Editorial: Process to progress? Investigative trials,mechanism and clinical science

In 2002 Helena Kraemer and colleagues published an important article on the analysis of clinical trials in mental health, which advocated a planned focus on mechanisms to investigate the processes behind treatment effects. Kraemer et al. considered not only new approaches to mediation analysis, but also a theoretical approach to factors, both pre‐treatment and during treatment, that might moderate this mediation. Trials should not just be about whether a treatment ‘worked’, but how it worked; with the results informing modification of the intervention for the next trial by discarding aspects that were not effective and reinforcing aspects that were – an iterative procedure towards greater effectiveness. Can we enjoy similar ambitions for complex interventions within mental health? It is not so long ago when the received wisdom within the clinical and much of the research community was that it was simply impossible in practice to mount randomised controlled trials relevant to the kind of psychosocial interventions we use in child and adolescent mental health (CAMHS). How different the situation is now, with burgeoning interest in a systematic evidence base for psychological treatment and the possibilities for unexpected advances (as well as unexpected harms). Nevertheless it is probably still fair to say that the systematic use of process and mechanism study within trials in our field is the exception rather than the rule. What are the possibilities and implications for our field?     

Designing a Primary Care–Based Deprescribing Intervention for Patients with Dementia and Multiple Chronic Conditions: a Qualitative Study

BackgroundPatients with dementia and multiple chronic conditions (MCC) frequently experience polypharmacy, increasing their risk of adverse drug events.ObjectivesTo elucidate patient, family, and physician perspectives on medication discontinuation and recommended language for deprescribing discussions in order to inform an intervention to increase awareness of deprescribing among individuals with dementia and MCC, family caregivers and primary care physicians. We also explored participant views on culturally competent approaches to deprescribing.DesignQualitative approach based on semi-structured interviews with patients, caregivers, and physicians.ParticipantsPatients aged ≥ 65 years with claims-based diagnosis of dementia, ≥ 1 additional chronic condition, and ≥ 5 chronic medications were recruited from an integrated delivery system in Colorado and an academic medical center in Maryland. We included caregivers when present or if patients were unable to participate due to severe cognitive impairment. Physicians were recruited within the same systems and through snowball sampling, targeting areas with large African American and Hispanic populations.ApproachWe used constant comparison to identify and compare themes between patients, caregivers, and physicians.Key ResultsWe conducted interviews with 17 patients, 16 caregivers, and 16 physicians. All groups said it was important to earn trust before deprescribing, frame deprescribing as routine and positive, align deprescribing with goals of dementia care, and respect caregivers’ expertise. As in other areas of medicine, racial, ethnic, and language concordance was important to patients and caregivers from minority cultural backgrounds. Participants favored direct-to-patient educational materials, support from pharmacists and other team members, and close follow-up during deprescribing. Patients and caregivers favored language that explained deprescribing in terms of altered physiology with aging. Physicians desired communication tips addressing specific clinical situations.ConclusionsCulturally sensitive communication within a trusted patient-physician relationship supplemented by pharmacists, and language tailored to specific clinical situations may support deprescribing in primary care for patients with dementia and MCC.Electronic supplementary materialThe online version of this article (10.1007/s11606-020-06063-y) contains supplementary material, which is available to authorized users.KEY WORDS: deprescribing, patient-physician communication, dementia     

Inhibition of insulin-like growth factor-I signaling by ethanol in neuronal cells

BACKGROUND: Ethanol inhibits insulin-like growth factor-I receptor (IGF-IR) activation. However, the potency of ethanol for inhibition of the IGF-IR and other receptor tyrosine kinases varies considerably among different cell types. We investigated the effect of ethanol on IGF-I signaling in several neuronal cell types. METHODS: IGF-I signaling was examined in SH-SY5Y neuroblastoma cells, primary cultured rat cerebellar granule neurons, and rat NG-108 neuroblastoma x glioma hybrids. The tyrosine phosphorylation of IGF-IR, IRS-2, Shc, and p42/p44 MAP kinase (MAPK), and the association of Grb-2 with Shc, were examined by immunoprecipitations and Western blotting. RESULTS: IGF-I-mediated tyrosine phosphorylation of MAPK was inhibited by ethanol in all cell lines. IGF-IR autophosphorylation was markedly inhibited by ethanol in SH-SY5Y cells, was only mildly inhibited in cerebellar granule neurons, and was unaffected in rat NG-108 cells. In vitro tyrosine autophosphorylation of immunopurified IGF-IR obtained from all cell lines was inhibited by ethanol. There was also differential ethanol sensitivity of IRS-2 and Shc phosphorylation, and the association of Shc with IRS-2, among the different cell types. CONCLUSIONS: The findings demonstrate that IGF-I-mediated MAPK activation is a sensitive target of ethanol in diverse neuronal cell types. The data are consistent with ethanol-induced inhibition of IGF-IR activity, although the extent of IGF-IR tyrosine autophosphorylation per se is a poor marker of the inhibitory action of ethanol on this receptor. Furthermore, despite uniform inhibition of MAPK in the different neuronal cell types, tyrosine phosphorylation of proximal mediators of the IGF-IR are differentially inhibited by ethanol.     

Onset of neck pain after a motor vehicle accident: a case-control study

OBJECTIVE: To assess the relative contribution of constitutional (individual) factors, pre-accident health, psychological and workplace psychosocial factors, and accident related (mechanical) factors in the development of neck pain (whiplash) following a motor vehicle accident. METHODS: We conducted a case-control study of drivers (ages 17-70 yrs) who reported a motor vehicle accident to their insurance company. A self-report mailed questionnaire retrospectively collected information on the driver's pre- and post-accident health, details of the accident, and other exposure data. Case/control status (post-accident neck pain) was ascertained using a preshaded manikin. RESULTS: In total, 26% of drivers reported post-accident neck pain. Women, younger individuals, and those with a history of neck pain were more likely to report neck pain following their accident (OR 1.50, 95% CI 0.98, 2.28; OR 1.62, 95% CI 0.96, 2.74; OR 1.75, 95% CI 1.09, 2.81, respectively). In addition, a number of accident related and psychosocial factors were independently associated with reporting post-accident neck pain: collision from behind (OR 2.55, 95% CI 1.41, 4.62); vehicle stationary at impact (OR 1.93, 95% CI 1.12, 3.33); collision severity (upper vs lowest tertile: OR 16.1, 95% CI 8.64, 30.1); not being at fault (OR 2.61, 95% CI 1.49, 4.59); and monotonous work (OR 2.19, 95% CI 1.19, 4.04). Based on these 8 factors, the likelihood of having neck pain increased from 7% with < or = 2 risk factors to 62% with > or = 5. CONCLUSION: Development of neck pain after a motor vehicle accident is a complex phenomenon resulting from the combined effects of constitutional, mechanical, and psychosocial factors. Using 8 such variables it is possible to identify those at high risk of developing neck pain.     

Mesoridazine: an open-channel blocker of human ether-a-go-go-related gene K+ channel

Mesoridazine, a phenothiazine antipsychotic agent, prolongs the QT interval of the cardiac electrocardiogram and is associated with Torsade de pointes-type arrhythmias. In this study, we examined the effects of mesoridazine on human ether-a-go-go-related gene (HERG) K+ currents. HERG channels were stably expressed in human embryonic kidney 293 cells and studied using standard whole-cell patch-clamp technique (37 degrees C). Mesoridazine blocked HERG currents in a concentration-dependent manner (IC50 550 nM at 0 mV); block increased significantly over the voltage range where HERG activates and saturated at voltages eliciting maximal HERG channel activation. Tonic block of HERG current by mesoridazine (1.8 microM) was minimal (< 2-4%). The rate of the onset of HERG channel block was rapid and dose dependent (tau = 54 +/- 7 ms at 0 mV and 1.8 microM mesoridazine), but not significantly affected by test potentials ranging from -30 to +30 mV. The V1/2 for steady-state activation was shifted from -31.2 +/- 1.0 to -39.2 +/- 0.5 mV (P < 0.01). The apparent rate of HERG channel deactivation was significantly reduced (fast tau = 153 +/- 8 vs. 102 +/- 6 ms at -50 mV, P < 0.01; slow tau = 1113 +/- 63 vs. 508 +/- 27 ms, P < 0.01). The inactivation kinetics and voltage dependence of steady-state inactivation of the HERG channel were not significantly altered by mesoridazine. These findings demonstrate that mesoridazine is a potent and rapid open-channel blocker of HERG channels. This block would explain the QT prolongation seen clinically at therapeutic concentrations (0.3-3.6 microM).     

The ratio of ELR+ to ELR- CXC chemokines affects the lung and liver injury following hepatic ischemia/ reperfusion in the rat

Hepatic ischemia/reperfusion (I/R) results in a neutrophil-dependent lung and liver injury. The process of neutrophil recruitment and activation in this injury is at least partially dependent on the presence of the ELR+ CXC chemokines. Other investigations have shown that ELR- CXC chemokines can block ELR+ CXC chemokine neutrophil recruitment and activation in vitro. To begin to investigate the role of the balance between these 2 types of molecules in vivo in neutrophil recruitment and activation following hepatic I/R, we used our rat model of lobar hepatic I/R and pretreated animals with pharmacologic doses of gamma-interferon (gamma-IFN). gamma-IFN is known to upregulate some of the ELR- CXC chemokines, including gamma-IFN-inducible protein (IP-10) and monokine-induced by gamma-IFN (MIG), as well as down-regulate ELR+ CXC chemokine production. Following hepatic I/R or sham laparotomy, hepatic and pulmonary levels of the ELR- chemokines, IP-10 and MIG, and the ELR+ chemokines, rat cytokine-induced neutrophil chemoattractant (KC), macrophage inflammatory protein-2 (MIP-2), and epithelial neutrophil activating protein (ENA-78) were determined by ELISA, and lung and liver injury were assessed. In response to gamma-IFN, hepatic and pulmonary levels of the ELR- chemokines were increased and the levels of the ELR+ chemokines were decreased. Immunohistochemical staining confirmed the hepatocyte as the source of these molecules, as well as the changes in chemokine levels in response to gamma-IFN. There was an associated significant decrease in liver and lung injury, although there was no significant decrease in neutrophil influx in either tissue. This suggests that the alteration in the balance of ELR+ to ELR- CXC chemokines results in a decrease in tissue injury through a mechanism other than through an alteration in tissue neutrophil levels.     

Microbiology of human immunodeficiency virus anorectal disease

PURPOSE: Individuals who are seropositive for the human immunodeficiency virus are at high risk for opportunistic infection and anorectal disorders. Little prospective information is available regarding anorectal pathogens in these patients. METHODS: One hundred sixty-three HIV-seropositive patients presented to the colorectal clinic between 1989 and 1992. Forty-seven (29 percent) patients were thought to have an infectious process and were prospectively studied using a standardized multiculture protocol. RESULTS: Mean age was 33 (range, 19–59) years. All were male; high-risk behavior accounted for 87 percent of HIV transmissions. Presenting complaints included anorectal pain (79 percent), pus per anum (28 percent), and blood per anum (26 percent). Examination revealed perianal tenderness (60 percent), condyloma (38 percent), perianal ulcers (38 percent), and anal fissures (34 percent). Sixty-six sets of cultures were performed; 28 patients had one set, 15 had two sets, and 4 had three sets. Thirty-two of these 47 patients (68 percent) had positive cultures including herpes (50 percent), cytomegalovirus (25 percent),Neisseria gonorrhoeae (16 percent), chlamydia (16 percent), acidfast bacilli (2 percent), and others (9 percent). Six of 32 patients with positive cultures had more than one organism cultured. Sixteen (50 percent) patients with positive cultures were treated medically, 8 (25 percent) were treated surgically and 8 (25 percent) were treated with both modalities. Sixty-one procedures were performed on 17 patients for condylomata. Eighteen patients had 20 procedures for abscesses, 50 percent of whom had positive cultures for other than common bowel flora; all improved. Fourteen patients underwent 33 procedures for perianal fistulas.Mycobacterium fortuitum was cultured from one patient who required 13 procedures for abscesses and fistulas. Forty-five (96 percent) patients were followed for an average of 12.5 months ±2.9 SEM (range, 1–94 months). Symptoms were improved or resolved in 22 of 32 (69 percent) patients with positive cultures and in 11 of 13 (84 percent) with negative cultures. CONCLUSIONS: Specific pathogens may often be identified in human immunodeficiency virus-seropositive patients with anorectal disorders if aggressively sought. Although patients without specific pathogens identified may be expected to improve with planned empiric treatment, positive identification allows more directed therapy.     

Infliximab for treatment of pyoderma gangrenosum associated with inflammatory bowel disease

OBJECTIVES: Pyoderma gangrenosum is an immune-mediated inflammatory condition characterized by ulcerative skin lesions affecting 1-2% of patients with inflammatory bowel disease (IBD). Treatment includes wound care, antibiotics, corticosteroids, and immunomodulators. However, response to therapy varies, and many patients with pyoderma gangrenosum have disease that is refractory to these agents. The aim of this study was to assess the response of medically refractory pyoderma gangrenosum to infliximab. METHODS: This was a multicenter retrospective study of patients with IBD and medically refractory pyoderma gangrenosum treated with infliximab. Data collected included the following: baseline demographics; duration of IBD; history of bowel resection; duration of skin lesions; number, size, and location of pyoderma gangrenosum lesions; prior medications; dose and number of infliximab infusions; bowel activity before and after infliximab; pyoderma gangrenosum activity before and after infliximab therapy; time to response and time to healing of pyoderma gangrenosum lesions; recurrence of pyoderma gangrenosum after infliximab; corticosteroid taper; and adverse reactions to infliximab. RESULTS: There were 13 patients with moderate to severe pyoderma gangrenosum and IBD treated with infliximab. All patients demonstrated complete healing of the skin lesions. Three patients had a complete response to induction infliximab therapy and did not require additional treatment. Ten patients responded to induction infliximab and have maintained pyoderma gangrenosum healing with infusions every 4-12 wk. All patients receiving corticosteroids were able to discontinue them completely after institution of infliximab treatment. Infliximab was well tolerated; the only treatment-related adverse events were sunburn in one patient and an infusion reaction in another. CONCLUSIONS: Infliximab is a safe and effective treatment for IBD-associated pyoderma gangrenosum.     

High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation as a treatment option in multiple sclerosis

High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic stem cell transplantation (auto-HSCT) is a new and promising approach to the treatment of multiple sclerosis (MS) patients because currently there are no effective treatment methods for this disease. In this article, we present results of a prospective clinical study of efficacy of HDIT + auto-HSCT in MS patients. The following treatment strategies were employed in the study: "early," "conventional," and "salvage/late" transplantation. Fifty patients with various types of MS were included in this study. No toxic deaths were reported among 50 MS patients; transplantation procedure was well-tolerated by the patients. The efficacy analysis was performed in 45 patients. Twenty-eight patients achieved an objective improvement of neurological symptoms, defined as at least 0.5-point decrease in the Expanded Disability Status Scale (EDSS) score as compared to the baseline and confirmed during 6 months, and 17 patients had disease stabilization (steady EDSS level as compared to the baseline and confirmed during 6 months). The progression-free survival at 6 years after HDIT + auto-HSCT was 72%. Magnetic resonance imaging data were available in 37 patients before transplantation showing disease activity in 43.3%. No active, new, or enlarging lesions were registered in patients without disease progression. In conclusion, HDIT + auto-HSCT suggests positive results in management of patients with different types of MS. Identification of treatment strategies based on the level of disability, namely "early," "conventional," and "salvage/late" transplantation, appears to be feasible to improve treatment outcomes.