Term Treatment Research Articles

Evaluation of psychosocial functioning in the acute treatment term of major depressive disorder: A 16-week multi-centered follow-up study.

Major depressive disorder is the leading cause of non-fatal burden, and disability in adulthood. Even though depression is well-treated in the acute term,psychosocial functioning does not get back to the premorbid level most of the time. In this present study, it is aimed to evaluate the outcome of the acute term treatment of major depressive disorder in terms of psychosocial functioning. The study is an open-label, observational, multi-center follow-up study for four months of patients with major depressive disorder according to DSM-5. Patients were evaluated with Montgomery Asberg Depression Rating Scale (MADRS), Sheehan Disability Scale (SDS) and Short Form-36 (SF-36) at the beginning, and at the 2., 4., 8., 12. and 16.weeks. 100 patients were invited to the study and 56 patients completed the study.As a result of the treatment, the mean MADRS and SDS scores decreased significantly. All domains of SF-36 were improved significantly with the treatment. Unfortunately patients suffering from MDD could not reach the normative data,especially on the domains of social functioning, role emotional, pain, and general health perception. Treatment outcomes show that SNRI users presented higher scores on the domains of pain and physical functioning. However SSRI users showed better outcomes on the domains of mental health and vitality. Our research corroborated that even patients gain symptomatic remission in MDD treatment, psychosocial dysfunction persists. It is also concluded that different antidepressant options may act differently on treatment outcomes.

Real‐world persistence of erenumab for preventive treatment of chronic and episodic migraine: Retrospective real‐world study

ObjectiveTo describe the real‐world treatment persistence (defined as the continuation of medication for the prescribed treatment duration), demographics and clinical characteristics, and treatment patterns for patients prescribed erenumab for migraine prevention in Canada.BackgroundThe effectiveness of prophylactic migraine treatments is often undermined by poor treatment persistence. In clinical trials, erenumab has demonstrated efficacy and tolerability as a preventive treatment, but less is known about the longer term treatment persistence with erenumab.MethodsThis is a real‐world retrospective cohort study where a descriptive analysis of secondary patient data was conducted. Enrollment and prescription data were extracted from a patient support program for a cohort of patients prescribed erenumab in Canada between September 2018 and December 2019 and analyzed for persistence, baseline demographics, clinical characteristics, and treatment patterns. Descriptive analyses and unadjusted Kaplan–Meier (KM) curves were used to summarize the persistence and dose escalation/de‐escalation at different timepoints.ResultsData were analyzed for 14,282 patients. Median patient age was 47 years, 11,852 (83.0%) of patients were female, and 9443 (66.1%) had chronic migraine at treatment initiation. Based on KM methods, 71.0% of patients overall were persistent to erenumab 360 days after treatment initiation. Within 360 days of treatment initiation, it is estimated that 59.3% (KM‐derived) of patients who initiated erenumab at 70 mg escalated to 140 mg, and 4.4% (KM‐derived) of patients who initiated at 140 mg de‐escalated to 70 mg.ConclusionsThe majority of patients prescribed erenumab remained persistent for at least a year after treatment initiation, and most patients initiated or escalated to a 140 mg dose. These results suggest that erenumab is well tolerated, and its uptake as a new class of prophylactic treatment for migraine in real‐world clinical practice is not likely to be undermined by poor persistence when coverage for erenumab is easily available.

Glucose transporter 4 mRNA expression in subcutaneous adipose tissue of women with PCOS remains unchanged despite metformin withdrawal: is there a cellular metabolic treatment legacy effect?

Metformin induces GLUT-4 mRNA expression in insulin target tissues in PCOS. It is unclear how long this impact is sustained after withdrawal of metformin. We aimed to compare the effect of metformin withdrawal on GLUT-4 mRNA expression in subcutaneous adipose tissue after prior short (ST, 1 year, N = 11) and long term (LT, at least 3 years, N = 13) treatment in obese PCOS women. At baseline and 6 months after withdrawal, biopsy of subcutaneous adipose tissue followed by quantitative PCR analysis was performed to determine GLUT-4 mRNA expression. We found no time/effect differences in GLUT-4 mRNA expression in ST (2-dCt at baseline 0.42 (0.16-0.48) vs 2-dCt after 6 months 0.31 (0.22-0.56), p = 0.594) and no time/effect difference in LT group (2-dCt at baseline 0.24 (0.14-0.39) vs 2-dCt after 6 months 0.25 (0.20-0.38), p = 0.382). There was also no difference in GLUT-4 mRNA expression between both groups at baseline and after 6 months. In summary, 6 months after metformin withdrawal, GLUT-4 mRNA expression in subcutaneous adipose tissue remained stable, regardless of the prior treatment duration.

Risk of Progression in Chronic Phase - Chronic Myeloid Leukemia (CML) Patients Eligible for Tyrosine Kinase Inhibitor Discontinuation (TFR-PRO study): Preliminary Results

Background.Over 50% of CP-CML patients will achieve a deep molecular response (DMR) at some point during treatment with Tyrosine Kinase Inhibitors (TKI), where DMR is defined as BCR-ABL1 transcript levels lower than 1/10000 (or MR4). Treatment discontinuation (TD) in CP-CML patients with stable DMR is successful in approximately half of cases, with a relapse free survival (RFS) of 48-61% at 3 years. TD is considered safe, since MMR is achieved in almost all cases when TKI re-initiation is required. As such, treatment-free remission (TFR) is now usually attempted outside of clinical trials and is part of many CML guidelines.The progression to accelerated phase/blast crisis (AP/BC) after TD was considered virtually impossible for a long time. However, recent reports document at least six cases of disease progression after TD, some of which were fatal. These observations raise concerns about the safety of TD, since now the practice can no longer be considered completely immune from the risk of disease progression, an occurrence that drastically changes the patient situation and perspective when it develops. To best counsel patients and more safely apply TD, a precise quantification of the risk of progression in this setting is needed.Study Design and MethodsThe TFR-PRO project monitor CML patients in long term treatment and with stable DMR, followed at 28 centers in 4 different countries (Canada, Italy, Germany, Spain). Each center is expected to enroll approximately 100 patients.The following variables were measured: time adjusted rates (TAR) of molecular relapse (loss of MR3) and of progression to AP/BC; progression free and overall survival.Primary ObjectiveTo quantify the risk of progression to AP/BP, expressed as TAR, after TKI discontinuation in CML patients who undergo a first or subsequent TKI discontinuation attempt.This value will be compared to that obtained in a similar population of patients with the same characteristics who do not discontinue TKI treatment.A flexible statistical approach will allow to attribute patients to the two groups according to their decision about TKI discontinuation and to the loss of MR3.Patients eligibility includes a history of at least 3 years of TKI treatment and at least 18 months of continuous DMR.ResultsThe study opened on July 24 th,2020. Twelve centers are presently active with 303 eligible patients registered, for a total of 1614 person years available for analysis. Median follow up is 4.99 years (range 0.39-15.00 years), median age at diagnosis is 50.4 years and 47.9% patients are female. Sokal score (available in 147 patients) is low in 44.90%, intermediate in 32.65% and high in 22.45%.A total of 116 patients (38.28%) attempted TD at some point; 10 patients (3.30%) attempted TD twice. Loss of MR3 occurreded in 44/116 (37.93%) patients after TD for a TAR of 15.69/100 person years, (95% confidence interval (CI) [11.68-21.09]), but also in patients who did not attempt TD (21/187, or 11.23%), TAR: 1.83/100 person years, 95%CI [1.19-2.81], p<0.0001.No patient progressed to AP/BC and therefore the TAR of progression is 0% with an upper value of 95%CI of 1.07/100 person years for patients who attempted TD, and with an upper value of 95%CI of 0.26/100 person years for patients who did not attempt TD.ConclusionsThese preliminary results obtained in a real world scenario indicate that approximately 40% of eligible patients attempt TD. The loss of MR3 after TD seem to happen less frequently (38%) than previously reported. Patients who discontinue treatment have a significantly higher risk of losingMR3 than those who continue treatment, and the risk of progression to AP/BC is lower than 1.07/100 person years. More patients need to be enrolled in this study in order to better estimate this latter number. DisclosuresAssouline: Gilead: Speakers Bureau; Jewish General Hospital, Montreal, Quebec: Current Employment; Johnson&Johnson: Current equity holder in publicly-traded company; Novartis: Honoraria, Research Funding; Eli Lilly: Research Funding; Roche/Genentech: Research Funding; Takeda: Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; Amgen: Current equity holder in publicly-traded company, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Abruzzese: Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Elena: CELGENE: Other: funding for meeting participation; PFIZER: Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Membership on an entity's Board of Directors or advisory committees; GILEAD: Membership on an entity's Board of Directors or advisory committees. Saussele: Roche: Honoraria; Pfizer: Honoraria; Incyte: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Gambacorti-Passerini: Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy.

A Phase I/II Study of Venetoclax in Combination with ASTX727 (cedazuridine/decitabine) in Treatment‐Naïve High‐Risk Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML)

A Phase I/II Study of Venetoclax in Combination with ASTX727 (cedazuridine/decitabine) in Treatment‐Naïve High‐Risk Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML)

Lysosomal Acid Lipase a (LIPA) Modulates Leukemia Stem Cell (LSC) Response to Venetoclax/TKI Combination Therapy in Blast Phase Chronic Myeloid Leukemia

Chronic myeloid leukemia (CML) is a heterogeneous disease, initiated by reciprocal translocation of chromosome 9 and 22, resulting in the generation of a BCR-ABL fusion protein and constitutive activation of the ABL kinase. ABL tyrosine kinase inhibitors (TKIs) have been very successful in suppressing CML disease. However, TKIs may not eliminate leukemia stem cells (LSCs), as evidenced by the frequent re-emergence of the disease upon TKI discontinuation. Moreover, blast phase CML (bpCML) remains a formidable challenge in disease management. Recent clinical evidence suggests that the BCL2 inhibitor venetoclax (Ven) in combination with ABL-targeting tyrosine kinase inhibitors (TKI) can eradicate bpCML LSCs. However, the exact mechanism by which this combination may targets LSCs is not known. In this report, we confirm the efficacy and LSC-targeting capacity of Ven/TKI combination in preclinical models of bpCML and we further identify that inhibition of free fatty acid (FFA) mobilization pathways may provide enhanced efficacy against LSCs.To establish the efficacy of Ven/TKI combination, we treated bpCML samples with Ven+Dasatinib (Das) combination for 24h, this resulted in a significant decrease in the viability of bulk and primitive populations (CD34+, CD38+). Patient-derived xenografts of bpCML samples in NSGS-mice, were treated with Ven/Das as well as single agents. The result showed a significant decrease in leukemia burden in the combination treated group, compared to either drug alone, albeit, some resistant cells survived in the combo treated group. Furthermore, using a syngeneic mouse model of bpCML, co-expressing Bcr-Abl and Nup98-HOXA9 translocations, the mouse leukemic cells treated with Ven/Dasatinib combination demonstrated a significant loss of viability of the bulk as well as phenotypically defined LSCs (Lin-/Sca1+). Treatment of leukemic mice with Ven/Das had a significant survival benefit and remained disease free at 80 days post treatment. We also showed significant survival benefits of Ven/ponatinib in NSGS-mice harboring syngeneic bpCML cells with the T315I gatekeeper mutation. Treatment of normal mice with Ven/Das combo did not affect the colony forming ability of LSK cells from the bone marrow, indicating a leukemia-specific response. Based on these results, we conclude that Ven/TKI combination effects were due to direct targeting of the LSC population.To investigate the potential mechanism of Ven/TKI activity in LSC targeting, we performed gene expression studies using RNA-seq based methods after short term treatment. Our findings indicated that the LSC population from Ven/TKI-treated mice showed enrichment of a gene signature associated with lysosome biology. Pre-treatment of mouse leukemia cells with bafilomycin, an inhibitor of lysosome function, resulted in increased sensitivity to Ven/TKI combo. Intriguingly, we also found significant induction of lysosomal acid lipase (LIPA), an enzyme involved in the generation of free fatty acids for energy needs.Metabolomic analysis of LSCs isolated after short term treatment with Ven/TKI, showed that a number of fatty acids were up-regulated in the Ven/Das treated group compared to control. Knocking down Lipa using CRISPR technology resulted in increased sensitivity to Ven/TKI combination, whereas overexpression of Lipa resulted in decreased sensitivity to the Ven/TKI combination, implicating Lipa upregulation and a resultant increase in free fatty acids as a protective response to Ven/TKI treatment. Furthermore, knocking down CPT1A, an important free fatty acid mitochondrial transporter, resulted in increased sensitivity to Ven/TKI combination both in mouse and primary human leukemic cells, leading to the hypothesis that activation of fatty acid processing through enhanced Lipa activity may represent a compensatory response to venetoclax based therapies in bpCML.In summary, we demonstrate the preclinical efficacy of Ven/TKI combination therapies for targeting of bpCML LSCs. Furthermore, our data suggest that blocking upregulation of free fatty acids through mechanisms such as inhibition of LIPA activity, might synergize with Ven/TKI combinations to eradicate LSCs, allowing for more durable response. Our findings provide a therapeutic rationale for blocking pathways involved in free fatty acids generation, as a potential strategy for increasing remission duration. DisclosuresPollyea: Amgen: Consultancy; Janssen: Consultancy; Genentech: Consultancy; AbbVie: Consultancy, Research Funding; Syndax: Consultancy; Daiichi Sankyo: Consultancy; Takeda: Consultancy; Pfizer: Consultancy; Celgene/BMS: Consultancy; Agios: Consultancy; Karyopharm: Consultancy; Novartis: Consultancy; Glycomimetics: Other. Smith: Syros: Research Funding; Kura: Research Funding; Argenx: Research Funding.

Bruton's Tyrosine Kinase (BTK) Inhibitors and Autoimmune Diseases: Making Sense of BTK Inhibitor Specificity Profiles and Recent Clinical Trial Successes and Failures.

Clinical development of BTK kinase inhibitors for treating autoimmune diseases has lagged behind development of these drugs for treating cancers, due in part from concerns over the lack of selectivity and associated toxicity profiles of first generation drug candidates when used in the long term treatment of immune mediated diseases. Second generation BTK inhibitors have made great strides in limiting off-target activities for distantly related kinases, though they have had variable success at limiting cross-reactivity within the more closely related TEC family of kinases. We investigated the BTK specificity and toxicity profiles, drug properties, disease associated signaling pathways, clinical indications, and trial successes and failures for the 13 BTK inhibitor drug candidates tested in phase 2 or higher clinical trials representing 7 autoimmune and 2 inflammatory immune-mediated diseases. We focused on rheumatoid arthritis (RA), multiple sclerosis (MS), and systemic lupus erythematosus (SLE) where the majority of BTK nonclinical and clinical studies have been reported, with additional information for pemphigus vulgaris (PV), Sjogren’s disease (SJ), chronic spontaneous urticaria (CSU), graft versus host disease (GVHD), and asthma included where available. While improved BTK selectivity versus kinases outside the TEC family improved clinical toxicity profiles, less profile distinction was evident within the TEC family. Analysis of genetic associations of RA, MS, and SLE biomarkers with TEC family members revealed that BTK and TEC family members may not be drivers of disease. They are, however, mediators of signaling pathways associated with the pathophysiology of autoimmune diseases. BTK in particular may be associated with B cell and myeloid differentiation as well as autoantibody development implicated in immune mediated diseases. Successes in the clinic for treating RA, MS, PV, ITP, and GVHD, but not for SLE and SJ support the concept that BTK plays an important role in mediating pathogenic processes amenable to therapeutic intervention, depending on the disease. Based on the data collected in this study, we propose that current compound characteristics of BTK inhibitor drug candidates for the treatment of autoimmune diseases have achieved the selectivity, safety, and coverage requirements necessary to deliver therapeutic benefit.

Transgenerational Evaluation of Elateriospermum tapos Extracts on the Male Offspring of Obesity-Induced Sprague Dawley Rats

Obesity has been considered as a great public health concern, that has spread in both economic and poor resources countries. This study aimed to investigate the effect of Elateriospermum tapos supplementation on the male offspring of female obesity-induced Sprague Dawley (SD) rats at weaning and adult age. A total of thirty (30) female and fifteen (15) male Sprague Dawley rats (N=45) were purchased for this study. Of the 30 female rats, six (n=6) were randomly selected as the control group (CG) and fed separately with male on standard chow diet, while the remaining rats (n=24) were fed on a high-fat diet for 5 weeks. The obese group were further randomly divided into 4 groups, positive control group (PG), orlistat treatment (DG) at 200 mg/kg, treatment 1 (TX1, 200 mg/kg E. tapos seed) and treatment 2 (TX2, 200 mg/kg E. tapos shell) for 6 weeks. One male pup from each dam was culled at weaning (postnatal day 21 (PND21)) and adulthood (12 weeks). The liver, kidney, retroperitoneal white adipose tissue (RpWAT) and brown adipose tissue (BAT) were collected for histopathological study. Serum lipid profiles, liver enzyme activities and creatinine were measured. The bodyweight of male offspring from treatment 1 (MTX1) and 2 (MTX2) was significantly lower (P&lt;0.05) compare to MNG group. The RpWAT weight in MTX1 and MTX2 for adult offspring also were significantly lower (P&lt;0.05) compared to MPG. The histopathological examination of liver in MCG, MDG, MTX1, and MTX2 showed normal hepatocytes while the MPG group showed the presence of ballooning cell and hypertrophy of adipocytes was also observed in MPG group compared to another group’s rat. The E. tapos extracts from the shell have greater therapeutic potential on maternal obesity in short and long term treatment.

A Phase Ib Dose Escalation Trial of RO4929097 (a γ-secretase inhibitor) in Combination with Exemestane in Patients with ER + Metastatic Breast Cancer (MBC)

Preclinical studieshave demonstrated a complex cross-talk between Notch and estrogen signaling in ERα-positive breast cancer. Gamma-secretase inhibitors (GSIs) are investigational agents that block the cleavage and activation of Notch receptors. In animal models of endocrine-resistant breast cancer, combinations of tamoxifen and GSIs produce additive or synergistic efficacy, while decreasing the intestinal toxicity of GSIs. However, results of a clinical trial of a GSI-endocrine therapy combination in the metastatic setting have not been published to date, nor had the safety of such combinations been investigated with longer term treatment. We conducted a phase 1b dose escalation trial (NCT01149356) of GSI RO4929097 with exemestane in patients with ERα+, metastatic breast cancer (MBC) Study objectivesTo determine the safety, tolerability and maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of RO4929097 when administered in combination with exemestane in patients with estrogen receptor positive metastatic breast cancer ResultsWe enrolled 15 patients with MBC. Of 14 evaluable patients, one had a partial response, 6 had stable disease and 7 progressive disease. Twenty % of patients had stable disease for ≥ 6 months. Common toxicities included nausea (73.3%), anorexia (60%), hyperglycemia (53.3%), hypophosphatemia (46.7%), fatigue (66.7%) and cough (33.0%). Grade 3 toxicities were uncommon, and included hypophosphatemia (13%) and rash (6.3%). Rash was the only DLT observed at 140 mg/d. Results suggest a possible recommended phase 2 dose of 90 mg/d. Ten patients with evaluable archival tissue showed expression of PKCα, which correlated with expression of Notch4. Mammospheres from a PKCα-expressing, endocrine-resistant T47D cell line were inhibited by a GSI-fulvestrant combination ConclusionsOur data indicate that combinations including endocrine therapy and Notch inhibitors deserve further investigation in endocrine-resistant ERα-positive breast cancer.

Therapeutic activity of sarpogrelate and dopamine D2 receptor agonists on cardiovascular and renal systems in rats with alloxan-induced diabetes

BackgroundDopamine D2 receptor agonists, bromocriptine and cabergoline, are notable medications in the treatment of Parkinsonism, hyperprolactinemia, and hyperglycemia. An affiliation was found between the initiation of myocardial injury ailment and long term treatment with dopamine D2 agonist drugs identified with the partial activation of 5-hydroxytryptamine receptor 2 A (5-HT2A). The investigation aimed to examine the activity of sarpogrelate (a 5-HT2A receptor blocker) in reducing myocardial injury prompted by extended haul utilisation of D2 receptor agonists in rats with alloxan-induced diabetes.MethodsBoth bromocriptine and cabergoline were managed independently and combined with sarpogrelate for about a month in diabetic nephropathy rats. Both tail-cuff blood pressure and the BGL were recorded weekly. For all animals, the kidney hypertrophy index, serum creatinine, blood urea nitrogen, alanine transaminase, and aspartate transaminase levels were measured after one month of treatment. The severity of the cardiac injury was assessed by the estimation of lactate dehydrogenase-1 (LDH-1), cardiac troponin I, and tumor necrosis factor alpha 1 (TNF1). The triphenyltetrazolium chloride (TTC) staining method was used to determine the experimental myocardial infarction (MI) size.ResultsBromocriptine and cabergoline created a significant reduction in BGL, BP, and kidney hypertrophy index in diabetic nephropathy rats. Administration of bromocriptine and cabergoline, alone, or in combination with sarpogrelate fundamentally diminished the blood concentrations of alkaline phosphatase (ALP), Aspartate aminotransferase (AST), urea, and creatinine. Bromocriptine and cabergoline alone showed a noteworthy increase in the LDH-1, Troponin I, and TNF1 levels in the serum (p < 0.05). Paradoxically, utilising bromocriptine or cabergoline with sarpogrelate treatment altogether decreased the levels of the myocardial biomarkers in the serum. A mix of bromocriptine or cabergoline with sarpogrelate diminished the level of the myocardial infarct size in the heart assessed through the TTC staining method.ConclusionsThe examination demonstrated that the combined use of sarpogrelate with bromocriptine or cabergoline decreased the potential adverse effects of these two drugs on the myocardial tissues.

Repurposing pentosan polysulfate sodium as hyaluronic acid linked polyion complex nanoparticles for the management of osteoarthritis: A potential approach

Osteoarthritis is still a disease burden for pharmaceutical scientists and strategy makers. It is associated with the chronic inflammation of joints especially weight-bearing joints like knee, hip, backbone, and phalanges. NSAIDs that are used for the management of inflammation associated with osteoarthritis have high side effects related to gastric upset, gastric ulcer, and long term treatment associated with liver and kidney damage. Nanotechnology has gained a huge scope for the management of arthritis as it can reach out to the deep inside the cell and alter cellular physiology as desired. The present study hypothesizes the use of polyion complex nanoparticles of hyaluronic acid linked Pentosan polysulfate sodium, a disease-modifying agent for the treatment of osteoarthritis administered through transdermal route. The hypothesis involves the use of drug repurposing as the drug was initially approved for interstitial cystitis, a condition of the urinary bladder associated with pain and swelling. Being very low oral bioavailability and gastric irritation profile, the transdermal route would be beneficial. To overcome the problem associated with the oral route, there is a need for the targeted approach that will particularly reach at inflammatory sites. Thereby transdermal delivery of hyaluronic acid linked Pentosan polysulfate sodium through polyion complex nanoparticle therapy will be a novel therapeutic approach to combat osteoarthritis.

What is the Evidence for Over the Counter Laxatives to Treat Childhood Constipation?

Functional constipation is a common pediatric GI disorder that is responsible for a significant portion of pediatric office visits each year. It presents a significant stressor for patients, their families, and providers alike. There are a variety of over the counter agents available for treatment of pediatric constipation. Osmotic laxatives, such as polyethylene glycol 3350 (PEG 3350) and lactulose, remain the most effective and safe therapy for both long and short term treatment of pediatric functional constipation. Stimulant laxatives, like Senna and Bisacodyl, probiotics, fiber preparations, enemas, and suppositories make excellent choices for adjunct therapies in specific clinical scenarios. There are multiple over the counter pharmacologic agents with various mechanisms of action that have demonstrated efficacy in pediatric functional constipation. These therapies are generally safe and well tolerated by patients.

21.1 Building Remote Bridges: Mental Health Care Coordination in the COVID-19 Pandemic

We will describe the impact of a pilot clinical program providing time-limited therapeutic and case management support for patients discharging from the hospital. The Community Advocacy, Resource, and Engagement (CARE) Team is a 30-day bridge service (with the option to extend if indicated) offering care coordination, short-term therapy and medication management, phone coaching, and community advocacy for patients identified as being high risk for readmission. A sample of 98 patients were referred to the CARE Team. Data were obtained via a semi-structured phone survey and chart review. A primary outcome measure was the number of emergency department (ED) visits and mental health hospitalizations in the 60 days post–CARE Team involvement; due to the absence of a control group, we compared these events with the 60-day period before CARE Team involvement for the same population. Other outcome measures were family satisfaction and linkage to longer term treatment. The IRB at Seattle Children’s Hospital approved this study. The average age was 13 years (range = 6-17 years) and the majority of patients lived with a caregiver, although a few were in state custody. This sample presented with a broad range of diagnoses. All CARE Team patients were linked with ongoing mental health treatment; the average patient and family satisfaction rating was 4.1 on a scale of 1 to 5. There was a 31% decrease in the number of mental health hospitalizations in the 60 days post–CARE Team compared to 60 days pre-index hospitalization (from 29 to 20). We also noticed a 52% decrease in ED visits for mental health reasons not resulting in hospitalization (from 33 to 16). The average duration of services was 6.4 weeks; the COVID-19 pandemic impacted availability of services, thus extending many patients’ involvement with the team. We saw a decrease in the number of hospitalizations and ED visits after patients discharged from the CARE Team compared to before their linkage with the team. Families were satisfied with the service. Given recent trends of increasing suicidality and hospitalizations in youth, there is an enormous need for novel clinical services like the CARE Team to provide case management and therapeutic support as patients transition out of the hospital.

DELAYED DIAGNOSIS OF COCCIDIODES IMMITIS INFECTION WITH PULMONARY ABSCESS AND ARDS DIAGNOSED IN CHICAGO

TOPIC: Chest Infections TYPE: Fellow Case Reports INTRODUCTION: Coccidiodes immitis is a highly pathogenic fungus that is found in western and southern California's desert's regions. It frequently presents as a pneumonia that does not get better after anti-biotic therapy. With less than 5% of immunocompetent patient's progressing to have disseminated or severe infections (1). A disseminated Coccididiodes infection can be treated with liposomal amphotericin B, fluconazole, and steroids when there is Acute Respiratory Distress Syndrome (ARDS) (1,2). CASE PRESENTATION: In this case, a relatively healthy 80-year-old male with a past medical history of gastroesophageal reflux disease, hypertension, and hyperlipidemia who comes in shortness of breath, cough, and congestion. He had completed a course of azithromycin without resolution of symptoms. His initial chest x-ray showed a right upper lobe consolidation (Figure 1a). Bronchoscopy with transbronchial biopsies was performed which showed an acute organizing pneumonia (Figure 2). Despite antibiotic therapy and steroids, the patient did not have significant clinical improvement. So liposomal amphotericin B was started. An open lung biopsy was performed on day 14 as his chest X-ray was significantly worse with significant hypoxia (Figure 1b). Open lung biopsy showed a large abscess. A chest tube was placed. The abscess was irrigated with saline containing antibiotics. Pathology reported numerous coccidiodes spores (Figure 3). Antibiotics were discontinued. The patient's hospital course was complicated by a persistent air leak post lung biopsy and ARDS. Adjunctive steroids were added with improvement of his hypoxia. The patient was transitioned to a lower dose of steroids and to high dose fluconazole for long term treatment of his Coccidiodes infection. He was stable for placement of a tracheostomy and discharged to a long term acute care hospital (LTACH) for further care. His chest x-ray showed significant fibrosis (Figure 1c). DISCUSSION: When we re-examined the patient's history, he had a short trip to the southwestern United states for a total of 10 days with his family. This is the source of the patient's exposure. A thorough history may have helped, but urine Coccidiodes antigen testing was negative even after the open lung biopsy was performed. Despite clinical improvement, the patient passed 6 weeks after discharge to long term acute care hospital. CONCLUSIONS: Severe Coccoidiodes pulmonary infections can progress to ARDS. While, it is responsive to liposomal amphotericin B and steroids, it is still associated with a high morbidity and mortality (2). A high index of suspicion for a fungal infection should be maintained in patient's who have pneumonia refractory to antibiotic therapy. Speaking directly with the pathologist will also aide in the diagnosis of fungal infections non-endemic to the area especially like in this case (3). REFERENCE #1: Kirkland TN, Fierer J. Coccidioides immitis and posadasii; A review of their biology, genomics, pathogenesis, and host immunity. Virulence. 2018;9(1):1426-1435. doi:10.1080/21505594.2018.1509667 REFERENCE #2: Shibli M, Ghassibi J, Hajal R, O'Sullivan M. Adjunctive corticosteroids therapy in acute respiratory distress syndrome owing to disseminated coccidioidomycosis. Crit Care Med. 2002 Aug;30(8):1896-8. doi: 10.1097/00003246-200208000-00037. PMID: 12163812. REFERENCE #3: Pitcher JH, Zuckerman JB. Coccidioides Immitis Infection with Involvement of the Airway. Conn Med. 2016 Oct;80(9):539-541. PMID: 29772139 DISCLOSURES: No relevant relationships by Justin Ching, source=Web Response

Long term treatment with ataluren\u2014the Swedish experience

IntroductionAtaluren is a relatively new treatment for male patients with Duchenne muscular dystrophy (DMD) due to a premature stop codon. Long-term longitudinal data as well as efficacy data on non-ambulant patients are still lacking. Here we present the results from a long-term follow-up study of all DMD patients treated with ataluren and followed at the Queen Silvia Children’s Hospital in Gothenburg, Sweden, with focus on the evolution of patients’ upper motor and respiratory function over time.MethodsThis is a retrospective longitudinal case-series study of all male DMD patients treated with ataluren and followed at the Queen Silvia Children’s Hospital in Gothenburg, Sweden, since 2008.ResultsOur eleven patients had a median exposure to ataluren of 2312 days which is almost a fourfold higher than previous studies. Loss of ambulation occurred at a median age of 13.2 years. Patients who lost ambulation prior to 13.2 years of age had received ataluren for 5 years, whereas patients who continued to be ambulatory after 13.2 years of age had received ataluren for 6.5 years until loss of ambulation or last follow-up if still ambulatory. Four of six non ambulatory patients had Performance of the Upper Limb scores above the expected mean values over time. All but one patient maintained a pulmonary decline above the expected over time. All ambulatory patients increased in their predicted forced vital capacity (FVC) with 2.8 to 8.2% annually. Following loss of ambulation, 5 of 6 patients declined in predicted FVC (%), with annual rate of decline varying from 1.8 to 21.1%. The treatment was safe and well tolerated throughout the follow-up period.ConclusionsThis is the first study to present long-term cumulative treatment outcomes over a median period of 6.3 years on ataluren treatment. Our results indicate a delay in loss of ambulation, as well as a slower decline in FVC and upper limb motor function even after loss of ambulation. We suggest that treatment with ataluren should be initiated as soon as the diagnosis is confirmed, closely monitored and, in case of sustainable benefit, continued even after loss of ambulation.

Acute and chronic toxicity evaluation of methanol leaf extract of Psidium guajava (Myrtaceae)

The medicinal value of herbal plants have been widely described in a number of studies, this has resulted in their increased usage. This study aimed to evaluate the safety of methanolic leaf extract of Psidium guajava extract in albino rats using biochemical, hematological and histological parameters. In acute toxicity, the extract was administered orally up to 5,000 mg/kg body weight once to male albino mice. While in chronic toxicity, twenty four adult male albino rats were randomly divided into four groups of six rats for each group. The control group received 10 ml/kg body weight distilled water daily. The other groups received 50, 200 and 400 mg/kg body weight of extract daily for 90 days. All the rats were observed daily for signs of toxicity and mortality. At the end of the treatment period, biochemical and hematological tests were carried out on prepared sera. Histology of vital organs was evaluated. Acute toxicology showed the LD50 of the extract to be less than 5000 mg/kg. Chronic toxicological study revealed that at 200 mg/kg, there was no significant (P &gt; 0.05) differences in hematological and biochemical parameters, and there was no alterations in the histology of the organs. However, at 400 mg/kg body weight, the concentrations of the liver biomarkers were increased, with distorted liver. Since no alterations was observed at 200 mg/kg, the extract may be considered to be relatively safe at this dose and could be used for long term treatment of infections.

Long term treatment with omalizumab in adolescent with refractory solar urticaria

BackgroundSolar urticaria represents an uncomfortable form of chronic inducible urticaria. First and second-line treatments are ineffective in some patients, leading to an impairment in their quality of life. Omalizumab represents a safe therapeutic option in case of refractory solar urticaria.Case presentationWe update a case of a 21-year-old Caucasian girl affected by solar urticaria from the age of 14. Poor disease control was achieved with standard or high-dose of H1-antihistamines. Several omalizumab courses, including a 1-year-long course, were practiced resulting in clinical remission and significant improvement in patient’s quality of life.ConclusionOur experience confirms the effectiveness and safety of omalizumab for the management of refractory solar urticaria. Future studies are awaited in order to monitor long term effects and chronic doses of this treatment, particularly in patients who need concomitant therapy with antihistamines.

Assessment of the structural and functional characteristics of human mesenchymal stem cells associated with a prolonged exposure of morphine

The discovery of the expression of opioid receptors in the skin and their role in orchestrating the process of tissue repair gave rise to questions regarding the potential effects of clinical morphine treatment in wound healing. Although short term treatment was reported to improve tissue regeneration, in vivo chronic administration was associated to an impairment of the physiological healing process and systemic fibrosis. Human mesenchymal stem cells (hMSCs) play a fundamental role in tissue regeneration. In this regard, acute morphine exposition was recently reported to impact negatively on the functional characteristics of hMSCs, but little is currently known about its long-term effects. To determine how a prolonged treatment could impair their functional characteristics, we exposed hMSCs to increasing morphine concentrations respectively for nine and eighteen days, evaluating in particular the fibrogenic potential exerted by the long-term exposition. Our results showed a time dependent cell viability decline, and conditions compatible with a cellular senescent state. Ultrastructural and protein expression analysis were indicative of increased autophagy, suggesting a relation to a detoxification activity. In addition, the enhanced transcription observed for the genes involved in the synthesis and regulation of type I collagen suggested the possibility that a prolonged morphine treatment might exert its fibrotic potential risk, even involving the hMSCs.

The Predictive Value of Degree of Preference for Extended-Release Naltrexone for Treatment Adherence, Opioid Use, and Relapse

Background: Extended-release naltrexone (XR-NTX) is effective for illicit opioid abstinence as an opioid maintenance treatment. To improve treatment outcomes, patient’s preference for the modality of treatment is an important factor. Objectives: We aimed to test the relationship between baseline preference for XR-NTX and adherence to treatment, use of illicit opioids, and risk of relapse. Methods: In an open-label, Norwegian clinical trial participants with opioid use disorder were randomized to either monthly injections with XR-NTX or daily sublingual buprenorphine-naloxone (BP-NLX) for 12 weeks. Subsequently, participants could continue with their preferred medication in a 36-week follow-up and in a prolonged period of 104 weeks. Results: Of 153 participants who completed detoxification, 72% were men, with a mean age of 36 years. Preference levels were similar across the randomized groups, with no significant associations between preference and adherence to treatment, opioid use, or relapse. The BP-NLX group had a significantly higher risk of first relapse to opioids than the XR-NTX group for all levels of preference (p < 0.001) and a significantly higher number of days of illicit opioid use. In the follow-up period, the adherence rate was twice as high among participants with the highest preference compared to participants with the lowest preference, both among those who switched to XR-NTX and those who continued (hazard ratio 2.2; 1.2–4.0, p = 0.013). Opioid use was significantly higher among participants who switched to XR-NTX with the lowest preference than the medium (p = 0.003) or the highest (p = 0.001) preference. The risk of relapse to opioids, however, was significantly higher among XR-NTX continuing participants with the lowest (p = 0.002) or the medium (p = 0.043) preference than those with the highest preference. Conclusions: Individuals who matched with their preferred treatment used less illicit opioids than those who did not during short-term treatment. However, baseline preference for XR-NTX treatment primarily influenced longer term opioid use and treatment adherence.

OCULAR CHANGES IN PATIENTS ON LONG TREATMENT WITH HYDROXYCHLOROQUINE

Introduction: To study the ocular changes in patients on long term treatment with Hydroxychloroquine (HCQ); and detect means for early detection of toxicity.Methods: We conducted a cross-sectional observational study at a tertiary care hospital, in which 100 patients, male and female, aged 35 years or more, taking HCQ for 5 years or more were included. Patients with any known ocular or systemic diseases were not included. Indication, dosage, duration and cumulative dose of HCQ intake were recorded. History of ocular symptoms, visual acuity, colour vision, complete ophthalmic examination, visual field using Amsler grid and 10-2 Humphrey’s automated fields (HVF), Spectral Domain Optical Coherence Tomography (SD-OCT), colour fundus photography, fundus fluorescein angiography (FFA) and fundus autofluorescence (FAF) were recorded. The data was analyzed using descriptive and inferential analysis.Result: 15% of the study population showed signs of HCQ related ocular toxicity. 17%, 21% and 10% patients had abnormal SD-OCT, HVF and FAF findings respectively.Conclusion: HCQ related ocular toxicity has been found in patients in the absence of symptoms. Objective tests like HVF, SD- OCT and FAF were more useful in early detection of toxicity than subjective tests such as Amsler grid, colour vision and FFA.