Complementary/integrative healthcare utilization in US Gulf-War era veterans: Descriptive analyses based on deployment history, combat exposure, and Gulf War Illness.

Complementary and integrative health (CIH) approaches have gained empirical support and are increasingly being utilized among veterans to treat a myriad of conditions. A cluster of medically unexplained chronic symptoms including fatigue, headaches, joint pain, indigestion, insomnia, dizziness, respiratory disorders, and memory problems, often referred to as Gulf War Illness (GWI) prominently affect US Gulf War era (GWE) veterans, yet little is known about CIH use within this population. Using data collected as part of a larger study (n = 1153), we examined the influence of demographic characteristics, military experiences, and symptom severity on CIH utilization, and utilization differences between GWE veterans with and without GWI. Over half of the sample (58.5%) used at least one CIH modality in the past six months. Women veterans, white veterans, and veterans with higher levels of education were more likely to use CIH. GWE veterans with a GWI diagnosis and higher GWI symptom severity were more likely to use at least one CIH treatment in the past six months. Over three quarters (82.7%) of veterans who endorsed using CIH to treat GWI symptoms reported that it was helpful for their symptoms. Almost three quarters (71.5%) of veterans indicated that they would use at least one CIH approach if it was available at VA. Results provide a deeper understanding of the likelihood and characteristics of veterans utilizing CIH to treat health and GWI symptoms and may inform expansion of CIH modalities for GWE veterans, particularly those with GWI.

Non-invasive brain stimulation modalities for the treatment and prevention of opioid use disorder: a systematic review of the literature.

The U.S. is currently facing an unprecedented epidemic of opioid-related deaths. Despite the efficacy of the current treatments for opioid use disorder (OUD), including psychosocial interventions and medication-assisted therapy (MAT), many patients remain treatment-resistant and at high risk for overdose. A potential augmentation strategy includes the use of non-invasive brain stimulation (NIBS) techniques, such as transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and auricular vagus nerve stimulation (aVNS). These approaches may have therapeutic benefits by directly or indirectly modulating the neurocircuitry affected in OUD. In this review, we evaluate the available studies on NIBS in the context of OUD withdrawal and detoxification, maintenance, and cravings, while also considering analgesia and safety concerns. In the context of opioid withdrawal and detoxification, a percutaneous form of aVNS has positive results in open-label trials, but has not yet been tested against sham. No randomized studies have reported on the safety and efficacy of NIBS specifically for maintenance treatment in OUD. TMS and tDCS have demonstrated effects on cravings, although published studies were limited by small sample sizes. NIBS may play a role in reducing exposure to opioids and the risk of developing OUD, as demonstrated by studies using tDCS in an experimental pain condition and TMS in a post-operative setting. Overall, while the preliminary evidence and safety for NIBS in the prevention and treatment of OUD appears promising, further research is needed with larger sample sizes, placebo control, and objective biomarkers as outcome measures before strong conclusions can be drawn.

The discovery of reverse tricyclic pyridone JAK2 inhibitors. Part 2: lead optimization.

This communication discusses the discovery of novel reverse tricyclic pyridones as inhibitors of Janus kinase 2 (JAK2). By using a kinase cross screening approach coupled with molecular modeling, a unique inhibitor-water interaction was discovered to impart excellent broad kinase selectivity. Improvements in intrinsic potency were achieved by utilizing a rapid library approach, while targeted structural changes to lower lipophilicity led to improved rat pharmacokinetics. This multi-pronged approach led to the identification of 31, which demonstrated encouraging rat pharmacokinetics, in vivo potency, and excellent off-target kinase selectivity.

Advances in MRI assessment of gliomas and response to anti-VEGF therapy.

Bevacizumab is thought to normalize tumor vasculature and restore the blood-brain barrier, decreasing enhancement and peritumoral edema. Conventional measurements of tumor response rely upon dimensions of enhancing tumor. After bevacizumab treatment, glioblastomas are more prone to progress as nonenhancing tumor. The RANO (Response Assessment in Neuro-Oncology) criteria for glioma response use fluid-attenuated inversion recovery (FLAIR)/T2 hyperintensity as a surrogate for nonenhancing tumor; however, nonenhancing tumor can be difficult to differentiate from other causes of FLAIR/T2 hyperintensity (e.g., radiation-induced gliosis). Due to these difficulties, recent efforts have been directed toward identifying new biomarkers that either predict treatment response or accurately measure response of both enhancing and nonenhancing tumor shortly after treatment initiation. This will allow for earlier treatment decisions, saving patients from the adverse effects of ineffective therapies while allowing them to try alternative therapies sooner. An active area of research is the use of physiologic imaging, which can potentially detect treatment effects before changes in tumor size are evident.

The discovery of tricyclic pyridone JAK2 inhibitors. Part 1: hit to lead.

This paper describes the discovery and design of a novel class of JAK2 inhibitors. Furthermore, we detail the optimization of a screening hit using ligand binding efficiency and log D. These efforts led to the identification of compound 41, which demonstrates in vivo activity in our study.

Real-time bioluminescence imaging of polycythemia vera development in mice.

Polycythemia vera (PV) is a myeloproliferative disorder involving hematopoietic stem cells. A recurrent somatic missense mutation in JAK2 (JAK2V617F) is thought to play a causal role in PV. Therefore, targeting Jak2 will likely provide a molecular mechanism-based therapy for PV. To facilitate the development of such new and specific therapeutics, a suitable and well-characterized preclinical animal model is essential. Although several mouse models of PV have been reported, the spatiotemporal kinetics of PV formation and progression has not been studied. To address this, we created a bone marrow transplant mouse model that co-expresses mutant Jak2 and luciferase 2 (Luc2) genes. Bioluminescent imaging (BLI) was used to visualize disease cells and analyze the kinetics of PV development in vivo. To better understand the molecular mechanism of PV, we generated mice carrying a kinase inactive mutant Jak2 (Jak2K882E), demonstrating that the PV disease was dependent on constitutive activation of the Jak2 kinase activity. We further showed that the Jak2V617F mutation caused increased stem cell renewal activity and impaired cell differentiation, which was at least in part due to deregulated transcriptional programming. The Jak2V617F-Luc2 PV mice will be a useful preclinical model to characterize novel JAK2 inhibitors for the treatment of PV.