Early Clearance Research Articles

Early posttherapy clearance of human papillomavirus and treatment response in cervical carcinoma.

Among patients with cervical cancer, little is known about the significance of persistent human papillomavirus (HPV) expression after chemoradiation (CRT). This study evaluated associations between early posttreatment HPV clearance and patient outcomes with an added focus on the value of posttherapy positron emission tomography (PET) imaging. Included patients underwent pretreatment testing indicating a high-risk HPV infection and posttreatment testing with a messenger RNA (mRNA)-based genital swab after CRT. Posttherapy responses were stratified on the basis of HPV mRNA detection into an early clearance (EC) group (no mRNA) and a persistent expression (PE) group (detectable mRNA) on the basis of an evaluation at a median of 6weeks after therapy. The Kaplan-Meier method was used to compare outcomes, and multivariable analysis was used to identify predictors of outcomes. Seventy-two of the 97 eligible patients (74.2%) had EC. The mean follow-up time was 25months (range, 4-56months), and 2-year pelvic control (76.9% vs 50.2%; P=.01) and overall survival (OS; 80.9% vs 52.2%; P<.01) were superior among EC patients. In the multivariable analysis, EC predicted for improved survival (hazard ratio [HR] for mortality, 0.46; 95% confidence interval [CI], 0.21-0.96; P=.047), as did a complete response (CR) on posttherapy PET (HR for less than a CR on PET, 6.17; 95% CI, 2.58-14.72; P<.01). In a subset analysis of patients with a posttherapy PET CR, HPV clearance retained prognostic significance (2-year OS, 95.6% with EC vs 66.7% with PE; P=.04), whereas PE patients without a PET CR had the worst survival (35.9%; P<.01 for trend). Early posttherapy clearance of HPV is associated with improved survival in cervical cancer. Evaluating HPV expression at this 6-week time point provides prognostic information beyond posttherapy PET imaging and may aid in risk stratification and decisions for treatment escalation.

Impact of Age of Patient and Experience of Surgeon on the Outcome after Kasai Portoenterostomy: Can We Delay the Surgery?

Age of patient and experience of biliary atresia (BA) center are well-known factors associated with early jaundice clearance (EJC) after Kasai portoenterostomy (KPE) in infants with BA. This study focused on the impact of age and surgeon factor on the short-term outcome after KPE within a single center. Fifty-four consecutive infants (18 boys and 36 girls) who underwent KPE from January 2010 to January 2020 were reviewed. KPE was performed in the earliest available operative session once the initial work-up was completed. In group A (n = 41), KPE was performed by surgeon A. In group B (n = 13), KPE was performed by specialists under the supervision of surgeon B (who is the mentor of surgeon A) when surgeon A was not available for operation. The demographics of patients, the EJC (total bilirubin <20 μmol/L within 6 months of KPE), and 2-year native liver survival (NLS) between the two groups were studied. The median age at operation was 52 days (range 26-135 days). The overall EJC rate and 2-year NLS were 85.2 and 89.4%, respectively. Group A (p = 0.015) and male gender (p = 0.029) were statistically associated with EJC but not the age at operation (p = 0.101). Group A was also statistically associated with superior 2-year NLS (p = 0.047). Balancing between the impact of age at operation and the experience of surgeon on the outcome after KPE, our result suggested that KPE may be deferred until a more experienced surgeon to operate.

Deletion of the lon gene augments expression of Salmonella Pathogenicity Island (SPI)-1 and metal ion uptake genes leading to the accumulation of bactericidal hydroxyl radicals and host pro-inflammatory cytokine-mediated rapid intracellular clearance

ABSTRACT In the present study, we characterized the involvement of Lon protease in bacterial virulence and intracellular survival in Salmonella under abiotic stress conditions resembling the conditions of a natural infection. Wild type (JOL401) and the lon mutant (JOL909) Salmonella Typhimurium were exposed to low temperature, pH, osmotic, and oxidative stress conditions and changes in gene expression profiles related to virulence and metal ion uptake were investigated. Expression of candidate genes invF and hilC of Salmonella Pathogenicity Island (SPI)-1 and sifA and sseJ of SPI-2 revealed that Lon protease controls SPI-1 genes and not SPI-2 genes under all stress conditions tested. The lon mutant exhibited increased accumulation of hydroxyl (OH·) ions that lead to cell damage due to oxidative stress. This oxidative damage can also be linked to an unregulated influx of iron due to the upregulation of ion channel genes such as fepA in the lon mutant. The deletion of lon from the Salmonella genome causes oxidative damage and increased expression of virulence genes. It also prompts the secretion of host pro-inflammatory cytokines leading to early clearance of the bacteria from host cells. We conclude that poor bacterial recovery from mice infected with the lon mutant is a result of disrupted bacterial intracellular equilibrium and rapid activation of cytokine expression leading to bacterial lysis.

Longitudinal Pharmacokinetic-Pharmacodynamic Biomarkers Correlate With Treatment Outcome in Drug-Sensitive Pulmonary Tuberculosis: A Population Pharmacokinetic-Pharmacodynamic Analysis.

BackgroundThis study aims to explore relationships between baseline demographic covariates, plasma antibiotic exposure, sputum bacillary load, and clinical outcome data to help improve future tuberculosis (TB) treatment response predictions.MethodsData were available from a longitudinal cohort study in Malawian drug-sensitive TB patients on standard therapy, including steady-state plasma antibiotic exposure (154 patients), sputum bacillary load (102 patients), final outcome (95 patients), and clinical details. Population pharmacokinetic and pharmacokinetic-pharmacodynamic models were developed in the software package NONMEM. Outcome data were analyzed using univariate logistic regression and Cox proportional hazard models in R, a free software for statistical computing.ResultsHigher isoniazid exposure correlated with increased bacillary killing in sputum (P < .01). Bacillary killing in sputum remained fast, with later progression to biphasic decline, in patients with higher rifampicin area under the curve (AUC)0-24 (P < .01). Serial sputum colony counting negativity at month 2 (P < .05), isoniazid CMAX (P < .05), isoniazid CMAX/minimum inhibitory concentration ([MIC] P < .01), and isoniazid AUC0-24/MIC (P < .01) correlated with treatment success but not with remaining free of TB. Slower bacillary killing (P < .05) and earlier progression to biphasic bacillary decline (P < .01) both correlate with treatment failure. Posttreatment recurrence only correlated with slower bacillary killing (P < .05).ConclusionsPatterns of early bacillary clearance matter. Static measurements such as month 2 sputum conversion and pharmacokinetic parameters such as CMAX/MIC and AUC0-24/MIC were predictive of treatment failure, but modeling of quantitative longitudinal data was required to assess the risk of recurrence. Pooled individual patient data analyses from larger datasets are needed to confirm these findings.

Insights into the Role of Innate Immunity in Cervicovaginal Papillomavirus Infection from Studies Using Gene-Deficient Mice.

We demonstrate that female C57BL/6J mice are susceptible to a transient lower genital tract infection with MmuPV1 mouse papillomavirus and display focal histopathological abnormalities resembling those of human papillomavirus (HPV) infection. We took advantage of strains of genetically deficient mice to study in vivo the role of innate immune signaling in the control of papillomavirus. At 4 months, we sacrificed MmuPV1-infected mice and measured viral 757/3139 spliced transcripts by TaqMan reverse transcription-PCR (RT-PCR), localization of infection by RNAscope in situ hybridization, and histopathological abnormities by hematoxylin and eosin (H&E) staining. Among mice deficient in receptors for pathogen-associated molecular patterns, MyD88-/- and STING-/- mice had 1,350 and 80 copies of spliced transcripts/μg RNA, respectively, while no viral expression was detected in MAVS-/- and Ripk2-/- mice. Mice deficient in an adaptor molecule, STAT1-/-, for interferon signaling had 46,000 copies/μg RNA. Among mice with targeted deficiencies in the inflammatory response, interleukin-1 receptor knockout (IL-1R-/-) and caspase-1-/- mice had 350 and 30 copies/μg RNA, respectively. Among mice deficient in chemokine receptors, CCR6-/- mice had 120 copies/μg RNA, while CXCR2-/- and CXCR3-/- mice were negative. RNAscope confirmed focal infection in MyD88-/-, STAT1-/-, and CCR6-/- mice but was negative for other gene-deficient mice. Histological abnormalities were seen only in the latter mice. Our findings and the literature support a working model of innate immunity to papillomaviruses involving the activation of a MyD88-dependent pathway and IL-1 receptor signaling, control of viral replication by interferon-stimulated genes, and clearance of virus-transformed dysplastic cells by the action of the CCR6/CCL20 axis.IMPORTANCE Papillomaviruses infect stratified squamous epithelia, and the viral life cycle is linked to epithelial differentiation. Additionally, changes occur in viral and host gene expression, and immune cells are activated to modulate the infectious process. In vitro studies with keratinocytes cannot fully model the complex viral and host responses and do not reflect the contribution of local and migrating immune cells. We show that female C57BL/6J mice are susceptible to a transient papillomavirus cervicovaginal infection, and mice deficient in select genes involved in innate immune responses are susceptible to persistent infection with variable manifestations of histopathological abnormalities. The results of our studies support a working model of innate immunity to papillomaviruses, and the model provides a framework for more in-depth studies. A better understanding of mechanisms of early viral clearance and the development of approaches to induce clearance will be important for cancer prevention and the treatment of HPV-related diseases.

Monitoring early clearance of circulating tumor DNA as an effective tool to predict clinical benefits of immune checkpoint inhibitors in lung cancer patients: The preliminary results from clinical trial NCT04203095.

e15056 Background: Immuno-checkpoint inhibitors (ICI)is the stand-of-care of lung cancer treatment nowadays. But it’s still challenging to find an effective biomarker to predict clinical benefits from ICIs. Early data suggested that monitoring early clearance of circulating tumor DNA (ctDNA) as a tool to predict clinical benefits. Here we started a clinical trial (NCT04203095) to further validate it. Methods: 19 advanced non-small cell lung cancer patients who were planned to be treated with ICIs with or without chemotherapy were recruited consecutively since April 2019 ( NCT04203095 ). Clinical response was evaluated by RECIST 1.1 assessments at 12 weeks of treatments and afterward during 3-month interval visiting in the first year. Fresh plasma samples were collected -1 (before),+3 weeks and +12 weeks after the first dose. Plasma cell-free DNA(cfDNA) was send to low-coverage whole genome sequencing, followed by chromosomal instability (CIN) analyses by a customized workflow (UCAD). CIN scores were calculated by summarizing the copy number variations genome wide. Results: Early clearance of ctDNA was defined as Pearson correlations co-efficiency of copy number variations of cf DNA was below 0.65 between the baseline and 3 weeks after ICIs were administered. These 19 patients included 11 squamous cell carcinoma (SCC) and 8 adenocarcinomas. 8 of 11 respoonding patients showed early clearance of ctDNA, and 7 of 8 patients with SD or PD didn’t obtain early clearance of ctDNA. Meanwhile, clinical stage, histology, treatments (PD1 single or PD1+chemo combinations), sequence of treatment (first line, second line or multiple lines) did not predict clinical response, and baseline CIN score was not significantly correlated with clinical responses. In summary, only ctDNA early clearance was statistically significantly associated with clinical response (P = 0.020). Conclusions: Early clearance of plasma circulating tumor DNA at 3 weeks after treatments might be used a predictive biomarker of immune-checkpoint inhibition response. Clinical trial information: NCT04203095 .

Dual Role of Toll-Like Receptor 7 in the Pathogenesis of Rabies Virus in a Mouse Model.

Rabies, caused by rabies virus (RABV), is a fatal encephalitis in humans and other mammals, which continues to present a public health threat in most parts of the world. Our previous study demonstrated that Toll-like receptor 7 (TLR7) is essential in the induction of anti-RABV antibodies via the facilitation of germinal center formation. In the present study, we investigated the role of TLR7 in the pathogenicity of RABV in a mouse model. Using isolated plasmacytoid dendritic cells (pDCs), we demonstrated that TLR7 is an innate recognition receptor for RABV. When RABV invaded from the periphery, TLR7 detected viral single-stranded RNA and triggered immune responses that limited the virus's entry into the central nervous system (CNS). When RABV had invaded the CNS, its detection by TLR7 led to the production of cytokines and chemokines and an increase the permeability of the blood-brain barrier. Consequently, peripheral immune cells, including pDCs, macrophages, neutrophils, and B cells infiltrated the CNS. While this immune response, triggered by TLR7, helped to clear viruses, it also increased neuroinflammation and caused immunopathology in the mouse brain. Our results demonstrate that TLR7 is an innate recognition receptor for RABV, which restricts RABV invasion into the CNS in the early stage of viral infection but also contributes to immunopathology by inducing neuroinflammation.IMPORTANCE Developing targeted treatment for RABV requires understanding the innate immune response to the virus because early virus clearance is essential for preventing the fatality when the infection has progressed to the CNS. Previous studies have revealed that TLR7 is involved in the immune response to RABV. Here, we establish that TLR7 recognizes RABV and facilitates the production of some interferon-stimulated genes. We also demonstrated that when RABV invades into the CNS, TLR7 enhances the production of inflammatory cytokines which contribute to immunopathology in the mouse brain. Taken together, our findings suggest that treatments for RABV must consider the balance between the beneficial and harmful effects of TLR7-triggered immune responses.

Factors Associated With Prolonged Viral RNA Shedding in Patients with Coronavirus Disease 2019 (COVID-19).

BackgroundAn outbreak of coronavirus disease 2019 (COVID-19) is becoming a public health emergency. Data are limited on the duration and host factors related to viral shedding.MethodsIn this retrospective study, risk factors associated with severe acute respiratory coronavirus 2 (SARS-CoV-2) RNA shedding were evaluated in a cohort of 113 symptomatic patients from two hospitals outside Wuhan.ResultsThe median duration of SARS-CoV-2 RNA detection was 17 days (Interquartile Range [IQR], 13–22 days) as measured from illness onset. When comparing patients with early (<15 days) and late viral RNA clearance (≥15 days after illness onset), prolonged SARS-CoV-2 RNA shedding was associated with male sex (p=0.009), old age (p=0.033), concomitated with hypertension (p=0.009), delayed admission to hospital after illness onset (p=0.001), severe illness at admission (p=0.049), invasive mechanical ventilation (p=0.006), and corticosteroid treatment (p=0.025). Patients with longer SARS-CoV-2 RNA shedding duration had slower recovery of body temperature (p<0.001) and focal absorption on radiograph images (p<0.001) than patients with early SARS-CoV-2 RNA clearance. Male sex (odds ratio [OR], 3.24 [95% CI, 1.31–8.02]), delayed hospital admission (OR, 1.30 [95% CI, 1.10–1.54]), and invasive mechanical ventilation (OR, 9.88 [95% CI, 1.11–88.02]) were independent risk factors for prolonged SARS-CoV-2 RNA shedding.ConclusionsMale sex, delayed admission to hospital after illness onset, and invasive mechanical ventilation were associated with prolonged SARS-CoV-2 RNA shedding. Hospital admission and general treatments should be started as soon as possible in symptomatic COVID-19 patients, especially male patients.

A new use of Lactobacillus rhamnosus GG administration in the NICU: colonized vancomycin-resistant enterococcus eradication in the gastrointestinal system

Introduction Enterococci are microbiota microorganisms that normally have low virulence; however, under some conditions they may cause community-acquired urinary tract and even hospital-acquired serious infections. Vancomycin-resistant enterococci (VRE) can cause aggressive infections in immunosuppressive patients; especially in newborns in intensive care units. Asymptomatic gastrointestinal system carriers are important sources of VRE. Asymptomatic patients colonized by VRE can infect both other patients and the environment. Prevention of gastrointestinal colonization of VRE is an important issue to prevent VRE infection, and for rational use of hospital source. Method This study was carried out at Hacettepe University, Faculty of Medicine in Newborn Intensive Care Unit between November 2015 and March 2017. The newborn infants who were find as colonized by VRE during weekly surveillance VRE rectal stool culture screening were taken into the study. A single dose of one million colonies of Lactobacillus rhamnosus GG (LGG®) was given to the study group daily. The probiotic supplement continued until consecutive three negative cultures were detected or maximum 6 months. Control group received conventional treatment. Results In the study group, VRE eradication was successful in 21 patients out of 22 within 6 months and 1 patient was still VRE positive at 6 months. In the control group, VRE was eradicated in 12 patients out of 23 and 11 patients continued to be colonized by VRE at 6 months. There was a statistically significant difference between the groups (p <.05). Conclusion Lactobacillus rhamnosus GG use is associated with early clearance of vancomycin-resistant enterococcus in newborn patients.

Diagnosis of active tuberculosis and latent tuberculosis infection based on Raman spectroscopy and surface-enhanced Raman spectroscopy

Current tools for screening LTBI are limited due to the long turnaround time required, cross-reactivity of tuberculin skin test to BCG vaccine and the high cost of interferon gamma release assay (IGRA) tests. We evaluated Raman spectroscopy (RS) for serum-protein fingerprinting from 26 active TB (ATB) cases, 20 LTBI cases, 34 early clearance (EC; TB-exposed persons with undetected infection) and 38 healthy controls (HC). RS at 532 nm using candidate peaks provided 92.31% sensitivity and 90.0% to distinguish ATB from LTBI, 84.62% sensitivity and 89.47% specificity to distinguish ATB from HC and 87.10% sensitivity and 85.0% specificity to distinguish LTBI from EC. RS at 532 nm with the random forest model provided 86.84% sensitivity and 65.0% specificity to distinguish LTBI from HC and 94.74% sensitivity and 87.10% specificity to distinguish EC from HC. Using preliminary sample sets (n = 5 for each TB-infection category), surface-enhanced Raman spectroscopy (SERS) showed high potential diagnostic performance, distinguishing very clearly among all TB-infection categories with 100% sensitivity and specificity. With lower cost, shorter turnaround time and performance comparable to that of IGRAs, our study demonstrated RS and SERS to have high potential for ATB and LTBI diagnosis.

Abstract P5-01-04: Personalized monitoring of circulating tumor DNA during neoadjuvant therapy in high-risk early stage breast cancer reflects response and risk of metastatic recurrence

Abstract Background: The detection of circulating tumor DNA (ctDNA) during neoadjuvant therapy (NAT) may serve as an early indicator of emerging resistance and disease progression. In this study, we analyzed ctDNA from high-risk early breast cancer patients who received NAT and definitive surgery in the I-SPY 2 TRIAL (NCT01042379). We hypothesized that ctDNA can serve as a biomarker of response and survival in this setting. Methods: ctDNA analysis was performed on 291 plasma samples from 84 high-risk stage II and III breast cancer patients randomized either to an investigational agent MK-2206, an AKT inhibitor, in combination with paclitaxel followed by doxorubicin and cyclophosphamide (AC) (n=52)—or standard-of-care (paclitaxel followed by AC) (n=32). HER2+ patients also received trastuzumab. Serial plasma was collected at pretreatment (T0), at 3 weeks after initiation of paclitaxel treatment (T1), between paclitaxel and AC regimens (T2), and after NAT prior to surgery (T3). A personalized ctDNA test was designed to detect a set of 16 patient-specific somatic variants, initially identified from whole exome sequencing of pretreatment tumor, then tested in plasma samples. Regions containing the somatic variants were amplified from cell-free DNA using specific polymerase chain reaction primers. Amplified products were subjected to ultra-deep sequencing (mean: 94,000x) to detect somatic variants. Association between ctDNA and clinicopathologic variables was assessed using Fisher’s exact test. Association of ctDNA with response and survival was analyzed using logistic and Cox regressions, respectively. The survival endpoint of the study was distant disease-free survival. The median follow-up was 4.8 years. Results: At pretreatment (T0), 61 of the 84 (73%) patients had detectable ctDNA. Pretreatment (T0) ctDNA positivity and levels (mean mutant molecules per mL of plasma) were significantly associated with increased tumor burden (clinical T stage T3/T4), more aggressive tumor biology (higher Mammaprint scores) and subtype (HER2+ and Triple negative). CtDNA detection during NAT decreased over time (T0- 73%; T1- 35%; T2- 14%; T3- 9%). Of the 84 patients, 23 (27%) achieved pCR and all were ctDNA-negative after NAT (T3), while all 6 patients who had detectable ctDNA at T3 did not achieve pCR. Patients who cleared ctDNA early at T1 (n=27, 48% pCR rate) had significantly increased probability of achieving a pathologic complete response (pCR) compared to those who remained ctDNA-positive (n=29, 17% pCR rate; Odds ratio=4.33, Likelihood ratio p=0.012). Patients who were ctDNA-positive at T3 (n=6) had significantly increased risk of metastatic recurrence (HR 14.7; 95% CI 1.6-131.5) compared to those who achieved pCR and were ctDNA-negative (n=17). The risk of metastatic recurrence in patients who cleared ctDNA during NAT was not significantly different from those who were negative at T0 and remained negative by T3 (hazard ratio, HR: 2.1, 95% CI: 0.22-20.2). Interestingly, patients who were ctDNA-negative (n=37) but failed to achieve pCR had similar risk of metastatic recurrence with those who achieved pCR (HR 1.4; 95% CI 0.15-13.5). Conclusions: Early clearance of ctDNA during NAT was significantly associated with increased likelihood of achieving pCR. Residual ctDNA after NAT was a significant predictor of metastatic recurrence, while clearance of ctDNA at any point during NAT was associated with improved outcomes. Taken together, personalized monitoring of ctDNA during NAT may aid in real-time assessment of treatment response and help fine-tune pCR as a surrogate endpoint of survival. Validation studies in a larger cohort are warranted. Citation Format: Mark Jesus M Magbanua, Lamorna Brown-Swigart, Gillian Hirst, Christina Yau, Denise Wolf, Hsin-Ta Wu, Antony Tin, Svetlana Shchegrova, Himanshu Sethi, Raheleh Salari, Alexey Aleshin, Maggie Louie, Bernhard Zimmermann, Angela DeMichele, Minetta Liu, Amy Delson, Amy Jo Chien, Smita Asare, Laura Esserman, I-SPY 2 TRIAL Consortium, Laura van't Veer. Personalized monitoring of circulating tumor DNA during neoadjuvant therapy in high-risk early stage breast cancer reflects response and risk of metastatic recurrence [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-01-04.

Role of Tamsulosin with or without Deflazacort to facilitate stone clearance after ESWL: a single-center randomized controlled study

BackgroundExtracorporeal shock wave lithotripsy (ESWL) is the treatment of choice for upper tract calculi of moderate size. After ESWL, various factors affect the passage of small fragments through ureter like fragment’s size and location. To facilitate fragment passage, a lot of medications have been tried and few have stood the test of the time. In this prospective study, we evaluated the role of Tamsulosin with or without Deflazacort versus no treatment after ESWL for ureteric and renal stones in terms of requirement of the number of ESWL sessions, stone clearance rate, stone expulsion time and analgesia requirements.ResultsPatients presenting between age-groups of 18–70 years with solitary renal/ureteric calculus of size between 6 and 15 mm in major axis with Hounsfield unit less than 1000 were recruited in one of the three groups (A, B and C) randomly. Patients in Group A were prescribed Tamsulosin (0.4 mg once daily) with Deflazacort (30 mg once daily), Group B were given Tamsulosin (0.4 mg once daily), and Group C received no treatment (analgesics SOS and hydration therapy) after undergoing ESWL. Two hundred and twenty-five patients were recruited in Group A, and 240 patients were recruited in Group B and Group C each. There was an insignificant difference for required mean ESWL sessions and stone clearance rate between three groups. There was an early clearance of stone fragments in Group A than in Groups B and C, and it was statistically significant between Group A and Group C, specifically in the subgroup of stone size 10.1–15 mm. The requirement of mean analgesic tablets difference was significant between Groups A and C.ConclusionsTamsulosin with Deflazacort decreases the number of required ESWL sessions and improves complete stone clearance, but the difference is not significant. There were significant improvement in facilitating early stone clearance and decrease in requirement of mean analgesic tablets after ESWL with Tamsulosin and Deflazacort. Thus, Tamsulosin with Deflazacort can be used safely to facilitate stone clearance without increased complication rate.

Evaluation of the Relationship between Early Troponin Clearance and Short-Term Mortality in Patients with Chronic Renal Failure

Objective In patients with CKD, cTn concentrations may be elevated in the absence of AMI, which is a predicted finding caused by chronic structural heart disease rather than acute injury. The increase in troponin level observed in noncardiac conditions provides conflicting results when predicting mortality. Low lactate clearance was associated with increased mortality. Lactate clearance is calculated as follows: (early lactate − late lactate/early lactate) ∗ 100. We aimed to investigate whether troponin clearance calculated according to this formula had an effect on short-term mortality. Methods The study included 300 patients with chronic renal failure who had a sepsis-related organ failure assessment (SOFA) score ≥3. By taking the baseline troponin at the time of emergency presentation as reference and comparing them with the fourth-hour troponin values, troponin clearance was investigated in the evaluation of mortality among hospitalized patients with CKD within the first month after discharge. The data obtained were analyzed using the SPSS data analysis software version 20.0. Student's t-test was used for the parametric data, and the Chi-squared test for the nonparametric data. Results Of the 300 patients evaluated, 189 patients survived (mean age 66.20 ± 14.597 years), and 111 died (mean age 74.81 ± 12.916 years). Troponin clearance was detected in 40 of the 111 patients in the mortality group and 119 of the 189 patients in the survival group. Troponin clearance was significantly more frequent in surviving patients (P=0.0000083). Conclusion Troponin clearance can be considered as a valuable leading indicator of survival, but higher levels of troponin clearance did not lead to higher survival rates.

Effects of lemon decoction on malaria parasite clearance and selected hematological parameters in Plasmodium berghei ANKA infected mice

BackgroundCitrus plants particularly lemon (Citrus limon L.) concoctions are ethno-medically used for treatment of infectious diseases including malaria. Therefore, we set an experiment to investigate the effects of lemon decoction in mice infected with Plasmodium berghei ANKA parasites.MethodsAntimalarial activity was determined using Rane’s curative test on 25 Theiler’s albino mice. Twenty mice were each injected with 2 × 107 infected red blood cells (iRBCs). The mice were divided into four groups, consisting of five mice per group. Each group received an oral dose of either 5% carboxymethyl cellulose/placebo (negative infected control), lemon decoction (Citrus limon [CILI extract]) alone or a combination of artemether/lumefantrine (A/LU, 28 mg/kg) and CILI extract and A/LU alone. A fifth group of mice consisted of uninfected mice as parasite-negative control.ResultsWithin 72 hours after initiation of treatment, the mean percentage parasitemia ± standard deviation of the CILI extract group (24.2% ± 9.83%) was lower compared to placebo group (40.0% ± 14.78%), p = 0.037. CILI extract group was found to have an increased survival rate (11 days ± 1.6 days) as compared to placebo group (8.6 days ± 3.4 days), p = 0.226. Mice in the combination group (A/LU + CILI extract) had the highest mean counts in terms of hemato-immunological parameters, whereas those in the CILI extract alone had the lowest hematocrit levels. The study also found that mice that received a combination of CILI extract and A/LU exhibited a decreased lag time with regards to time required to clear 99% of parasites (58.8 h vs. 64.2 h, p = 0.681) as compared to the A/LU alone group.ConclusionLemon decoction demonstrated antimalarial activity in mice infected with P. berghei ANKA through parasites suppression by 39% as compared to those received placebo. However, when used alone, lemons did not suffice as a cure but in combination with standard antimalarials, lemons promoted early parasite clearance with an improved hematological parameters.

Early peripheral clearance of leukemia-associated immunophenotypes in AML: centralized analysis of a randomized trial

AbstractAlthough genetics is a relevant risk factor in acute myeloid leukemia (AML), it can be minimally informative and/or not readily available for the early identification of patients at risk for treatment failure. In a randomized trial comparing standard vs high-dose induction (ClinicalTrials.gov #NCT00495287), we studied early peripheral blast cell clearance (PBC) as a rapid predictive assay of chemotherapy response to determine whether it correlates with the achievement of complete remission (CR), as well as postremission outcome, according to induction intensity. Individual leukemia-associated immunophenotypes (LAIPs) identified pretherapy by flow cytometry were validated and quantified centrally after 3 days of treatment, expressing PBC on a logarithmic scale as the ratio of absolute LAIP+ cells on day 1 and day 4. Of 178 patients, 151 (84.8%) were evaluable. Patients in CR exhibited significantly higher median PBC (2.3 log) compared with chemoresistant patients (1.0 log; P < .0001). PBC < 1.0 predicted the worst outcome (CR, 28%). With 1.5 log established as the most accurate cutoff predicting CR, 87.5% of patients with PBC >1.5 (PBChigh, n = 96) and 43.6% of patients with PBC ≤1.5 (PBClow, n = 55) achieved CR after single-course induction (P < .0001). CR and PBChigh rates were increased in patients randomized to the high-dose induction arm (P = .04) and correlated strongly with genetic/cytogenetic risk. In multivariate analysis, PBC retained significant predictive power for CR, relapse risk, and survival. Thus, PBC analysis can provide a very early prediction of outcome, correlates with treatment intensity and disease subset, and may support studies of customized AML therapy.

A head-to-head comparison of ixekizumab vs. guselkumab in patients with moderate-to-severe plaque psoriasis: 12-week efficacy, safety and speed of response from a randomized, double-blinded trial.

SummaryBackgroundPatients with psoriasis value rapid and complete skin clearance. No head‐to‐head studies have focused on early responses to interleukin (IL)‐17 vs. IL‐23 inhibitors.ObjectivesTo compare early and complete skin clearance by the IL‐17A inhibitor ixekizumab vs. the IL‐23p19 inhibitor guselkumab.Methods IXORA‐R, a 24‐week, randomized, double‐blinded study, enrolled adults with moderate‐to‐severe plaque psoriasis [static Physician's Global Assessment of Disease (sPGA) score of ≥ 3, Psoriasis Area and Severity Index (PASI) ≥ 12, and ≥ 10% body surface area]. Patients were randomized (1 : 1) to receive the approved dose of subcutaneous ixekizumab or guselkumab. Primary end point was 100% improvement in PASI (PASI 100) at week 12. Major secondary end points included other levels of improved PASI and sPGA at different time points. Comparisons were made using the Cochran–Mantel–Haenszel test with a multiple testing strategy. Nonresponder imputation was used for missing data. After the completion of the study, the final secondary end point (PASI 100 at 24 weeks) and safety data through week 24 will be reported.ResultsIn total, 1027 patients were randomized. The primary end point PASI 100 at week 12 was met [215/520 ixekizumab (41%); 126/507 guselkumab (25%); P < 0·001]. All major secondary end points measured up to week 12 were met, including PASI 50 at week 1 and PASI 75 at week 2. Serious adverse event frequency was 3% for each group; no new safety signals were identified.ConclusionsIxekizumab was superior to guselkumab for rapidly improving signs and symptoms in patients with moderate‐to‐severe plaque psoriasis by week 12. Adverse events were similar to previous ixekizumab and guselkumab studies. Compared with the IL‐23 inhibitor guselkumab, ixekizumab can offer complete skin clearance more rapidly to patients with moderate‐to‐severe plaque psoriasis. What's already known about this topic? Patients with plaque psoriasis desire both high levels of clearance and rapid onset of treatment effects.Ixekizumab, a high‐affinity monoclonal antibody that selectively targets interleukin (IL)‐17A, has demonstrated greater and faster skin clearance than etanercept and ustekinumab, with consistent long‐term efficacy, safety and durability of response.Clinical trial data and systematic reviews have suggested that IL‐17 inhibitors can improve a patient's psoriasis more rapidly than IL‐23 inhibitors. What does this study add? The head‐to‐head study design directly compares the efficacy and speed of response of ixekizumab and the IL‐23 inhibitor guselkumab in moderate‐to‐severe plaque psoriasis.The primary end point was met, showing superiority of ixekizumab over guselkumab for achieving complete skin clearance at week 12.The safety profile of ixekizumab was consistent with previous studies.Ixekizumab can deliver patients complete skin clearance and improved quality of life more rapidly than guselkumab.

Identifying possible risk factors for cesarean scar pregnancy based on a retrospective study of 291 cases.

AimCesarean scar pregnancy (CSP) is a rare but life‐threatening type of ectopic pregnancy. This study's aim is to investigate the clinical characteristics and possible risk factors for cesarean scar pregnancy.MethodsA clinically randomized, unpaired and retrospective case–control study was implemented. A study group of 291 CSP patients and a control group of 317 full‐term pregnant women with a history of cesarean section (CS) were recruited in our hospital from May 2013 to October 2018. Their demographic characteristics and medical and obstetric history were collected.ResultsOnly symptoms suggestive of an impending abortion, such as vaginal bleeding with or without abdominal pain, were identified as the clinical characteristics of CSP. Maternal age older than 35 years, gravidity higher than 3 (especially gravidity higher than 5), more than two induced abortions (especially more than five abortions), an interval of less than 5 years (especially less than 2 years) between the current pregnancy and the last CS, history of CS performed in a rural hospital, history of induced abortions after CS and retroposition of the uterus were possible independent risk factors for CSP.ConclusionCSP is a result of a combination of multiple factors associated with CS. There are no unique early clinical features of CSP. As a unique type of ectopic pregnancy, early diagnosis, early termination and early clearance should be the treatment principles. Further research is needed to evaluate the relationship between the cesarean scar defect and CSP in the future.

Drainage procedure for pancreatolithiasis: re-examination of the pancreatic duct diameter standard.

PurposePancreatic duct decompression relieves pancreatic duct stone (PDS)-associated abdominal pain, though a consensus indication for the drainage procedure of the main pancreatic duct (MPD) is lacking. Moreover, major prognostic factors for postsurgical long-term pain relief and recurrence are largely unknown.MethodsThe clinical outcomes of 65 consecutive PDS patients undergoing surgery from 2008–2012 with 3+ years of follow-up were assessed.ResultsAt postsurgical follow-up (median, 4.5 years; range, 3–7 years; procedure: Partington, n = 32; Frey, n = 27; pancreatoduodenectomy, n = 3; distal pancreatectomy, n = 3), the early complication and complete stone clearance rates were 29.2% and 97%, respectively. Long-term, complete and partial pain relief were 93.9%, 83.1%, and 10.8%, respectively. The risk of pancreatic fistula was higher in the <8 mm group than in the >8 mm group (P < 0.05), and 80% of the pancreatic fistula cases occurred in the <8 mm group. A shorter pain duration (P = 0.007), smaller MPD diameter (P = 0.04), and lower Izbicki pain score (P < 0.001) predicted long-term pain relief. Pain recurrence after initial remission occurred in 5 patients and was only related to pain duration (P = 0.02). Stone recurrence and pancreatic exocrine functional and endocrine functional deterioration occurred in 2, 5, and 11 patients, respectively.ConclusionSurgery provides excellent stone clearance, long-term pain relief, and acceptable postoperative morbidity. Using 8 mm as the criterion for drainage surgery can minimize the postoperative pancreatic fistula risk. Individualized and timely surgical treatment may improve the effect of surgery.

Serial Arterial Lactate Clearance and Outcome in Patients with Cardio-respiratory Insufficiency Presenting in Emergency Ward at Tertiary Level Hospital

Introduction: Acute cardio-respiratory failure is one of the acute common problems encountered in emergency and which required immediately intervention. It creates an imbalance between energy supply, demand, and consumption. Earlier lactate clearance should be useful to identify patient able to reverse the metabolic derangement and failure to rapidly resolve the oxygen debt, indicated by poor lactate clearance, would be correlated with negative outcome. For this purpose lactate clearance at 2 hour is more useful. Methods: This was a prospective study conducted at B. P. Koirala Institute of Health Sciences, Dharan, Nepal. Preliminary diagnosis was made according to clinical history, physical examination, arterial blood gas and chest radio graph. A national emergency warning system was used for patient evaluation. Gas exchange and lactate blood concentration was assessed at Emergency ward at arrival, 2 & 6 hr. Two-hour lactate clearance was calculated as (Lactate start − lactate 2 hour)/lactate start (%). Blood gas-analysis and arterial lactate was performed by intermittent blood sampling and co-oximetry. Results: Out of 74 patients the COPD was the most common co-morbidity condition (25.7%), followed by congestive heart failure (18.9%). Comprising of lactate clearance at two hours and the lactate clearance at six hours, the lactate clearance at two hours and its outcomes was more significant (P=0.001, OR=10.133) than lactate clearance at six hours (P=0.213). Conclusions: Early lactate clearance was associated with positive outcome rather than late clearance.

Early Lactate Clearance Rate in Sepsis

Early Lactate Clearance Rate in Sepsis