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Cefiderocol is a novel siderophore cephalosporin with potent activity against gram-negative bacteria, including multidrug-resistant strains. This Phase I study was conducted to assess the tolerability of single-ascending doses of cefiderocol (part 1) and the effect of cefiderocol on cardiac repolarization, assessed using the electrocardiographic corrected QT interval (QTcF) and other ECG parameters (part 2), in healthy adult subjects. Part 1 was a randomized, double-blind, placebo-controlled, single-ascending dose study in healthy adult male and female subjects. Part 2 was a 4-period crossover study in which subjects received a single 2-g dose of cefiderocol (therapeutic dose), a single 4-g dose of cefiderocol (supratherapeutic dose), or saline (placebo), each infused over 3 hours, and a single oral 400-mg dose of moxifloxacin. In each treatment period, continuous cardiac monitoring was used to assess the effects of cefiderocol on ECG parameters. The QT interval corrected using the Fridericia formula (QTcF) was the primary ECG parameter; the time-matched placebo- and baseline-adjusted (dd)-QTcF interval was the primary end point. The plasma pharmacokinetic properties of cefiderocol were calculated on the basis of concentration–time profiles in all evaluable subjects. All point estimates for the ddQTcF interval were <5 ms and the upper bound of the 90% CIs were <10 ms at each timepoint after the initiation of the cefiderocol 3-hour infusion. Concentration-effect modeling showed a slightly negative slope and predicted modestly negative values of the ddQTcF interval at the Cmax of cefiderocol. Both doses of cefiderocol were well tolerated. All adverse events were mild in severity, with no deaths or serious adverse events reported. Overall, therapeutic and supratherapeutic doses of cefiderocol had no apparent clinically significant effect on the QTcF.

Introduction To determine the optimal dose of sivopixant, a highly selective P2X3 receptor antagonist, for refractory or unexplained chronic cough (RCC/UCC). Methods In this phase 2b, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial, patients received sivopixant 50, 150, or 300 mg or placebo once daily for 4 weeks. The primary endpoint was a change from baseline in 24-h cough frequency (coughs/h) with sivopixant vs placebo. Results Overall, 390/406 randomized patients completed the study. Placebo-adjusted changes in hourly cough count over 24 h were 13.17% ( P  = 0.3532), − 1.77% ( P  = 0.8935), and − 12.47% ( P  = 0.3241) and in cough severity (visual analog scale) were 1.75 mm ( P  = 0.5854), − 1.21 mm ( P  = 0.7056), and − 6.55 mm ( P  = 0.0433) with sivopixant 50, 150, and 300 mg, respectively. Placebo-adjusted changes from baseline in Leicester Cough Questionnaire total scores were − 0.37 ( P  = 0.4207), − 0.07 ( P  = 0.8806), and 0.69 ( P  = 0.1473) with sivopixant 50, 150, and 300 mg, respectively. Additionally, 61.3%, 78.3%, 86.8%, and 71.4% of patients receiving sivopixant 50, 150, and 300 mg and placebo, respectively, reported any improvements in Patient Global Impression of Change. The incidence of treatment-emergent adverse events (TEAEs) was 25.7%, 32.0%, 49.0%, and 20.6% in sivopixant 50, 150, and 300 mg and placebo groups, respectively; all TEAEs in the sivopixant group were mild-to-moderate. Conclusion Sivopixant did not demonstrate a statistically significant difference vs placebo in change from baseline in 24-h cough frequency. The dose of 300 mg has potential for RCC/UCC, showing the greatest improvements in cough frequency and patient-reported outcomes and dose-related mild to moderate reversible taste disturbance, although further trials are needed. Clinical Trial Registration ClinicalTrials.gov identifier NCT04110054; registered September 26, 2019.

Carbapenem-resistant Gram-negative bacteria represent the highest priority for addressing global antibiotic resistance. Cefiderocol (S-649266), a new siderophore cephalosporin, has broad activity against Enterobacteriaceae and non-fermenting bacteria, such as Pseudomonas aeruginosa and Acinetobacter baumannii, including carbapenem-resistant strains. We assessed the efficacy and safety of cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infection in patients at risk of multidrug-resistant Gram-negative infections. We did a phase 2, multicentre, double-blind, parallel-group non-inferiority trial at 67 hospitals in 15 countries. Adults (≥18 years) admitted to hospital with a clinical diagnosis of complicated urinary tract infection with or without pyelonephritis or those with acute uncomplicated pyelonephritis were randomly assigned (2:1) by an interactive web or voice response system to receive 1 h intravenous infusions of cefiderocol (2 g) or imipenem-cilastatin (1 g each) three times daily, every 8 h for 7–14 days. Patients were excluded if they had a baseline urine culture with more than two uropathogens, a fungal urinary tract infection, or pathogens known to be carbapenem resistant. The primary endpoint was the composite of clinical and microbiological outcomes at test of cure (ie, 7 days after treatment cessation), which was used to establish non-inferiority (15% and 20% margins) of cefiderocol versus imipenem-cilastatin. The primary efficacy analysis was done on a modified intention-to-treat population, which included all randomly assigned individuals who received at least one dose of study drug and had a qualifying Gram-negative uropathogen (≥1 × 105 colony-forming units [CFU]/mL). Safety was assessed in all randomly assigned individuals who received at least one dose of study drug, according to the treatment they received. This study is registered with ClinicalTrials.gov, number NCT02321800. Between Feb 5, 2015, and Aug 16, 2016, 452 patients were randomly assigned to cefiderocol (n=303) or imipenem-cilastatin (n=149), of whom 448 patients (n=300 in the cefiderocol group; n=148 in the imipenem-cilastatin group) received treatment. 371 patients (n=252 patients in the cefiderocol group; n=119 patients in the imipenem-cilastatin group) had qualifying Gram-negative uropathogen (≥1 × 105 CFU/mL) and were included in the primary efficacy analysis. At test of cure, the primary efficacy endpoint was achieved by 183 (73%) of 252 patients in the cefiderocol group and 65 (55%) of 119 patients in the imipenem-cilastatin group, with an adjusted treatment difference of 18·58% (95% CI 8·23–28·92; p=0·0004), establishing the non-inferiority of cefiderocol. Cefiderocol was well tolerated. Adverse events occurred in 122 (41%) of 300 patients in the cefiderocol group and 76 (51%) of 148 patients in the imipenem-cilastatin group, with gastrointestinal disorders (ie, diarrhoea, constipation, nausea, vomiting, and abdominal pain) the most common adverse events for both treatment groups (35 [12%] patients in the cefiderocol group and 27 [18%] patients in the imipenem-cilastatin group). Intravenous infusion of cefiderocol (2 g) three times daily was non-inferior compared with imipenem-cilastatin (1 g each) for the treatment of complicated urinary tract infection in people with multidrug-resistant Gram-negative infections. The results of this study will provide the basis for submission of a New Drug Application to the US Food and Drug Administration. Clinical trials of hospital-acquired pneumonia and carbapenem-resistant infections are ongoing. Shionogi & Co Ltd, Shionogi Inc.

Background Cefiderocol, a novel siderophore cephalosporin with broad activity against Gram-negative bacteria, requires dose adjustment in patients with renal impairment or augmented renal clearance, similarly to other β-lactams. The efficacy and safety of cefiderocol were assessed according to degree of renal impairment as part of a pivotal study vs. imipenem–cilastatin (IPM/CS) in patients with cUTI (NCT02321800). Methods A total of 448 randomized adults with cUTI received cefiderocol (2 g) or IPM/CS (1 g / 1 g), IV, q8h, for 7–14 days (safety population), with 371 patients in the microbiological intent-to-treat (Micro-ITT) population. Dose adjustments were made based on body weight (to enable IPM/CS blinding) and creatinine clearance (CrCL). The composite (clinical and microbiological) outcome at a test of cure (TOC; 7 days after treatment cessation) was analyzed by CrCL subgroup. Adverse events (AEs) according to renal subgroup were monitored throughout the study. Results A treatment difference in the composite outcome at TOC in favor of cefiderocol vs. IPM/CS was observed across renal subgroups (table), with greater differences in moderate and severe groups, consistent with that observed in the overall population (n = 371; 18.0%, 95% confidence interval: 7.5; 28.5). The incidence of AEs in the cefiderocol group was comparable across all renal subgroups. Conversely, AE incidence increased with the degree of impairment in the IPM/CS group (table). Conclusion In contrast to IPM/CS, the efficacy of cefiderocol was maintained across all renal function subgroups with no increase in the rate of AEs. These findings underscore the efficacy and safety of cefiderocol in patients with renal impairment and support the adequacy of the dose adjustment. Disclosures All authors: No reported disclosures.

Abstract Background Cefiderocol (CFDC, S-649266) is a novel siderophore cephalosporin with potent activity against Gram-negative bacteria that is being developed to treat serious MDR Gram-negative infections. Methods APEKS-cUTI was a, multicenter, double-blind, randomized trial in patients with complicated urinary tract infections (cUTI) or acute uncomplicated pyelonephritis (AUP). Patients >18 yrs with a cUTI or AUP and a positive urine culture were randomized 2:1 to intravenous CFDC (2 g) or imipenem/cilastatin (IPM/CS) (1/1 g) over 1 hour, every 8-hours for 7 to 14 days. No oral step down antibiotics were allowed. The primary endpoint was a composite of clinical and microbiological response rate at test of cure (TOC, 7 days following the end of treatment) in the Microbiological Intent to Treat (MITT) population. Clinical response at TOC in the MITT population was included in the key secondary endopoints. Results Of 452 randomized patients, 371 had a baseline GN uropathogen and met the Micro-ITT population definition. The composite of clinical and microbiological response rate and clinical response rates are shown in the table. CFDC was non-inferior (NI margin 15%) to IPM/CS on the primary composite endpoint response. The 95% CI excluded 0 showing superiority of CFDC vs. IPM/CS. CFDC was associated with a numerically lower incidence of AEs compared with IPM/CS. Conclusion CFDC, the first siderophore antibiotic in clinical development, was superior to IPM/CS in pateints with cUTI and AUP caused by Gram-negative bacteria and was generally well tolerated. Disclosures S. Portsmouth, SHIONOGI INC.: Employee, Salary; D. Van Veenhuyzen, Shionogi Inc: Employee, Salary; R. Echols, Shionogi & CO., LTD: Consultant, Consulting fee; M. Machida, Shionogi Co. Ltd.: Employee, Salary; J. C. Arjona Ferreira, SHIONOGI INC.: Employee, Salary; M. Ariyasu, SHIONOGI & CO., LTD.: Employee, Salary; T. D. Nagata, Shionogi: Employee, Salary Table: Clinical Response Rate at TOC (Micro-ITT population) CFDC IPM/CS adjusted difference (95% CI) Composite of clinical and microbiological response rate 72.6% (183/252) 54.6% (65/119) 28.92% (8.23, 28.92) Clinical response rate per patient 89.7 % (226/252) 87.4 % (104/119) 2.39% (-4.66, 9.44) Clinical response rate per uropathogen Monomicrobial Escherichia coli 131/146 (89.7%) 68/77 (88.3%) Klebsiella pneumoniae 41/46 (89.1%) 21/25 (84.0%) Proteus mirabilis 13/13 (100.0 %) 1/1 (100.0%) Pseudomonas aeruginosa 11/15 (73.3 %) 3/4 (75.0 %) Polymicrobial 10/11 (90.9 %) 3/4 (75.0 %)

Guanosine triphosphate cyclohydrolase I (GCH1) mutations are associated with increased risk for dopa-responsive dystonia (DRD) and Parkinson’s disease (PD). Herein, we investigated the frequency of GCH1 mutations and clinical symptoms in patients with clinically diagnosed PD and DRD. We used the Sanger method to screen entire exons in 268 patients with PD and 26 patients with DRD, with the examinations of brain magnetic resonance imaging scans, striatal dopamine transporter scans, and [123I] metaiodobenzylguanidine (MIBG) myocardiac scintigraphy scans. We identified 15 patients with heterozygous GCH1 mutations from seven probands and five sporadic cases. The prevalence of GCH1 mutations in probands was different between PD [1.9% (5/268)] and DRD [26.9% (7/26)] (p value < 0.0001). The onset age tends to be different between PD and DRD patients: 35.4 ± 25.3 and 16.5 ± 13.6, respectively (average ± SD; p = 0.08). Most of the patients were women (14/15). Dystonia was common symptom, and dysautonomia and cognitive decline were uncommon in our PD and DRD. All patients presented mild parkinsonism or dystonia with excellent response to levodopa. Seven of seven DRD and three of five PD presented normal heart-to-mediastinum ratio on MIBG myocardial scintigraphy. Five of six DRD and three of four PD demonstrated normal densities of dopamine transporter. Our findings elucidated the clinical characteristics of PD and DRD patients due to GCH1 mutations. PD patients with GCH1 mutations also had different symptoms from those seen in typical PD. The patients with GCH1 mutations had heterogeneous clinical symptoms.

Background In recent years, there has been considerable research on the use of artificial intelligence to estimate age and disease status from medical images. However, age estimation from chest X-ray (CXR) images has not been well studied and the clinical significance of estimated age has not been fully determined. Methods To address this, we trained a deep neural network (DNN) model using more than 100,000 CXRs to estimate the patients’ age solely from CXRs. We applied our DNN to CXRs of 1562 consecutive hospitalized heart failure patients, and 3586 patients admitted to the intensive care unit with cardiovascular disease. Results The DNN’s estimated age (X-ray age) showed a strong significant correlation with chronological age on the hold-out test data and independent test data. Elevated X-ray age is associated with worse clinical outcomes (heart failure readmission and all-cause death) for heart failure. Additionally, elevated X-ray age was associated with a worse prognosis in 3586 patients admitted to the intensive care unit with cardiovascular disease. Conclusions Our results suggest that X-ray age can serve as a useful indicator of cardiovascular abnormalities, which will help clinicians to predict, prevent and manage cardiovascular diseases. Plain language summary Chest X-ray is one of the most widely used medical imaging tests worldwide to diagnose and manage heart and lung diseases. In this study, we developed a computer-based tool to predict patients’ age from chest X-rays. The tool precisely estimated patients’ age from chest X-rays. Furthermore, in patients with heart failure and those admitted to the intensive care unit for cardiovascular disease, elevated X-ray age estimated by our tool was associated with poor clinical outcomes, including readmission for heart failure or death from any cause. With further testing, our tool may help clinicians to predict outcomes in patients with heart disease based on a simple chest X-ray. Ieki et al. train a deep learning model to estimate patients’ age from chest X-ray images. X-ray age is found to be an indicator of poor prognosis in patients with heart failure and patients admitted to the intensive care unit with cardiovascular disease.

Vasohibin‐2 (VASH2) is a homolog of vasohibin‐1 and exhibits pro‐angiogenic activity. We recently reported that VASH2 is expressed in certain ovarian cancers and promotes tumor growth through angiogenesis. To further demonstrate the effectiveness of molecular targeting of VASH2 for anticancer treatment, we applied in vivo delivery of siRNA targeting VASH2 (siVASH2) using atelocollagen to a xenograft model of ovarian cancer. We inoculated mice s.c. with DISS and SKOV‐3, two representative human ovarian serous adenocarcinoma cell lines. When tumors were measurable, we initiated treatment with control or siVASH2 mixed with atelocollagen, which enveloped the whole tumor. Treatment with siVASH2 significantly inhibited s.c. tumor growth by abrogating tumor angiogenesis. We confirmed that expression of VASH2 mRNA in the tumor was downregulated by siVASH2 treatment. In addition, the siVASH2‐treated tumor contained more blood vessels covered with pericytes, indicating that knockdown of VASH2 contributes to the normalization of tumor blood vessels. Based on these results, VASH2 may be a promising molecular target for ovarian cancer treatment. Administration of siRNA targeting a novel angiogenesis stimulator, vasohibin‐2, with atelocollagen biomaterial retarded ovarian tumor growth through decrease of angiogenesis and acceleration of vascular normalization. These results demonstrated the effectiveness of molecular targeting of vasohibin‐2 in ovarian cancer.

OBJECTIVEEndometrial cancer often coexists with uterine adenomyosis. However, little is known about the clinical characteristics of these cases. Thus, cases of endometrial cancer occurring with and without uterine adenomyosis were compared, and the influences of uterine adenomyosis on the clinical progress of endometrial cancer were examined. MATERIALS AND METHODSOf endometrial cancer patients who underwent hysterectomies in our facility from 2002 to 2011, we included only endometrioid adenocarcinoma patients in our study. The patients were divided into 2 groups, adenomyosis group and nonadenomyosis group, according to the presence/absence of uterine adenomyosis. Patient characteristics, stage, histopathological grade, muscle invasion, recurrence, and mortality were retrospectively compared and examined. RESULTSThere were 362 cases of endometrioid adenocarcinoma of the uterine body, of which 121 (33.4%) and 241 cases (66.6%) were in the adenomyosis and nonadenomyosis group, respectively. There were no significant differences with respect to the disease stages or ratios of the histopathological grade between the 2 groups. In the adenomyosis group/nonadenomyosis group, 5-year progression-free survival for International Federation of Gynecology and Obstetrics (FIGO) stages I and II was 89.9%/93.7% and that for stages III and IV was 70.6%/62.0%; the 5-year overall survival was 100%/95.9% for FIGO stages I and II, and 88.0%/73.5% for stages III and IV. There were no significant between-group differences for either progression-free survival or overall survival. When limiting the results to only FIGO stage I endometrioid adenocarcinoma, despite no grade variance between the 2 groups, a significant difference was observed in the ratios of outer-half muscle invasion between the adenomyosis and nonadenomyosis groups (19.5% [17/87] vs 10.1% [16/158], P < 0.05); however, the prognosis was similar in the 2 groups. CONCLUSIONSUterine adenomyosis is associated with deep myometrial invasion in stage I endometrioid adenocarcinoma; however, it did not affect the recurrence or mortality rates.

The purpose of this study was to examine the effect of various community-based interventions in support of HPV vaccination implemented by cities and towns within Tochigi prefecture, Japan with a view to identifying useful indicators which might guide future interventions to improve HPV vaccination coverage in the prefecture. A postal questionnaire survey of all 27 local governments in Tochigi Prefecture was conducted in December 2010. All 27 responded, and 22 provided the exact numbers of the targeted and vaccinated populations of 13- to 15-year-old girls from April to December 2010. The local governments also answered questions on the type of interventions implemented including public subsidies, school-based programs, direct mail, free tickets and recalls. Local governments that conducted a school-based vaccination program reported 96.8% coverage for the 1(st) dose, 96.2% for the 2(nd) dose, and 91.2% for the 3(rd) dose. Those that provided subsidies without school-based programs reported a wide range of vaccination rates: 45.7%-95.0% for the 1(st) dose, 41.1%-93.7% for the 2(nd) dose and 3.1%-90.1% for the 3(rd) dose. Among this group, the combination of a free ticket, direct mail and recall was most effective, with 95.0% coverage for the 1(st) dose, 93.7% for the 2(nd) dose, and 90.1% for the 3(rd) dose. The governments that did not offer a subsidy had the lowest vaccination coverage, with 0.8%-1.4% for the 1(st) dose, 0.0%-0.8% for the 2(nd) dose, and 0.1%-0.1% for the 3(rd) dose. The results of this survey indicate that school-based vaccinations and public subsidies are the most effective method to improve HPV vaccination coverage; however, the combination of a free ticket, direct mail, and recalls with public subsidies are also important measures in increasing the vaccination rate. These data may afford important indicators for the successful implementation of future HPV vaccination programs.