Safety of Ocrelizumab in Patients With Relapsing and Primary Progressive Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: To report safety of ocrelizumab (OCR) up to 7 years in patients with relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS) enrolled in clinical trials or treated in real-world postmarketing settings. METHODS: Safety analyses are based on integrated clinical and laboratory data for all patients who received OCR in 11 clinical trials, including the controlled treatment and open-label extension (OLE) periods of the phase 2 and 3 trials, plus the phase 3b trials VELOCE, CHORDS, CASTING, OBOE, ENSEMBLE, CONSONANCE, and LIBERTO. For selected adverse events (AEs), additional postmarketing data were used. Incidence rates of serious infections (SIs) and malignancies were contextualized using multiple epidemiologic sources. RESULTS: At data cutoff (January 2020), 5,680 patients with multiple sclerosis (MS) received OCR (18,218 patient-years [PY] of exposure) in clinical trials. Rates per 100 PY (95% confidence interval) of AEs (248; 246-251), serious AEs (7.3; 7.0-7.7), infusion-related reactions (25.9; 25.1-26.6), and infections (76.2; 74.9-77.4) were similar to those within the controlled treatment period of the phase 3 trials. Rates of the most common serious AEs, including SIs (2.01; 1.81-2.23) and malignancies (0.46; 0.37-0.57), were consistent with the ranges reported in epidemiologic data. DISCUSSION: Continuous administration of OCR for up to 7 years in clinical trials, as well as its broader use for more than 3 years in the real-world setting, are associated with a favorable and manageable safety profile, without emerging safety concerns, in a heterogeneous MS population. CLASSIFICATION OF EVIDENCE: This analysis provides Class III evidence that long-term, continuous treatment with OCR has a consistent and favorable safety profile in patients with RMS and PPMS. This study is rated Class III because of the use of OLE data and historical controls.

Omalizumab-associated eosinophilic granulomatosis with polyangiitis: cause or coincidence?

Omalizumab is an anti-IgE monoclonal antibody used in severe allergic asthma. Herein, we describe a case of eosinophilic granulomatosis with polyangiitis, which manifested 3 months after initiation of omalizumab therapy, while maintenance corticosteroid therapy dose was unchanged.

Efficacy and safety of ocrelizumab vs interferon beta-1a in participants of African descent with relapsing multiple sclerosis in the Phase III OPERA I and OPERA II studies.

BACKGROUND: People of African descent with multiple sclerosis (MS) appear to have a more severe disease course and may have an attenuated response to some medications compared with people of European descent. METHODS: This is a post hoc subgroup analysis of participants of African descent with relapsing forms of MS who were enrolled in the Phase III OPERA I or OPERA II clinical trials and treated with ocrelizumab (OCR) 600 mg every 6 months or interferon beta-1a (IFN ß-1a) 44 µg 3 times per week. RESULTS: Among the 1,656 participants enrolled in OPERA I and II, 72 (4.3%) were of African descent (OCR, 40; IFN ß-1a, 32). A trend for reduction in annualized relapse rate (ARR) was observed in participants of African descent, with an ≈50% reduction with OCR vs IFN ß-1a. The relative rate of the mean number of gadolinium-enhancing lesions on magnetic resonance imaging (MRI) was 0.04 (95% CI, 0.01-0.22; p=0.001) in participants of African descent treated with OCR compared with IFN ß-1a. Similarly, the relative rate of the number of new or enlarging T2 lesions on MRI was 0.14 (95% CI, 0.06-0.32; p<0.001). In participants of African descent, those treated with OCR were 2.61 times more likely than those who received IFN ß-1a to be classified as having no evidence of disease activity (95% CI, 1.24-5.49; p=0.003) and 4.17 times more likely to be classified as having no evidence of disease activity or progression (95% CI, 1.27-13.65; p=0.006). African-descent participants tended to have a greater radiographic burden of disease at baseline, develop more brain lesions when treated with IFN ß-1a, and be at greater risk of disability progression than non-African-descent participants. Participants of African descent experienced slightly more adverse events, serious adverse events, and hypersensitivity reactions than non-African-descent participants. CONCLUSION: In this small sample of participants of African descent with relapsing MS from the OPERA studies, OCR demonstrated treatment benefits in clinical, MRI, and composite efficacy outcomes vs IFN ß-1a, consistent with what was observed in the complete OPERA intention-to-treat cohorts.

Risk factors for postoperative voiding dysfunction following surgery for pelvic organ prolapse.

OBJECTIVE: Short-term postoperative voiding dysfunction (POVD) is common in women undergoing surgery for pelvic organ prolapse. It results in increased catheter burden for patients and health services, and catheter-associated urinary tract infections (CAUTIs), thereby escalating the overall cost of treatment. Our aim was to determine the risk factors for voiding dysfunction following surgery for POP in our unit. STUDY DESIGN: A retrospective case-control study conducted in a tertiary center in the U.K. The study cohort included all women who underwent surgery for pelvic organ prolapse between March 2017 and March 2019 and had a failed trial without catheter (TWOC). The control group comprised consecutive women on the surgical database who passed TWOC. Relevant data, including demographic details, past medical history, intraoperative and postoperative factors, were collected. We used the Chi-square test to calculate the statistical significance and multiple logistic regression analysis using SPSS software to identify the risk factors. RESULTS: 286 surgeries were performed. After exclusion, 43 patients were included in each group. Baseline demographics were similar in both groups. The incidence of POVD was 15%, and none of our patients had long-term voiding problems. Logistic regression analysis identified five risk factors - advanced pelvic organ prolapse (OR = 2.654, p = 0.029), comorbidities (OR = 4.583, p = 0.019), preoperative anticholinergics and/or antidepressants (OR = 4.440, p = 0.004), sacrospinous hysteropexy/colpopexy (OR = 2.613, p = 0.041) and postoperative opioid use (OR = 3.529, p = 0.004). CONCLUSION: We identified five risk factors to recognize the women who would benefit from advanced counseling and management plan following surgery for pelvic organ prolapse.

Safety evaluation of shorter infusion for ocrelizumab in a substudy of the Phase IIIb CHORDS trial.

The CHORDS trial evaluated ocrelizumab (OCR) in patients with relapsing-remitting multiple sclerosis who had a suboptimal response to previous disease-modifying treatment. The objective of the present study was to assess the safety of shorter OCR infusions in a substudy of CHORDS. After completing four doses of OCR per initial US prescribing recommendations in the main study, participants in the substudy (N = 129) received a fifth dose over a 2-h duration (vs. 3.5 h). Infusion-related reactions occurred in 12.4% of patients. None were severe, life-threatening or led to treatment discontinuation. Shorter infusion time did not change the safety profile of OCR. Clinicaltrials.gov (NCT0237856).

Preclinical Evaluation of the Versius Surgical System, a New Robot-assisted Surgical Device for Use in Minimal Access Renal and Prostate Surgery.

BACKGROUND: Minimal access surgery (MAS) is well-established in urological surgery. However, MAS is technically demanding and associated with a prolonged learning curve. Robot-assisted laparoscopy has made progress in overcoming these challenges. OBJECTIVE: The aim of this study was to evaluate the feasibility of a new robot-assisted surgical system (the Versius Surgical System; CMR Surgical, Cambridge, UK) for renal and prostate procedures in a preclinical setting, at the IDEAL-D phase 0. DESIGN, SETTING, AND PARTICIPANTS: Cadaveric sessions were conducted to evaluate the ability of the system to complete all surgical steps required for a radical nephrectomy, prostatectomy, and pelvic lymph node dissection. A live animal (porcine) model was also used to assess the surgical device in performing radical nephrectomy safely and effectively. Procedures were performed by experienced renal and prostate surgeons, supported by a full operating room team. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Surgical access and reach were evaluated by the lead surgeon using a visual analogue scale. The precise surgical steps conducted to make the assessment that the procedures could be completed fully were recorded, as well as instruments used (including manual laparoscopic instruments) and endoscope angle. RESULTS AND LIMITATIONS: In total, all 24 procedures were completed successfully in cadavers by eight different lead surgeons. Positioning of the ports and bedside units reflected the lead surgeon's preferred laparoscopic set-up and enabled good surgical access and reach, as quantified by a median visual analogue score of ≥6.5. Radical nephrectomies performed in pigs were all completed successfully, with no device- or non-device-related intraoperative complications recorded. Testing in human cadavers and pig models balances the bias introduced by each model; however, it is impossible to completely replicate the experience and performance of the robot for surgery in live humans. CONCLUSIONS: This is the first preclinical assessment of the Versius Surgical System for renal and prostate procedures. The safety and effectiveness of the system have been demonstrated and warrant progressive assessment in a clinical setting utilising the IDEAL-D framework. PATIENT SUMMARY: In this report, we looked at the usability of a new robot-assisted surgical device for renal and prostate surgery by testing the system in cadavers and pigs. We found that a number of different surgeons and operating team personnel were able to use the system to successfully complete the procedures under evaluation. We conclude that the system is ready to be tested in live human studies.

Current trends in pessary management of vaginal prolapse: a multidisciplinary survey of UK practice.

INTRODUCTION AND HYPOTHESIS: Symptomatic vaginal prolapse affects 6-28% of women and significantly impacts their quality of life. Pessaries for prolapse are used by three-quarters of clinicians as a first-line treatment; however, current clinical use in the UK is unknown and there is a lack of clinical guidance or training. This study is aimed at informing the upcoming UK Clinical Guidance on best practice for the use of pessaries document. METHODS: A 19-question, anonymised, electronic survey was sent to members of the nine professional bodies delivering pessary care in the UK. RESULTS: Of 917 respondents, 403 (246 nurses, 134 doctors, 22 physiotherapists and 1 other profession) currently deliver pessary care. PVC/vinyl ring, silicone ring, Gellhorn and shelf pessaries are most popular, and are used frequently by 93% of respondents. Further pessary training was deemed necessary by 62% of those currently providing pessary care, and 70% of those who do not. The most highly rated method for previous and future training is shadowing another clinician. One in three respondents receive no ancillary support and nearly 1 in 7 (predominantly nurses) report the absence of cross-cover arrangements, leaving a gap in care provision. CONCLUSIONS: Service provision, support and pessary training in the UK vary greatly. This calls for the standardisation of care, training and development of a national guideline. We present a clear rationale and need for a UK guideline on pessary management of vaginal prolapse and a standardised pessary training model for multi-professional use.

Safety results of administering ocrelizumab per a shorter infusion protocol in patients with primary progressive and relapsing multiple sclerosis.

BACKGROUND: Ocrelizumab is an approved MS treatment administered as two 300-mg intravenous infusions 2 weeks apart (Dose 1), each lasting approximately 2.5 hours, followed by single 600-mg infusions every 6 months lasting approximately 3.5 hours. Our objective was to evaluate shorter-duration ocrelizumab infusions in the Phase IIIb open-label SaROD study (NCT03606460). METHODS: Eligible patients received ocrelizumab 600-mg Dose 2 or 3 infused over approximately 2 hours (Cohort 1) or ocrelizumab 300-mg Dose 1, Infusion 2 over approximately 1.5 hours (Cohort 2). The primary endpoint was the number and proportion of patients experiencing Grade 3-4 infusion-related reactions (IRRs) in Cohort 1. Secondary endpoints included Grade 1-4 IRRs in both cohorts and Grade 3-4 IRRs in Cohort 2. RESULTS: Mean infusion times decreased by approximately 1.09 and 0.79 hours in Cohorts 1 and 2, respectively, compared with US prescribing information. IRRs, reported by 36% of 141 patients, were mild-to-moderate, with no observed Grade 3-4 IRRs. No IRR-related discontinuations occurred. No serious AEs, deaths, or new safety signals were observed. CONCLUSION: The IRR rate with ocrelizumab shorter-duration infusions was similar to that observed in the pivotal Phase III trials. Ocrelizumab can be infused over a shorter time without sacrificing patient safety.

Management of urethral caruncle - A systematic review of the current literature.

Urethral caruncle is a benign fleshy outgrowth at the urethral meatus that occurs mainly at posterior lip of urethra and is most commonly seen in postmenopausal women. They are typically asymptomatic and are mostly reported as incidental findings during pelvic examination. When symptomatic, they commonly present with bleeding, haematuria, pain, dysuria or a lump. Despite being a recognised condition in medicine for more than two centuries, urethral caruncle is still a very poorly understood condition and the current literature is largely deficient to guide the general practitioners and gynaecologists in the appropriate management of the condition. The aim of the paper is to systematically review the current literature on the management options available for urethral caruncle and highlight the need for high quality research to develop better management strategies for this condition. We searched the following electronic databases from 1946 until January 2019: MEDLINE, EMBASE, COCHRANE and WEB OF SCIENCE. The search identified a total of 41 articles on the treatment of the condition in pre- and postmenopausal women, out of which only eight studies were relevant for our review. Most of these studies were retrospective case series or small cohort studies, mainly on the surgical treatment of the lesion. We found no systematic studies in the current literature on the conservative management of urethral caruncles. The most common method of surgical treatment encountered in these studies was simple excision. In conclusion, the current literature is largely deficient to guide us in the appropriate management of this common condition and there is need for more robust studies to develop evidence based management of this distressing condition that can guide the general practitioners and gynaecologists.

An exploratory analysis of the efficacy of ocrelizumab in patients with multiple sclerosis with increased disability.

BACKGROUND: Ocrelizumab, an anti-CD20 humanized monoclonal antibody, reduced disease progression in pivotal trials of patients with relapsing (OPERA I, OPERA II) and primary progressive (ORATORIO) multiple sclerosis (MS). These effects may be particularly important among patients with increased disability. OBJECTIVE: In this post hoc exploratory analysis, we evaluated the efficacy of ocrelizumab on disability progression among a subgroup of patients with MS who had increased baseline disability levels (Expanded Disability Status Scale scores ≥4.0) in the pivotal trials. METHODS: During the double-blind period, patients received ocrelizumab 600 mg intravenously every 24 weeks for 96 weeks in the OPERA trials (versus interferon ß-1a 44 µg subcutaneously three times per week) and for 120 weeks in ORATORIO (versus placebo). Kaplan-Meier and Cox survival analyses were used to assess disability outcome measures. RESULTS: Baseline demographic, disease, and treatment characteristics were generally comparable across treatment groups in patients with increased disability from the OPERA and ORATORIO trials. Ocrelizumab treatment numerically, and in some instances significantly, reduced confirmed disability progression versus the comparator in these patients. CONCLUSIONS: In patients with increased baseline disability, ocrelizumab reduced the risk of confirmed disability progression versus interferon ß-1a in patients with relapsing-onset MS and versus placebo in patients with progression-onset MS.

Impact of the EPISCISSORS-60 mediolateral episiotomy scissors on obstetric anal sphincter injuries: a 2-year data review in the United Kingdom.

INTRODUCTION AND HYPOTHESIS: This time-series analysis was carried out to determine if the use of the EPISCISSORS-60®, episiotomy scissors specifically designed to achieve a cutting angle of 60°, would continue to sustain obstetric anal sphincter injuries (OASIS) reductions at our hospital 2 years after its introduction. METHODS: We compared data from 2,342 women delivered in 2014 (prior to the introduction of EPISCISSORS-60®) with that of 4,498 women delivered from 2016 to 2017 (after the introduction of EPISCISSORS-60®). RESULTS: There was a reduction of OASIS in all nulliparous vaginal deliveries (NVD; 7.2% vs 5.1% p = 0.05), and a 50% reduction of OASIS (7.5% vs 3.7%) in operative vaginal deliveries (OVD) (p = 0.02). There was a statistically significant association between episiotomies performed with EPISCISSORS-60® and a reduction in OASIS (SVD: 6.9% vs 1.5% p = 0.006; OVD:28.6% vs 2.6% p < 0.0001). Additionally, there was an increase in the use of episiotomies in all nulliparous vaginal deliveries (29% vs 33.7%; p = 0.01). We also found a 78% reduction of OASIS with episiotomies compared with no episiotomies in the 2016-2017 group (6.9% vs 1.5% p = 0.006). CONCLUSIONS: Our results suggest that there might have been a sustained reduction in OASIS rates associated with using EPISCISSORS-60®.

The impact of pelvic floor multidisciplinary team on patient management: the experience of a tertiary unit.

PURPOSE: Pelvic floor dysfunction is a common and heterogenous condition with numerous clinical manifestations, making the optimal management challenging. The traditional single-specialty approach may fail to address its complex nature. Currently, there are no published data on the impact of joint pelvic floor multidisciplinary team (MDT) meetings on patient management. PATIENTS AND METHODS: This study represents a retrospective analysis of prospectively collected data on female patients discussed at a joint pelvic floor MDT over a 12-month period in a tertiary referral center. RESULTS: One hundred fifty-two cases were included with a median age of 55 years (range 18-83) and a BMI of 32 kg/m2 (range 17-58). Lower urinary tract dysfunction was the predominant symptom in 75% (114/152). The pelvic organ prolapse symptom of a vaginal bulge was present in 11% (17/152). All cases of vaginal prolapse were accompanied by either urinary incontinence, 59% (10/17), or obstructive defecation, 41% (7/17). Fecal incontinence was recorded in 10% (15/152). Mesh-related complications were reported in 3% (4/152). The MDT recommended a change in the initial management plan in 20% (31/152) of cases, of whom 80% (25/31) were patients with complex urinary incontinence. The MDT agreed a change in the primary care team in 16% (25/152) of cases. CONCLUSION: There is an increasing regulatory requirement for patients with pelvic floor dysfunction to be discussed in an MDT setting. Findings demonstrate that joint pelvic floor MDT meetings are feasible and contribute to a change in the management of complex patients.

Responsibility toward affordable healthcare: disposable versus reusable methods for pelvic floor repair.

BACKGROUND: The adverse publicity surrounding the use of mesh for correction of pelvic organ prolapse has driven a renewed interest in native tissue repair. Established techniques used reusable instruments, while recent innovations have generally involved disposable equipment. Here, we compare outcomes between the two techniques used for sacrospinous ligament fixation for the correction of apical prolapse: Miya Hook (reusable) and Capio® (single-use) suturing devices. METHODS: A prospective cohort study of women undergoing vaginal sacrospinous colpopexy or hysteropexy was undertaken. The patients were assessed preoperatively and 1 year post-operatively. The primary outcomes were improvement in vaginal scores and patient-reported absence of a vaginal bulge. Secondary outcomes included impact on sexual function, quality of life, perioperative complications and apical recurrence. The cost of instruments, operative times and length of stay were analyzed. RESULTS: In total, 133 women with advanced prolapse in the apical compartment underwent colpopexy or hysteropexy (63 using the reusable Miya Hook and 40 with the disposable Capio device). Mean follow-up was 16.9 months (SD 7.8) and 14 months (SD 3.1), respectively. There were no significant differences in baseline characteristics or preoperative Pelvic Organ Prolapse Quantification staging between the two cohorts. Significant improvements in vaginal scores, sexual function and quality of life (International Consultation on Incontinence Questionnaire - Vaginal Symptoms) were observed in both groups postoperatively (P<0.01). Both groups had low apical recurrence in the medium term (<3%). There were no significant differences in operative times or length of stay. The use of disposable equipment was associated with higher cost. CONCLUSION: Sacrospinous fixation using either the Miya Hook or the Capio device is equally effective for the management of apical prolapse. In the absence of clinical benefit, the choice of instrument should reflect the cost in a financially constrained health-sector environment.

Predicting Autism Spectrum Disorder Using Domain-Adaptive Cross-Site Evaluation.

The advances in neuroimaging methods reveal that resting-state functional fMRI (rs-fMRI) connectivity measures can be potential diagnostic biomarkers for autism spectrum disorder (ASD). Recent data sharing projects help us replicating the robustness of these biomarkers in different acquisition conditions or preprocessing steps across larger numbers of individuals or sites. It is necessary to validate the previous results by using data from multiple sites by diminishing the site variations. We investigated partial least square regression (PLS), a domain adaptive method to adjust the effects of multicenter acquisition. A sparse Multivariate Pattern Analysis (MVVPA) framework in a leave one site out cross validation (LOSOCV) setting has been proposed to discriminate ASD from healthy controls using data from six sites in the Autism Brain Imaging Data Exchange (ABIDE). Classification features were obtained using 42 bilateral Brodmann areas without presupposing any prior hypothesis. Our results showed that using PLS, SVM showed poorer accuracies with highest accuracy achieved (62%) than without PLS but not significantly. The regions occurred in two or more informative connections are Dorsolateral Prefrontal Cortex, Somatosensory Association Cortex, Primary Auditory Cortex, Inferior Temporal Gyrus and Temporopolar area. These interrupted regions are involved in executive function, speech, visual perception, sense and language which are associated with ASD. Our findings may support early clinical diagnosis or risk determination by identifying neurobiological markers to distinguish between ASD and healthy controls.

Microbial Diversity of Genital Ulcers of HSV-2 Seropositive Women.

We measured the microbial community structure of genital ulcers in women. Swabs from clinically detected ulcers were tested for HSV-2 and Treponema pallidum by polymerase chain reaction (PCR). HSV-2 and T. pallidum were detected by serum antibody testing. Microbial community structure was characterized by high-throughput 16 s rRNA gene amplicon sequencing. Multiple group testing and Elastic net and Lasso regressions identified taxa associated with differences in factors of interest. Among 49 ulcer specimens from 49 HSV-2 seropositive women, by PCR HSV-2 was recovered from 28 (57%) specimens and T. pallidum from none; one woman showed serologic evidence of syphilis. Overall, 63% of women were HIV-positive and 49% had an uncircumcised male sex partner. By both multiple group testing and regression, Porphyromonas (FDR p-value = 0.02), Prevotella (FDR p-value = 0.03), Anaerococcus (FDR p-value = 0.07), and Dialister (FDR p-value = 0.09) were detected at higher relative abundance in HSV-2 PCR-positive than negative ulcers. The presence of HSV-2 in a lesion was associated with presumed bacterial agents of Bacterial vaginosis. Differences in bacterial communities may contribute to HSV-2 ulcer pathogenesis, severity, or prolonged healing. If these results are confirmed, future studies may consider the influence of BV treatment on women's GUD and HSV-2 incidence and recurrence.

Comparative study of episiotomy angles achieved by cutting with straight Mayo scissors and the EPISCISSORS-60 in a birth simulation model.

INTRODUCTION AND HYPOTHESIS: We compared the clinician's ability to cut episiotomies at the recommended 60° angle with traditional straight Mayo scissors compared with patented fixed-angle episiotomy scissors EPISCISSORS-60® in a simulated setting using mounted incision pads. The hypothesis was that fixed-angle episiotomies would achieve a more accurate cutting angle of 60°. METHODS: Angles were cut on episiotomy incision pads in a mounted birth model simulating crowning: 110 midwives and doctors cut an 60° episiotomy with Mayo scissors and then EPISCISSORS-60. Angles were measured with protractors. Average angles were calculated and the one-tailed paired t test was used to compare groups. RESULTS: Mean angle was 45° with Mayo scissors [SD = 9, 95% confidence interval (CI) = 43.3-46.7, interquartile range (IQR) 38-50] and 60° with the EPISCISSORS-60 (SD = 3, 95% CI = 59.3-60.7, IQR = 58-60). Two-thirds of cuts with Mayo scissors were below 50°. CONCLUSIONS: In a simulated setting the majority of operators are unable to cut an episiotomy at the recommended 60° angle with Mayo scissors. The EPISCISSORS-60 cut an episiotomy a statistically significant 15° wider than regular Mayo scissors and achieved the recommended 60° in the vast majority of cases. If these findings translate into real life situations, then cutting episiotomies at 60° is expected to make a valuable contribution in reducing third- and fourth-degree tears in both spontaneous and operative vaginal deliveries. Variability in mediolateral episiotomies should be reduced by use of fixed-angle scissors or through validated health professional training programmes to improve visual accuracy.

Meta-Analysis of the Prognostic Impact of Anemia in Patients Undergoing Percutaneous Coronary Intervention.

Anemia is common in patients undergoing percutaneous coronary intervention (PCI), and current guidelines fail to offer recommendations for its management. This review aims to examine the relation between baseline anemia and mortality, major adverse cardiovascular events (MACE), and major bleeding in patients undergoing PCI. We searched MEDLINE and EMBASE for studies that evaluated mortality and adverse outcomes in anemic and nonanemic patients who underwent PCI. Data were collected on study design, participant characteristics, definition of anemia, follow-up, and adverse outcomes. Random effects meta-analysis of risk ratios was performed using inverse variance method. A total of 44 studies were included in the review with 230,795 participants. The prevalence of baseline anemia was 26,514 of 170,914 (16%). There was an elevated risk of mortality and MACE with anemia compared with no anemia-pooled risk ratio (RR) 2.39 (2.02 to 2.83), p <0.001 and RR 1.51 (1.34 to 1.71), p <0.001, respectively. The risk of myocardial infarction and bleeding with anemia compared with no anemia was elevated, pooled RR 1.33 (1.07 to 1.65), p = 0.01 and RR 1.97 (1.03 to 3.77), p <0.001, respectively. The risk of mortality per unit incremental decrease in hemoglobin (g/dl) was RR 1.19 (1.09 to 1.30), p <0.001 and the risk of mortality, MACE, and reinfarction per 1 unit incremental decrease in hematocrit (%) was RR 1.07 (1.05 to 1.10), p = 0.04, RR 1.09 (1.08 to 1.10) and RR 1.06 (1.03 to 1.10), respectively. The prevalence of anemia in contemporary cohorts of patients undergoing PCI is significant and is associated with significant increases in postprocedural mortality, MACE, reinfarction, and bleeding. The optimal strategy for the management of anemia in such patients remains uncertain.

A novel ciprofloxacin-resistant subclade of H58 Salmonella Typhi is associated with fluoroquinolone treatment failure.

The interplay between bacterial antimicrobial susceptibility, phylogenetics and patient outcome is poorly understood. During a typhoid clinical treatment trial in Nepal, we observed several treatment failures and isolated highly fluoroquinolone-resistant Salmonella Typhi (S. Typhi). Seventy-eight S. Typhi isolates were genome sequenced and clinical observations, treatment failures and fever clearance times (FCTs) were stratified by lineage. Most fluoroquinolone-resistant S. Typhi belonged to a specific H58 subclade. Treatment failure with S. Typhi-H58 was significantly less frequent with ceftriaxone (3/31; 9.7%) than gatifloxacin (15/34; 44.1%)(Hazard Ratio 0.19, p=0.002). Further, for gatifloxacin-treated patients, those infected with fluoroquinolone-resistant organisms had significantly higher median FCTs (8.2 days) than those infected with susceptible (2.96) or intermediately resistant organisms (4.01)(pS. Typhi clade internationally, but there are no data regarding disease outcome with this organism. We report an emergent new subclade of S. Typhi-H58 that is associated with fluoroquinolone treatment failure.