Higher Daily Dose Research Articles

Oral Corticosteroids Dependence and Biologic Drugs in Severe Asthma: Myths or Facts? A Systematic Review of Real-World Evidence.

Airway inflammation represents an important characteristic in asthma, modulating airflow limitation and symptom control, and triggering the risk of asthma exacerbation. Thus, although corticosteroids represent the cornerstone for the treatment of asthma, severe patients may be dependent on oral corticosteroids (OCSs). Fortunately, the current humanised monoclonal antibodies (mAbs) benralizumab, dupilumab, mepolizumab, omalizumab, and reslizumab have been proven to induce an OCS-sparing effect in randomized controlled trials (RCTs), thus overcoming the problem of OCS dependence in severe asthma. Nevertheless, a large discrepancy has been recognized between selected patients enrolled in RCTs and non-selected asthmatic populations in real-world settings. It is not possible to exclude that the OCS-sparing effect of mAbs resulting from the RCTs could be different than the real effect resulting in clinical practice. Therefore, we performed a systematic review and correlation analysis to assess whether mAbs are effective in eliciting an OCS-sparing effect and overcoming the OCS dependence in severe asthmatic patients in real-world settings. Overall, real-world studies support the evidence that OCS dependence is a real condition that, however, can be found only in a small number of really severe asthmatic patients. In most patients, the dependence on OCS can be related to modifying factors that, when adequately modulated, may lead to a significant reduction or suspension of OCS maintenance. Conversely, in severe asthmatics in whom OCS resistance is proved by a high daily dose intake, mAbs allow reversion of the OCS dependence, leading to the suspension of OCS therapy in most patients or >50% reduction in the daily OCS dose.

Hematopoietic Stem Cell Transplantation May Lower the Risk of Leukemia in ELANE Neutropenia: Historical Trends from a French Severe Chronic Neutropenia Registry (FSCNR) Cohort

Context: Congenital neutropenia (CN) is associated with high leukemia risk and high risk of severe infections. The risk of leukemia depends on the genotype (ELANE , SBDS…) and also on the exposure to GCSF, which can be measured by the cumulative dose or as the mean dose received by the patient (1, 2). Since 2005, in France, patients that receive a high daily dose of GCSF, above the threshold of 15 µg/kg/day, are eligible for hematopoietic stem cell transplantation (HSCT), in addition to patients with classic indications, like myelodysplasia/acute leukemia (MDS-AL), or GCSF refractoriness (typically above 50 µg/kg/day) (3). The FSCNR prospectively monitors all patients with CN, and a genetic diagnosis is recommended for all patients with CN (4). Here, we analyzed the effect of this policy among patients with the ELANE mutation, because this group is currently one of the most heavily treated with GCSF. The GCSF dose was calculated according to a previous publication(1). The follow up of the cohort, expressed in person-years, included data from each patient, followed from birth to the last follow up visit of the study, to the date of the event (MDS-AL), or to the date of HSCT.Results: Since 1993, a total of 935 patients with chronic neutropenia were registered in France. Among those patients, 138 carried ELANE mutations, including 47 with cyclic and 91 with permanent neutropenia. Patients were grouped by whether they were born before (n=86) or after (n=52) 2005. The cumulative observation times were 1483 person-years for the 86 patients born before 2005 till 2005, and 1053 person-years for the 52 patients born after 2005 and the 80 patients born before 2005, but followed since 2005 (6 patients born before 2005 no longer contributed to the follow up after 2005, because they presented with MDS-AL or were treated with HSCT). In the entire cohort, 108 patients received GCSF at a mean dose of 9.8 µg/kg/day and 30 patients did not receive GCSF. The maximum doses were less than 5 µg/kg/day (n=38, 27%), between 5 and 10 µg/kg/day (n=30, 21%), between 10 and 30µg/kg/day (n=25), and above 30 µg/kg/day (n=15, 10%) patients. Both the mean and the maximum doses received by these patients did not change with time. Five patients were considered fully refractive (ANC < 0.2 G/l after more than 50 µg/kg/day GCSF); 16 patients received allogeneic HSCTs; and 6 patients presented with MDS-AL. The total number of HSCTs and the incidence of MDS-AL significantly changed over the study period. Before 2005, 4 out 86 patients underwent HSCTs; since 2005, 12 out 132 patients susceptible to receive a HSCT underwent transplantations (i.e., the 52 patients born after 2005 and the 80 patients born before 2005, but were followed after 2005). The rate of HSCTs per person-year increased from 2.7 10-3 to 11.4 10-3 (p<0.001). The incidence rate of MDS-AL per person-year decreased from 4 10-3 to zero (p<0.02). After 2005, HSCT was indicated for GCSF refractoriness in 3 patients and for high GCSF doses (10-30 µg/kg/day) in 9 patients. Before 2005, HSCT was indicated for MDS in 2 patients and for GCSF refractoriness in 2 patients. Noteworthy, 14 out the 16 HSCT survived. The 2 deaths observed after HSCT were related to the procedure, as one patient dyed before 2005 from sepsis and one dyed after 2005 from a refractory grade IV GVHD with Transplant-associated thrombotic microangiopathy .Conclusion: Our results supported early HSCT in patients with ELANE mutations that received high GCSF doses (15 µg/kg and more but not considered as refractory to GCSF) might lower the risk of leukemic transformation and might be benefit for the survival of the patients.Acknowledgments: The French SCN registry is supported by grants from Amgen, Chugai, Prolong Pharma, Inserm, the Association 111 les Arts, the Association RMHE, the Association Sportive de Saint Quentin Fallavier and « Le Fond de dotation Contre la Leucémie“. The authors thank the association IRIS and Mrs Grosjean and Mr Gonnot (ASSQF) for their support..Reference List1. J. Donadieu et al., Haematologica90, 45 (2005).2. P. S. Rosenberg et al., Blood107, 4628 (2006).3. L. R. Peffault de la Tour et al., Bone Marrow Transplant.50, 1168 (2015).4. J. Donadieu, O. Fenneteau, B. Beaupain, N. Mahlaoui, C. C. Bellanne, Orphanet. J. Rare. Dis.6, 26 (2011). [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

PDG1 Opioid Overdose Risk Factors and Naloxone Prescribing Among Adults Enrolled in Mississippi Medicaid

Naloxone, which is a safe, rapid-acting, and easy to use opioid antagonist medication, has become a critical tool to prevent opioid overdose deaths in recent years. The objective of this study was to describe naloxone use among patients receiving opioids enrolled in Mississippi Medicaid. A retrospective analysis was conducted using Mississippi Medicaid data from August 2018 to August 2020. Beneficiaries aged 18 and older and received opioid prescriptions were included. Receiving naloxone was defined as patients receiving any outpatient fill for a naloxone prescription. Risk factors for opioid overdose emphasized in the CDC guidelines were identified for eligible beneficiaries. A chi-square test, Fisher’s Exact test, or t-test was used to analyze differences in naloxone use among various demographic variables and risk factors. A total of 113,739 beneficiaries receiving opioids were included. Of these beneficiaries, 0.52% (597 beneficiaries) received naloxone. Beneficiaries who were between 46 and 65 years of age, African American, and covered by Magnolia health plan were more likely to receive naloxone compared with other groups (p < 0.001). Higher percentages of naloxone users had risk factors for overdose including high Morphine Equivalent Daily Dose (MEDD) use, long-term opioid use, concomitant use of benzodiazepine, concomitant use of antipsychotic, high-risk diagnosis (i.e., alcohol dependence, opioid dependence, other substance abuse dependence, and depression), and history of opioid overdose compared with non-naloxone users (p < 0.001). This study provided evidence on naloxone fills among Medicaid beneficiaries receiving opioids. The results showed that the use of naloxone was still very low, even after the emphasis of considering naloxone use for patients with risk factors in 2018. Further studies are needed to investigate the barriers contributing to the low rate of naloxone use, and interventions are needed for improving the appropriate use of naloxone.

Impact of the VA opioid safety initiative on pain management for cancer patients.

102 Background: Limited research exists on how risk reduction policies in response to the opioid epidemic have impacted pain management among cancer patients. This study investigated the impact of the Veteran’s Health Administration (VHA) Opioid Safety Initiative (OSI) on opioid prescribing patterns and opioid-related toxicity among patients undergoing definitive cancer treatment. Methods: This retrospective cohort study included 42,064 opioid-naïve patients receiving definitive local therapy for prostate, lung, breast, and colorectal cancer at the VHA from 2011-2016. Interrupted time series analysis with segmented regression was used to evaluate the impact of the OSI, which launched October 2013. The primary outcome was the incidence of new opioid prescriptions with diagnosis or treatment. Secondary outcomes included rates of high daily dose opioid (≥ 100 morphine milligram equivalent) and concomitant benzodiazepine prescriptions. Additional long-term outcomes included persistent opioid use, opioid abuse diagnoses, pain-related ED visits, and opioid-related admissions. Results: Prior to OSI implementation, the incidence of opioid prescriptions among new cancer patients increased from 26.7% (95% CI 25.0 – 28.4) in the first quarter (Q1) of 2011 to 50.6% (95% CI 48.3 – 53.0) in Q3 2013. There was a monthly increase in opioid prescription rate pre-OSI followed by a monthly decrease post-OSI (Table). High-dose opioid prescriptions were rare, and the monthly rate was stable before and after the OSI. Monthly incidence of concomitant benzodiazepine prescriptions was stable pre-OSI and decreased post-OSI. Persistent opioid use increased pre-OSI and decreased post-OSI. Pain-related ED visits had an incidence of 0.8% (95% CI 0.4 – 1.0) in Q1 2011, 0.3% (95% CI 0.1 – 0.6) in Q3 2013, and 1.8% (95% CI 0.9 – 2.7) in Q4 2016, with an increasing monthly rate after the OSI. At three years, the cumulative incidence of opioid abuse was 1.2% for both the pre- and post-OSI groups but opioid-related admissions were greater in the pre-OSI cohort than the post-OSI cohort (0.9% vs. 0.5%, p &lt; 0.001). Conclusions: The OSI was associated with a decrease in new, persistent, and certain high-risk opioid prescribing as well as an increase in pain-related ED visits. Further research on patient-centered outcomes is required to optimize opioid prescribing policies for patients with cancer.[Table: see text]

Rescue-free laxation response with methylnaltrexone treatment in cancer patients with opioid-induced constipation: The impact of baseline ECOG status.

e24083 Background: Opioid-induced constipation (OIC) is a common side effect of opioid treatment for cancer-related pain. Methylnaltrexone (MNTX) is a peripherally active µ-opioid receptor antagonist indicated for OIC that does not affect opioid central analgesia. We assessed if baseline Eastern Cooperative Oncology Group (ECOG) status impacted the rescue-free laxation (RFL) responses among cancer patients with OIC treated with repeated doses of MNTX. Methods: This pooled post hoc analysis from 2 randomized, placebo-controlled, institutional review board–approved clinical studies included cancer patients with OIC (study 302, NCT00402038; study 4000, NCT00672477). Study 302 compared subcutaneous MNTX 0.15 mg/kg vs placebo and study 4000 compared body weight‒based subcutaneous MNTX 8 mg (38–&lt; 62 kg) or 12 mg (³ 62 kg) vs placebo. The data were stratified by baseline ECOG status (&lt; 2 vs ≥ 2). Endpoints included the number of patients with RFL responses within 4 hours after ≥ 2 of the first 4 doses and the number of patients with RFL response within 4 hours of treatment for patients who received all 7 doses. Results: The intent-to-treat analysis included 43 patients with an ECOG &lt; 2 (placebo = 20; MNTX = 23) and 187 patients with an ECOG ≥ 2 (placebo = 94; MNTX = 93). Those with an ECOG &lt; 2 were younger (mean age 58 vs 65 years), predominantly male (60.5% vs 51.3%), and used a higher daily dose of oral morphine equivalent (190.7 vs 180.0 mg/d) compared with those with an ECOG ≥ 2. Cancer patients with an ECOG &lt; 2 treated with MNTX had a significantly greater RFL response within 4 hours after ≥ 2 of the first 4 doses compared with placebo (56.5% vs 5.0%, P = 0.0003). Similar results were reported for patients with an ECOG ≥ 2 (57.0% vs 5.3%, P &lt; 0.0001). Compared with placebo, the MNTX group had a greater proportion of patients with an RFL response, whether they had at least 1 RFL response or up to 7 RFL responses out of 7 doses, with significant treatment differences with each additional RFL per 7 doses among cancer patients with an ECOG ≥ 2 (Table). Conclusions: RFL response rates in cancer patients were significantly greater in the MNTX group vs the placebo group regardless of baseline ECOG status; responses were similar between the 2 groups despite a higher daily dose of opioids in the group with an ECOG &gt; 2. Clinical trial information: NCT00402038; NCT00672477. [Table: see text]

OP0286 CHARACTERISTICS ASSOCIATED WITH SEVERE COVID-19 OUTCOMES IN SYSTEMIC LUPUS ERYTHEMATOSUS (SLE): RESULTS FROM THE COVID-19 GLOBAL RHEUMATOLOGY ALLIANCE (COVID-19 GRA)

OP0286 CHARACTERISTICS ASSOCIATED WITH SEVERE COVID-19 OUTCOMES IN SYSTEMIC LUPUS ERYTHEMATOSUS (SLE): RESULTS FROM THE COVID-19 GLOBAL RHEUMATOLOGY ALLIANCE (COVID-19 GRA)

Chronic High Risk Prescription Opioid Use Among Persons With HIV.

Persons with HIV (PWH) are a population at risk for adverse sequelae of opioid use. Yet, few studies have examined correlates of chronic high risk opioid use and its impact on HIV outcomes. Trends in prescribing patterns and identification of factors that impact the use of opioid prescriptions among PWH are crucial to determine prevention and treatment interventions. This study examined electronic medical records (EMR) of patients receiving HIV care to characterize prescribing patterns and identify risk factors for chronic high risk prescription opioid use and the impact on HIV outcomes among PWH in primary care from July 1, 2016–December 31, 2017. EMR were analyzed from 8,882 patients who were predominantly male and ethnically and racially diverse with half being 50 years of age or older. The majority of the 8,744 prescriptions (98% oral and 2% transdermal preparations) given to 1,040 (12%) patients were oxycodone (71%), 8% were morphine, 7% tramadol, 4% hydrocodone, 4% codeine, 2% fentanyl, and 4% were other opioids. The number of monthly prescriptions decreased about 14% during the study period. Bivariate analyses indicated that most demographic and clinical variables were associated with receipt of any opioid prescription. After controlling for patient socio-demographic characteristics and clinical factors, the odds of receipt of any prescription were higher among patients with pain diagnoses and opioid use and mental health disorders. In addition, the odds of receipt of high average daily morphine equivalent dose (MED) prescriptions were higher for patients with pain diagnoses. Lastly, patients with substance use disorders (SUD) had an increased likelihood of detectable viral load compared to patients with no SUD, after adjusting for known covariates. Our findings show that despite opioid prescribing guidelines and monitoring systems, additional efforts are needed to prevent chronic high risk prescriptions in patients with comorbid conditions, including pain-related, mental health and substance use disorders. Evidence about the risk for chronic high risk use based on prescribing patterns could better inform pain management and opioid prescribing practices for patients receiving HIV care.

Denosumab Induced Severe Prolonged Hypocalcemia in Metastatic Prostate Cancer

Background: Denosumab is a RANK-l inhibitor that, in addition to the treatment of osteoporosis, is used in patients with advanced cancer and metastatic bone disease to prevent skeletal-related events. Although denosumab is generally safe and effective, it can cause hypocalcemia which in some patients can be severe and life threatening. We present a case of severe prolonged hypocalcemia after a single dose of denosumab in a patient with metastatic prostate cancer. Case: A 78-year-old male with a past medical history of stage 4 prostate cancer on antiandrogen treatment with GnRH antagonist presented with severe hypocalcemia. Physical exam revealed a blood pressure 125/80 mm Hg, pulse 115 per min and weight 135 lb with negative Chvostek’s and Trousseau’s signs. The electrocardiogram showed supraventricular tachycardia with prolonged QTc interval of 503 ms (<430 ms). Labs showed serum calcium 4.9mg/dL (8.5–10.5), albumin 2.5g/dL (3.6–5.1), corrected calcium 5.7 mg/dL, ionized serum calcium 0.64mmol/L (1.05–1.3), creatinine 1.10mg/dL (0.7–1.2), eGFR >60, phosphorus 2.0mg/dL (2.5–4.5), magnesium 1.9 mg/dL (1.6–2.6), 25-OH vitamin D 29.7 ng/mL (30–100), 1,25 dihydroxy vitamin D 174 pg/mL (18–64), iPTH 244.0 pg/mL (11–68) and PSA 1860 ng/mL. Three weeks prior to presentation, the patient received 120 mg of subcutaneous denosumab. Pre-treatment serum calcium was 9.2 mg/dL (8.5–10.5), and Tc-99m bone scan showed multiple osteoblastic osseous metastatic lesions involving both axial and appendicular skeleton. The patient was diagnosed with denosumab-induced severe hypocalcemia and started on intravenous (IV) calcium gluconate infusion, oral phosphate 250 mg twice daily, and ergocalciferol 50,000 IU twice weekly. He required IV calcium gluconate up to 10 g per day in addition to oral calcium carbonate 2 g t.i.d. for 2 weeks to resolve hypocalcemia and normalize QTc interval. Patient was discharged to nursing home on calcium carbonate 2 g q.i.d. with IV calcium gluconate as needed to keep corrected calcium >8.0 mg/dL. After discharge he required up to 4 g of IV calcium and 8 g of oral calcium per day. Unfortunately, he presented again with severe hypocalcemia 5 weeks after discharge. In addition to current regimen of oral and IV calcium boluses, low dose calcitriol was started. We were only able to maintain his serum calcium>8.0 mg/dL by administering high daily dose of oral calcium carbonate 8 g /day and calcitriol 2 mcg daily. Due to poor prognosis, he was transitioned to hospice care and died 2 weeks later. Discussion: There are not many case reports on severe prolonged hypocalcemia secondary to denosumab in cancer patients but normal kidney function. Our patient remained on high dose of calcium even 101 days after denosumab administration. Reference: 1. Milat F et al. Prolonged hypocalcemia following denosumab therapy in metastatic hormone refractory prostate cancer. Bone. 2013 Aug 1;55(2):305–8.

Effect of Daily Dosage of Morphine Milligram Equivalents on Free Flap Complications: A Single-Institution Retrospective Study

There appears to be an association between preoperative opioid use and postoperative complications. We sought to determine whether patients with a history of chronic opiate use (defined as 3 months or more of sustained use) prior to undergoing free flap surgery have higher rates of 30-day complications. A retrospective review of patients undergoing free flaps from 2015 to 2020 was performed. Patient characteristics were analyzed, including daily preoperative dose of opiates, which were then converted to morphine milligram equivalents; intra-operative variables such as estimated blood loss and operating room time; and 30-day outcomes, including wound and flap complications, return to the operating room, and readmissions. One hundred fifty-five patients received 160 free flaps. Of these flaps, 50/160 (31%) were performed on patients with an opiate prescription for at least three months prior to surgery. Using multivariable analysis, morphine milligram equivalents, a surrogate for opioid dose, were significantly associated with flap complications (odds ratio (OR) 1.011, 95% confidence interval (CI) 1.003-1.020, p<0.01), partial flap loss (OR 1.010, 95% CI 1.003-1.019, p<0.01), and surgical site infections (OR 1.017, 95% CI 1.007-1.027, p<0.01). Additionally, estimated blood loss was associated with partial flap loss (OR 4.838, 95% CI 1.589-14.728, p<0.006), and operating room time was also associated with flap complications (OR 1.337, 95% CI 1.152-1.150, p<0.01). Chronic preoperative opioid use is common for free flap surgery, and according to our single-center experience, higher daily doses are a risk factor for flap complications and surgical site infections. These findings add to the growing body of evidence that opioid use is a modifiable risk factor that may increase surgical morbidity.

A Placebo-Controlled, Pseudo-Randomized, Crossover Trial of Botanical Agents for Gulf War Illness: Reishi Mushroom (Ganoderma lucidum), Stinging Nettle (Urtica dioica), and Epimedium (Epimedium sagittatum)

This report is third in a three-part clinical trial series screening potential treatments for Gulf War Illness (GWI). The goal of the project was to rapidly identify agents to prioritize for further efficacy research. We used a placebo-controlled, pseudo-randomized, crossover design to test the effects of reishi mushroom (Ganoderma lucidum), stinging nettle (Uritca dioica), and epimedium (Epimedium sagittatum) in 29 men with GWI. Participants completed 30 days of symptom reports for baseline, then a botanical line consisting of 30 days of placebo, followed by 30 days each of lower-dose and higher-dose botanical. After completing a botanical line, participants were randomized to complete the protocol with another botanical, until they completed three botanical trials. GWI symptom severity, pain, and fatigue were contrasted between the four conditions (baseline, placebo, lower-dose, higher dose) using linear mixed models. GWI symptom severity was unchanged from placebo in the reishi lower-dose condition (p = 0.603), and was higher in the higher-dose condition (p = 0.012). Symptom severity was not decreased from placebo with lower-dose stinging nettle (p = 0.604), but was significantly decreased with higher-dose stinging nettle (p = 0.048). Epimedium showed no significant decreases of GWI symptoms in the lower (p = 0.936) or higher (p = 0.183) dose conditions. Stinging nettle, especially at higher daily dosages, may help reduce the symptoms of GWI. Epimedium does not appear to beneficially affect GWI symptom severity, and reishi may exaggerate symptoms in some GWI sufferers. These results are in a small sample and are preliminary. Further research is required to determine if stinging nettle is indeed helpful for the treatment of GWI, and what dosage is optimal. This trial was registered on ClinicalTrials.gov (NCT02909686).

Optimal empiric treatment for KPC-2-producing Klebsiella pneumoniae infections in critically ill patients with normal or decreased renal function using Monte Carlo simulation

BackgroundLimited clinical studies describe the pharmacodynamics of fosfomycin (FOS), tigecycline (TGC) and colistin methanesulfonate (CMS) in combination against KPC-producing Klebsiella pneumoniae (KPC-Kp). Population pharmacokinetic models were used in our study. Monte Carlo simulation was conducted to calculate probability of target attainment (PTA) and cumulative fraction of response (CFR) of each agent alone and in combination against KPC-Kp in patients with normal or decreased renal function.ResultsThe simulated regimen of FOS 6 g q8h reached ≥90% PTA against a MIC of 64 mg/L in patients with normal renal function. For patients with renal impairment, FOS 4 g q8h could provide sufficient antimicrobial coverage against a MIC of 128 mg/L. And increasing the daily dose could result to the cut-off value to 256 mg/L in decreased renal function. For TGC, conventional dosing regimens failed to reach 90% PTA against a MIC of 2 mg/L. Higher loading and daily doses (TGC 200/400 mg loading doses followed by 100 mg q12h/200 mg q24h) were needed. For CMS, none achieved 90% PTA against a MIC of 2 mg/L in normal renal function. Against KPC-Kp, the regimens of 200/400 mg loading dose followed by 100 q12h /200 mg q24h achieved > 80% CFRs regardless of renal function, followed by CMS 9 million IU loading dose followed by 4.5/3 million IU q12h in combination with FOS 8 g q8h (CFR 75–91%).ConclusionsThe use of a loading dose and high daily dose of TGC and CMS in combination with FOS can provide sufficient antimicrobial coverage against critically ill patients infected with KPC-Kp.

Cholestyramine treatment in two dogs with presumptive bile acid diarrhoea: a case report

BackgroundIn people, bile acid diarrhoea is a prevalent complication of Crohn’s disease and diarrhoea-associated irritable bowel syndrome. Affected patients typically respond to bile acid sequestrants, such as cholestyramine, but human gastroenterologists often fail to recognize bile acid diarrhoea. Consequently, bile acid diarrhoea is regarded as an underrecognized and undertreated condition in human medicine. Due to lack of diagnostic tools, clinical response to bile acid sequestrants is often used to confirm a diagnosis of bile acid diarrhoea in people.Several recent studies have shown that bile acid dysmetabolism also occurs in dogs with chronic enteropathies. It has further been shown that dogs with chronic enteropathies have significantly decreased expression of a bile acid transport protein in the ileum compared to healthy dogs, which correlates with faecal bile acid dysmetabolism. Consequently, in spite of the lack of reports in the literature, bile acid diarrhoea is likely to exist in dogs as well.Case descriptionsTwo dogs, an 8-year old Rottweiler and a 4.5-year old Siberian Husky were evaluated for chronic watery diarrhoea. Neither dog responded to dietary trials, probiotics, cyclosporine, faecal microbial transplantations or metronidazole. One of the dogs responded to high daily doses of corticosteroids, which were however associated with unacceptable side effects. The other dog was refractory to all standard treatment protocols, including cyclosporine and corticosteroids. Since none of the dogs responded satisfactorily to standard treatment or modulation of the intestinal microbiome, a suspicion of possible bile acid diarrhoea was raised. Treatment with cholestyramine, a bile acid sequestrant was initiated and resulted in marked improvement of faecal consistency, frequency of defecation and activity level in both dogs.ConclusionThis report presents two dogs with presumed bile acid diarrhoea that were successfully treated with cholestyramine. Therefore, bile acid diarrhoea should be considered as a possible diagnosis in dogs with treatment-refractory chronic diarrhoea.

Individual and structural correlates of willingness for intravenous buprenorphine treatment among people who inject sublingual buprenorphine in France

BackgroundSome people do not benefit from oral administration of opioid agonist treatment, and an intravenous (IV) formulation may be more suitable. Our objective was to evaluate the willingness of people who regularly inject sublingual buprenorphine to receive IV buprenorphine as a prescribed treatment, and to examine related correlates.MethodsWe performed a secondary analysis of data from the cross-sectional study PrebupIV, conducted in France in 2015 among 557 people who inject opioids. The study comprised questionnaires completed either face to face or online and community-based workshops. We only included participants who reported buprenorphine as their main injected drug (n = 209). Willingness to receive IV buprenorphine treatment was measured on a scale from 0 to 10. Ordinal logistic regression identified correlates of willingness. Artworks and testimonies from participants in the workshops were also used to illustrate correlates of willingness.ResultsAmong the 209 participants, the mean score (SD) for willingness to receive IV buprenorphine was 8.0 (2.8). Multivariate analysis showed that participants who reported using non-prescribed buprenorphine (AOR = 4.82, p = 0.019), a higher daily dosage of buprenorphine (AOR (for 1 mg) = 1.05, p = 0.043), and a higher number of complications due to injection (AOR = 2.28, p = 0.037), were more willing to receive IV buprenorphine treatment.ConclusionsWillingness to initiate IV buprenorphine treatment was high among people who regularly inject sublingual buprenorphine. A prescribed IV formulation could attract and retain more people into care and reduce harms associated with the injection of buprenorphine tablets.

Daylength influences reproductive success and sporophyte growth in the Arctic kelp species Alaria esculenta

Many organisms have endogenous clocks that synchronize biological processes with environmental changes, leading to optimized development and reproduction. However, certain environments, like the Arctic, pose a special challenge to circadian clocks, particularly due to extreme seasonal changes in daylength, ranging from permanent sunlight to complete darkness. Kelps seem to be well adapted to the variable environmental conditions characteristic of this region. However, daylength might affect kelp species that use circadian rhythms to control the timing of daily egg release from female gametophytes. We aimed to investigate how daylength and light intensity affect gametogenesis and reproductive success of summer-reproducing kelp species (using Alaria esculenta as a model). As daylength and temperature co-vary most of the year, we also investigated the thermal resilience of the sporophytes developed under different daylengths to understand if there is a cross-tolerance between light doses and temperature tolerance. Although continuous daylight, characteristic of Arctic summers, enhanced gametogenesis and increased gametophyte vegetative growth, and thereby the number of potential reproductive gametophyte cells, sporophyte production was higher under long (16 h light:8 h dark) and intermediate (12:12 h) days. Sporophyte growth was triggered by changing daylength from short to long days, suggesting a synchronization with annual daylength variation. High daily light doses during reproduction and early development improved subsequent sporophyte survival at high (sub)lethal temperatures, indicating cross-tolerance between light and temperature. Reproductive success in Arctic A. esculenta was hampered under continuous light, and we hypothesize that this might result from disturbance of synchronized egg release and subsequent fertilization.

PH-responsive release system of topiramate transported on silica nanoparticles by melting method

Incorporating drugs into silica matrices by the melting method can be applied to obtain drug delivery systems because they are governed by electrostatic type interactions, hydrogen bonding and hydrophilic-hydrophobic interactions between the drug and the silica surface. the melting method is an environmentally correct tool since it is free of organic solvent, low cost and with easy execution for the incorporation of drugs in silicas. Drugs delivery systems are very important for improving the treatment of chronic diseases. Topiramate (TPM) is a potent antiepileptic used in high daily doses as it has low bioavailability. In this context, silica nanoparticles (NPS) were used as an inorganic matrix for TPM transport in (in vitro) release studies. The TPM was incorporated into the NPS by hot melt loading employing a new carrier preparation methodology (NPS/TPM) using a thermobalance (by Thermogravimetry-TG) with high temperature control system. The release study using dissolution media simulating gastrointestinal at pH 1.2 (stomach) and 7.4 (intestine), showed that NPS release TPM in a prolonged and pH-responsive manner. The drug was released at intestinal pH ensuring greater absorption, allowing fewer daily doses and less adverse effects. The kinetic study demonstrated the best fit to the zero-order model proving the pH-responsive profile of the developed system.

Concomitant use of oral glucocorticoids and proton pump inhibitors and risk of osteoporotic fractures among patients with rheumatoid arthritis: a population-based cohort study

BackgroundPatients with rheumatoid arthritis (RA) commonly use oral glucocorticoids (GCs) and proton pump inhibitors (PPIs), both associated with osteoporotic fractures. We investigated the association between concomitant use of oral GCs...

Salvage Radiation Therapy for Patients With Relapsing Glioblastoma Multiforme and the Role of Slow Fractionation.

BackgroundSalvage radiation therapy (SRT) can be offered to patients with relapsing glioblastoma multiforme (GBM). Here we report our experience with a schedule extending the treatment time of SRT with the aim to prolong the cytotoxic effect of ionizing radiation while minimizing the cytotoxic hazards for the surrounding brain.Methods and PatientsFrom 2009 until 2017, 124 of 218 patients received radical resection, adjuvant chemo-radiation with photons and temozolomide (TMZ) followed by adjuvant TMZ. Re-irradiation was performed in 26 patients due to local relapse. Treatment schedules varied. Survival and molecular markers were assessed.ResultsThe median survival was respectively 12 months (9–14.5) of the 124 patients treated with tri-modal therapy and 19.2 months (14.9–24.6) for the 26 patients retreated with SRT (p=0.038). Patients who received daily fractions of 1,6 to 1,65 Gy to a total dose of >40 Gy had a median survival time of 24,6 months compared to patients treated with higher daily doses or a total dose of <40 Gy (p= 0.039), consistent with the observation that patients treated with 21–28 fractions had a median survival of 21,9 months compared to 15,8 months of patients who received 5–20 fractions (p=.0.05). Patients with Ki-67 expression of >30% seemed to perform better than patients with expression levels of ≤20% (p=0.03). MGMT methylation status, TERT promoter or ATRX mutations, overexpression of p53, p16, PD-L1, and EGFR were not prognostic.ConclusionsRe-irradiation of relapsing GBM is a highly valid treatment option. Our observation challenges hypofractionated stereotactic radiotherapy for retreatment and controlled trials on the fractionation dose for SRT are needed. Robust predictive molecular markers could be beneficial in the selection of patients for SRT.

High and low ambient temperature at night and the prescription of hypnotics.

This study investigated the association between ambient nighttime temperature and sleep problems assessed by the prescription dose of sleeping pills in South Korean adults. We used the 2002-2015 National Health Insurance Service-National Sample Cohort. A total of 711,079 adults who were 20 years old or older were included, wherein 42,858 adults (~6%) had been prescribed hypnotic medications including zolpidem (N05CF02) and triazolam (N05CD05). Ambient temperature data was calculated as the mean highest temperature of nighttime (23:00-07:00) for every month from January to December. We combined the drug-prescribed date with the administrative districts-level daily nighttime temperature between 2002 and 2015. We found that a non-linear, U-shaped relationship between nighttime temperature and hypnotic medication prescription. With an increase per 1°C temperature or an increase in a square per 1°C, the prescription dose of sleeping pills was significantly increased (both p < 0.05). At each 5°C nighttime temperature, subjects belonging to low (≤0°C and 0-5°C) or high (20-25°C and ≥25°C) temperature categories had significantly higher doses of sleeping pills than those at the reference temperature (10-15°C). Changes in nighttime temperature had a significant non-linear effect on the prescribed dosage of hypnotic medications for both adults (p < 0.0001) and the elderly (p = 0.0006). We found that either a high or low nighttime temperature was significantly associated with a high daily dose of hypnotic medications in the Korean population.

Update on Safety Profiles of Vitamins B1, B6, and B12: A Narrative Review.

The neurotropic B vitamins B1 (thiamine), B6 (pyridoxine), and B12 (cobalamin) are essential for proper functioning of the nervous system. Deficiencies may induce neurological disorders like peripheral neuropathy (PN) and mainly occur in vulnerable populations (eg, elderly, diabetics, alcoholics). As epidemiologic cohort studies raised safety concerns about vitamin B6/B12 intake being potentially associated with increased risks of hip fracture (HF) and lung cancer (LC), we explored these aspects and performed comprehensive literature searches. However, we suggest not to neglect actual high-risk factors (eg, smoking in LC, higher age in HF) by focusing on individual nutrients, but to examine the complex interaction of numerous factors involved in disease development. Because it warrants continued consideration, we also provide an update on neurotoxicity associated with vitamin B6. We consider that neurological side effects due to vitamin B6 intake are rare and only occur with high daily doses and/or longer treatment duration. The benefit-risk ratio of high-dose treatment with neurotropic B vitamins in indications like PN is therefore considered advantageous, particularly if dosing recommendations are followed and serum levels monitored.

Association of sleep disturbance and freezing of gait in Parkinson disease: prevention/delay implications.

Freezing of gait (FOG) severely impairs life quality of Parkinson disease (PD) patients. The relationship between sleep disturbance and FOG in PD remains unclear, so in this study, we aimed to investigate that relationship. First, we assessed clinical characteristics of freezers and nonfreezers among PD patients. Next, we assessed clinical characteristics of PD patients with different PDSS1 scores (score on first item of Parkinson's Disease Sleep Scale). Finally, we prospectively followed a cohort of nonfreezers from a baseline clinical visit and to a maximum of 18 months and performed a Cox regression analysis to further investigate the relationship between PDSS1 score and FOG in PD. A total of 163 participants with PD were included in the baseline analysis. The freezers had significantly worse sleep compared with the nonfreezers. The proportion of freezers in the patients with low PDSS1 score (PDSS1 < 6) was significantly higher than that in the patients with high PDSS1 score (PDSS1 ≥ 6). A total of 52 nonfreezers were prospectively followed. During a maximum 18-month follow-up, FOG incidence (73%) in the PDSS1 < 6 group was significantly higher than that (24%) in the PDSS1 ≥ 6 group (P = .008). Low PDSS1 score (hazard ratio = 4.23, 95% CI 1.64-10.92, P = .003) and high levodopa equivalent daily dose (hazard ratio = 4.18, 95% CI 1.62-10.75, P = .003) were significantly associated with an increased hazard of FOG. Our study indicated that low PDSS1 score may be a risk indicator for the development of FOG and provided important insights into potential targets for the prevention/delay of FOG in PD.