Numerical studies on shortening the duration of HIFU ablation therapy and their experimental validation.

High Intensity Focused Ultrasound (HIFU) is used in clinical practice for thermal ablation of malignant and benign solid tumors located in various organs. One of the reason limiting the wider use of this technology is the long treatment time resulting from i.a. the large difference between the size of the focal volume of the heating beam and the size of the tumor. Therefore, the treatment of large tumors requires scanning their volume with a sequence of single heating beams, the focus of which is moved in the focal plane along a specific trajectory with specific time and distance interval between sonications. To avoid an undesirable increase in the temperature of healthy tissues surrounding the tumor during scanning, the acoustic power and exposure time of each HIFU beam as well as the time intervals between sonications should be selected in such a way as to cover the entire volume of the tumor with necrosis as quickly as possible. This would reduce the costs of treatment. The aim of this study was to quantitatively evaluate the hypothesis that selecting the average acoustic power and exposure time for each individual heating beam, as well as the temporal intervals between sonications, can significantly shorten treatment time. Using 3D numerical simulations, the dependence of the duration of treatment of a tumor with a diameter of 5 mm or 9 mm (requiring multiple exposure to the HIFU beam) on the sonication parameters (acoustic power, exposure time) of each single beam capable of delivering the threshold thermal dose (CEM43 = 240 min) to the treated tissue volume was examined. The treatment duration was determined as the sum of exposure times to individual beams and time intervals between sonications. The tumor was located inside the ex vivo tissue sample at a depth of 12.6 mm. The thickness of the water layer between the HIFU transducer and the tissue was 50 mm. The sonication and scanning parameters selected using the developed algorithm shortened the duration of the ablation procedure by almost 14 times for a 5-mm tumor and 20 times for a 9-mm tumor compared to the duration of the same ablation plan when a HIFU beam was used of a constant acoustic power, constant exposure time (3 s) and constant long time intervals (120 s) between sonications. Results of calculations of the location and size of the necrotic lesion formed were experimentally verified on ex vivo pork loin samples, showing good agreement between them. In this way, it was proven that the proper selection of sonication and scanning parameters for each HIFU beam allows to significantly shorten the time of HIFU therapy.

Duration of Endocrine Treatment for DCIS impacts second events: Insights from a large cohort of cases at two academic medical centers.

Ductal carcinoma in situ (DCIS) incidence has risen rapidly with the introduction of screening mammography, yet it is unclear who benefits from both the amount and type of adjuvant treatment (radiation therapy, (RT), endocrine therapy (ET)) versus what constitutes over-treatment. Our goal was to identify the effects of adjuvant RT, or ET+/- RT versus breast conservation surgery (BCS) alone in a large multi-center registry of retrospective DCIS cases (N = 1,916) with median follow up of 8.2 years. We show that patients with DCIS who took less than 2 years of adjuvant ET alone have a similar second event rate as BCS. However, patients who took more than 2 years of ET show a significantly reduced second event rate, similar to those who received either RT or combined ET+RT, which was independent of age, tumor size, grade, or period of diagnosis. This highlights the importance of ET duration for risk reduction.

Risk and effect modifiers for poor glycemic control among the chinese diabetic adults on statin therapy: the kailuan study.

BACKGROUND: Limited studies have investigated the association between statin therapy and poor glycemic control, especially in the Chinese diabetic population. METHODS: Two prospective diabetes cohorts were drawn from the Kailuan Cohort. In Cohort 1, linear regression models were used to evaluate the association between statin therapy and glycated hemoglobin (HbA1c) level change. In Cohort 2, new user design and conditional logistic models were used to assess associations between statin initiation and poor glycemic control which was a composite outcome comprised of hypoglycemic agent escalation and new-onset hyperglycemia. RESULTS: Among 11,755 diabetic patients with medication information, 1400 statin users and 1767 statin nonusers with repeated HbA1c measurements were included in Cohort 1 (mean age: 64.6 ± 10.0 years). After a median follow-up of 3.02 (1.44, 5.00) years, statin therapy was associated with higher HbA1c levels (ß: 0.20%; 95%CI: 0.05% to 0.34%). In Cohort 2, 1319 pairs of matched cases/controls were included (mean age: 61.6 ± 9.75 years). After a median follow-up of 4.87 (2.51, 8.42) years, poor glycemic control occurred in 43.0% of statin new users and 31.8% of statin nonusers (OR: 1.69; 95% CI: 1.32 to 2.17; P < 0.001). The statin-associated poor glycemic control risk was significantly higher among patients with lower body mass index (Pint = 0.089). Furthermore, a nonlinear association was observed between statin therapy duration and poor glycemic control (P = 0.003). CONCLUSIONS: Among Chinese diabetic adults, statin therapy was associated with a higher level of HbA1c, and a higher risk of hypoglycemic agent escalation and new-onset hyperglycemia, especially among those who had lower body mass index levels and longer statin therapy duration.

Decision-making regarding antibiotic therapy duration: An observational study of multidisciplinary meetings in the intensive care unit.

PURPOSE: Antibiotic therapy is commonly prescribed longer than recommended in intensive care patients (ICU). We aimed to provide insight into the decision-making process on antibiotic therapy duration in the ICU. METHODS: A qualitative study was conducted, involving direct observations of antibiotic decision-making during multidisciplinary meetings in four Dutch ICUs. The study used an observation guide, audio recordings, and detailed field notes to gather information about the discussions on antibiotic therapy duration. We described the participants' roles in the decision-making process and focused on arguments contributing to decision-making. RESULTS: We observed 121 discussions on antibiotic therapy duration in sixty multidisciplinary meetings. 24.8% of discussions led to a decision to stop antibiotics immediately. In 37.2%, a prospective stop date was determined. Arguments for decisions were most often brought forward by intensivists (35.5%) and clinical microbiologists (22.3%). In 28.9% of discussions, multiple healthcare professionals participated equally in the decision. We identified 13 main argument categories. While intensivists mostly used arguments based on clinical status, clinical microbiologists used diagnostic results in the discussion. CONCLUSIONS: Multidisciplinary decision-making regarding the duration of antibiotic therapy is a complex but valuable process, involving different healthcare professionals, using a variety of argument-types to determine the duration of antibiotic therapy. To optimize the decision-making process, structured discussions, involvement of relevant specialties, and clear communication and documentation of the antibiotic plan are recommended.

The Impact of Antimicrobial Therapy Duration in the Treatment of Prosthetic Joint Infections Depending on Surgical Strategies: A Systematic Review and Meta-analysis.

The aim of this systematic review was to address the question if short antibiotic treatment (SAT; at least 4 but <12 weeks) versus long antibiotic treatment (LAT) affects outcomes in prosthetic joint infections (PJIs). Database research (Medline, Embase, Web of Science, Scopus, Cochrane) retrieved 3740 articles, of which 10 studies were included in the analysis. Compared to LAT, 11% lower odds of treatment failure in the SAT group were found, although the difference was not statistically significant (pooled odds ratio, 0.89 [95% confidence interval, .53-1.50]). No difference in treatment failure was found between SAT and LAT once stratified by type of surgery, studies conducted in the United States versus Europe, study design, and follow-up. There is still no conclusive evidence that antibiotic treatment of PJIs for 12 weeks or longer is associated with better outcomes, irrespective of the type of surgical procedure. Most recent, high-quality studies tend to favor longer antibiotic courses, making them preferable in most situations.

Drawbacks of immune checkpoint inhibition and rigorous management for immune-related adverse events along with a mathematical model to assess therapy success and optimum therapy duration and a strategy against tumor plasticity.

PURPOSE: Immune checkpoint inhibition therapy (ICIT) is an emerging field in oncology especially opening new horizons to chemotherapy refractory patients. However, immune-related adverse events (irAEs) and undesired response patterns such as progression after the initial good response in a subset of patients pose a major challenge and drawback to ICIT. This paper provides deep insight into ICIT related bottlenecks and corresponding effective management and combat strategies for very complex complications. METHODS: The relevant literatures from PubMed have been reviewed. Based on obtained information, rigorous and exhaustive analyses have been made to present novel methods and strategies against ICIT drawbacks and bottlenecks. RESULTS: The results show that baseline biomarker tests are very crucial to identify suitable candidates for ICIT and frequent assessments throughout ICIT help to recognize possible irAEs at early stages. Equally important are the necessity for mathematical definitions for the ICIT success rate and optimum duration, and the development of combat mechanisms against loss of sensitivity within the tumor microenvironment (TME). CONCLUSION: Rigorous management approaches are presented for mostly observed irAEs. Furthermore, for the first time in the literature, a non-linear mathematical model is invented to measure the ICIT success rate and to decide about the optimum ICIT duration. Finally, a strategy against tumor plasticity is introduced.

The impact of pharmacist intervention on the intravenous-to-oral switch therapy of proton pump inhibitors in cardiovascular surgery.

BACKGROUND: The prescriptions of proton pump inhibitors (PPIs) have been widely concerned due to both huge increase in medical costs and possible long-term adverse events (AEs) caused by the improper route of drug administration. The aim of this study was to assess the effectiveness of pharmacist interventions on the clinical outcome and safety of switching from intravenous (IV) to oral PPIs therapy. PATIENTS AND METHODS: A retrospective, single-center, pre- intervention (early -stage)- and intervention (later -stage) study was performed in a Chinese hospital. RESULTS: A total of 1736 patients were included in the study. After 12 months of interventions, significant improvements in the number of rational IV to oral switch in patients with oral switch indications were found. The median duration of oral therapy was increased, while the duration of PPIs therapy was decreased. Pharmacist interventions led to significant reductions in mean PPI costs, mean total drug costs, mean hospitalization costs, and the risk for long-term adverse events. CONCLUSION: This study provides important evidence on the beneficial effect of pharmacist interventions on promoting an optimal IV to oral switch of PPIs and substantial cost saving by shortening the duration of IV PPIs therapy and reducing the risk for long-term AEs.

Impact of antiretroviral therapy (ART) duration on ART adherence among men who have sex with men (MSM) living with HIV in Jinan of China.

BACKGROUND: Consistent and complete adherence is considered an essential requirement for patients on antiretroviral therapy (ART). This study aimed to evaluate the impact of ART duration on ART adherence, identify the trend of complete adherence, and compare the factors associated with ART adherence between short-term and long-term ART group among men who have sex with men (MSM) living with HIV in Jinan of China. METHODS: MSM living with HIV aged 18 or above and currently on ART were recruited from October to December 2020 using convenience sampling. Univariate and multivariable logistic regressions were used to evaluate the impact of ART duration on adherence and compare factors associated with ART adherence between subgroups. The Mann-Kendall test was used to identify the trend of complete adherence. RESULTS: A total of 585 participants were included in analysis, consisting of 352 on short-term ART (ART initiation ≤ 3 years) and 233 on long-term ART (ART initiation > 3 years). Significant difference of complete ART adherence between short-term and long-term ART group was detected (79.8% vs. 69.1%, P = 0.003). Multivariable analysis showed that men with longer ART duration were less likely to report complete ART adherence (AOR = 0.88, 95% CI 0.81-0.95). A descending trend of complete adherence was identified (Z = 1.787, P = 0.037). Alcohol use and lack of medication reminders were barriers to complete adherence for both of the subgroups. CONCLUSIONS: Sustained efforts to encourage maintaining adherence for a lifetime are necessary, especially for those on long-term ART. Future interventions should be tailored to subgroups with different ART duration and individuals with specific characteristics.

Antibiotic treatment of community-acquired pneumonia: A questionnaire survey in Danish general practice.

BACKGROUND: Discrepancies exist in Danish guidelines for the treatment of bacterial community-acquired pneumonia (CAP). This study aimed to investigate how general practitioners (GPs) treat adults with CAP and explore associations between GP characteristics and treatment duration. METHODS: In autumn 2020, GPs in the North Denmark Region were asked to complete an electronic questionnaire on antibiotic prescribing for CAP. Information about GP gender, age, experience and type of practice was obtained. Multivariable logistic regression was used to analyse the association between GP characteristics and treatment duration. RESULTS: A total of 298 GPs were invited to participate of whom 108 completed the survey. Penicillin V was used as first line treatment for CAP by all participants. Treatment duration varied from 5 (54.6%) to 10 days (8.3%). A 5-day course of penicillin was less likely to be prescribed by male GPs (odds ratio [OR] 0.35, 95% confidence interval [CI] 0.13-0.94) and more likely to be prescribed by GPs with 5-9 years of experience in general practice (OR 5.03, 95% CI 1.09-23.21) compared to those with 10-19 years of experience. CONCLUSION: Variation in antibiotic treatment of CAP emphasises the importance of generating solid evidence about the optimal duration regarding both effectiveness and safety.

Comparison of Short-Term DAPT and Long-Term DAPT on the Prognosis of PCI Patients: A Meta-Analysis of Randomized Controlled Trials.

Background: Dual antiplatelet therapy (DAPT) is the primary medication for patients after percutaneous coronary intervention (PCI). However, the best DAPT duration is still controversial. This systematic review and meta-analysis aims to assess the safety and effectiveness of short-term (3-6 months) DAPT compared to long-term (12 months) DAPT. Methods: We searched PubMed, Embase, Cochrane Library, and Web of Science systematically for all the randomized controlled trials (RCTs) which compared the different strategies for DAPT in patients undergoing PCI within ten years prior to January 2021. Major bleeding and any bleeding were identified as the safe endpoints. All causes of death, cardiac death, myocardial infarction, definite/probable stent thrombosis, target vessel revascularization, and stroke were identified as the efficacy endpoints. The hazard ratio (HR) and 95% confidence interval (CI) in each study were abstracted. Results: Overall, 11 trials and 24,242 patients were included in this meta-analysis with 15-month median follow-up time. Short-term DAPT was related to reduced risks of major bleeding (HR 0.65, 95% CI 0.48-0.89) and any bleeding (HR 0.64, 95% CI 0.53-0.79). No obvious differences in any of the other endpoints were observed. In acute coronary syndrome (ACS) patients with drug-eluting stents (DES), short-term compared with long-term DAPT was related to a decreased risk of major bleeding (HR 0.57, 95% CI 0.37-0.87) without significant increasing in the risks of any bleeding and ischemic endpoints. Furthermore, short-term DAPT followed by P2Y12 receptor inhibitor monotherapy appreciably lowered the risk of major bleeding (HR 0.64, 95% CI 0.42-0.96) and any bleeding (HR 0.58, 95% CI 0.36-0.93). There were no obvious differences concerning death between the different strategies for DAPT. Conclusions: After PCI with DES, short-term DAPT is safer than long-term DAPT, and is not inferior in effectiveness, even in ACS patients. P2Y12 receptor inhibitor monotherapy following short-term DAPT is also related to a decreased risk of bleeding and may be an alternative anti-platelet strategy.

Modeling of Urinary Microbiota Associated With Cystitis.

A decade ago, when the Human Microbiome Project was starting, urinary tract (UT) was not included because the bladder and urine were considered to be sterile. Today, we are presented with evidence that healthy UT possesses native microbiota and any major event disrupting its "equilibrium" can impact the host also. This dysbiosis often leads to cystitis symptoms, which is the most frequent lower UT complaint, especially among women. Cystitis is one of the most common causes of antimicrobial drugs prescriptions in primary and secondary care and an important contributor to the problem of antimicrobial resistance. Despite this fact, we still have trouble distinguishing whether the primary cause of majority of cystitis cases is a single pathogen overgrowth, or a systemic disorder affecting entire UT microbiota. There are relatively few studies monitoring changes and dynamics of UT microbiota in cystitis patients, making this field of research still an unknown. In this study variations to the UT microbiota of cystitis patients were identified and microbial dynamics has been modeled. The microbial genetic profile of urine samples from 28 patients was analyzed by 16S rDNA Illumina sequencing and bioinformatics analysis. One patient with bacterial cystitis symptoms was prescribed therapy based on national guideline recommendations on antibacterial treatment of urinary tract infections (UTI) and UT microbiota change was monitored by 16S rDNA sequencing on 24 h basis during the entire therapy duration. The results of sequencing implied that a particular class of bacteria is associated with majority of cystitis cases in this study. The contributing role of this class of bacteria - Gammaproteobacteria, was further predicted by generalized Lotka-Volterra modeling (gLVM). Longitudinal microbiota insight obtained from a single patient under prescribed antimicrobial therapy revealed rapid and extensive changes in microbial composition and emphasized the need for current guidelines revision in regards to therapy duration. Models based on gLVM indicated protective role of two taxonomic classes of bacteria, Actinobacteria and Bacteroidia class, which appear to actively suppress pathogen overgrowth.

Mycobacterium tuberculosis sterilizing activity of faropenem, pyrazinamide and linezolid combination and failure to shorten the therapy duration.

BACKGROUND: Faropenem (F), an orally bioavailable ß-lactam, kills Mycobacterium tuberculosis (Mtb) without the help of a ß-lactamase inhibitor. This study explored the sterilizing effect of adding F once or twice daily to a linezolid (L) plus pyrazinamide (Z) backbone regimen. METHODS: In vitro studies were performed using the hollow fiber model of tuberculosis (HFS-TB) to compare the kill rates of: 1) ZL two-drug combination; 2) F administered once daily plus ZL (F1ZL); 3) F administered twice-daily plus once daily ZL (F2ZL); 4) F2ZL with high-dose Z (F2ZhiL); 5) standard therapy of isoniazid, rifampin and Z; and 6) non-treated controls. The study was performed over 56 days with three HFS-TB replicates for each regimen. RESULTS: Mtb in the non-treated HFS-TB grew at a rate of 0.018 ± 0.007 log10 CFU/mL/day. The exponential kill rates for standard therapy were 6.6-13.2-fold higher than ZL dual therapy. The F1ZL and F2ZL regimens ranked third. The pre-existing isoniazid-resistant sub-population in the inoculum (1.34 ± 0.57 log10 CFU/mL) grew to 4.21 ± 0.58 log10 CFU/mL in 56 days in non-treated HFS-TB. However, no isoniazid-resistant sub-population was recorded in any of the FZL combination regimens. CONCLUSION: Due to the slow kill rate compared to standard therapy, FZL regimens are unlikely to shorten therapy duration. Efficacy of these regimens against drug-resistant tuberculosis needs to be determined.

Antibiotic Therapy of 3 Days May Be Sufficient After Biliary Drainage for Acute Cholangitis: A Systematic Review.

BACKGROUND: The optimal antibiotic therapy duration for cholangitis is unclear. Guideline recommendations vary between 4 and 14 days after biliary drainage. Clinical observations and some evidence however suggest that shorter antibiotic therapy may be sufficient. OBJECTIVE: To compare the effectiveness and safety of short-course therapy of ≤ 3 days with long-course therapy of ≥ 4 days after biliary drainage in cholangitis patients. METHODS: We searched the databases PubMed, EMBASE, Cochrane Library, and trial registers for literature up to August 5, 2020. RCTs and observational studies including case series reporting on antibiotic therapy duration for acute cholangitis were eligible for inclusion. Two reviewers independently evaluated study eligibility, extracted data, assessed risk of bias and quality of evidence. A meta-analysis was planned if the included studies were comparable with regard to important study characteristics. Primary outcomes included recurrent cholangitis, subsequent other infection, and mortality. RESULTS: We included eight studies with 938 cholangitis patients. Four observational studies enrolled patients treated for ≤ 3 days. Recurrent cholangitis occurred in 0-26.8% of patients treated with short-course therapy, which did not differ from long-course therapy (range 0-21.1%). Subsequent other infection and mortality rates were also comparable. Quality of available evidence was very low. CONCLUSION: There is no high-quality evidence available to draw a strong conclusion, but heterogeneous observational studies suggest that antibiotic therapy of ≤ 3 days is sufficient in cholangitis patients with common bile duct stones.

How much therapy is enough? The dose-response effect and its moderators in a psychology training clinic.

OBJECTIVE: The current study aims to sharpen the understanding of the psychotherapy dose-response effect and its moderators in a psychology training clinic. METHOD: Data were extracted from 58 client records. Weekly Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7, as well as Outcomes Questionnaire-45.2, administered every fifth session, assessed whether clients achieved reliable change (RC) and clinically significant and reliable change (CSR) during treatment. Survival analyses were conducted to determine the sessions required for 50% of the sample to achieve these outcomes. Multilevel Cox frailty regressions were used to investigate client-and-therapy-based moderators. RESULTS: The median time for 50% of the sample to achieve RC was 8-10 sessions and 11 sessions to achieve initial CSR. Past treatment history was a significant moderator of time to achieve RC. CONCLUSIONS: From a population perspective, psychotherapy is most beneficial to patients early in treatment. Sharper understanding of the number of sessions required to achieve meaningful change can inform practice in training settings.

Use of Proton Pump Inhibitors in Hungary: Mixed-Method Study to Reveal Scale and Characteristics.

BACKGROUND: Due to their efficacy and tolerability, utilization of proton pump inhibitors (PPI) has significantly increased worldwide. Parallel to the clinical benefits, potential long-term side effects have been observed, which, along with increasing medical expenses and potential drug interactions, justifies the analysis of the trends of utilization. OBJECTIVE: The aim of the present study was to show the level, pattern, and characteristics of PPI use. METHODS: We assessed the nationwide use of proton pump inhibitors in ambulatory care based on aggregated utilization data from the National Health Insurance database. The annual PPI utilization was expressed as the number of packages and as number of DDDs per 1,000 inhabitants and per year. For 2018, we estimated PPI exposure as the number of packages and as the number of DDDs per user per year. The annual reimbursement costs of proton pump inhibitors were also calculated. Moreover, three patient-level surveys were carried out in non-gastroenterological inpatient hospital departments to reveal characteristics of proton pump inhibitor use, namely dose, duration, and indication. RESULTS: The PPI utilisation increased from 5867.8 thousand to 7124.9 thousand packages and from 41.9 to 50.4 DDD per 1,000 inhabitants and per day between 2014 and 2018. Nationwide data showed that 14% of the adult population was exposed to proton pump inhibitors in 2018, while among hospitalized patients, the prevalence of proton pump inhibitor use was between 44.5% and 54.1%. Pantoprazole was the most frequently used active ingredient, both in the nationwide data and in the patient-level surveys. In the patient-level survey in majority of patients (71.5%-80.0%) proton pump inhibitors were prescribed for prophylaxis. Many inpatients (29.4%-36.9%) used 80 mg pantoprazole per day. The average number of PPI packages per user was 6.5 in 2018 in the nationwide data. The duration of PPI therapy was typically between 1 and 5 years in the patient-level surveys and nearly 20% of the inpatients had been taking proton pump inhibitors for more than 5 years. CONCLUSIONS: Our data suggests that Hungarian patients receive proton pump inhibitors in high doses and for a long time. Use of proton pump inhibitors beyond their recommended indications was also found.

A proof-of-concept study in HCV-infected Huh7.5 cells for shortening the duration of DAA-based triple treatment regimens.

With the development of more effective direct-acting antivirals (DAAs), dual- or triple-therapy regimens represent the major strategy used to cure chronic hepatitis C virus (HCV) infection. Thus, shorter treatment duration regimens with low burden, few adverse effects and good patient adherence are urgently needed. This study theoretically demonstrates a proof-of-concept approach for shortening therapy duration by examining HCV-infected Huh7.5 cells after treatment with a high or low fixed dose of three DAAs (simeprevir + daclatasvir + sofosbuvir) for 6-15 days. The results demonstrated that HCV-infected Huh7.5 cells achieved an ultrarapid virologic response with undetectable HCV RNA and protein and were cured after treatment with the triple-therapy regimen for 15 days. When the treatment duration was shortened, virologic relapse might occur after treatment with a low fixed dose of the three DAAs for 9 days and did occur after treatment with a low fixed dose for 6 days, although HCV was below detectable levels at the end of treatment. However, virologic relapse could be avoided with treatment of a high fixed dose of the three DAAs for 9 or 6 days. Although a virologic breakthrough occurred after an intermittent treatment regimen at the low fixed dose, the high fixed dose cured HCV-positive Huh7.5 cells with intermittent treatment. In conclusion, HCV is persistently present below detectable levels in HCV-infected Huh7.5 cells for a long time after treatment, and a shortened therapy duration is associated with an increased risk of virologic relapse, but virologic relapse or breakthrough might be avoided by treatment with a combination of more highly effective DAAs.

Evaluation of Healed Status in Tuberculosis of Spine by Fluorodeoxyglucose-positron Emission Tomography/Computed Tomography and Contrast Magnetic Resonance Imaging.

BACKGROUND: The healed status (end-point of treatment) in tuberculosis (TB) spine is not defined; hence optimum antitubercular therapy (ATT) duration is unresolved. We, for the first time, prospectively evaluated the healed status in TB spine by fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) and contrast magnetic resonance imaging (MRI) with the objective to define end-point of treatment in TB spine. MATERIALS AND METHODS: Thirty seven patients of TB spine diagnosed on clinicoradio imaging/cytology/histologically/molecular methods were enrolled, treated and were evaluated radiologically, by contrast MRI and FDG-PET/CT at 9 months. ATT was stopped on contrast MRI-based healing or absence of FDG uptake on PET-CT. ATT was continued in active/resolving lesion. Repeat evaluation was done at 12, 18, 24, and 30 months till healing is demonstrated. In this research work, we got contrast MRI and FDG-PET/CT done for the patients from government institution free of cost, so patients did not have to bear the burden of cost of these investigations. RESULTS: Twenty-eight patients achieved healed status out of which 11 demonstrated healed status on contrast MRI and FDG-PET/CT both, 6 were MRI active (contrast enhancement) but FDG-PET/CT healed, 2 were MRI healed but FDG-PET/CT active (soft-tissue standardized uptake value <2.0), 9 patients were MRI incompatible due to stainless steel implants (n = 6), and in 3 patients MRI could not be done due to financial constraints and were declared healed on FDG-PET/CT. FDG-PET/CT showed healed bone lesion in 28/28 (100%) and on MRI 13/19 (68.42%), respectively. We had 6 patients whose spine was stabilized with stainless steel implants where MRI could not be performed, MRI was useful in 13/25 cases (52%) to demonstrate healed lesion. 7, 6, 6, 5, 1, 2, and 1 cases achieved healed status at 9, 12, 18, 24, 30, 36, and 48 months of ATT intake, respectively. CONCLUSIONS: FDG-PET/CT is more useful to demonstrate the healed status than MRI and is the only imaging to demonstrate healed status when MRI could not be performed due to metallic implants. All patients achieved healed status at variable length of ATT intake; hence TB spine should be treated by ATT till healed status (end-point of treatment) is demonstrated by FDG-PET/CT (absence of FDG uptake) or contrast MRI.

Discontinuation of tyrosine kinase inhibitors in CML patients in real-world clinical practice at a single institution.

BACKGROUND: Most patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs) will relapse if treatment is withdrawn, but various trials have recently demonstrated that a significant proportion of patients who achieved a stable and deep molecular response (DMR) can stop therapy without relapsing. However, most information on treatment cessation was obtained from clinical trials with strict recruiting criteria. METHODS: We evaluated the outcome of 25 patients with CML that discontinued TKI therapy in our institute in real-world clinical practice. RESULTS: Of the 25 patients, 76% discontinued therapy in sustained deep molecular response (SDMR) and 24% were in unsustained DMR (UDMR). Discontinuation of therapy due to adverse effects was observed in 5 and 50% of the patients in the SDMR and UDMR groups, respectively. After TKI discontinuation, patients were followed for a median of 24 months. At the time of this analysis, 56% patients had a molecular relapse after a median of 4 months. SDMR and longer treatment duration were associated with lower probability of molecular relapse: 25% in SDMR patients with TKI treatment > 96 months and 85% in UDMR patients with TKI treatment ≤96 months. All relapsed patients promptly resumed TKI therapy and regained at least major molecular response (MMR). CONCLUSIONS: Our results suggest that TKI discontinuation is safe outside clinical trials and particularly effective in CML patients who are in SDMR with longer TKI treatment duration.

Norepinephrine in Combination with Antibiotic Therapy Increases both the Bacterial Replication Rate and Bactericidal Activity.

We previously demonstrated that the rate and extent of an antimicrobial agent's bactericidal effects were coupled to the bacterial replication rate, the latter of which was modulated with the sodium chloride concentration. Herein, we describe the results from a 24-h one-compartment in vitro infection model study that was designed to demonstrate that an antimicrobial agent's bactericidal effects could be amplified when it is administered with a pharmaceutical agent that increases the bacterial replication rate. The antimicrobial and growth-promoting agents selected were levofloxacin and norepinephrine, respectively. The challenge isolate was Escherichia coli JMI 21711R (levofloxacin MIC, 8 mg/liter). Within the in vitro infection model, a human levofloxacin concentration-time profile (half-life, 7 h) was simulated and the challenge isolate was subjected to an ineffective monotherapy exposure (free-drug area under the concentration-time curve over 24 h divided by the MIC [AUC/MIC] ratio of 6) with and without norepinephrine as a continuous infusion (275 mg/liter). Samples were collected from the model during the course of the study for bacterial density determinations and drug concentration assay using liquid chromatography-tandem mass spectrometry (LC-MS/MS). As expected, the norepinephrine and no-treatment control arms failed immediately, followed by the levofloxacin monotherapy arm, which failed slowly over time. The levofloxacin-epinephrine regimen resulted in a 2-log10 CFU reduction in bacterial density over the first 6 to 8 h of the study, which was followed by regrowth of a highly levofloxacin-resistant subpopulation (MIC, 64 mg/liter). These data demonstrate that increasing the rate of bacterial replication with a pharmaceutical product in combination with antimicrobial therapy represents an opportunity to increase the rate and magnitude of bactericidal effect.