Prospective validation of the Parkland Grading Scale for Cholecystitis

Background

The Parkland Grading Scale for Cholecystitis (PGS) was developed as an intraoperative grading scale to stratify gallbladder (GB) disease severity during laparoscopic cholecystectomy (LC). We aimed to prospectively validate this scale as a measure of LC outcomes.

Variables associated with subjective cognitive change among Iraq and Afghanistan war Veterans with blast-related mild traumatic brain injury

Introduction: This study investigated variables associated with subjective decline in executive function among Veterans of Operations Enduring Freedom, Iraqi Freedom, and New Dawn (OEF/OIF/OND) following a history of blast-related mild traumatic brain injury (mTBI).

Method: Fifty-six male U.S. Veterans (M_Age = 35.3 ± 8.8 years) with a history of blast-related mTBI (6.6 ± 3.2 years post injury) completed a battery of self-report questionnaires and neuropsychological measures. Participants rated current and retrospectively estimated pre-mTBI executive function difficulties on the Frontal Systems Behavior Scale (FrSBe). A difference score (post- minus pre-mTBI ratings) was the dependent variable (?FrSBe). Linear regression models examined variables predicting ?FrSBe, including: pre-injury characteristics (education, premorbid intelligence), injury-related characteristics (number of blast exposures, losses of consciousness), post-injury clinical symptoms (PTSD Checklist–Military version; Pittsburgh Sleep Quality Index), and post-injury neuropsychological performances on executive function measures (Trail Making Test Part B; Controlled Oral Word Association Test; Auditory Consonant Trigrams; Wisconsin Card Sorting Test).

Results: While 11% of participants had a clinically elevated pre-injury FrSBe total score, 82% had a clinically elevated post-injury FrSBe total score. Only self-reported PTSD symptom severity independently predicted perceived change in executive function.

Conclusions: Many OEF/OIF/OND Veterans with a history of blast-related mTBI experience subjective decline in executive function following injury. Perceived executive function decline was associated with higher PTSD symptom severity, aligning with previous research associating PTSD with cognitive complaints. Results did not support a correspondence between perceived cognitive change and neuropsychological performances.     

Model-based clinical drug development in the past,present and future: a commentary

Clinical drug development remains a mostly empirical, costly enterprise, in which decision-making is often based on qualitative assessment of risk, without properly leveraging all the relevant data collected throughout the development programme. Model-based drug development (MBDD) has been proposed by regulatory agencies, academia and pharmaceutical companies as a paradigm to modernize drug research through the quantification of risk and combination of information from different sources across time. We present here a historical account of the use of MBDD in clinical drug development, the current challenges and further opportunities for its application in the pharmaceutical industry.     

Obatoclax potentiates the cytotoxic effect of cytarabine on acute myeloid leukemia cells by enhancing DNA damage

Resistance to cytarabine and anthracycline‐based chemotherapy is a major cause of treatment failure for acute myeloid leukemia (AML) patients. Overexpression of Bcl‐2, Bcl‐xL, and/or Mcl‐1 has been associated with chemoresistance in AML cell lines and with poor clinical outcome of AML patients. Thus, inhibitors of anti‐apoptotic Bcl‐2 family proteins could be novel therapeutic agents. In this study, we investigated how clinically achievable concentrations of obatoclax, a pan‐Bcl‐2 inhibitor, potentiate the antileukemic activity of cytarabine in AML cells. MTT assays in AML cell lines and diagnostic blasts, as well as flow cytometry analyses in AML cell lines revealed synergistic antileukemic activity between cytarabine and obatoclax. Bax activation was detected in the combined, but not the individual, drug treatments. This was accompanied by significantly increased loss of mitochondrial membrane potential. Most importantly, in AML cells treated with the combination, enhanced early induction of DNA double‐strand breaks (DSBs) preceded a decrease of Mcl‐1 levels, nuclear translocation of Bcl‐2, Bcl‐xL, and Mcl‐1, and apoptosis. These results indicate that obatoclax enhances cytarabine‐induced apoptosis by enhancing DNA DSBs. This novel mechanism provides compelling evidence for the clinical use of BH3 mimetics in combination with DNA‐damaging agents in AML and possibly a broader range of malignancies.