKAs). The indication for intravenous vancomycin usage was allergy (61%), methicillin-resistant staphylococcus aureus colonization (17%), both allergy and colonization (14%), and other (8%). 50.4% of patients began infusion >30 minutes preoperatively (group A), and 49.6% began infusion <30 minutes preoperatively (group B). Group B had significantly higher rates of readmissions for infectious causes (3.6 vs 1.3%, P = .017). This included a statistically significant increase in confirmed prosthetic joint infections (2.2% vs 0.6%, P = .023). Regression analysis confirmed <30 minutes of vancomycin infusion as an independent risk factor for PJI when controlling for comorbidities (OR 5.22, P = .012)., Conclusion: Late infusion of vancomycin is common and associated with increased rates of infectious causes for readmission and PJI. Preoperative protocols should be created to ensure appropriate vancomycin administration when indicated., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The early detection of blood in urine (hematuria) can play a crucial role in the treatment of serious diseases ( e . g ., infections, kidney disease, schistosomiasis, and cancer). Therefore, the development of low-cost portable biosensors for blood detection in urine has become necessary. Here, we designed an ultrasensitive whole-cell bacterial biosensor interfaced with an optoelectronic measurement module for heme detection in urine. Heme is a red blood cells (RBCs) component that is liberated from lysed cells. The bacterial biosensor includes Escherichia coli cells carrying a heme-sensitive synthetic promoter integrated with a luciferase reporter ( luxCDABE ) from Photorhabdus luminescens . To improve the bacterial biosensor performance, we re-engineered the genetic structure of luxCDABE operon by splitting it into two parts ( luxCDE and luxAB ). The luxCDE genes were regulated by the heme-sensitive promoter, and the luxAB genes were regulated by either constitutive or inducible promoters. We examined the genetic circuit's performance in synthetic urine diluent supplied with heme and in human urine supplied with lysed blood. Finally, we interfaced the bacterial biosensor with a light detection setup based on a commercial optical measurement single-photon avalanche photodiode (SPAD). The whole-cell biosensor was tested in human urine with lysed blood, demonstrating a low-cost, portable, and easy-to-use hematuria detection with an ON-to-OFF ratio of 6.5-fold for blood levels from 5 × 10 4 to 5 × 10 5 RBC per mL of human urine.

Background: Medicare's Bundled Payments for Care Initiative (BPCI) is a risk-sharing alternative payment model. There is a concern that BPCI providers may avoid operating on obese patients and active smokers to reduce costs. We sought to understand if increased focus on these patient factors has led to a change in patient demographics in Medicare-insured patients undergoing total knee arthroplasty (TKA)., Methods: We retrospectively reviewed all patients who underwent TKA at an academic orthopedic specialty hospital between 1/1/13 and 8/31/19. Surgical date, insurance provider, BMI, and smoking status were collected. Patients were categorized as a current, former, or never smoker. Patients were categorized as obese if their BMI was >30 kg/m 2 , morbidly obese if their BMI was >40 kg/m 2 , and super obese if their BMI was >50 kg/m 2 ., Results: In total, 10,979 patients with complete insurance information were analyzed. There was no statistically significant change in the proportion of Medicare patients who were active smokers (4.34% in 2013, 4.85% in 2019, Pearson correlation coefficient = 0.6092, P = .146). The proportion of Medicare patients with BMI >30 kg/m 2 increased over the study period (35.84% in 2013, 55.77% in 2019, Pearson correlation coefficient = 0.8505, P = .015). When looking at patients with BMI >40 kg/m 2 and >50 kg/m 2 , there was no significant change., Conclusions: Despite concern that reimbursement payments could alter access to care for patients with certain risk factors, this study did not find a noticeable difference in the representation of patients with obesity and smoking status undergoing TKA following the installation of BPCI., Level of Evidence: III, retrospective observational analysis., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The current laser atherectomy technologies to treat patients with challenging (to-cross) total chronic occlusions with a step-by-step (SBS) approach (without leading guide wire), are lacking real-time signal monitoring of the ablated tissues, and carry the risk for vessel perforation. We present first time post-classification of ablated tissues using acoustic signals recorded by a microphone placed nearby during five atherectomy procedures using 355 nm solid-state Auryon laser device performed with an SBS approach, some with highly severe calcification. Using our machine-learning algorithm, the classification results of these ablation signals recordings from five patients showed 93.7% classification accuracy with arterial vs nonarterial wall material. While still very preliminary and requiring a larger study and thereafter as commercial device, the results of these first acoustic post-classification in SBS cases are very promising. This study implies, as a general statement, that online recording of the acoustic signals using a noncontact microphone, may potentially serve for an online classification of the ablated tissue in SBS cases. This technology could be used to confirm correct positioning in the vasculature, and by this, to potentially further reduce the risk of perforation using 355 nm laser atherectomy in such procedures., (© 2020 Wiley-VCH GmbH.)

One of the key knowledge gaps in the field of Alzheimer's disease research is the lack of understanding of how amyloid beta and tau cooperate to cause neurodegeneration. We recently generated a mouse model (APP/PS1 + Tau) that develops amyloid plaque pathology and expresses human tau in the absence of endogenous murine tau. These mice exhibit an age-related behavioural hyperactivity phenotype and transcriptional deficits which are ameliorated by tau transgene suppression. We hypothesized that these mice would also display memory and hippocampal synaptic plasticity deficits as has been reported for many plaque bearing mouse models which express endogenous mouse tau. We observed that our APP/PS1 + Tau model does not exhibit novel object memory or robust long-term potentiation deficits with age, whereas the parent APP/PS1 line with mouse tau did develop the expected deficits. These data are important as they highlight potential functional differences between mouse and human tau and the need to use multiple models to fully understand Alzheimer's disease pathogenesis and develop effective therapeutic strategies., (© 2020 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Purpose: To examine finger, thumb, hand, wrist, and forearm fractures in the National Hockey League (NHL) and determine: (1) basic demographic data, (2) return to sport (RTS) rates, (3) performance after RTS, and (4) the difference in RTS between players treated operatively versus conservatively., Methods: NHL players with finger, thumb, hand, wrist, and forearm fractures between the 1995-1996 and 2014-2015 seasons were identified through team injury reports and archives on public record. Player demographics, RTS rate, games played per season, and performance score for each player were recorded and compared between the preinjury season and one season following injury., Results: A total of 247 total NHL players with hand, wrist, and forearm fractures were identified, consisting of 30.8% finger, 38.5% hand, 13.8% thumb, 14.6% wrist, and 2.4% forearm fractures. Defenseman comprised the majority of players (40.1%). The overall RTS rate was 98.0%, with no significant difference between players with surgery or between injury location groups. In total, 52 players (21.1%) underwent surgery with no significant correlation of surgery rates based on fracture location. The mean number of missed games was 13.8 ± 9.9, with players sustaining wrist and forearm fractures missing the largest number of games (21.6 ± 17.7and 22.8 ± 7.5 games missed, respectively). There was no significant change in games played or performance scores 1 year after injury for players with any of the fracture types compared with baseline preoperative games played and performance., Conclusions: NHL players have a high RTS rate following hand, wrist, and forearm fractures. Players were able to return to preinjury performance within 1 year, regardless of treatment or type of fracture., Level of Evidence: Level IV, case series., (© 2020 by the Arthroscopy Association of North America. Published by Elsevier Inc.)

Background: There are no studies to date analyzing the effect of spinal malalignment on outcomes of total knee arthroplasty (TKA). Knee flexion is a well-described lower extremity compensatory mechanism for maintaining sagittal balance with increasing spinal deformity. The purpose of this study was to determine whether a subset of patients with poor range of motion (ROM) after TKA have unrecognized spinal deformity, predisposing them to knee flexion contractures and stiffness., Methods: We retrospectively evaluated a consecutive series of patients who underwent manipulation under anesthesia (MUA) for poor ROM after TKA. Using standing full-length biplanar images, knee alignment and spinopelvic parameters were measured. Patients were stratified by pelvic incidence minus lumbar lordosis as a measure of spinal sagittal alignment with a mismatch of ≥10° defined as abnormal, and we calculated the incidence of sagittal spinal deformity., Results: Average ROM before MUA was extension 3° and flexion 83°. About 62% of patients had a pelvic incidence minus lumbar lordosis mismatch of ≥10°. In the spinal deformity group, post-MUA ROM was improved for flexion only, whereas both flexion and extension were improved in the nondeformity group., Conclusion: Compensatory knee flexion because of sagittal spinal deformity may predispose to poor ROM after TKA. Patients with clinical suspicion should be worked up preoperatively and counseled accordingly., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Patients with hematological malignancies and allogeneic hematopoietic stem-cell transplant recipients carry a high risk of rare (non-Aspergillus molds and non-Candida yeasts) invasive fungal infections (IFI)., Methods: We retrospectively evaluated and described the patient profile, clinical manifestations, isolated species, treatment and outcome of patients with hematological malignancies diagnosed with these rare IFIs during 15 years in a large single hemato-oncology center., Results: Eighty-seven patients with hematological malignancies treated in our center had at least one positive culture or molecular identification of a rare fungus. Ninety-three isolates were considered the etiological agents of the infection. The most common underlying hematological malignancy was acute myeloid leukemia, 36 patients (41.4%). Eighty patients (91%) received chemotherapy less than 30 days prior to IFI diagnosis. The most frequent site of infection was the respiratory tract: 34 patients (39%) had pulmonary and 19 patients (22%) had a sinusal or nasopharyngeal infections. Disseminated infection, defined as positive blood cultures or parallel infection in multiple organ systems, was documented in 20 patients (23%). The most common fungal species were Fusarium (35%) and Zygomycetes (25%). Coinfection with more than one fungus was noted in 20 patients (23%). Forty-seven of 87 patients (54%) in this study died within 90 days of IFI diagnosis., Conclusions: Rare IFIs in patients with hematological malignancy become increasingly frequent. Early identification with traditional and molecular methods is important in management of these patients.

Despite the important role of tropical forest ecosystems in the uptake and storage of atmospheric carbon dioxide (CO2), the carbon (C) dynamics of tropical tree species remains poorly understood, especially regarding belowground roots. This study assessed the allocation of newly assimilated C in the fast-growing pioneer tropical tree species Ceiba pentandra (L.), with a special focus on different root categories. During a 5-day pulse-labelling experiment, 9-month-old (~3.5-m-tall) saplings were labelled with 13CO2 in a large-scale aeroponic facility, which allowed tracing the label in bulk biomass and in non-structural carbohydrates (sugars and starch) as well as respiratory CO2 from the canopy to the root system, including both woody and non-woody roots. A combined logistic and exponential model was used to evaluate 13C mean transfer time and mean residence time (MRT) to the root systems. We found 13C in the root phloem as early as 2 h after the labelling, indicating a mean C transfer velocity of 2.4 ± 0.1 m h-1. Five days after pulse labelling, 27% of the tracers taken up by the trees were found in the leaves and 13% were recovered in the woody tissue of the trunk, 6% in the bark and 2% in the root systems, while 52% were lost, most likely by respiration and exudation. Larger amounts of 13C were found in root sugars than in starch, the former also demonstrating shorter MRT than starch. Of all investigated root categories, non-woody white roots (NRW) showed the largest 13C enrichment and peaked in the deepest NRW (2-3.5 m) as early as 24 ± 2 h after labelling. In contrast to coarse woody brown roots, the sink strength of NRW increased with root depth. The findings of this study improve the understanding of C allocation in young tropical trees and provide unique insights into the changing contributions of woody and non-woody roots to C sink strengths with depth., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: There is an increasing utilization of same-day discharge total hip arthroplasty (SDD THA). As the Center for Medicare and Medicaid Services considers removing THA from the inpatient-only list, there is likely to be a significant increase in the number of Medicare patients undergoing SDD THA. Thus, there is a need to report on outcomes of SDD THA in this population., Methods: A retrospective review was performed on 850 consecutive SDD THA patients including 161 Medicare patients. We compared failure to launch, complication, emergency department visit, and 90-day readmission rates between the Medicare and non-Medicare cohorts., Results: The Medicare group was older and had less variability in their admission diagnosis. There was no significant difference in failure to launch, complication, emergency department visit, or 90-day readmission rates between Medicare and non-Medicare groups., Conclusion: The benefits of SDD THA can be safely extended to the carefully indicated and motivated Medicare patient., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Carbon (C) dynamics in canopy and roots influence whole-tree carbon fluxes, but little is known about canopy regulation of tree-root activity. Here, the patterns and dynamics of canopy-root C coupling are assessed in tropical trees. Large aeroponics facility was used to study the root systems of Ceiba pentandra and Khaya anthotheca saplings directly at different light intensities. In Ceiba, root respiration (R r ) co-varied with photosynthesis (A n ) in large saplings (3-to-7-m canopy-root axis) at high-light, but showed no consistent pattern at low-light. At medium-light and in small saplings (c. 1-m axis), R r tended to decrease transiently towards midday. Proximal roots had higher R r and nonstructural carbohydrate concentrations than distal roots, but canopy-root coupling was unaffected by root location. In medium-sized Khaya, no R r pattern was observed, and in both species, R r was unrelated to temperature. The early-afternoon increase in R r suggests that canopy-root coupling is based on mass flow of newly fixed C in the phloem, whereas the early-morning rise in R r with A n indicates an additional coupling signal that travels faster than the phloem sap. In large saplings and potentially also in higher trees, light and possibly additional environmental factors control the diurnal patterns of canopy-root coupling, irrespective of root location., (© 2019 The Authors. New Phytologist © 2019 New Phytologist Trust.)

Background: Greater trochanteric apophyseodesis and isolated trochanteric descent seek to prevent abductor weakness in patients with a hip deformity because of Legg-Calvé-Perthes disease; however, no studies have evaluated radiographic findings or abductor strength in children treated with these procedures., Questions/purposes: (1) Do children with Waldenström Stage III Legg-Calvé-Perthes disease treated with either isolated greater trochanteric descent or isolated greater trochanteric apophyseodesis achieve improved radiographic findings (Stulberg classification or neck-shaft angle) compared with those who underwent no surgical treatment? (2) Do children treated with one of those procedures achieve greater abductor strength than those who did not have surgery?, Methods: Between 2006 and 2010, we treated 89 children with Waldenström Type III Legg-Calvé-Perthes disease (reossification). Of these, 27.9% (12 patients) underwent greater trochanteric descent, 25.6% (11 patients) underwent greater trochanteric apophyseodesis, and 46.5% (20 patients) did not have surgery. During that time, the decision to perform either apophyseodesis or trochanteric descent was made by the surgeon based on the subjective appearance of remaining growth from the greater trochanter. Nonsurgical management was chosen by the parents of the patients after the risks and benefits of surgery were discussed. During greater trochanteric descent, the greater trochanter was osteotomized and fixed distally with two 7.0-mm screws. During greater trochanteric apophyseodesis, the physis was identified fluoroscopically, and the lateral half of the growth plate was drilled. Nonoperative treatment involved serial clinical and radiographic evaluations every 3 to 6 months. All children in all groups were available for follow-up at a minimum of 6 years. The median follow-up durations for children undergoing greater trochanteric descent, greater trochanteric apophyseodesis, and control cohorts were 6.6 years (range 6.0-8.2 years), 6.5 years (range 6.1-9.2 years), and 7.4 years (range 6.0-9.1 years), respectively. On presentation, each patient's affected hip was classified according to the Stulberg classification by the operating surgeon and an orthopaedic surgeon not involved in the child's care. The neck-shaft angle was measured for each patient before surgery and at the final follow-up examination. Abductor strength was assessed by a pediatric orthopaedic fellow and a physical therapist with the patient in the lateral decubitus position. Each patient was given a muscle strength score on a scale of 0 to 10 points, per a modification of the Medical Research Council scale to allow for a narrower range. We had 80% power to detect an 8° difference in the neck-shaft angle between the greater trochanteric apophyseodesis and nonoperative management cohorts. A sample size of 6.8 patients per cohort would be necessary to detect the above endpoint., Results: With the numbers available, we found no differences among the groups in the proportion of patients with Stulberg Class 2 femoral heads (two of 12 patients in the isolated trochanteric descent group, three of 11 in the isolated trochanteric apophyseodesis group, and two of 20 who did not undergo surgery; p = 0.46). Likewise, there were no differences among the three groups in terms of the neck-shaft angle at a minimum of 6 years of follow-up (122° ± 6°, 119° ± 7°, and 126° ± 8° in the isolated trochanteric descent, isolated trochanteric apophyseodesis, and nonoperative groups, respectively). There were no differences among the groups in term of the median abductor strength test result: seven of 10 (range 6-8), six of 10 (range 6-8), and six of 10 (range 6-10; p = 0.34)., Conclusion: Because neither isolated greater trochanteric descent nor greater trochanteric apophyseodesis alone had an effect on hip morphology or abductor strength in children with sequellae of Legg-Calvé-Perthes disease, we conclude these types of extraarticular surgery are ineffective. Therefore, we no longer perform isolated trochanteric descent or apophyseodesis., Level of Evidence: Level III, therapeutic study.

A key knowledge gap blocking development of effective therapeutics for Alzheimer's disease (AD) is the lack of understanding of how amyloid beta (Aβ) peptide and pathological forms of the tau protein cooperate in causing disease phenotypes. Within a mouse tau-deficient background, we probed the molecular, cellular, and behavioral disruption triggered by the influence of wild-type human tau on human Aβ-induced pathology. We find that Aβ and tau work cooperatively to cause a hyperactivity behavioral phenotype and to cause downregulation of transcription of genes involved in synaptic function. In both our mouse model and human postmortem tissue, we observe accumulation of pathological tau in synapses, supporting the potential importance of synaptic tau. Importantly, tau reduction in the mice initiated after behavioral deficits emerge corrects behavioral deficits, reduces synaptic tau levels, and substantially reverses transcriptional perturbations, suggesting that lowering synaptic tau levels may be beneficial in AD., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Cystinosis is a rare disorder caused by recessive mutations of the CTNS gene. Current therapy decreases cystine accumulation, thus slowing organ deterioration without reversing renal Fanconi syndrome or preventing eventual need for a kidney transplant.15-20% of cystinosis patients harbour at least one nonsense mutation in CTNS, leading to premature end of translation of the transcript. Aminoglycosides have been shown to permit translational read-through but have high toxicity level, especially in the kidney and inner ear. ELX-02, a modified aminoglycoside, retains it read-through ability without the toxicity., Methods and Findings: We ascertained the toxicity of ELX-02 in cells and in mice as well as the effect of ELX-02 on translational read-through of nonsense mutations in cystinotic mice and human cells. ELX-02 was not toxic in vitro or in vivo, and permitted read-through of nonsense mutations in cystinotic mice and human cells., Conclusions: ELX-02 has translational read-through activity and produces a functional CTNS protein, as evidenced by reduced cystine accumulation. This reduction is comparable to cysteamine treatment. ELX-02 accumulates in the kidney but neither cytotoxicity nor nephrotoxicity was observed., Competing Interests: Dr. Goodyer was the recipient of an unrestricted grant from Eloxx Pharmaceuticals, Inc. for parts of this work. RIMUHC-affiliated authors were not Eloxx employees nor did they have any commercial affiliation or patent interests related to ELX-02. Idit Eshkar-Oren, Iris Alroy and Pedro Huertas were employees of Eloxx Pharmaceuticals, Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Invasive pulmonary aspergillosis (IPA) has dire consequences in hemato-oncological patients. We report our experience with performing routine baseline chest computed tomography for early diagnosis of IPA. We found high rates of proven or probable IPA diagnosed on admission among patients with newly diagnosed acute myeloid leukemia., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: This study aimed to evaluate the diagnostic role of PCR detection of Aspergillus DNA in the broncho-alveolar lavage (BAL) fluid in a large cohort of patients suspected to have invasive pulmonary aspergillosis (IPA)., Methods: Consecutive immunocompromised patients who underwent bronchoscopy with BAL sampling and PCR detection of Aspergillus DNA for the diagnosis of pulmonary infiltrates were included in the study. Galactomannan (GM) antigen testing in BAL and serum and BAL fungal culture were also performed. Patients were classified as having IPA (proven/probable/possible) or no-IPA according to the EORTC/MSG diagnostic criteria., Results: During 12 years (2005-2016), 1248 bronchoscopies were performed for 1072 patients. 77% had hematological malignancy, of them 40% had AML and 35.6% underwent HSCT. IPA was diagnosed in 531 patients (42.5%), 7-proven, 280-probable and 244-possible. PCR was positive in 266 cases, of them 213 had IPA, indicating a true positive rate of 80% (213/266) and a false positive rate of 20% (53/266). These results establish the diagnostic performance of PCR to have sensitivity of 40%, specificity of 93%, PPV- 80% and NPV-68%. Of 244 patients with possible IPA, 80 had positive PCR. Including PCR in the diagnostic criteria would move 80 cases from the possible group to the probable one. A combination of positive PCR and/or BAL-GM increases sensitivity to 74%, while positivity of both tests elevates PPV to 99.4%., Conclusions: Inclusion PCR for the detection of Aspergillus-DNA in BAL in the mycological criteria of the EORTC/MSG definitions increases the rate and the certainty of IPA diagnosis., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Treatment options for carbapenem-resistant Enterobacteriaceae (CRE) infections are limited and CRE infections remain associated with high clinical failure and mortality rates, particularly in vulnerable patient populations. A Phase 3, multinational, open-label, randomized controlled trial (TANGO II) was conducted from 2014 to 2017 to evaluate the efficacy/safety of meropenem-vaborbactam monotherapy versus best available therapy (BAT) for CRE., Methods: A total of 77 patients with confirmed/suspected CRE infection (bacteremia, hospital-acquired/ventilator-associated bacterial pneumonia, complicated intra-abdominal infection, complicated urinary tract infection/acute pyelonephritis) were randomized, and 47 with confirmed CRE infection formed the primary analysis population (microbiologic-CRE-modified intent-to-treat, mCRE-MITT). Eligible patients were randomized 2:1 to meropenem-vaborbactam (2 g/2 g over 3 h, q8h for 7-14 days) or BAT (mono/combination therapy with polymyxins, carbapenems, aminoglycosides, tigecycline; or ceftazidime-avibactam alone). Efficacy endpoints included clinical cure, Day-28 all-cause mortality, microbiologic cure, and overall success (clinical cure + microbiologic eradication). Safety endpoints included adverse events (AEs) and laboratory findings., Results: Within the mCRE-MITT population, cure rates were 65.6% (21/32) and 33.3% (5/15) [95% confidence interval (CI) of difference, 3.3% to 61.3%; P = 0.03)] at End of Treatment and 59.4% (19/32) and 26.7% (4/15) (95% CI of difference, 4.6% to 60.8%; P = 0.02) at Test of Cure;.Day-28 all-cause mortality was 15.6% (5/32) and 33.3% (5/15) (95% CI of difference, - 44.7% to 9.3%) for meropenem-vaborbactam versus BAT, respectively. Treatment-related AEs and renal-related AEs were 24.0% (12/50) and 4.0% (2/50) for meropenem-vaborbactam versus 44.0% (11/25) and 24.0% (6/25) for BAT. Exploratory risk-benefit analyses of composite clinical failure or nephrotoxicity favored meropenem-vaborbactam versus BAT (31.3% [10/32] versus 80.0% [12/15]; 95% CI of difference, - 74.6% to - 22.9%; P < 0.001)., Conclusions: Monotherapy with meropenem-vaborbactam for CRE infection was associated with increased clinical cure, decreased mortality, and reduced nephrotoxicity compared with BAT., Clinical Trials Registration: NCT02168946., Funding: The Medicines Company.

Data regarding treatment of rare invasive fungal diseases (IFDs) are scarce. We documented the efficacy and safety of isavuconazole for treatment of uncommonly diagnosed IFDs. VITAL was a single-arm, international, open-label study evaluating the efficacy and safety of isavuconazole (200 mg orally or intravenously every 8 hours for 48 hours, then once daily). The primary outcome was overall response at Day 42; key secondary outcomes were overall responses at Day 84 and end of treatment (EOT), mortality at Days 42 and 84, and safety. This analysis includes patients with IFD caused by rare or unidentified pathogens. Twenty-six patients with IFDs caused by rare moulds (n = 17), non-Candida yeasts (n = 2), or unidentified moulds (n = 7) were enrolled (median treatment duration [range], 114.5 [1-496]) days. Overall treatment success was observed in 11/26 (42.3%), 10/26 (38.5%), and 15/26 (57.7%) patients at Days 42, 84, and EOT, respectively. All-cause mortality rates were 2/26 patients (7.7%) at Day 42 and 4/26 patients (15.4%) at Day 84; another two patients died after Day 84. All patients had ≥1 treatment-emergent adverse event (TEAE); 15 patients (57.7%) had serious TEAEs, and TEAEs led to discontinuation of isavuconazole in four patients (15.4%). Isavuconazole may be efficacious for treatment of a range of rare IFDs., (© 2018 The Authors. Mycoses Published by Blackwell Verlag GmbH.)

The optimal approach to treat invasive fungal disease (IFD) caused by more than one fungal species is unknown. We documented the efficacy and safety of isavuconazole for treatment of IFDs caused by more than one fungal species. VITAL was a single-arm, international, open-label study evaluating the efficacy and safety of isavuconazole (200 mg orally or intravenously every 8 hours for 48 hours, then once daily) for treatment of rare IFDs. The primary outcome was the overall response at Day 42; key secondary outcomes were overall responses at Day 84 and end of treatment (EOT), mortality at Days 42 and 84, and safety. This analysis includes patients with IFD caused by multiple fungal species. Fifteen patients were included in this analysis (including Aspergillus spp., n = 11; without Aspergillus spp., n = 4); median treatment duration was 97 days [range, 6-544] days). Overall treatment success was observed in 2/15 patients (13.3%) at Days 42 and 84, and 2/14 (14.3%) at EOT. All-cause mortality was 2/15 (13.3%) at Day 42 and 4/15 (26.7%) at Day 84. All patients had ≥1 treatment-emergent adverse event (TEAE); 12 patients (80.0%) had serious TEAEs; TEAEs led to discontinuation of isavuconazole in two patients (13.3%). Isavuconazole may be useful to treat some IFDs caused by multiple fungal species., (© 2018 The Authors. Mycoses Published by Blackwell Verlag GmbH.)

Purpose: Available data suggest that respiratory infections are associated with increased morbidity and mortality in patients hospitalized due to acute leukemia and allogeneic stem cell transplantation (allo-SCT). However, the precise incidence, risk factors, and severity of respiratory infection, mainly community-acquired, in patients with lymphoma and multiple myeloma (MM) are not fully determined. The current study aimed to investigate risk factors for respiratory infections and their clinical significance in patients with B cell non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) in the first year of diagnosis., Methods: Data of consecutive patients diagnosed with NHL or MM and treated at the Rambam Hematology Inpatient and Outpatient Units between 01/2011 and 03/2012 were evaluated. Information regarding anticancer treatment, incidence and course of respiratory infections, and infection-related outcomes was analyzed., Results: One hundred and sixty episodes of respiratory infections were recorded in 103 (49%) of 211 (73-MM, 138-NHL) patients; 126 (79%) episodes were community-acquired, 47 (29%) of them required hospitalization. In univariate analysis, age < 60 years, MM diagnosis, and autologous SCT increased the respiratory infection risk (P = 0.058, 0.038, and 0.001, respectively). Ninety episodes (56% of all respiratory episodes) were examined for viral pathogens. Viral infections were documented in 25/90 (28%) episodes, 21 (84%) of them were community-acquired, requiring hospitalization in 5 (24%) cases. Anti-flu vaccination was performed in 119 (56%) patients. Two of the six patients diagnosed with influenza were vaccinated., Conclusions: Respiratory infections, including viral ones, are common in NHL and MM. Most infections are community-acquired and have a favorable outcome. Rapid identification of viral pathogens allows avoiding antibiotic overuse in this patient population.

Network hyperexcitability is a feature of Alzheimer' disease (AD) as well as numerous transgenic mouse models of AD. While hyperexcitability in AD patients and AD animal models share certain features, the mechanistic overlap remains to be established. We aimed to identify features of network hyperexcitability in AD models that can be related to epileptiform activity signatures in AD patients. We studied network hyperexcitability in mice expressing amyloid precursor protein (APP) with mutations that cause familial AD, and compared a transgenic model that overexpresses human APP (hAPP) (J20), to a knock-in model expressing APP at physiological levels (APP NL/F ). We recorded continuous long-term electrocorticogram (ECoG) activity from mice, and studied modulation by circadian cycle, behavioral, and brain state. We report that while J20s exhibit frequent interictal spikes (IISs), APP NL/F mice do not. In J20 mice, IISs were most prevalent during daylight hours and the circadian modulation was associated with sleep. Further analysis of brain state revealed that IIS in J20s are associated with features of rapid eye movement (REM) sleep. We found no evidence of cholinergic changes that may contribute to IIS-circadian coupling in J20s. In contrast to J20s, intracranial recordings capturing IIS in AD patients demonstrated frequent IIS in non-REM (NREM) sleep. The salient differences in sleep-stage coupling of IIS in APP overexpressing mice and AD patients suggests that different mechanisms may underlie network hyperexcitability in mice and humans. We posit that sleep-stage coupling of IIS should be an important consideration in identifying mouse AD models that most closely recapitulate network hyperexcitability in human AD.

Introduction: Plain radiographs of the shoulder are routinely obtained for patients presenting with atraumatic shoulder pain. The diagnostic utility of these radiographs is debatable., Methods: Patients presenting for the first time to a shoulder clinic with atraumatic shoulder pain received a plain radiographic series. After considering their medical history and physical examination, we made a preliminary diagnosis and formulated a tentative treatment plan. We then reviewed the radiographs and determined whether the addition of these radiographs altered the diagnosis and/or treatment., Results: A total of 343 patients met the inclusion criteria. Age >50 years (odds ratio, 3.3; 95% confidence interval, 1.9 to 5.8; P < 0.00001) and weakness in forward elevation (odds ratio, 2.9; 95% confidence interval, 1.6 to 5.4; P = 0.0003) were associated with the presence of radiographic findings. Plain radiographs altered the proposed diagnosis in only 14.9% (51/343) of cases. However, clinical management was changed in only 1.7% of cases. Plain radiographs had no effect on clinical management in 97.4% of patients younger than 50 years., Discussion: Plain radiographs rarely alter the diagnosis or affect management in the setting of atraumatic shoulder pain, particularly in patients younger than 50 years. Patients may be exposed to unnecessary radiation, and the healthcare system as a whole may be burdened with the increased cost of this imaging modality., Level of Evidence: Level II (diagnostic).

Introduction: Antibiotic stewardship programs (ASP) are designed to optimize antibiotic use in hospitals. Antibiotic consumption is one of the measures assessing the effects of ASPs., Aims: To evaluate the effect of an ASP on antibiotic consumption in our hospital and compare it to hospitals in Israel and worldwide., Methods: Between October 2012 and March 2013 an ASP was implemented in Rambam Hospital. The program included educational activities, publication of local guidelines for empirical antibiotic treatment, structured infectious diseases consultations, pre-authorization antibiotic restrictions and stop orders. We compared antibacterial antibiotic consumption in defined daily doses (DDD)/100 hospital days (HD) between the periods before (1/2010-3/2013) and after (4/2013-9/2014) implementing the ASP. The study was conducted in the medical departments, hematology, the intensive care unit (ICU) and all pediatric wards., Results: Total antibiotic consumption before implementing the ASP was 96±11.2 DDD/100 HD in medical departments, 186.4±42.8 in the ICU and 185.5±59 in hematology; all values were higher than the worldwide-reported averages for these departments. Following the ASP, total antibiotic consumption decreased by 12% (p=0.008) in the medical departments and by 26% (p=0.002) in hematology, mostly due to reductions in non-restricted antibiotics. No significant changes were observed overall in the ICU and in pediatric wards. There was a significant reduction in consumption of vancomycin and carbapenems in all settings, the latter was reduced to nearly half. Amikacin use quadrupled in the medical departments., Conclusions: Implementation of an ASP lead to a reduction in non-restricted and restricted antibiotic consumption, especially carbapenems.

Background: Campylobacter bacteraemia (CB) is rare and usually occurs in immune-compromised patients. In this study we examined the incidence and epidemiology of CB in one institution over 15.5 years., Methods: The medical records of all the consecutive patients with CB admitted to our hospital from 2000 to 2015 were retrospectively reviewed. Clinical characteristics, microbiologic and outcome data were collected., Results: During the study period, 65 patients with CB were identified. The majority of the patients were middle aged and immune-compromised. Campylobacter jejuni was the most commonly identified species (33/47, 70%). The main underlying conditions were haematological malignancies (43%) and chronic liver disease (14%). Fifty-seven percent of the patients were receiving immunosuppressive therapy at the time of bacteraemia. The most common presenting symptoms were fever (85%), diarrhoea (40%), abdominal pain (40%), and nausea and vomiting (40%). Of the isolates tested, 97% were susceptible to macrolides, and only 35% were susceptible to quinolones. Susceptibility to quinolones decreased over the years. Most patients did not receive adequate empiric antibiotic treatment (81.5%) and about 20% never received directed therapy. Mortality and relapse rates were low (5% each). There was no association between adequate empirical or definitive antibiotic therapy and adverse outcomes., Conclusion: The main predisposing factor for Campylobacter bacteraemia in our cohort was immunosuppression. Prognosis was generally favourable regardless of appropriateness of antibiotic therapy.

Septic arthritis of the shoulder girdle remains relatively uncommon, with Staphylococcus aureus and β-hemolytic streptococci the typical offending organisms in adult patients. Rare cases of Streptococcus viridans, an oral bacterium with low virulence, have been reported in the setting of septic arthritis, mostly involving the knee joint or the sternoclavicular joint. In this article, we report a case of Streptococcus mitis infection of the glenohumeral joint that likely resulted from hematogenous spread after oral trauma in a patient with poor underlying dentition. Prompt diagnosis followed by arthroscopic irrigation and débridement of the glenohumeral joint resulted in a satisfactory clinical outcome.

Objectives: The identification of the specific pathogen responsible for a respiratory infection in patients with hematological malignancies (HM) would ensure relevant treatment and prevent toxicity associated with anti-infective therapy. This large-scale study aimed to explore the clinical impact of fiberoptic bronchoscopy with bronchoalveolar lavage (FOB-BAL) in conjunction with molecular analysis on the diagnosis and management of respiratory infections in hemato-oncological patients., Methods: All consecutive patients with HM and pulmonary infiltrates, who underwent FOB-BAL between January 2008 and January 2013, were included in the analysis. Clinical characteristics, FOB-BAL results, and treatment adjustments were recorded, and factors predicting a positive BAL were assessed., Results: Four hundred and twenty-five FOB-BAL procedures were analyzed. BAL revealed a specific diagnosis in 219 (51.5%) patients, 208 of them with a pulmonary infection. Infectious etiological agents found were mainly Aspergillus spp (n=142), bacterial species (n=44), and Pneumocystis jirovecii (n=34). Multivariate analysis showed that a lymphoproliferative disease, ≥2 symptoms (dyspnea/cough/hemoptysis/pleuritic pain), and less than 4 days between symptom appearance and FOB-BAL, predicted a positive FOB-BAL result. BAL results prompted a treatment modification in 48% of subjects., Conclusions: FOB-BAL in conjunction with molecular assays is efficient in the rapid detection of life-threatening infections, allowing for adjustment of anti-infective therapy, which may result in better outcomes and reduce treatment-related toxicity., (Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: The frequency and clinical significance of polymicrobial pneumonia in patients with hematological malignancies (HM) are poorly understood. The aim of the present study is to describe the prevalence, risk factors, clinical characteristics, and outcome of patients with HM and polymicrobial pneumonia., Methods: Over a 5 year period, 436 consecutive adult patients with HM and pulmonary infiltrates underwent diagnostic fiberoptic bronchoscopy with bronchoalveolar lavage. For 219 patients an infectious etiology was diagnosed, of them 45 (20.5 %) had polymicrobial etiology. Risk factors, clinical course and outcome of polymicrobial pulmonary infection in patients with HM were established., Results: 45 patients with HM were identified with polymicrobial pulmonary infection, 39 of them with two pathogens, and 6 with three. The most common co-pathogen identified was Aspergillus sp. (87 %). Allogeneic hematopoietic stem cell transplantation (HSCT) and graft versus host disease (GVHD) were predictors of polymicrobial infection. Compared to patients with monomicrobial pneumonia, patients with polymicrobialpulmonary infection had a more severe clinical course with more dyspnea (69 vs. 49 %, P = 0.016), hemoptysis (16 vs. 7 %, P = 0.065) and more required respiratory support (27 vs. 17 %, P = 0.125). In-hospital mortality was significantly higher in patients with polymicrobial pulmonary infection than in patients with monomicrobial pulmonary infection (49 vs. 19 %, P < 0.001)., Conclusions: Polymicrobial pulmonary infection occurs quite frequently in patients with HM, especially in allogeneic HSCT recipients and in patients with GVHD. The clinical course of polymicrobial pulmonary infection is severe and mortality approaches 50 %. The clinician taking care of these patients should always look for additional copathogens in profoundly immunosuppressed patients with pneumonia.

Background: Mucormycosis is an uncommon invasive fungal disease with high mortality and few treatment options. Isavuconazole is a triazole active in vitro and in animal models against moulds of the order Mucorales. We assessed the efficacy and safety of isavuconazole for treatment of mucormycosis and compared its efficacy with amphotericin B in a matched case-control analysis., Methods: In a single-arm open-label trial (VITAL study), adult patients (≥18 years) with invasive fungal disease caused by rare fungi, including mucormycosis, were recruited from 34 centres worldwide. Patients were given isavuconazole 200 mg (as its intravenous or oral water-soluble prodrug, isavuconazonium sulfate) three times daily for six doses, followed by 200 mg/day until invasive fungal disease resolution, failure, or for 180 days or more. The primary endpoint was independent data review committee-determined overall response-ie, complete or partial response (treatment success) or stable or progressive disease (treatment failure)-according to prespecified criteria. Mucormycosis cases treated with isavuconazole as primary treatment were matched with controls from the FungiScope Registry, recruited from 17 centres worldwide, who received primary amphotericin B-based treatment, and were analysed for day-42 all-cause mortality. VITAL is registered with ClinicalTrials.gov, number NCT00634049. FungiScope is registered with ClinicalTrials.gov, number NCT01731353., Findings: Within the VITAL study, from April 22, 2008, to June 21, 2013, 37 patients with mucormycosis received isavuconazole for a median of 84 days (IQR 19-179, range 2-882). By day 42, four patients (11%) had a partial response, 16 (43%) had stable invasive fungal disease, one (3%) had invasive fungal disease progression, three (8%) had missing assessments, and 13 (35%) had died. 35 patients (95%) had adverse events (28 [76%] serious). Day-42 crude all-cause mortality in seven (33%) of 21 primary-treatment isavuconazole cases was similar to 13 (39%) of 33 amphotericin B-treated matched controls (weighted all-cause mortality: 33% vs 41%; p=0·595)., Interpretation: Isavuconazole showed activity against mucormycosis with efficacy similar to amphotericin B. Isavuconazole can be used for treatment of mucormycosis and is well tolerated., Funding: Astellas Pharma Global Development, Basilea Pharmaceutica International., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Isavuconazole is a novel triazole with broad-spectrum antifungal activity. The SECURE trial assessed efficacy and safety of isavuconazole versus voriconazole in patients with invasive mould disease., Methods: This was a phase 3, double-blind, global multicentre, comparative-group study. Patients with suspected invasive mould disease were randomised in a 1:1 ratio using an interactive voice-web response system, stratified by geographical region, allogeneic haemopoietic stem cell transplantation, and active malignant disease at baseline, to receive isavuconazonium sulfate 372 mg (prodrug; equivalent to 200 mg isavuconazole; intravenously three times a day on days 1 and 2, then either intravenously or orally once daily) or voriconazole (6 mg/kg intravenously twice daily on day 1, 4 mg/kg intravenously twice daily on day 2, then intravenously 4 mg/kg twice daily or orally 200 mg twice daily from day 3 onwards). We tested non-inferiority of the primary efficacy endpoint of all-cause mortality from first dose of study drug to day 42 in patients who received at least one dose of the study drug (intention-to-treat [ITT] population) using a 10% non-inferiority margin. Safety was assessed in patients who received the first dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00412893., Findings: 527 adult patients were randomly assigned (258 received study medication per group) between March 7, 2007, and March 28, 2013. All-cause mortality from first dose of study drug to day 42 for the ITT population was 19% with isavuconazole (48 patients) and 20% with voriconazole (52 patients), with an adjusted treatment difference of -1·0% (95% CI -7·8 to 5·7). Because the upper bound of the 95% CI (5·7%) did not exceed 10%, non-inferiority was shown. Most patients (247 [96%] receiving isavuconazole and 255 [98%] receiving voriconazole) had treatment-emergent adverse events (p=0·122); the most common were gastrointestinal disorders (174 [68%] vs 180 [69%]) and infections and infestations (152 [59%] vs 158 [61%]). Proportions of patients with treatment-emergent adverse events by system organ class were similar overall. However, isavuconazole-treated patients had a lower frequency of hepatobiliary disorders (23 [9%] vs 42 [16%]; p=0·016), eye disorders (39 [15%] vs 69 [27%]; p=0·002), and skin or subcutaneous tissue disorders (86 [33%] vs 110 [42%]; p=0·037). Drug-related adverse events were reported in 109 (42%) patients receiving isavuconazole and 155 (60%) receiving voriconazole (p<0·001)., Interpretation: Isavuconazole was non-inferior to voriconazole for the primary treatment of suspected invasive mould disease. Isavuconazole was well tolerated compared with voriconazole, with fewer study-drug-related adverse events. Our results support the use of isavuconazole for the primary treatment of patients with invasive mould disease., Funding: Astellas Pharma Global Development, Basilea Pharmaceutica International., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objectives: Carbapenem-resistant Gram-negative bacteria (CRGNB) pose a clinical challenge. We attempted to estimate the mortality burden of CRGNB among haematological cancer patients., Methods: This was a retrospective cohort study. We included adult patients hospitalized in the haemato-oncological/bone marrow transplantation departments for chemotherapy, between 2008 and 2014, with Gram-negative aerobic bacteraemia. We compared patients with CRGNB and carbapenem-susceptible Gram-negative bacteraemia (CSGNB). The primary outcome was 14 day all-cause mortality. In addition, we assessed 1 year survival. Multivariable logistics regression analysis and adjusted Cox regression analysis were conducted. Analyses were adjusted to the propensity for CRGNB bacteraemia., Results: The cohort included mostly young patients (mean age 50.1 years) with acute leukaemia (264/423, 62.4%) and the median absolute neutrophil count at bacteraemia onset was 0 × 10(9)/L. The unadjusted 14 day mortality rate was higher for patients with CRGNB compared with CSGNB [45.6% (47/103) versus 15% (48/320), respectively (P < 0.001)]. Adjusting to baseline prognostic factors, infection characteristics and the propensity score retained a significant association between CRGNB and 14 day mortality (OR 5.14, 95% CI 2.32-11.38). Including only the first bacteraemic episode per patient, 1 year mortality was 74.7% (68/91) for patients with CRGNB versus 49.8% (119/239) for patients with CSGNB (P < 0.001). Adjusting for risk factors associated with 1 year mortality, the HR for mortality with CRGNB was 1.48 (95% CI 1-2.2). CRGNB bacteraemia was associated with several risk factors for mortality, including inappropriate empirical antibiotic treatment and less effective definitive antibiotics., Conclusions: This study demonstrated a significant adjusted association between CRGNB and mortality up to 1 year among haemato-oncological patients receiving chemotherapy., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Extended application of allogeneic stem cell transplantation (alloSCT) is expected to increase the frequency of JC polyomavirus (JCPyV)-related progressive multifocal leukoencephalopathy (PML). The aim of this study was to assess frequency, risk factors and course of JCPyV reactivation in allografted hematology patients. This retrospective study included consecutive adult patients, treated with alloSCT between January 2008 and December 2011. Quantitative JCPyV-PCR analysis was performed on whole blood DNA samples, originally drawn for cytomegalovirus detection since transplant date. The study included 164 patients diagnosed with hematological malignancies. Patients received reduced-intensity conditioning (n=74) or myeloablative conditioning (n=90), followed by alloSCT. Twenty patients developed transient and 20 had persistent JCPyV reactivation. Two of the patients with persistent reactivation showed a gradual increase in JCPyV levels, preceding PML development by 96 and 127 days. Cessation of immunosuppression resulted in complete resolution of neurological symptoms in one patient, while the other died of PML. Seventy percent of the 'persistently reactivating' patients died. Multivariate analysis confirmed age to be the only significant predictive factor for JCPyV reactivation. In conclusion, JCPyV reactivation occurs in a quarter of allografted patients. Preemptive detection of JCPyV reactivation in high-risk subjects and early discontinuation of immunosuppressive therapy may prevent development of lethal PML.

Background: PCV7 was introduced as a universal childhood vaccination in Israel on July 2009 and was gradually replaced by PCV13 from November 2010. We report data on adult invasive pneumococcal disease (IPD), two years post PCV13 implementation., Methods: An ongoing nationwide active surveillance (all 27 laboratories performing blood/CSF cultures nationwide), initiated in 2009, providing all blood/CSF Streptococcus pneumoniae isolated from persons ≥18 years. Capture-recapture method assured reporting of >95% cases. All isolates were serotyped in one central laboratory. Medical history and outcomes were recorded in ∼90%., Results: Of 1809 IPD episodes, S. pneumoniae was isolated from the blood in 95% and most cases had pneumonia. Predisposing comorbidities were present in >70%. During the four study years, overall IPD incidence decreased from 9.2 to 7.2/100,000, incidence of pneumonia and particularly severe pneumonia cases decreased significantly from 6.6 to 4.7/100,000, (p=0.029). Vaccine type (VT7/VT13) serotypes decreased by 70%/57% within 4 years. This was accompanied by a 52% increase in non-VT13 strains. These changes were most apparent in winter. PCV impact was most pronounced in younger adults (39% decrease in overall IPD with only a non-significant increase in non-VT13 cases) while in those >65 years a non-significant decrease in overall IPD was observed with a 64% increase in non-VT13 cases. Non-VT13 serotypes that increased significantly were 12F, 15A 10A and 6C. A continuous reduction in isolates with penicillin MIC>0.06μg/ml was observed (26% to 11%, p<0.001)., Conclusions: Four years after PCV7 and 2.5 years after PCV13 universal implementation in children, incidence of adult IPD caused by VT7 and VT13 decreased in all ages, mainly in younger adults. Despite increase in non-VT13 IPD, overall IPD decreased. Additional follow-up is needed to determine the long-term impact of PCV13., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Blood vessels serve as key regulators of organogenesis by providing oxygen, nutrients and molecular signals. During limb development, programmed cell death (PCD) contributes to separation of the digits. Interestingly, prior to the onset of PCD, the autopod vasculature undergoes extensive patterning that results in high interdigital vascularity. Here, we show that in mice, the limb vasculature positively regulates interdigital PCD. In vivo, reduction in interdigital vessel number inhibited PCD, resulting in syndactyly, whereas an increment in vessel number and distribution resulted in elevation and expansion of PCD. Production of reactive oxygen species (ROS), toxic compounds that have been implicated in PCD, also depended on interdigital vascular patterning. Finally, ex vivo incubation of limbs in gradually decreasing oxygen levels led to a correlated reduction in both ROS production and interdigital PCD. The results support a role for oxygen in these processes and provide a mechanistic explanation for the counterintuitive positive role of the vasculature in PCD. In conclusion, we suggest a new role for vascular patterning during limb development in regulating interdigital PCD by ROS production. More broadly, we propose a double safety mechanism that restricts PCD to interdigital areas, as the genetic program of PCD provides the first layer and vascular patterning serves as the second., (© 2015. Published by The Company of Biologists Ltd.)

Background: Non-adherence to antipsychotic therapy among patients with schizophrenia is a key driver of relapse, which can lead to costly inpatient stays. Long-acting injectables (LAIs) may improve adherence, thus reducing hospitalizations, but inpatient cost reductions need to be balanced against higher drug acquisition costs of LAIs. Real-world evidence is needed to help quantify the economic value of oral atypical antipsychotics compared with LAIs., Objective: The objective of this study was to compare healthcare costs and resource utilization between once-monthly paliperidone palmitate (PP) and oral antipsychotic therapy (OAT) in a population of Medicaid beneficiaries with schizophrenia., Methods: A retrospective, observational study was performed using Truven Health MarketScan Medicaid claims data from 2009 to 2012. Marginal structural modeling, a form of weighted repeated measures analysis to control for differences between cohorts and time-varying confounding, was used to estimate monthly costs of care in 2012 US dollars and resource utilization over a 12-month period for patients in each cohort., Results: While per-month mental-health prescription costs were US$1019 higher in the PP cohort, approximately 55 % of this premium was offset by lower inpatient and outpatient care costs, producing a mean monthly total cost differential of US$434 (95 % CI 298-569, p  < 0.0001) for all-cause costs and US$463 (95 % CI 374-552, p  < 0.0001) for mental-health-related costs. Use of PP also resulted in a 0.44 and 0.47 reduction in the odds of all-cause and mental-health-related hospitalizations and a 0.09 reduction in the odds of all-cause emergency department visits ( p  < 0.0001, p  < 0.0001, and p  = 0.0134, respectively) over the 12-month follow-up period., Conclusions: Treatment with long-acting injectable antipsychotics, such as PP, may reduce inpatient and outpatient healthcare services utilization and associated costs. These findings also suggest that patients with schizophrenia taking once-monthly PP may stand a lower risk of hospitalization than patients on OAT., Competing Interests: Compliance with Ethical Standards Funding This study was funded by Janssen Scientific Affairs, LLC. Conflicts of interest J. A. Pesa and E. Muser are employees of Janssen Scientific Affairs, LLC and are Johnson & Johnson stockholders. L. B. Montejano, D. M. Smith and O. I. Meyers are employees of Truven Health Analytics, an independent healthcare data and research company that received funding from Janssen Scientific Affairs, LLC to conduct this study. Ethical approval This study was conducted using a pre-existing database of de-identified healthcare claims and, as such, did not require institutional review board (IRB)/independent ethics committee (IEC) approval.