Clinical Cures Research Articles

An Honest Reckoning With the Amygdala and Mental Illness.

Anxiety disorders are a leading source of human misery, morbidity, and premature mortality. Existing treatments are far from curative for many, underscoring the need to clarify the underlying neural mechanisms. Although many brain regions contribute, the amygdala has received the most intense scientific attention. Over the past several decades, this scrutiny has yielded a detailed understanding of amygdala function, but it has failed to produce new clinical assays, biomarkers, or cures. Rising to this urgent public health challenge demands an honest reckoning with the functional-neuroanatomical complexity of the amygdala and a shift from theories anchored on "the amygdala" to models centered on specific amygdala nuclei and cell types. This review begins by examining evidence from studies of rodents, monkeys, and humans for the "canonical model," the idea that the amygdala plays a central role in fear- and anxiety-related states, traits, and disorders. Next, the authors selectively highlight work indicating that the canonical model, while true, is overly simplistic and fails to adequately capture the actual state of the evidentiary record, the breadth of amygdala-associated functions and illnesses, or the complexity of the amygdala's functional architecture. The authors describe the implications of these facts for basic and clinical neuroimaging research. The review concludes with some general recommendations for grappling with the complexity of the amygdala and accelerating efforts to understand and more effectively treat amygdala-related psychopathology.

Characteristics and outcomes of pediatric brucellosis cases collected from a tertiary academic hospital in Saudi Arabia

Brucellosis is a zoonotic disease caused by Brucella spp., affecting different body systems and leading to multiple complications. Although brucellosis is prevalent in several regions, including Saudi Arabia, limited research has focused on childhood brucellosis. This study aimed to characterize the features and outcomes of brucellosis in pediatric patients. We conducted a retrospective descriptive study involving children (<18 years) with confirmed brucellosis (diagnosed through culture, serology, or both) who received antibiotic therapy. Subjects were stratified into two groups based on age: younger (≤8 years) and older (>8 years). We assessed treatment outcomes, including clinical cure, mortality, and hospital length of stay. A total of 20 patients were included, with 52.3% in the younger group and 47.7% in the older group. The majority were male (65%), with a mean age of 8.9 years, and 45% required hospitalization. Out of all the patients, only 6 (30%) reported consuming dairy products. Serologically, the baseline median antibody titers for Brucella melitensis and Brucella abortus were 1:1280 and 1:640, respectively. In the younger group, half reported arthralgia and presented with fever. While white blood cell elevation was not significant, C-reactive protein, erythrocyte sedimentation rate, and liver enzymes were elevated at baseline. The administered regimen varied, but about half of the patients received at least three antibiotics. All patients experienced clinical cures, and there were no deaths. This study highlights the characteristics of pediatric brucellosis in a country where the disease is endemic and provides evidence of positive prognosis associated with appropriate antibiotic therapy.

Clinical Characteristics and Outcome of Brucella Endocarditis: A Case Series.

Brucella endocarditis is a rare complication with a high mortality risk. This research aims to evaluate patients diagnosed with Brucella Endocarditis and review clinical characteristics, diagnosis, and treatment strategies to serve as a foundation for future research in managing Brucella endocarditis and improving patient care and outcomes. This retrospective study reviewed the medical records of patients diagnosed with Brucella endocarditis from 2011 to 2022. The study included patients of all ages and genders who were diagnosed based on positive serum serology or blood culture in conjunction with clinical presentation. Diagnostic criteria for endocarditis were based on evidence of endocardial involvement, as confirmed by echocardiographic findings consistent with infective endocarditis. Descriptive statistics were used for data analysis. Nine patients were included in this study. The most common presenting symptom was shortness of breath. Treatment regimens included Doxycycline and Rifampicin, always in combination with other antibiotics. Surgical intervention was necessary for two-thirds of the patients. Complications, such as septic shock, stroke, and heart failure, were observed in most cases. Six patients achieved clinical and microbiological cures, while one-third of the patients died. The deaths were primarily attributed to patients being deemed unsuitable for surgery due to a high surgical risk, based on their comorbidities and clinical assessments. This study highlights the importance of initiating an appropriate antibiotic regimen in a timely manner. Particularly in patients with pre-existing heart diseases, surgical intervention can significantly improve patient outcomes and reduce complications associated with Brucella endocarditis.

Cefiderocol-Based Regimen for Acinetobacter NDM-1 Outbreak.

Variable outcomes have been reported with cefiderocol in infections due to carbapenem-resistant Acinetobacter baumannii (CRAB). Nonetheless, it may be the only option for metallo-beta-lactamase-producing strains. We describe an outbreak of NDM-CRAB infections treated with cefiderocol. Thirty-eight patients were colonized and/or infected. Thirteen patients developed a systemic infection. A clinical cure was achieved in 10 (83%) patients, one VAP and 9 BSIs, at day 7. In vitro, the activity of cefiderocol does not appear to match in vivo effectiveness using currently available commercial tests. Despite high clinical cures, overall mortality remains high in severely ill patients. Cefiderocol may be considered in this specific setting, though the implementation of susceptibility tests and infection control measures is mandatory.

Prolonged Beta-Lactam Infusions in Children: A Systematic Review and Meta-Analysis

ObjectiveTo assess whether beta-lactam extended or continuous beta-lactam infusions (EI/CI) improve clinical outcomes in children with proven or suspected bacterial infections. Study designWe included observational and interventional studies that compared beta-lactam EI or CI with standard infusions in children less than 18 years old, and reported on mortality, hospital or intensive care unit LOS, microbiological cure and/or clinical cure. Data sources included PubMed, Medline, EBM Reviews, EMBASE, and CINAHL and were searched from January 1, 1980, to November 3, 2023. Thirteen studies (2,945 patients) were included: 5 randomized control trials (RCTs), and 8 observational studies. Indications for antimicrobial therapies and clinical severity varied, ranging from cystic fibrosis exacerbation to critically ill children with bacteriemia. ResultsEI and CI were not associated with a reduction in mortality in RCTs (n = 1,464; RR 0.93, 95% CI 0.71, 1.21), but were in observational studies (n = 833; RR 0.43, 95% CI 0.19, 0.96). We found no difference in hospital length of stay. Results for clinical and microbiological cures were heterogeneous and reported as narrative review. The included studies were highly heterogeneous, limiting the strength of our findings. The lack of shared definitions for clinical and microbiological cure outcomes precluded analysis. ConclusionsEI and CI were not consistently associated with reduced mortality or LOS in children. Results were conflicting regarding clinical and microbiological cures. More well-designed studies targeting high-risk populations are necessary to determine the efficacy of these alternative dosing strategies.

A phase III randomized controlled clinical trial evaluating the efficacy and safety of naftifine 2% cream versus terbinafine 1% cream in patients with superficial fungal infection of the skin

Background: Dermatophytosis is the prevailing fungal infection, typically addressed through topical, systemic antifungal medications, or a combination of both. Naftifine hydrochloride, belonging to the allylamine group, is a topical antifungal, exhibiting fungicidal properties alongside antibacterial and anti-inflammatory effects. This study evaluated the efficacy and safety of naftifine hydrochloride 2% w/w in 268 patients with dermatophytosis versus terbinafine hydrochloride 1% w/w. Methods: The drugs were applied daily for two weeks, with the primary endpoint being a clinical cure at the end of the treatment. Secondary endpoints included mycological cure, composite cure, global efficacy assessment, and post-treatment relapse. Results: In both groups, most patients experienced both clinical and mycological cures, with composite cures observed in 94.07% of the test group and 87.97% of the reference group. The global assessment of efficacy was 3.59 in the test group and 3.48 in the reference group, showing no notable difference between the two groups. All adverse events in both groups were mild and resolved within four days. Overall tolerability was comparable between the study groups. Conclusions: The study concluded that topical naftifine was effective and safe in patients with dermatophytosis and its efficacy and safety were found comparable to topical terbinafine.

Optimal Treatment Based on Interferon No Longer Makes Clinical Cure of Chronic Hepatitis B Far Away: An Evidence-Based Review on Emerging Clinical Data.

Chronic hepatitis B (CHB) remains a major global public health problem. The functional cure is the ideal therapeutic target recommended by the latest guidelines, and pursuing a functional cure has become the key treatment end point of current therapy and for upcoming clinical trials. In this review, based on the latest published clinical research evidence, we analyzed the concept and connotation of clinical cures and elaborated on the benefits of clinical cures in detail. Secondly, we have summarized various potential treatment methods for achieving clinical cures, especially elaborating on the latest research progress of interferon-based optimized treatment strategies in achieving clinical cures. We also analyzed which populations can achieve clinical cures and conducted a detailed analysis of relevant virological and serological markers in screening clinical cure advantage populations and predicting clinical cure achievement. In addition, we also introduced the difficulties that may be encountered in the current pursuit of achieving a clinical cure.

Therapeutic Drug Monitoring of Voriconazole in Critically Ill Pediatric Patients: A Single-Center Retrospective Study.

Voriconazole pharmacokinetics are highly variable in pediatricpatients, and the optimal dosage has yet to be determined. The purpose of this study was to describe voriconazole pharmacokinetic and pharmacodynamic targets achieved and evaluate the efficacy and safety of voriconazole for critically ill pediatrics. This is a single-center retrospective study conducted at a pediatric intensive care unit at a tertiary/quaternary hospital. Pediatrics admitted to the pediatric intensive care unit and who received voriconazole for a proven or suspected fungal infection with at least one measured trough concentration were included. The primary outcomes included the percentage of pediatric patients who achieved the pharmacokinetic and pharmacodynamic targets. Secondary outcomes included assessing the correlation between voriconazole trough concentrations and clinical/microbiological outcomes. All statistical analyses were performed using the R statistical software and Microsoft Excel. Multiple logistic regression was used to assess the predictors of both clinical and microbiologic cures. Multiple linear regression was used to determine significant factors associated with trough concentrations. A total of 129 voriconazole trough concentrations were measured from 71 participants at steady state after at least three doses of voriconazole. The mean (± standard deviation) of the first and second trough concentrations were 2.9 (4.2) and 2.3 (3.3) mg/L, respectively. Among the first trough concentrations, only 33.8% were within the therapeutic range (1-5 mg/L), 46.5% were below the therapeutic range, and 19.7% were above the therapeutic range. A clinical cure occurred in 78% of patients, while a microbiologic cure occurred in 80% of patients. Voriconazole trough concentrations vary widely in critically ill pediatric patients and only a third of the patients achieved therapeutic concentrations with initial doses.

In Vitro Susceptibility Tests in the Context of Antifungal Resistance: Beyond Minimum Inhibitory Concentration in Candida spp.

Antimicrobial resistance is a matter of rising concern, especially in fungal diseases. Multiple reports all over the world are highlighting a worrisome increase in azole- and echinocandin-resistance among fungal pathogens, especially in Candida species, as reported in the recently published fungal pathogens priority list made by WHO. Despite continuous efforts and advances in infection control, development of new antifungal molecules, and research on molecular mechanisms of antifungal resistance made by the scientific community, trends in invasive fungal diseases and associated antifungal resistance are on the rise, hindering therapeutic options and clinical cures. In this context, in vitro susceptibility testing aimed at evaluating minimum inhibitory concentrations, is still a milestone in the management of fungal diseases. However, such testing is not the only type at a microbiologist's disposal. There are other adjunctive in vitro tests aimed at evaluating fungicidal activity of antifungal molecules and also exploring tolerance to antifungals. This plethora of in vitro tests are still left behind and performed only for research purposes, but their role in the context of invasive fungal diseases associated with antifungal resistance might add resourceful information to the clinical management of patients. The aim of this review was therefore to revise and explore all other in vitro tests that could be potentially implemented in current clinical practice in resistant and difficult-to-treat cases.

Clinical characteristics and management outcomes in isolated nail lichen planus: A retrospective case series.

Background Isolated nail lichen planus (NLP) without mucocutaneous involvement is rare. Literature about the clinical profile and management is scarce. Aims/Objective We attempted to characterize the clinico-demographic profile and analyze the management outcome of patients with isolated nail lichen planus. Methods Records of 15 patients were evaluated, and their demographic profile, clinical features of the nail matrix and nail bed disease, onychoscopy findings, histopathological features, treatment given, and follow-up progress were analysed. Results Data from 15 patients were collected. The mean age of the patients was 28.6 ± 19.0 years (range 3.5 years to 56 years). The gender ratio was 0.8 with 7 males and 8 females. The average disease duration at presentation was 2.8 ± 2.6 years (6 months-9 years). The average number of nails involved was 16.4 ± 4.6 (8-20 nails). All 20 nails were involved in 9 (60%) patients. Nail matrix -involvement was seen in all, with onychorrhexis being the most common manifestation, which was seen in 11 (73.3%) patients. Nail bed involvement was seen in 11 (73.3%) patients, with onycholysis being the most common presentation. Severe nail disease was seen in 7 (46.7%) patients, and 5 (33.3%) had pterygium involving an average of 3.4 nails. Moderate to good improvement was observed in 9 (60%) patients after an average of 6.1 ± 2.4 (3-9) treatment sessions with intramuscular and intramatricial triamcinolone acetonide injection. Of these, 2/9 (22.2%) developed disease recurrence in a few nails after an interval of 1 and 1.5 years, respectively. Two patients achieved complete clinical cures that persisted beyond 2 years of follow-up. Limitations Retrospective nature of the series and the small sample size are the major limitations. Conclusion The risk of permanent disfigurement is high in NLP and calls for an early diagnosis and prompt treatment. Intralesional and intramuscular steroids are first-line therapeutic options depending upon the number of nails involved.

Daily fosfomycin versus levofloxacin for complicated urinary tract infections.

Concerns over resistance and safety have been identified in the current treatment regimen for complicated urinary tract infections. Fosfomycin is a drug that is routinely used for the treatment of uncomplicated cystitis. This study shows that fosfomycin could be an oral alternative as step-down therapy for the treatment of complicated urinary tract infections, with a clinical cure rate comparable to levofloxacin but a lower microbiological success rate 3 weeks from start of antibiotics.

Chronic Hepatitis B Infection: Current and Emerging Therapeutic Strategies.

The chronic infection of the hepatitis B virus (CHB) represents a major public health problem worldwide. Despite the availability of an effective prophylactic vaccine, millions of hepatitis B patients are at increased risk of developing chronic liver disease. The currently available treatments for HBV infection include interferon and nucleos(t)ide analogues that are effective at suppressing viral load and preventing or delaying the progression of liver disease. However, these treatments offer somewhat unsatisfactory clinical cures due to the persistence of the intrahepatic pool of covalently closed circular DNA (cccDNA) that serves as a reservoir for viral progenies and a potential source of recurring infections. Elimination of viral cccDNA remains a challenge for scientists and pharmaceutical industries in order to achieve the eradication and control of HBV infection. This would involve a detailed understanding of the molecular mechanisms of cccDNA formation, its intracellular stability, and regulation during replication and transcription. Recent advances in drug therapy have heralded a new horizon of novel therapeutic approaches for CHB infection, with several promising antiviral and immunomodulatory agents currently in preclinical or clinical testing. However, approval of any new curative therapy would involve rigorous evaluation of the efficacy and safety of each treatment and defining correct endpoints associated with improved clinical outcomes. This article summarizes the current landscape of HBV treatments, and drugs in clinical trials and highlights the most recent anti-HBV small molecules designed to directly target HBV or to improve immune response during chronic infection.

Pediatric tinea capitis in Jilin Province: analyzing previous results from a new perspective.

To investigate the current etiological, diagnostic, and therapeutic characteristics of tinea capitis in children in Jilin Province. Sixty pediatric patients with tinea capitis were enrolled between August 2020 and December 2021. Data on calcofluor white (CFW) fluorescence microscopy, fungal culture, Wood's lamp examination, dermoscopy, treatment, and follow-up were collected and analyzed. 1. Of all the enrolled patients, 48 had a history of animal contact, mostly with cats and dogs. Fifty-one strains were isolated, of which 46 were Microsporum canis (M. canis). 2. All enrolled patients were examined using fluorescence microscopy, and 59 were positive. Forty-one cases of tinea alba were examined using Wood's lamp, and 38 were positive. Forty-two cases of tinea alba were examined using dermoscopy, and 39 demonstrated specific signs. Effective treatment manifested as a fading bright green fluorescence, decreased mycelial/spore load, reduced specific dermoscopic signs, and hair regrowth. 3. Treatment was terminated in 23 and 37 cases based on mycological and clinical cures, respectively. No recurrence occurred during follow-up. 1. M. canis is the predominant pathogen causing tinea capitis in children in Jilin Province. Animal contact is considered the main risk factor. 2. CFW fluorescence microscopy, Wood's lamp, and dermoscopy can be used to diagnose ringworms and follow-up patients. 3. Both mycological and clinical cures can be the endpoint of adequate treatment for tinea capitis.

Real-Life Data on the Effectiveness and Safety of Cefiderocol in Severely Infected Patients: A Case Series.

Real-life data about cefiderocol use to treat extensively drug-resistant bacteria are scarce. We aim to report our early experience in patients with difficult-to-treat infections and limited therapeutic options. Patients treated with cefiderocol from March 2018 to April 2022 in a tertiary-care hospital in Spain were included. Demographic, clinical, and microbiological data were collected up to 90days after the end of treatment or until death. Survival status was recorded at 30 and 90days. Ten patients were included, seven of them critically ill. Ventilator-associated pneumonia (40%) and bacteremia (40%) were the main infections. Multidrug-resistant or extensively drug-resistant P. aeruginosa was the most frequently isolated pathogen (70%, of which six patients were infected with bacteria with difficult-to-treat resistance), followed by A. baumannii, E. coli, and A. xylosoxidans (10% each). Seven patients received combination therapy. Clinical and microbiological cures were achieved in 90% and 80% of patients, respectively. Two previously susceptible strains (20%) developed resistance to cefiderocol. Overall, 30-day and 90-day mortality rates were 10% and 50%, respectively, although two out of five patients died due to the infection. No serious adverse events were reported, except for one patient who developed thrombocytopenia. Cefiderocol seems to be an effective and safe rescue therapy for patients infected with difficult-to-treat pathogens, although there is a definite risk of the emergence of resistance.

Fecal pharmacokinetics/pharmacodynamics characteristics of fidaxomicin and vancomycin against Clostridioides difficile infection elucidated by in vivo feces-based infectious evaluation models

ObjectivesThe pharmacokinetics (PK)/pharmacodynamics (PD; PK/PD) characteristics of fidaxomicin (FDX) and vancomycin (VCM) against Clostridioides difficile infection (CDI) are yet to be elucidated because of the lack of an established PK/PD analysis method for intestinal infections and unabsorbed oral drugs. Here, we developed a feces-based PK/PD analysis method and determined the fecal PK/PD index, with target values of FDX and VCM against CDI. MethodsThe antimicrobial susceptibility, time-kill curves, and post-antibiotic effects (PAEs) of FDX and VCM against C. difficile were determined in vitro. The optimal fecal PK/PD indices, with target values, were determined from the results of PK and PD studies involving 5-week-old female C57BL/6J mice infected with C. difficile ATCC® 43255. The minimum inhibitory concentration (MIC) breakpoints for C. difficile were estimated based on clinical data concerning fecal antibiotic concentrations in patients with CDI. ResultsFDX and VCM inhibited C. difficile growth via time-dependent antibacterial activity and exerted PAEs. In the CDI mouse model experiments, the changes in C. difficile load and clinical cures (72-hour survival rates and clinical sickness score grading) were most highly correlated with the ratio of area under the fecal drug concentration-time curve to MIC (AUC0→∞/MIC). The target AUC0→∞/MIC values of FDX and VCM for 3 log10 reduction in C. difficile load was 13,173 and 8,308, respectively. The MIC breakpoints of FDX and VCM for C. difficile was estimated to be 1.0 and 2.0 μg/mL, respectively. ConclusionsThe developed in vivo feces-based PK/PD analysis method elucidated the optimal fecal PK/PD index, with target values of FDX and VCM against CDI.

732. Microbiologic and clinical outcome concordance in the global phase 3 ATTACK trial: Sulbactam-durlobactam (SUL-DUR) versus colistin therapy in patients with Acinetobacter baumannii-calcoaceticus complex (ABC) infections

Abstract Background SUL-DUR is a β-lactam/β-lactamase inhibitor combination in development for the treatment of ABC, which is a cause of severe infections with substantial mortality. ATTACK evaluated the efficacy and safety of SUL-DUR versus colistin (COL) in patients with serious ABC infections. Methods Part A was a randomized, blinded non-inferiority study (SUL-DUR versus COL) in ABC pneumonia or bacteremia; Part B was an open label study (SUL-DUR only) that enrolled patients with ABC infections who did not tolerate COL or whose pathogens were resistant to COL (COL-R). All subjects received imipenem/cilastatin as background therapy. Primary endpoint included 28-day all-cause mortality (ACM) in Part A patients with carbapenem-resistant ABC at baseline (CRABC m-MITT). Clinical and microbiologic outcomes were measured at the End of Therapy (EOT), Test of Cure (TOC) and Late Follow-up (LFU) visits in CRABC m-MITT patients. In this study, COL-R was defined as MIC ≥ 4 µg/ml and SUL-DUR-non-susceptible (NS) was defined as MIC ≥ 8 µg/ml. Results SUL-DUR was non-inferior to COL in 28-day ACM; 19.0% SUL-DUR versus 32.3% in the COL group (Table 1). SUL-DUR therapy resulted in statistically significant higher clinical cures at EOT and TOC. Similarly, a significant treatment difference in microbiological favorable assessment was observed at EOT and TOC (24.4% and 26.3%, respectively, in Part A). Similar mortality differences were observed in subgroups including infection type, severity of illness, mechanical ventilation, and duration of stay of at least 5 days in the ICU prior to starting study treatment (Table 2). All 149 baseline ABC isolates from CRABC m-MITT patients were multi-drug resistant; the SUL-DUR MIC50/90 was 2/4 µg/ml (range of 0.25 – 8 µg/ml). At baseline 33% of ABC infections were polymicrobial. Conclusion In ATTACK, patients treated with SUL-DUR had lower mortality, higher clinical cure rates and significantly greater microbiologically favorable outcomes than those treated with COL. The correlation between clinical and microbiologic outcomes provides additional evidence that, if approved, SUL-DUR could be an important therapeutic option for Acinetobacter infections including carbapenem-resistant and multidrug-resistant strains. Disclosures David Altarac, MD, MPA, Entasis Therapeutics: Ownership Interest|Entasis Therapeutics: Stocks/Bonds Alita Miller, PhD, Entasis Therapeutics: Employee Sarah McLeod, PhD, Entasis Therapeutics: Employee Adam B. Shapiro, Ph.D, Entasis Therapeutics: Employee|Entasis Therapeutics: Stocks/Bonds Khurram Rana, PharmD, Entasis Therapeutics: Employee|Entasis Therapeutics: Ownership Interest|Entasis Therapeutics: Stocks/Bonds Drew Lewis, MD, MTM&H, Entasis Therapeutics: employee|Entasis Therapeutics: employee|Entasis Therapeutics: Stocks/Bonds|Entasis Therapeutics: Stocks/Bonds Gabrielle Poirier, BS, Entasis Therapeutics: Ownership Interest|Entasis Therapeutics: Stocks/Bonds Daria Chabas, BS, Entasis Therapeutics: Ownership Interest|Entasis Therapeutics: Stocks/Bonds.

Choline Kinase a Is Required for Alkylating Agent Resistance in T-Cell Acute Lymphoblastic Leukemia

Conventional chemotherapy is responsible for most clinical cures achieved in oncology, but these drugs are toxic, and resistance is a major problem. Indeed,10-20% of children and >50% of adults with T-cell acute lymphoblastic leukemia (T-ALL) exhibit resistance to front-line therapy, leading to a dismal prognosis. Improved treatment options are needed for these patients. To identify mechanisms of alkylating agent resistance, we performed a genome-wide CRISPR screen in T-ALL cells treated with the alkylating agent nitrogen mustard, the active functional group of drugs such as cyclophosphamide and melphalan. The results revealed a number of internal positive controls, including genes implicated in the Fanconi and other DNA repair pathways. This screen also implicated a role for choline kinase A (CHKA) in nitrogen mustard resistance. CHKA is best-known for its ability to catalyze phosphocholine synthesis, a key step in phosphatidylcholine biosynthesis, and has no known role in DNA damage repair. We found that CHKA shRNA knockdown induces profound sensitivity to nitrogen mustard treatment in leukemia cells (p= 0.0012), but not in normal hematopoietic progenitor CD34+ cells. This effect was rescued by restoring expression of wild-type CHKA, but not by an ATPase-deficient CHKA point mutant. This indicates that CHKA kinase activity is required for resistance. We next assessed the role of CHKA in resistance to a panel of therapeutics with distinct mechanisms of action. We found that CHKA loss induced selective sensitivity to drugs that induce bulky DNA adducts. By contrast, CHKA had little effect on drugs that induce other forms of DNA damage, such as free radical damage or double-strand DNA breaks. Studies to elucidate the mechanism through which CHKA mediates resistance to these drugs are underway. To investigate the therapeutic potential of CHKA inhibition, we tested a small molecule CHKA inhibitor (CK2) in combination with alkylating agents in a panel of patient-derived T-ALL models. In vitro, we found that the pharmacologic inhibition of CHKA is synergistic with alkylating agent treatment with a bliss score of 16.683 for PDX9 and 21.982 for PDX CBAT (score >10 indicating strong synergy). We then tested the potential of this approach in these T-ALL PDX models when engrafted in vivo in NRG mice and treated with CK2 and cyclophosphamide alone or in combination. We found that the addition of CK2 further improved the survival benefit of cyclophosphamide in this model (p= 0.0260). Taken together, our findings support a new role of choline kinase A in alkylating agent resistance in T-ALL and provide a rationale to explore the possibility of increasing the efficacy of conventional chemotherapy in the context of drug-resistant leukemias by combining CHKA inhibition with alkylating agents.

Comparative Analysis of Complicated Urinary Tract Infections Caused by Extensively Drug-Resistant Pseudomonas aeruginosa and Extended-Spectrum β-Lactamase-Producing Klebsiella pneumoniae.

The objective was to compare clinical characteristics, outcomes, and economic differences in complicated urinary tract infections (cUTI) caused by extensively drug-resistant Pseudomonas aeruginosa (XDR P. aeruginosa) and extended-spectrum beta-lactamase-producing Klebsiella pneumoniae (ESBL-K. pneumoniae). A retrospective study was conducted at a tertiary care hospital. Patients with XDR P. aeruginosa and ESBL-K. pneumoniae cUTIs were compared. The primary outcome was clinical failure at day 7 and at the end of treatment (EOT). Secondary outcomes: 30- and 90-day mortality, microbiological eradication, and economic cost. Two-hundred and one episodes were included, of which 24.8% were bloodstream infections. Patients with XDR P. aeruginosa cUTI more frequently received inappropriate empirical therapy (p < 0.001). Nephrotoxicity due to antibiotics was only observed in the XDR P. aeruginosa group (26.7%). ESBL-K. pneumoniae cUTI was associated with worse eradication rates, higher recurrence, and higher infection-related readmission. In multivariate analysis, XDR P. aeruginosa was independently associated with clinical failure on day 7 of treatment (OR 4.34, 95% CI 1.71-11.04) but not at EOT, or with mortality. Regarding hospital resource consumption, no significant differences were observed between groups. XDR P. aeruginosa cUTI was associated with worse early clinical cures and more antibiotic side effects than ESBL-K. pneumoniae infections. However, no differences in mortality or in hospitalization costs were observed.

A multicenter, retrospective study to evaluate the effectiveness, safety, and utilization patterns of super bioavailable itraconazole 50 mg in superficial dermatophytic infections

<p class="abstract"><strong>Background:</strong> Objectives of the study were to assess the clinical characteristics of patients with superficial dermatophytic infections, and to evaluate the safety and effectiveness of super bioavailable (SB) itraconazole 50 mg.</p><p class="abstract"><strong>Methods:</strong> In this cross-sectional observational study, data of patients with superficial dermatophytic infections treated as per physician’s discretion was collected retrospectively from 71 centers across India between April 2021 and March 2022. Patient’s demographics, prescribing patterns of SB-itraconazole, and clinician-rated effectiveness and safety were evaluated.<strong></strong></p><p class="abstract"><strong>Results:</strong> Of 432 analyzed patients, 72.22% (n=312) had new infections, 27.77% (n=120) had recalcitrant/recurrent infections. Majority of the patients were males (66%) and aged 21-40 years (72.45%). <em>Tinea corporis</em> (27.08%) was the most common fungal infection followed by <em>Tinea cruris</em> (20.60%). SB-itraconazole was most commonly prescribed with water (63.88%; n=276); majority (55.8%) of the patients received SB-itraconazole post-meals. Majority of the patients achieved clinical (naïve: 71.47%; recalcitrant: 79.17%) cures within 4 weeks. The efficacy was excellent/good in 71.95% of patients who received SB-itraconazole as the first choice over conventional itraconazole for overall benefits as per the clinician’s global assessment; and in 87.22% of patients who received concomitant acid-lowering drugs. Most (83.33%) patients reported excellent/good compliance with SB-itraconazole. The clinicians’ rated this newer formulation of itraconazole (SB-itraconazole) as excellent/good in efficacy (83.33%) and safety (79.17%) for most patients.</p><p class="abstract"><strong>Conclusions:</strong> SB-itraconazole was effective and safe in patients with superficial dermatophytic infections. The effectiveness of SB-itraconazole was similar with high response rates for naïve and recalcitrant cases. Further, the efficacy was excellent/good in most patients receiving SB-itraconazole as the first choice over conventional itraconazole, or who received concomitant acid-lowering drugs.</p>

Research on acute phase proteins and inflammatory cytokines biomarkers in dromedary camels (Camelus dromedarius) with clinical endometritis.

Uterine diseases are prevalent in camels and lead to economic losses because of decreased fertility. The aim of this study is to look into the expression patterns of acute-phase proteins (APPs) and inflammatory cytokines in dromedary camels with clinical endometritis (CE) to highlight their role in the immune pathogenesis of the disease. Moreover, to identify the use of these parameters as a complementary tool for CE screening as well as investigate the efficacy of ceftiofur antibiotic, APPs and inflammatory cytokines were estimated in camels with CE. Values of APPs (Hp, SAA, and Fg), pro-inflammatory (IFN-γ, TNF-α, IL-1α, IL-1β, and IL-6), and anti-inflammatory cytokines (IL-10) were higher in camels with CE than in healthy controls (P < 0.05). The strongest correlations were observed between HP and IFN-γ (r = 0.73) and IL-1β and IL-6 (r = 0.73), while the weakest correlations were observed between Fg and IFN-γ (r = 0.25). Corynebacterium pyogenes and Arcanobacterium pyogenes were the most common pathogens involved in the etiology of CE. All investigated biomarkers demonstrated a high degree of recognition between CE camel and healthy controls (AUC was > 0.90). A higher proportion of camels with CE that were treated with ceftiofur (90%, P < 0.0001) scored clinical cures after the first dose, while 10% required a second dose. In conclusion, CE causes increased APPs and inflammatory cytokine biomarkers, indicating a significant acute phase response in diseased camels with CE. These changes in biomarkers could be beneficial for understanding the immune pathogenesis of CE in dromedary camels, clinical practice, and basic clinical research.