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In regions such as hawai'i, south australia, Tasmania, Texas, and Ireland, power systems are commonly experiencing instantaneous penetration levels of inverter-based power sources (IBPSs) such as wind, solar photovoltaics (PV), and battery storage in excess of 50n60% relative to system demands.

Context Urethral stricture management guidelines are an important tool for guiding evidence-based clinical practice. Objective To present a summary of the 2021 version of the European Association of Urology (EAU) guidelines on management of urethral strictures in females and transgender patients. Evidence acquisition The panel performed a literature review on these topics covering a time frame between 2008 and 2018 and used predefined inclusion and exclusion criteria for study selection. Key papers beyond this time period could be included as per panel consensus. A strength rating for each recommendation was added based on the review of the available literature and after panel discussion. Evidence synthesis Management of urethral strictures in females and transgender patients has been described in a few case series in the literature. Endoluminal treatments can be used for short, nonobliterative strictures in the first line. Repetitive endoluminal treatments are not curative. Urethroplasty encompasses a multitude of techniques and adaptation of the technique to the local conditions of the stricture is crucial to obtain durable patency rates. Conclusions Management of urethral strictures in females and transgender patients is complex and a multitude of techniques are available. Selection of the appropriate technique is crucial and these guidelines provide relevant recommendations. Patient summary Although different techniques are available to manage narrowing of the urethra (called a stricture), not every technique is appropriate for every type of stricture. These guidelines, developed on the basis of an extensive literature review, aim to guide physicians in selecting the appropriate technique(s) to treat a specific type of urethral stricture in females and transgender patients. Take Home Message Although different techniques are available to manage urethral strictures, not every technique is appropriate for every type of stricture. Management of urethral strictures in females and transgender patients is complex and a multitude of techniques are available. Selection of the appropriate technique is crucial and these guidelines provide relevant recommendations.

The Combination HIV Antiretroviral Rectal Microbicide-3 (CHARM-03) study was a randomized, open-label, crossover Phase 1 safety and pharmacokinetic (PK) study of oral maraviroc (MVC) and MVC 1% gel. At a single site, healthy HIV-uninfected men and women were enrolled and randomized to an open label crossover sequence of eight consecutive daily exposures to MVC 300 mg dosed orally, MCV 1% gel dosed rectally, and MVC 1% gel dosed vaginally. Male participants received oral and rectal dosing and female participants received oral, rectal, and vaginal dosing. Assessments were undertaken at baseline and following each 8-day period and included collection of plasma, rectal/cervical tissue (CT), and rectal/endocervical/vaginal fluids. Eleven men and nine women were enrolled. Two participants withdrew from the study before receiving study product. There were 25 adverse events, of which 24 were Grade 1 (G1) and one was G2 (unrelated). After eight doses, MVC was quantifiable in all samples following oral, rectal, or vaginal product administration. The highest drug concentrations in plasma, rectal tissue (RT), and CT were associated with oral, rectal, and vaginal drug delivery, respectively. There were significant reductions in tissue drug concentrations when rectal and cervical biopsies were incubated in media before tissue processing for PK (p

Summary Purpose With the increase in the aging population, the level of frailty has become an important metric for assessing preoperative patient risk. Although medical and surgical specialties continue to adopt and standardize the use of frailty instruments, few studies within the plastic surgery literature have utilized such instruments to predict poor postoperative outcomes. The purpose of this article is two-fold: (1) to provide a comprehensive review of the existing frailty instruments and (2) to summarise the existing evidence regarding the role of pre-operative frailty assessments on peri‑operative morbidity and mortality in plastic surgery. Methods This systematic review was registered a priori on the Open Science Framework ( https://osf.io/vfzw8 ). A computerized database search of Ovid MEDLINE, EMBASE, and Cochrane was performed from database inception to December 13, 2020. All articles that examined the effect of preoperative patient frailty on perioperative morbidity and mortality outcomes following plastic surgery interventions were included for data extraction. Results From the 11 studies included in this review, ten unique frailty instruments were identified. The modified Frailty Index (mFI) and the Fried Frailty Index (FFI) were the most commonly reported frailty measurement tools; however, the FRAIL scale was the only outcome measure identified to be valid, reliable, and responsive to change. Regardless of the frailty measure used, nearly all studies reported that worse surgical outcomes were associated with a higher patient frailty score. Conclusion There is a strong association between higher frailty scores and worse postoperative outcomes in plastic surgery. The FRAIL scale is a clinimetrically sound frailty instrument that should be used in all patients to assess perioperative risk in plastic surgery.

Hip fractures in the geriatric population are associated with high morbidity and mortality rate. Early surgical fixation is of major importance, as it is one of the factors that contribute to patient optimization. However, these patients usually present a high burden of comorbidities, including aortic stenosis that could affect their treatment. Despite major advances in anesthetic and surgical techniques, severe aortic stenosis remains an independent, important risk factor for patients undergoing anesthesia for noncardiac surgery. In these patients, general and/or neuraxial anesthesia should be avoided; peripheral nerve blockade is a viable option. This article presents a 96-year-old hip fracture patient with severe aortic stenosis and aspiration pneumonia that successfully underwent hip hemiarthroplasty under peripheral nerve blockade as sole anesthesia.

Summary Introduction Volume Replacement (VR-OBCS) and Volume Displacement Oncoplastic Breast Conserving Surgery (VD-OBCS) are commonly used in the management of breast cancer. Many studies summarize the individual postoperative outcomes of these two procedures; however, there is a lack of research that compares outcomes of these approaches. This review summarizes the available VR and VD-OBCS literature in terms of oncological, cosmetic, and clinical outcomes. Methods An online literature search (MEDLINE, EMBASE, PubMed, and CINAHL) was performed. Studies were included if they were written in English, had more than 10 adult (18+) female patients who underwent VR-OBCS or VD-OBCS, and reported at least one well-described oncological, clinical, or cosmetic outcome Results Thirty-three studies (26 VR-OBCS and 7 VD-OBCS) were included in this review; VR-OBCS studies were separated based on the use of latissimus dorsi (LD) flaps. Studies utilizing VR-OBCS with LD flaps reported the highest rate of all oncological outcomes; VR-OBCS studies without LD flaps reported the lowest. Rates of hematoma, seroma, and wound dehiscence were highest in VR-OBCS with LD flaps; partial flap loss and fat necrosis were highest in VR-OBCS without LD flaps and infection was highest in VD-OBCS studies. Inconsistencies in methodology (cosmetic outcome measures, outcome definitions, and time horizons) were found in all procedural groups. Conclusion Differences in outcomes for both OBCS procedures may be due to the heterogeneity of patient populations. “Doers” and “Users” of breast oncoplastic research should consider tumor size, laterality of tumor, breast size, measurement scales, and defensible time horizons before the application of a study's conclusions.

Allogeneic hematopoietic cell transplantation (alloHCT) survivors have been recently recognized as patients at increased cardiovascular risk. We hypothesized that vascular function remains impaired in alloHCT survivors free of graft-versus-host-disease or relapse. We enrolled consecutive adult alloHCT survivors and non-HCT control individuals (January 2019-March 2020), matched for traditional cardiovascular risk factors. Microvascular dysfunction was dynamically assessed in real time by Laser Speckle Contrast Analysis (LASCA). Carotid-femoral pulse-wave velocity (PWV) and carotid intima media thickness (IMT) were assessed as surrogate markers of cardiovascular disease. We studied 75 patients after a median of 3.2 (range 2.1-4.9) years from alloHCT, who had suffered from grade 2 to 3 acute (20%) and/or moderate/severe chronic GVHD (42%), and 75 controls. Although traditional cardiovascular risk factors and surrogate markers of cardiovascular disease did not differ between groups, alloHCT survivors showed significantly impaired microvascular function (baseline and peak flux, time to peak, base to peak and base to occlusion change). LASCA indices were also independently associated with alloHCT. Our study shows for the first-time impaired microcirculation dynamics in alloHCT survivors, independently of cardiovascular risk factors. Additional studies are needed to address the role of novel markers in cardiovascular risk prediction, along with effects of disease type, phase, and pre-transplant treatments.

Background Recent data suggest that novel biologic agents are associated with increased risk of thrombotic microangiopathy (TMA). Ruxolitinib, an approved treatment for graft-vs-host-disease (GVHD), has been associated with thrombocytopenia of unclear etiology. Methods We investigated factors and outcomes associated with transplant-associated thrombotic microangiopathy (TA-TMA) in patients with GVHD. We retrospectively enrolled consecutive allogeneic hematopoietic cell transplantation recipients with overlap or chronic GVHD at our Joint Accreditation Committee ISCT-Europe & EBMT-accredited unit (January 2016-June 2019). Ruxolitinib has been administered off-label since 2016. Results Among 160 patients with GVHD, 18 were diagnosed with TA-TMA. TA-TMA developed at a median of 150 posttransplant days (range, 98-3013). Among pre- and posttransplant factors, TA-TMA was associated only with ruxolitinib administration and severe GVHD. Interestingly, these 2 variables did not correlate with each other. In the multivariate analysis, both were independent predictors of TA-TMA. Time-dependent analysis confirmed ruxolitinib's association with TA-TMA. With a follow-up of 38.4 months (4.6-83.9) in surviving patients, 5-year overall survival was 52.9%, independently predicted by TA-TMA, severe acute GVHD, and CD34+ cells infused. Ruxolitinib was not associated with survival outcomes. Conclusions Our data suggest that ruxolitinib and GVHD severity are associated with TA-TMA. Given the expanding use of ruxolitinib in GVHD and ongoing trials on chronic GVHD, further studies are warranted to confirm these findings.

Objective To assess efficacy, cycle control, and safety of an oral contraceptive containing estetrol (E4) 15 mg and drospirenone (DRSP) 3 mg. Study design Women aged 16 to 50 years with a body mass index ≤35 kg/m2 enrolled in this multicenter, open-label, 13-cycle, phase 3 trial evaluating E4/DRSP in a 24-active/4-placebo regimen. Follow-up was scheduled at Cycles 2, 4, 7, and 10 and within 3 weeks of completing Cycle 13. Participants used daily diaries to record pill use and vaginal bleeding. We evaluated efficacy outcomes in women 16 to 35 years and bleeding patterns and safety (adverse events [AEs]) in all participants. We assessed overall and method-failure pregnancy rates using the Pearl index (PI) and life-table analysis. Scheduled bleeding included spotting or bleeding starting during the 4-day placebo period or first 3 days of the next cycle. Results We enrolled 1864 women of whom 1674 were 16 to 35 years. Women 16 to 35 years had a PI of 2.65 (95% CI 1.73–3.88), method-failure PI of 1.43 (95% CI 0.7–2.39) and 13-cycle life-table pregnancy rate of 2.1%. Scheduled bleeding occurred in 82.9% to 87.0% of women per cycle; median duration was 4.5 days. Unscheduled bleeding decreased from 30.3% in Cycle 1 to 21.3% to 22.1% during Cycles 2 to 4 and remained stable (15.5% to 19.2%) thereafter. The most frequently reported AEs were headache (5.0%) and metrorrhagia (4.6%). One-hundred thirty-two (7.1%) women discontinued the study early for an AE, most commonly for metrorrhagia (0.9%) and menorrhagia (0.8%). No thromboembolic events occurred. Conclusion E4/DRSP is an effective oral contraceptive with a predictable bleeding pattern for most women and low AE rates. Implications statement A new oral contraceptive with a novel estrogen, estetrol, combined with drospirenone has efficacy and safety within the range of other available oral contraceptives. Large phase 4 studies will be needed to confirm if this combination is associated with an improved adverse event profile or lower thrombosis risk.

The benefits and harms of the available types of surgical management for lichen sclerosus-related (LS) strictures remain unclear and, thus, clear and robust clinical practice recommendations cannot be given. To assess the role of single-stage OMGU in the management of LS strictures and explore how its benefits and harms compare with the alternative management options. Medline, Embase and Cochrane controlled trial databases (CENTRAL, CDSR) were systematically searched. Randomized (RCTs) and nonrandomized studies (NRCSs) comparing single-stage OMGU with other surgical management options for LS strictures and single-arm studies on single-stage OMGU were included. Risk of bias (RoB) was assessed. Of the 1912 abstracts identified, 15 studies (1 NRCS and 14 single-arm studies) were included, recruiting in total 649 patients. All studies were at high RoB. In the only NRCS available, stricture-free rate (SFR) for single-stage and staged OMGU was 88% vs 60%, respectively (p = 0.05), at a mean follow-up of 66.5 months. SFR range for single-stage OMGU in single-arm studies was 65–100% (mean/median follow-up, 12–59 months). Single-stage OMGU had low complication rates and beneficial impact on LUTS and QoL. The present SR highlights the methodological limitations of the available literature. In the absence of adverse local tissue conditions, and taking into consideration benefit–harm balance and surgeon’s skills and expertise, single-stage OMGU can be justified in patients with LS strictures.

Agriculture 4.0, as the future of farming technology, includes several key enabling technologies towards sustainable agriculture. The use of state-of-the-art technologies, such as the Internet of Things, transform traditional cultivation practices, like irrigation, to modern solutions of precision agriculture. In this paper, we present in detail the subsystems and the architecture of an intelligent irrigation system for precision agriculture, the AREThOU5A IoT platform. We describe the operation of the IoT node that is utilized in the platform. Moreover, we apply the radiofrequency energy harvesting technique to the presented IoT platform, as an alternative technique to deliver power to the IoT node of the platform. To this end, we fabricate and validate a rectenna module for radiofrequency energy harvesting. Experimental results of the fabricated rectenna exhibit a satisfactory performance as a harvester of ambient sources in an outdoor environment.

Objective To present a summary of the 2021 version of the European Association of Urology (EAU) guidelines on management of male urethral stricture disease. Evidence acquisition The panel performed a literature review on these topics covering a time frame between 2008 and 2018, and used predefined inclusion and exclusion criteria for the literature to be selected. Key papers beyond this time period could be included as per panel consensus. A strength rating for each recommendation was added based on a review of the available literature and after panel discussion. Evidence synthesis Management of male urethral strictures has extensively been described in literature. Nevertheless, few well-designed studies providing high level of evidence are available. In well-resourced countries, iatrogenic injury to the urethra is one of the most common causes of strictures. Asymptomatic strictures do not always need active treatment. Endoluminal treatments can be used for short, nonobliterative strictures at the bulbar and posterior urethra as first-line treatment. Repetitive endoluminal treatments are not curative. Urethroplasty encompasses a multitude of techniques, and adaptation of the technique to the local conditions of the stricture is crucial to obtain durable patency rates. Conclusions Management of male urethral strictures is complex, and a multitude of techniques are available. Selection of the appropriate technique is crucial, and these guidelines provide relevant recommendations. Patient summary Injury to the urethra by medical interventions is one of the most common reasons of male urethral stricture disease in well-resourced countries. Although different techniques are available to manage urethral strictures, not every technique is appropriate for every type of stricture. These guidelines, developed based on an extensive literature review, aim to guide physicians in the selection of the appropriate technique(s) to treat a specific type of urethral stricture.

Urethral stricture management guidelines are an important tool for guiding evidence-based clinical practice.To present a summary of the 2021 European Association of Urology (EAU) guidelines on diagnosis, classification, perioperative management, and follow-up of male urethral stricture disease.The panel performed a literature review on the topics covering a time frame between 2008 and 2018, and using predefined inclusion and exclusion criteria for the literature. Key papers beyond this time period could be included if panel consensus was reached. A strength rating for each recommendation was added based on a review of the available literature after panel discussion.Routine diagnostic evaluation encompasses history, patient-reported outcome measures, examination, uroflowmetry, postvoid residual measurement, endoscopy, and urethrography. Ancillary techniques that provide a three-dimensional assessment and may demonstrate associated abnormalities include sonourethrography and magnetic resonance urethrogram, although these are not utilised routinely. The classification of strictures should include stricture location and calibre. Urethral rest after urethral manipulations is advised prior to offering urethroplasty. An assessment for urinary extravasation after urethroplasty is beneficial before catheter removal. The optimal time of catheterisation after urethrotomy is72 h, but is unclear following urethroplasty and depends on various factors. Patients undergoing urethroplasty should be followed up for at least 1 yr. Objective and subjective outcomes should be assessed after urethral surgeries, including patient satisfaction and sexual function.Accurate diagnosis and categorisation is important in determining management. Adequate perioperative care and follow-up is essential for achieving successful outcomes. The EAU guidelines provide relevant evidence-based recommendations to optimise patient work-up and follow-up.Urethral strictures have to be assessed adequately before planning treatment. Before surgery, urethral rest and infection prevention are advised. After urethral surgery, x-ray dye tests are advised before removing catheters to ensure that healing has occurred. Routine follow-up is required, including patient-reported outcomes. These guidelines aim to guide doctors in the diagnosis, care, and follow-up of patients with urethral stricture.

Background Electronic prescriptions are often created and delivered electronically to the pharmacy while paper-based/handwritten prescriptions may be delivered to the pharmacy by the patients. These differences in the mode of creation and transmission of the two types of prescription could influence the rate at which outpatients fill new prescriptions of previously untried medications. Objectives This study aimed to evaluate literatures to determine the impact of electronic prescribing compared with paper-based/handwritten prescribing on primary medication adherence in an outpatient setting. Methods The keywords and phrases “outpatients,” “e-prescriptions,” “paper-based prescriptions,” and “primary medication adherence” were combined with their relevant synonyms and medical subject headings. A comprehensive literature search was conducted on EMBASE, CINAHL, and MEDLINE databases, and Google Scholar. The results of the search were screened and selected using predefined inclusion and exclusion criteria. The Critical Appraisal Skills Program (CASP) was used for quality appraisal of included studies. Data relevant to the objective of the review were extracted and analyzed through narrative synthesis. Results A total of 10 original studies were included in the final review, including 1 prospective randomized study and 9 observational studies. Nine of the 10 studies were performed in the United States. Four of the studies indicated that electronic prescribing significantly increases initial medication adherence, while four of the studies suggested the opposite. The remaining two studies found no significant difference in primary medication adherence between the two methods of prescribing. The variations in the studies did not allow the homogeneity required for meta-analysis to be achieved. Conclusion The conflicting findings relating to the efficacy of primary medication adherence across both systems demonstrate the need for a standardized measure of medication adherence. This would help further determine the respective benefits of both approaches. Future research should also be conducted in different countries to give a more accurate representation of adherence.

Radio Frequency (RF) energy harvesting has been emerged as a potentially reliable method to replace the costly and difficult to maintain source of low-power wireless sensor networks. A plethora of dual-band rectifier designs has been proposed in the literature operating in various frequency bands. In this paper, a triple-band RF-to-DC rectifier that operates in the frequency bands of LoRaWAN, GSM-900, and WiFi 2.4 GHz is presented. The system is composed of an impedance-matching circuit, an RF-to-DC rectifier, that converts the ambient RF energy into DC voltage able to feed low-power devices, and an output load. The proposed system resonates at three different frequencies of 866 MHz, 948 MHz and 2423 MHz, which fall within the aforementioned frequency bands of interest. The feasible solution of the proposed system was based on a dual-band rectifier operating in the frequency bands of LoRaWAN and GSM-900. A series of shunt stubs was utilized in the initial design to form the feasible solution of the proposed system. The proposed triple-band rectifier was optimized using a powerful optimization algorithm, i.e., the genetic algorithm. The overall system exhibited improved characteristics compared to the initial design in terms of its resonance. Numerical results demonstrated that the overall system exhibited an efficiency of 81% with 3.23 V of the output voltage, for an input power of 0 dBm and a load of 13 kOhm.

Context Four techniques for graft placement in one-stage bulbar urethroplasty have been reported: dorsal onlay (DO), ventral onlay (VO), dorsolateral onlay (DLO), and dorsal inlay (DI). There is currently no systematic review in the literature comparing these techniques. Objective To assess if stricture recurrence and secondary outcomes vary between the four techniques and to assess if one technique is superior to any other. Evidence acquisition The EMBASE, MEDLINE, and Cochrane Systematic Reviews—Cochrane Central Register of Controlled Trials (CENTRAL; Cochrane HTA, DARE, HEED) databases and ClinicalTrials.gov were searched for publications in English from 1996 onwards. Randomised controlled trials (RCTs), nonrandomised comparative studies (NRCSs), observational studies (cohort, case-control/comparative, single-arm), and case series with ≥20 adult male participants were included. Evidence synthesis A total of 41 studies were included involving 3683 patients from one RCT, four NRCSs, and 36 case series. Owing to the overall low quality of the evidence, a narrative synthesis was performed. Conclusions No single technique appears to be superior to another for bulbar free graft urethroplasty. Both DO and VO are suitable for bulbar augmentation urethroplasty, with a ≤20% recurrence rate over medium-term follow-up. No recommendations can be made regarding DI or DLO techniques owing to the paucity of evidence. Secondary outcomes including sexual function, and complications are infrequently reported. Recurrence rates deteriorate in the long term for both DO and VO procedures. Patient summary We reviewed the evidence for four different skin-graft techniques used to repair narrowing of a section of the urethra (bulbar urethra, under the scrotum and perineum) in men. Two of the techniques seem to give consistent results, with recurrence rates lower than 20%. Recurrence rates increase over time, so patients should continue to monitor their symptoms. There is poorer reporting of other outcomes such as sexual function, urinary symptoms, and complications, and it is possible that these occur more frequently than the current data suggest.

Despite routine post-transplant viral monitoring and pre-emptive therapy, viral infections remain a major cause of allogeneic hematopoietic cell transplantation-related morbidity and mortality.We here aimed to prospectively assess the kinetics and the magnitude of cytomegalovirus-(CMV), Epstein Barr virus-(EBV), and BK virus-(BKV)-specific T cell responses post-transplant and evaluate their role in guiding therapeutic decisions by patient risk-stratification.The tri-virus-specific immune recovery was assessed by Elispot, in 50 consecutively transplanted patients, on days +20, +30, +60, +100, +150, +200 post-transplant and in case of reactivation, weekly for 1 month.The great majority of the patients experienced at least one reactivation, while over 40% of them developed multiple reactivations from more than one of the tested viruses, especially those transplanted from matched or mismatched unrelated donors. The early reconstitution of virus-specific immunity (day +20), favorably correlated with transplant outcomes. Εxpanding levels of CMV-, EBV-, and BKV-specific T cells (VSTs) post-reactivation coincided with decreasing viral load and control of infection. Certain cut-offs of absolute VST numbers or net VST cell expansion post-reactivation were determined, above which, patients with CMV or BKV reactivation had 90% probability of complete response (CR).Immune monitoring of virus-specific T-cell reconstitution post-transplant may allow risk-stratification of virus reactivating patients and enable patient-tailored treatment. The identification of individuals with high probability of CR will minimize unnecessary overtreatment and drug-associated toxicity while allowing candidates for pre-emptive intervention with adoptive transfer of VSTs to be appropriately selected.

Introduction The potential advantages of oncoplastic breast conserving surgery (BCS) have not been validated in robust studies that constitute high levels of evidence, despite oncoplastic techniques being widely adopted around the globe. There is hence the need to define the precise role of oncoplastic BCS in the treatment of early breast cancer, with consensual recommendations for clinical practice. Methods A panel of world-renowned breast specialists was convened to evaluate evidence, express personal viewpoints and establish recommendations for the use of oncoplastic BCS as primary treatment of unifocal early stage breast cancers using the GRADE approach. Results According to the results of the systematic review of literature, the panelists were asked to comment on the recommendation for use of oncoplastic BCS for treatment of operable breast cancer that is suitable for breast conserving surgery, with the GRADE approach. Based on the voting outcome, the following recommendation emerged as a consensus statement: Oncoplastic breast conserving surgery should be recommended versus standard breast conserving surgery for the treatment of operable breast cancer in adult women who are suitable candidates for breast conserving surgery (with very low certainty of evidence). Discussion This review has revealed a low level of evidence for most of the important outcomes in oncoplastic surgery with lack of any randomized data and absence of standard tools for evaluation of clinical outcomes and especially patients’ values. Despite areas of controversy, about one-third (36%) of panel members expressed a strong recommendation in support of oncoplastic BCS. Presumably, this reflects a synthesis of views on the relative complexity of these techniques, associated complications, impact on quality of life and costs.

Advances in immunotherapy with T cells armed with chimeric antigen receptors (CAR-Ts), opened up new horizons for the treatment of B-cell lymphoid malignancies. However, the lack of appropriate targetable antigens on the malignant myeloid cell deprives patients with refractory acute myeloid leukaemia of effective CAR-T therapies. Although non-engineered T cells targeting multiple leukaemia-associated antigens [i.e. leukaemia-specific T cells (Leuk-STs)] represent an alternative approach, the prerequisite challenge to obtain high numbers of dendritic cells (DCs) for large-scale Leuk-ST generation, limits their clinical implementation. We explored the feasibility of generating bivalent-Leuk-STs directed against Wilms tumour 1 (WT1) and preferentially expressed antigen in melanoma (PRAME) from umbilical cord blood units (UCBUs) disqualified for allogeneic haematopoietic stem cell transplantation. By repurposing non-transplantable UCBUs and optimising culture conditions, we consistently produced at clinical scale, both cluster of differentiation (CD)34+ cell-derived myeloid DCs and subsequently polyclonal bivalent-Leuk-STs. Those bivalent-Leuk-STs contained CD8+ and CD4+ T cell subsets predominantly of effector memory phenotype and presented high specificity and cytotoxicity against both WT1 and PRAME. In the present study, we provide a paradigm of circular economy by repurposing unusable UCBUs and a platform for future banking of Leuk-STs, as a 'third-party', 'off-the-shelf' T-cell product for the treatment of acute leukaemias.

Background The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic poses an urgent need for the development of effective therapies for coronavirus disease 2019 (COVID-19). Methods We first tested SARS-CoV-2–specific T-cell (CοV-2-ST) immunity and expansion in unexposed donors, COVID-19–infected individuals (convalescent), asymptomatic polymerase chain reaction (PCR)–positive subjects, vaccinated individuals, non–intensive care unit (ICU) hospitalized patients, and ICU patients who either recovered and were discharged (ICU recovered) or had a prolonged stay and/or died (ICU critical). CoV-2-STs were generated from all types of donors and underwent phenotypic and functional assessment. Results We demonstrate causal relationship between the expansion of endogenous CoV-2-STs and the disease outcome; insufficient expansion of circulating CoV-2-STs identified hospitalized patients at high risk for an adverse outcome. CoV-2-STs with a similarly functional and non-alloreactive, albeit highly cytotoxic, profile against SARS-CoV-2 could be expanded from both convalescent and vaccinated donors generating clinical-scale, SARS-CoV-2–specific T-cell products with functional activity against both the unmutated virus and its B.1.1.7 and B.1.351 variants. In contrast, critical COVID-19 patient-originating CoV-2-STs failed to expand, recapitulating the in vivo failure of CoV-2–specific T-cell immunity to control the infection. CoV-2-STs generated from asymptomatic PCR-positive individuals presented only weak responses, whereas their counterparts originating from exposed to other seasonal coronaviruses subjects failed to kill the virus, thus disempowering the hypothesis of protective cross-immunity. Conclusions Overall, we provide evidence on risk stratification of hospitalized COVID-19 patients and the feasibility of generating powerful CoV-2-ST products from both convalescent and vaccinated donors as an “off-the shelf” T-cell immunotherapy for high-risk patients.

Chondrosarcomas of the small bones of the hands and feet are uncommon and account for less than 2% of all chondrosarcomas in the skeleton; a 4.2% rate of malignant degeneration of enchondromas to secondary chondrosarcomas has been reported. We performed this study to assess the outcome of the patients with chondrosarcomas of the small bones. We hypothesized that the presumed better prognosis of chondrosarcomas in these locations could be biased as the majority of these tumors tend to be of lower grades and are removed when still small sized, and that less aggressive surgery has an adverse effect on local control MATERIALS AND METHODS: We retrospectively studied the files of 44 patients with chondrosarcomas of the small bones of the hands and feet. There were 23 female and 21 male patients with a mean age of 50.9 years (range, 6-86 years). The mean follow-up was 13 years (range, 5-40 years). We recorded the patients' details including gender and age at diagnosis, type and duration of symptoms, tumor location and histology, type of surgery and complications, and outcome (local recurrences and metastases).The most common anatomical location for chondrosarcomas of the hands was the metacarpals and proximal phalanges. The most common presenting symptom was a slowly enlarging palpable mass. Overall, 36 chondrosarcomas were secondary to a pre-existing cartilaginous tumor. Patients with syndromes were affected in younger age compared to the others. The mean age at diagnosis was higher for higher grade chondrosarcomas. Overall, 13 patients (29.5%) experienced a local recurrence; the rate of local recurrence was higher after curettage regardless the histological grade of the tumors. After wide resection of the first local recurrence, five patients experienced local re-recurrence. Five patients (11.4%) experienced lung metastases, two patients at presentation. All these patients had a high grade chondrosarcomas. At the last follow-up, one patient with lung metastases died from disease, and another patient died from unrelated cause.The patients with chondrosarcomas of the small bones of the hands and feet may have a dismal outcome if treated improperly. A careful treatment planning is required to avoid unnecessary amputations. Curettage is associated with a high rate for local recurrence that should be treated with a more aggressive surgical resection to avoid re-recurrences. Although the risk is low, the patients may develop lung metastases, especially those with higher grade chondrosarcomas, therefore, they should be staged and followed closely.

To summarize the evolution of intramedullary nailing, highlight important milestones, introduce the atmosphere of the era concerning the first uses and development of intramedullary nailing, and present the status of nailing in modern international orthopaedics and traumatology. A thorough literature search was undertaken in PubMed and Google Scholar as well as in physical books in libraries to summarize the literature on the history and evolution of intramedullary nailing. The first use of an intramedullary device was attested in ancient Egypt; however, the first use of intramedullary nailing was reported in 1524 in Mexico, and the first medical journals reported on intramedullary nailing around the mid-1800s. The evolutions of intramedullary nailing including approach, material, cross-section and shape, and reaming technique occurred in the twentieth century. During the 1960s, intramedullary nailing was abandoned in favour of plate and screws osteosynthesis; however, in the 1970s, 1980s, and 1990s, a surge of novelties including flexible reaming, interlocking, and use of image intensification and titanium nails led to the advent of the second-generation intramedullary nailing. Today, intramedullary nailing has become the standard treatment of long bone fractures with low infection rates, small scars, excellent stabilization of the fractures, and immediate mobilization of the patients. Intramedullary nailing has revolutionized the treatment of long bone fractures. However, with numerous nail designs, a lot of information on their efficacy is lacking. Considerably more work will need to be done to determine the optimal nail specifications.

The expected trend in serum beta-human chorionic gonadotropin (β-hCG) following treatment of an undesired heterotopic pregnancy with uterine aspiration and systemic methotrexate is not known. Thus, monitoring for treatment success is challenging. We describe an undesired heterotopic pregnancy treated with aspiration and two-dose methotrexate and report the observed β-hCG trend.

Background: In Uganda, 12% of previously treated TB cases and 1.6% of new cases have MDR-TB and require specialized treatment and care. Adherence is crucial for improving MDR-TB treatment outcomes. There is paucity of information on the extent to which these patients adhere to treatment and what the drivers of non-adherence are. Methods: We conducted a cohort study using retrospectively collected routine program data for patients treated for MDR- TB between January 2012 – May 2016 at Mulago Hospital. We extracted anonymized data on non-adherence (missing 10% or more of DOT), socio-economic, demographic, and treatment characteristics of the patients. All participants were sen- sitive to MDR-TB drugs after second line Drug Susceptible Testing (DST) at entry into the study. Factors associated with non-adherence to MDR-TB treatment were determined using generalized linear models for the binomial family with log link and robust standard errors. We considered a p- value less than 0.05 as statistically significant. Results: The records of 227 MDR- TB patients met the inclusion criteria, 39.4% of whom were female, 32.6% aged be- tween 25 – 34 years, and 54.6% living with HIV/AIDS. About 11.9% of the patients were non-adherent. The main driver for non-adherence was history of previous DR-TB treatment; previously treated DR-TB patients were 3.46 (Adjusted prev- alence ratio: 3.46, 95 % CI: 1.68 - 7.14) times more likely to be non-adherent. Conclusion: One in 10 MDR-TB patients treated at Mulago hospital is non-adherent to treatment. History of previous DR- TB treatment was significantly associated with non-adherence in this study. MDR-TB program should strengthen adherence counselling, strengthen DST surveillance, and close monitoring for previously treated DR-TB patients. Keywords: Non-adherence; multi-drug resistant tuberculosis; treatment.

Background: Peritoneal dialysis (PD) can offer patients more autonomy and flexibility compared with in-center hemodialysis (HD). However, burnout – defined as mental, emotional, or physical exhaustion that leads to thoughts of discontinuing PD – is associated with an increased risk of transfer to HD. We aimed to describe the perspectives of burnout among patients on PD and their caregivers. Methods: In this focus group study, 81 patients and 45 caregivers participated in 14 focus groups from 9 dialysis units in Australia, Hong Kong, and the United States. Transcripts were analyzed thematically. Results: We identified two themes. Suffering an unrelenting responsibility contributed to burnout, as patients and caregivers felt overwhelmed by the daily regimen, perceived their life to be coming to a halt, tolerated the PD regimen for survival, and had to bear the burden and uncertainty of what to expect from PD alone. Adapting and building resilience against burnout encompassed establishing a new normal, drawing inspiration and support from family, relying on faith and hope for motivation, and finding meaning in other activities. Conclusions: For patients on PD and their caregivers, burnout was intensified by perceiving PD as an unrelenting, isolating responsibility that they had no choice but to endure, even if it held them back from doing other activities in life. More emphasis on developing strategies to adapt and build resilience could prevent or minimize burnout.

Medulloscopy refers to the visualization of the intramedullary canal with an arthroscope, providing access to the infection site without the need for an extensive approach therefore not compromising the surrounding soft tissue. It provides information regarding the extent of the infected endosteal surface of bone, and it allows a thorough debridement of the intramedullary canal in a controlled manner. Therefore, it can be used as an adjunct to traditional open surgical techniques, to perhaps help to visualize hard to see intramedullary areas. This article reports a patient with chronic osteomyelitis of the distal metaphysis of the femur that was treated successfully with intramedullary debridement through medulloscopy. The sinus tract reaching down to the femoral bone and communicating with the intramedullary canal was excised, and a cortical window was formed through which the arthroscope was inserted and thorough irrigation of the intramedullary canal and excision of necrotic and infected bone was done. A second medulloscopy through the same approach was necessary 3 months later because of persistent infection. At 3-year follow-up, the patient was well without any clinical or radiographic evidence of recurrent infection. Medulloscopy can be very useful in localized osteomyelitis as an adjunct to traditional surgical techniques; it helps to visualize hard to see intramedullary areas and adequately addresses the infection, while the damage to surrounding soft-tissue is limited.

One of the biggest challenges in building sustainable smart cities of the future is skill management and development. Developing the digital skills of the municipalities’ workforce is crucial for all occupational profiles and specifically for those that are actively involved in the development and operation of digital services for a smart city. In this context, the current paper presents a semantically enhanced cloud-based IT approach which integrates learning pathways with competence management of personnel working as management and technical employees in a smart city municipality. The proposed approach combines a rule-based expert system with a semantically rich infrastructure in order to map skill gap diagnosis to required learning objects and, thus, to contribute in developing appropriate competences of smart city professionals. The semantic infrastructure of the learning platform consists of an ontology which encapsulates the appropriate knowledge and a rule-base for modeling the steps of an employee training process. In order to achieve efficiency in competence management the semantic model has been transformed into a relational database schema, which is further utilized by the system for the execution of useful queries. The paper presents the key modeling artifacts of the proposed approach and the architecture of the implemented CMUTE system.

Background Depot medroxyprogesterone acetate (DMPA) is a commonly used contraceptive in areas where use of tenofovir disoproxil fumarate and emtricitabine for HIV pre-exposure prophylaxis (PrEP) is increasing. Objectives We aimed to investigate the impact of DMPA on PrEP drug pharmacokinetics and pharmacodynamics in women using PrEP before and after DMPA administration. Methods In this pilot study, twelve HIV-negative women ages 18-45 underwent biological sample collection at three time points: before study drug, after 2 weeks of daily PrEP use alone, and after 2 weeks of daily PrEP and concomitant DMPA use. We measured drug and drug metabolites in plasma, peripheral blood mononuclear cells, cervicovaginal fluid, cervical tissue, and rectal fluid after each 2-week course of PrEP. We measured HIV replication ex vivo in genital tissue biopsies and innate anti-HIV activity in cervicovaginal fluid before PrEP and after both courses. We compared drug concentrations after PrEP alone to after PrEP and DMPA in the same participant using Wilcoxon signed-rank tests. We used mixed effects linear regression models to compare pharmacodynamic measures for each participant at pre-drug baseline, after PrEP alone, and after PrEP and DMPA. Results We found no significant differences in PrEP drug and drug metabolite concentrations in any compartment during concomitant DMPA use compared to use of PrEP alone, except for a reduction in emtricitabine concentration in cervical tissue. We found no difference in HIV replication in cervical tissue or anti-HIV activity in cervicovaginal fluid during concomitant DMPA and PrEP use compared to during PrEP use alone. Conclusions Concomitant use of DMPA does not clinically alter pharmacokinetics or pharmacodynamics of PrEP in women. These data support the safety of DMPA use in women using PrEP.

Accumulating evidence points toward a protective role of intestinal microbiota diversity in allogeneic hematopoietic cell transplantation (allo-HCT). The purpose of this systematic review and meta-analysis is to determine the effect of antibiotic-mediated disruption of microbiota on main allo-HCT outcomes (graft-versus-host disease [GVHD], treatment-related mortality [TRM], overall survival [OS]). Following literature search, 2 reviewers screened eligible studies and assessed risk of bias (RoB). Meta-analysis was performed using Review Manager Software. Among 443 screened references, 18 were eligible for meta-analysis. In studies with genomic markers, grade II to IV acute GVHD was significantly reduced in patients not receiving gut decontamination (GD) (odds ratio [OR], 1.56; 95% confidence interval [CI], 1.20 to 2.04). In subgroup analysis, prophylaxis with systemic antibiotics conferred an increased risk of acute GVHD (OR, 1.65; 95% CI, 1.08 to 2.53). When we incorporated RoB, we found a positive correlation of intestinal GVHD with GD (OR, 1.77; 95% CI, 1.29 to 2.44). Patients with higher microbiota diversity presented increased OS (risk ratio [RR], 1.58; 95% CI, 1.19 to 2.09) and lower TRM (RR, 0.45; 95% CI, 0.26 to 0.76). Our findings confirm that GD and prophylaxis with systemic antibiotics increase acute and intestinal GVHD. Importantly, our meta-analysis was the first to show a significant effect of microbiota diversity on TRM and OS.

Context Surgical repair of a vesicovaginal fistula (VVF) has been described extensively in the literature for several decades. Advances in robotic repair have been adopted since 2005. Objective A consensus review of existing data based on published case series, expert opinion, and a survey monkey. Evidence acquisition This document summarizes the consensus group meeting and survey monkey results convened by the European Association of Urology Robotic Urology Section (ERUS) relating to the robotic management of VVF. Evidence synthesis Current data underline the successful robotic repair of supratrigonal nonobstetric VVF. The panel recommends preoperative marking of the fistula by a guidewire or ureteral catheter, and placement of a protective ureteral JJ stent. An extravesical robotic approach usually provides a good anatomic view for adequate and wide dissection of the vesicovaginal space, as well as bladder and vaginal mobilization. Careful sharp dissection of fistula edges should be performed. Tension-free closure of the bladder is of utmost importance. Tissue interposition seems to be beneficial. The success rate of published series often reaches near 100%. An indwelling bladder catheter should be placed for about 10 d postoperatively. Conclusions When considering robotic repair for VVF, it is essential to establish the size, number, location, and etiology of the VVF. Robotic assistance facilitates dissection of the vesicovaginal space, harvesting of a well-vascularized tissue flap, and a tension-free closure of the bladder with low morbidity for the patient being operated in the deep pelvis with delicate anatomical structures. Patient summary Robotic repair of a vesicovaginal fistula can be applied safely with an excellent success rate and very low morbidity. This confirms the use of robotic surgery for vesicovaginal fistula repair, which is recommended in a consensus by the European Association of Urology Robotic Section Scientific Working Group for reconstructive urology.

The regimen of 5-azacytidine for patients with myelodysplastic syndrome (MDS) has remained unchanged since its first approval. Although several modifications have since been made and delays and dose reductions are common especially during the first treatment cycles, there are minimal data on the prognostic effect of these modifications. In this study, based on data from 897 patients with MDS treated with 5-azacytidine recorded in a national registry, the effect of treatment delays and dose reductions on response, transformation to acute myeloid leukaemia, and survival (after 5-azacytidine initiation, OST ) were analysed. Delays during the first two cycles were noted in 150 patients (16·7%) and were found to adversely affect OST independently of the International Prognostic Scoring System score [hazard ratio (HR), 1·368; P = 0·033] or pre-existing neutropenia (HR, 1·42; P = 0·015). In patients achieving a response, delays before response achievement were correlated with its type (complete remission, 2·8 days/cycle; partial remission, 3·3 days/cycle; haematologic improvement, 5·6 days/cycle; P = 0·041), while delays after response achievement did not have any effect on retention of response or survival. Dose reductions were found to have no prognostic impact. Based on our results, treatment delays especially during the first cycles should be avoided, even in neutropenic patients. This strict strategy may be loosened after achieving a favourable response.

The purpose of this study was to analyze the results of second autologous hematopoietic stem cell transplantation (ASCT2) for patients with relapsed/refractory Hodgkin lymphoma (HL) after a first transplantation (ASCT1). Outcomes for 56 patients receiving an ASCT2 registered in the EBMT database were analyzed. The 4-year cumulative incidences of non-relapse mortality and disease relapse/progression were 5% and 67%, respectively. The 4-year overall survival (OS) and progression-free survival (PFS) were 62% and 28%. In univariate analysis, relapse of HL within 12 months of ASCT1 was associated with a worse OS (35% versus 76%

Background Routine tuberculosis (TB) notifications are geographically heterogeneous, but their utility in predicting the location of undiagnosed TB cases is unclear. We aimed to identify small-scale geographic areas with high TB notification rates based on routinely collected data and to evaluate whether these areas have a correspondingly high rate of undiagnosed prevalent TB. Methods We used routinely collected data to identify geographic areas with high TB notification rates and evaluated the extent to which these areas correlated with the location of undiagnosed cases during a subsequent community-wide active case finding intervention in Kampala, Uganda. We first enrolled all adults who lived within 35 contiguous zones and were diagnosed through routine care at four local TB Diagnosis and Treatment Units. We calculated average monthly TB notification rates in each zone and defined geographic areas of “high risk” as zones that constituted the 20% of the population with highest notification rates. We compared the observed proportion of TB notifications among residents of these high-risk zones to the expected proportion, using simulated estimates based on population size and random variation alone. We then evaluated the extent to which these high-risk zones identified areas with high burdens of undiagnosed TB during a subsequent community-based active case finding campaign using a chi-square test. Results We enrolled 45 adults diagnosed with TB through routine practices and who lived within the study area (estimated population of 49 527). Eighteen zones reported no TB cases in the 9-month period; among the remaining zones, monthly TB notification rates ranged from 3.9 to 39.4 per 100 000 population. The five zones with the highest notification rates constituted 62% (95% CI: 47–75%) of TB cases and 22% of the population–significantly higher than would be expected if population size and random chance were the only determinants of zone-to-zone variation (48%, 95% simulation interval: 40–59%). These five high-risk zones accounted for 42% (95% CI: 34–51%) of the 128 cases detected during the subsequent community-based case finding intervention, which was significantly higher than the 22% expected by chance (P P = 0.02). Conclusions There is substantial heterogeneity in routine TB notification rates at the zone level. Using facility-based TB notification rates to prioritize high-yield areas for active case finding could double the yield of such case-finding interventions.

To evaluate the feasibility of measuring the intrapelvic pressure (IPP) during f-URS with a wire including a pressure sensor and to assess IPP profiles during the procedure. Patients undergoing f-URS for stone disease were recruited. A wire with pressure sensor was placed in the renal cavities to measure IPP. For these cases, either no ureteral access sheath (UAS) or 10/12 or 12/14-Fr UASs were used according to surgeon discretion. Irrigation was ensured by a combination of a continuous pressure generator set at 80 cmH2O and a hand-assisted irrigation system providing on-demand forced irrigation to provide proper visibility. Pressures were monitored in real time and recorded for analysis. Four patients undergoing five f-URS were included. IPP monitoring was successful in all patients. Mean baseline IPP was 6 cmH2O. During f-URS with only the endoscope in the renal cavities and irrigation pressure set at 80 cmH2O without any forced irrigation, the mean IPP was 63 cmH2O. Mean IPP during laser lithotripsy with the use of on-demand forced irrigation was 115.3 cmH2O. The maximum pressure peaks recorded during this therapeutic period using forced irrigation ranged from 289.3 to 436.9 cmH2O. High IPP levels may be achieved during f-URS with on-demand irrigation systems. The impact of these high pressures on the risk of complications and long-term consequences still need to be evaluated adequately. But, in this preliminary pilot study, IPP could be reliably and conveniently monitored and recorded using a wire with a digital pressure sensor.

Background and objectives Shared decision making in patients with glomerular disease remains challenging because outcomes important to patients remain largely unknown. We aimed to identify and prioritize outcomes important to patients and caregivers and to describe reasons for their choices. Design, setting, participants, & measurements We purposively sampled adult patients with glomerular disease and their caregivers from Australia, Hong Kong, the United Kingdom, and the United States. Participants identified, discussed, and ranked outcomes in focus groups using the nominal group technique; a relative importance score (between zero and one) was calculated. Qualitative data were analyzed thematically. Results Across 16 focus groups, 134 participants (range, 19–85 years old; 51% women), including 101 patients and 33 caregivers, identified 58 outcomes. The ten highest-ranked outcomes were kidney function (importance score of 0.42), mortality (0.29), need for dialysis or transplant (0.22), life participation (0.18), fatigue (0.17), anxiety (0.13), family impact (0.12), infection and immunity (0.12), ability to work (0.11), and BP (0.11). Three themes explained the reasons for these rankings: constraining day-to-day experience, impaired agency and control over health, and threats to future health and family. Conclusions Patients with glomerular disease and their caregivers highly prioritize kidney health and survival, but they also prioritize life participation, fatigue, anxiety, and family impact.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication of allogeneic hematopoietic cell transplantation (HCT). We hypothesized that pretransplant genetic susceptibility is evident in adult TA-TMA and further investigated the association of TMA-associated variants with clinical outcomes. We studied 40 patients with TA-TMA, donors of 18 patients and 40 control non-TMA HCT recipients, without significant differences in transplant characteristics. Genomic DNA from pretransplant peripheral blood was sequenced for TMA-associated genes. Donors presented significantly lower frequency of rare variants and variants in exonic/splicing/untranslated region (UTR) regions, compared with TA-TMA patients. Controls also showed a significantly lower frequency of rare variants in ADAMTS13, CD46, CFH, and CFI. The majority of TA-TMA patients (31/40) presented with pathogenic or likely pathogenic variants. Patients refractory to conventional treatment (62%) and patients that succumbed to transplant-related mortality (65%) were significantly enriched for variants in exonic/splicing/UTR regions. In conclusion, increased incidence of pathogenic, rare and variants in exonic/splicing/UTR regions of TA-TMA patients suggests genetic susceptibility not evident in controls or donors. Notably, variants in exonic/splicing/UTR regions were associated with poor response and survival. Therefore, pretransplant genomic screening may be useful to intensify monitoring and early intervention in patients at high risk for TA-TMA.

Background The World Health Organization (WHO) recommends household contact investigation for tuberculosis (TB) in high-burden countries. However, household contacts who complete evaluation for TB during contact investigation may have difficulty accessing their test results. Use of automated short-messaging services (SMS) to deliver test results could improve TB status awareness and linkage to care. We sought to explore how household contacts experience test results delivered via SMS, and how these experiences influence follow-up intentions. Methods We conducted semi-structured interviews with household contacts who participated in a randomized controlled trial evaluating home sputum collection and delivery of TB results via SMS (Pan-African Clinical Trials Registry #201509000877140). We asked about feelings, beliefs, decisions, and behaviors in response to the SMS results. We analyzed the content and emerging themes in relation to the Theory of Planned Behavior. Results We interviewed and achieved thematic saturation with ten household contacts. Nine received TB-negative results and one a TB-positive result. Household contacts reported relief upon receiving SMS confirming their TB status, but also said they lacked confidence in the results delivered by SMS. Some worried that negative results were incorrect until they spoke to a lay health worker (LHW). Household contacts said their long-term intentions to request help or seek care were influenced by perceived consequences of not observing the LHW’s instructions related to the SMS and follow-up procedures; beliefs about the curability of TB; anticipated support from LHWs; and perceived barriers to responding to an SMS request for further evaluation. Conclusion Household contacts experienced relief when they received results. However, they were less confident about results delivered via SMS than results delivered by LHWs. Delivery of results by SMS should complement continued interaction with LHWs, not replace them.

Objective We evaluated ibrutinib, a once-daily inhibitor of Bruton's tyrosine kinase, combined with bortezomib and dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma who had received 1-3 prior therapies. Methods This was a phase 2, single-arm, open-label, multicentre study (NCT02902965). The primary endpoint was progression-free survival (PFS). Results Seventy-six patients were enrolled; 74 received >= 1 dose of study treatment. After median follow-up of 19.6 months, median PFS was 8.5 months (95% CI: 6.2-10.8); median overall survival was not reached. Overall response rate was 57% (95% CI: 45-68), and median duration of response was 9.5 months (95% CI: 6.9-10.6). Grade 3/4 AEs occurred in 73% of patients and fatal AEs occurred in 15% of patients. Incidence of major haemorrhage was 5%; one patient died from cerebral haemorrhage. After an observed increased incidence of serious (42%) and fatal (11%) infections, enrolment was suspended to implement risk-minimisation measures. The safety profile was otherwise consistent with known safety profiles of the individual drugs. Conclusion Ibrutinib combined with bortezomib and dexamethasone elicited clinical responses. However, efficacy assessments conducted at potential restart of enrolment indicated that the targeted PFS could not be reached with additional patient enrolment, and the study was terminated.

Rationale: A reduced rate of myocardial infarction has been reported in patients with atrial fibrillation treated with FXa (factor Xa) inhibitors including rivaroxaban compared with vitamin K antagonists. At the same time, low-dose rivaroxaban has been shown to reduce mortality and atherothrombotic events in patients with coronary artery disease. Yet, the mechanisms underlying this reduction remain unknown. Objective: In this study, we hypothesized that rivaroxaban’s antithrombotic potential is linked to a hitherto unknown rivaroxaban effect that impacts on platelet reactivity and arterial thrombosis. Methods and Results: In this study, we identified FXa as potent, direct agonist of the PAR-1 (protease-activated receptor 1), leading to platelet activation and thrombus formation, which can be inhibited by rivaroxaban. We found that rivaroxaban reduced arterial thrombus stability in a mouse model of arterial thrombosis using intravital microscopy. For in vitro studies, atrial fibrillation patients on permanent rivaroxaban treatment for stroke prevention, respective controls, and patients with new-onset atrial fibrillation before and after first intake of rivaroxaban (time series analysis) were recruited. Platelet aggregation responses, as well as thrombus formation under arterial flow conditions on collagen and atherosclerotic plaque material, were attenuated by rivaroxaban. We show that rivaroxaban’s antiplatelet effect is plasma dependent but independent of thrombin and rivaroxaban’s anticoagulatory capacity. Conclusions: Here, we identified FXa as potent platelet agonist that acts through PAR-1. Therefore, rivaroxaban exerts an antiplatelet effect that together with its well-known potent anticoagulatory capacity might lead to reduced frequency of atherothrombotic events and improved outcome in patients.

Background Hypomethylating agents have altered the prognosis of myelodysplastic syndrome (MDS) so that long-term survival is now a feasible treatment goal. Patients and Methods We analyzed data from patients with MDS treated with 5-azacytidine recorded in the Hellenic 5-azacytidine registry. We divided patients, on the basis of their survival after 5-azacytidine initiation (OST), in groups of long-term survivors (Q3 and P90 group with OST above the third quartile and the 90th percentile of the whole group, respectively) and short-term survivors comprising the remaining patients, and compared the characteristics between the groups. The study included 626 patients, 157 in the Q3 group and 63 in the P90 group. Results Categorization per the International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R), and World Health Organization–based prognostic scoring system (WPSS) was found to predict long-term survival, while multivariate analysis revealed that response to 5-azacytidine was the strongest predictor of long-term survival. Nevertheless, patients with hematologic improvement (HI) and stable disease (SD) were equally distributed in the groups of short- and long-term survival. Conclusion SD should not be considered a poor treatment response and should not be grouped with failure, while HI offers similar prognosis to SD and thus should not be grouped with complete and partial remission. Patients with SD should continue treatment with 5-azacytidine.

The present research work proposes the development of an integrated framework for the personalization and parameterization of learning pathways, aiming at optimizing the quality of the offered services by the Higher Educational Institutions (HEI). In order to achieve this goal, in addition to the educational part, the EDUC8 framework encloses the set of parameters that cover both the technical and the financial dimensions of a learning pathway, thus providing a complete tool for the optimization and calculation of the offered services by the HEIs in combination with the minimization of respective costs. Moreover, the proposed framework incorporates simulation modeling along with machine learning for the purpose of designing learning pathways and evaluating quality assurance indicators and the return on investment of implementation. The study presents a case study in relation to tertiary education in Greece, with a particular focus on Computer Science programs. Data clustering is specifically applied to learn potential insights pertaining to student characteristics, education factors and outcomes. Generally, the framework is conceived to provide a systematic approach for developing tertiary policies that help optimize the quality and cost of education.

Primary hyperparathyroidism (PHPT) is the most common cause of hypercalcemia; patients are usually asymptomatic and the cause in 80-85% of cases is a single parathyroid adenoma (PA). Parathyroid adenomas arise from clonal expansion of tumor cells and may be located either posteriorly to the thyroid lobes or in ectopic sites. The incidence of intrathyroidal PAs varies from 1% to 6% and although uncommon, they pose certain diagnostic difficulties which may complicate treatment. The identification of the adenoma requires a combination of clinical evidence, imaging information and cytological findings due to the challenging distinction between thyroid and parathyroid lesions. We present the case of a patient with a large, partially cystic intrathyroidal parathyroid adenoma which was initially identified as a malignant thyroid nodule. We discuss the caveats that present in these rare cases and the important clinical and histological features that aid in the final diagnosis. In the case of our patient the cytological similarities between thyroid malignant cells and parathyroid cells, in combination with the negative sestamibi scan, resulted in a more invasive surgery than that a single parathyroid adenoma would require. Clinicians need to be vigilant in terms of the similarities between parathyroid and thyroid cytology in order to provide optimal patient care in these rare cases.

With the reduction of the allowed emission values, the need for fast and emission-free passenger transport is growing - even on coastal or inner city waterways. Many cities and regions are therefore striving to quickly replace their existing conventional diesel ferries with electrically powered passenger ferries. Shipbuilding, however, is characterized by individual applications and corresponding one-off productions. While the concept of modularization has proven itself in many industries to realize individual products in a short development time, such approaches are hardly found in the maritime industry. In particular, the high degree of dependency between the individual system elements of a ship represents a major challenge in the development of modular ships and ship architectures. This dependencies are further increased in the case of electrically driven high-speed ships, which in the present case are used for passenger transport in urban areas. This paper presents an approach for identifying reusable and standardized modules in shipbuilding for high-speed vessels using Model-Based Systems Engineering methods. The goal of the approach is to create a multi-domain system model that enables developers to identify use-case spanning standard modules and interfaces.

Introduction Patients with glomerular disease experience symptoms that impair their physical and mental health while managing their treatments, diet, appointments and monitoring general and specific indicators of health and their illness. We sought to describe the perspectives of patients and their care partners on self-management in glomerular disease. Methods We conducted 16 focus groups involving adult patients with glomerular disease (n = 101) and their care partners (n = 34) in Australia, Hong Kong, the United Kingdom, and United States. Transcripts were analyzed thematically. Results We identified the following 4 themes: empowered in autonomy (gaining confidence through understanding, taking ownership of disease and treatment, learning a positive health approach); overwhelmed by compounding treatment burdens (financially undermined and depleted, demoralized by side effects and harms, frustrated by fragmented and inflexible care, fear of possible drug harms); striving for stability and normalcy (making personal sacrifices, maximizing life participation, attentiveness to bodily signs, avoiding precarious health states, integrating medicines into routines); and necessity of health-sustaining relationships (buoyed by social support, fulfilling meaningful responsibilities, sharing and normalizing experiences, seeking a trusting and respectful alliance). Conclusion Patients with glomerular disease and their care partners value their capacity for autonomy and disease ownership, stability of their health, and relationships that support self-management. Strategies directed at strengthening these factors may increase self-efficacy and improve the care and outcomes for patients with glomerular disease., Graphical abstract

Outcomes of end-to-end nerve repairs are more successful compared with outcomes of repairs bridged by nerve grafts. However, end-to-end repairs are not always possible for large nerve gaps, as excessive tension may cause catastrophic failure. In this study, we built on previous nerve-lengthening studies to test the hypotheses that gradual lengthening of the proximal stump across a large nerve gap enables an end-to-end repair and such a repair results in more favourable regenerative outcomes than autografts, which represent the gold standard in bridging nerve gaps. To test these, we compared structural and functional outcomes in Lewis rats after repair of sciatic nerve gaps using either autografts or a novel compact internal fixator device, which was used to lengthen proximal nerve stumps towards the distal stump over 2 weeks, prior to end-to-end repair. Twelve weeks after the initial injury, outcomes following nerve lengthening/end-to-end repair were either comparable or superior in every measure compared with repair by autografting. The sciatic functional index was not significantly different between groups at 12 weeks. However, we observed a reduced rate of contracture and corresponding significant increase in paw length in the lengthening group. This functional improvement was consistent with structural regeneration; axonal growth distal to the injury was denser and more evenly distributed compared with the autograft group, suggesting substantial regeneration into both tibial and peroneal branches of the sciatic nerve. Our findings show that end-to-end repairs following nerve lengthening are possible for large gaps and that this strategy may be superior to graft-based repairs.