Infect Dis Ther. 2021 Oct 1. doi: 10.1007/s40121-021-00539-y. Online ahead of print.

ABSTRACT

INTRODUCTION: The findings of randomized controlled trials (RCTs), observational studies, and meta-analyses vary regarding the effectiveness and safety of combination therapy for patients with Staphylococcus aureus bacteraemia (SAB). We aimed to identify the effectiveness and safety of combination therapy in patients with SAB compared with those of monotherapy.

METHODS: We performed a systematic review and meta-analysis to compare combination therapy versus monotherapy in patients with SAB. Two authors independently searched PubMed, Embase, and the Cochrane Library of clinical trials until 17 February 2021. Any RCT comparing mortality or adverse events (AEs) of combination therapy versus monotherapy for patients with SAB was eligible. Summary risk ratios (RRs) and 95% confidence intervals (CIs) were evaluated using a random-effects model. The primary outcome was all-cause mortality at any time point. This meta-analysis is registered with the PROSPERO database (CRD42020188176) and reported according to PRISMA guidelines.

RESULTS: In total, 1906 articles were identified and screened, and 14 studies (2367 patients) were included in the meta-analysis. There was no significant difference in the risk of all-cause mortality between the two groups (RR = 1.00; 95% CI 0.83-1.20; P = 0.99; I2 = 0%). Similar results were obtained by subgroup analysis of mortality recording time, endocarditis, pathogen resistance, article publication time, number of patients, and adjuvant antibiotics. Notably, combination treatment might significantly increase the risk of drug-related AEs (RR = 1.68; 95% CI 1.06-2.66; P = 0.03; I2 = 67%) and nephrotoxicity (RR = 2.30; 95% CI 1.68-3.16; P < 0.00001; I2 = 0%), although the occurrences of AEs leading to treatment discontinuation and serious AEs were not significantly different between the two groups.

CONCLUSIONS: The meta-analysis suggested that combination therapy could not reduce mortality but might increase the risk of drug-related AEs and nephrotoxicity and should be applied very cautiously. Future studies on combined drug therapy for SAB need careful and rigorous design for specific antibiotic combinations.

PMID:34596881 | DOI:10.1007/s40121-021-00539-y

Korean J Pain. 2021 Oct 1;34(4):427-436. doi: 10.3344/kjp.2021.34.4.427.

ABSTRACT

BACKGROUND: Pharmacological and non-pharmacological therapies have been used to treat patients with chemotherapy-induced peripheral neuropathy (CIPN). However, the effect of therapies in cancer patients has yet to be investigated comprehensively. We hypothesized that cyclic thermal therapy would improve blood flow and microcirculation and improve the symptoms driven by CIPN.

METHODS: The criteria of assessment were blood volume in region of interest (ROI) in the images, and European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20 questionnaire scores. The blood volume was quantified by using red blood cell (RBC) scintigraphy. All patients were treated 10 times during 10 days. The thermal stimulations, between 15° and 41°, were repeatedly delivered to the patient's hands.

RESULTS: The total score of the questionnaires, the score of questions related to the upper limbs, the score of questions closely related to the upper limbs, and the score excluding the upper limbs questions was decreased. The blood volume was decreased, and the variance of blood volume was decreased. During cooling stimulation, the blood volume was decreased, and its variance was decreased. During warming stimulation, the blood volume was decreased, and its variance was decreased.

CONCLUSIONS: We suggest that cyclic thermal therapy is useful to alleviate CIPN symptoms by blood circulation improvement. RBC scintigraphy can provide the quantitative information on blood volume under certain conditions such as stress, as well as rest, in peripheral tissue.

PMID:34593660 | DOI:10.3344/kjp.2021.34.4.427

Sr Care Pharm. 2021 Oct 1;36(10):493-500. doi: 10.4140/TCP.n.2021.493.

ABSTRACT

Drug-induced dystonias are rare but can occur with second-generation antipsychotics. They are usually dose-related and occur soon after dose initiation. This case describes the development of dystonia after two years of olanzapine 5 mg daily in an older person with Alzheimer's dementia. The dystonia resolved after diphenhydramine treatment on day two of hospitalization, but then the patient became delirious, which was treated with lorazepam on day three. Six days after admission, she developed tremors and rigidity that self-resolved. Her dystonia resolved after 11 days. The recurrence of symptoms during the hospitalization may have been a result of the progression of her dementia. This is the first known case of a patient developing dystonia after chronic use of low-dose olanzapine. This was not characterized as tardive dystonia because the dystonia was resolved with anticholinergic medication. This case illustrates the difficulty of using anticholinergics to treat dystonias in older people, which can precipitate delirium. Choosing an alternative antipsychotic with less extrapyramidal symptom risk is challenging as she had previous trials with quetiapine and risperidone. Clozapine was deemed an unfavorable alternative, as laboratory monitoring would be burdensome. Olanzapine-induced dystonias can develop anytime during therapy. Families must balance the desire for mood stabilization with antipsychotics side effects.

PMID:34593091 | DOI:10.4140/TCP.n.2021.493

Front Public Health. 2021 Sep 13;9:696818. doi: 10.3389/fpubh.2021.696818. eCollection 2021.

NO ABSTRACT

PMID:34589461 | PMC:PMC8473612 | DOI:10.3389/fpubh.2021.696818

MMWR Morb Mortal Wkly Rep. 2021 Oct 1;70(39):1379-1384. doi: 10.15585/mmwr.mm7039e4.

ABSTRACT

On August 12, 2021, the Food and Drug Administration (FDA) amended Emergency Use Authorizations (EUAs) for the Pfizer-BioNTech and Moderna COVID-19 vaccines to authorize administration of an additional dose after completion of a primary vaccination series to eligible persons with moderate to severe immunocompromising conditions (1,2). On September 22, 2021, FDA authorized an additional dose of Pfizer-BioNTech vaccine ≥6 months after completion of the primary series among persons aged ≥65 years, at high risk for severe COVID-19, or whose occupational or institutional exposure puts them at high risk for COVID-19 (1). Results from a phase 3 clinical trial conducted by Pfizer-BioNTech that included 306 persons aged 18-55 years showed that adverse reactions after receipt of a third dose administered 5-8 months after completion of a 2-dose primary mRNA vaccination series were similar to those reported after receipt of dose 2; these adverse reactions included mild to moderate injection site and systemic reactions (3). CDC developed v-safe, a voluntary, smartphone-based safety surveillance system, to provide information on adverse reactions after COVID-19 vaccination. Coincident with authorization of an additional dose for persons with immunocompromising conditions, the v-safe platform was updated to allow registrants to enter information about additional doses of COVID-19 vaccine received. During August 12-September 19, 2021, a total of 22,191 v-safe registrants reported receipt of an additional dose of COVID-19 vaccine. Most (97.6%) reported a primary 2-dose mRNA vaccination series followed by a third dose of the same vaccine. Among those who completed a health check-in survey for all 3 doses (12,591; 58.1%), 79.4% and 74.1% reported local or systemic reactions, respectively, after dose 3, compared with 77.6% and 76.5% who reported local or systemic reactions, respectively, after dose 2. These initial findings indicate no unexpected patterns of adverse reactions after an additional dose of COVID-19 vaccine; most of these adverse reactions were mild or moderate. CDC will continue to monitor vaccine safety, including the safety of additional doses of COVID-19 vaccine, and provide data to guide vaccine recommendations and protect public health.

PMID:34591835 | DOI:10.15585/mmwr.mm7039e4

J Oncol Pharm Pract. 2021 Sep 30:10781552211035368. doi: 10.1177/10781552211035368. Online ahead of print.

ABSTRACT

PURPOSE: To evaluate adherence (as measured by the medication possession ratio) to the first ever course of oral antineoplasic treatment in cancer patients before and after the implementation of a multidisciplinary consultation program (involving an oncologist, a pharmacist, and a nurse) and to investigate the program's impact on adverse events and drug-related problems.

PATIENTS AND METHODS: In a retrospective single-center study, we compared the medication possession ratio 2 months after treatment initiation in a control group (before multidisciplinary consultation program implementation) versus an interventional group (after multidisciplinary consultation program implementation).

RESULTS: Two months after oral antineoplasic treatment initiation, the mean ± standard deviation medication possession ratio did not differ significantly when comparing the interventional (multidisciplinary consultation program) group (n = 33; 0.99 ± 0.06) with the control group (n = 64; 0.94 ± 0.16) (p = 0.062). Patients in the multidisciplinary consultation program group had fewer adverse events in general (41, vs 109 in the control group; p = 0.048) and digestive adverse events in particular (6 vs 29, respectively; p = 0.007). A total of 53 and 40 drug-related problems were identified in the control and multidisciplinary consultation program groups, respectively (p = 0.074).

CONCLUSIONS: Implementation of an multidisciplinary consultation program was not associated with a significant difference in drug adherence (as assessed by the medication possession ratio), which was good before and after implementation. The multidisciplinary consultation program was associated with a lower incidence of adverse events.

PMID:34590521 | DOI:10.1177/10781552211035368

JTO Clin Res Rep. 2021 Jul 10;2(9):100206. doi: 10.1016/j.jtocrr.2021.100206. eCollection 2021 Sep.

ABSTRACT

INTRODUCTION: Insulin-like growth factor signaling has been implicated in acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in NSCLC. This phase 1 trial (NCT02191891) investigated the combination of xentuzumab (an insulin-like growth factor-ligand neutralizing monoclonal antibody) and afatinib (an EGFR TKI) in patients with previously treated EGFR mutation-positive NSCLC.

METHODS: The trial comprised dose escalation (part A) and expansion (part B). Patients had advanced or metastatic NSCLC that had progressed on EGFR TKI monotherapy or platinum-based chemotherapy (nonadenocarcinoma only, part A) or irreversible EGFR TKI monotherapy (part B). Absence of EGFR T790M mutation was required in part B. Part A used a 3 + 3 design, with a starting dose of xentuzumab 1000 mg/wk (intravenous) and afatinib 30 mg/d (oral). Primary endpoints were the maximum tolerated dose of the combination (part A) and objective response (part B).

RESULTS: A total of 16 patients each were treated in parts A and B. Maximum tolerated dose was xentuzumab 1000 mg/wk plus afatinib 40 mg/d. No patients in part B had an objective response, but 10 had stable disease (median [range] duration of disease control: 2.3 [0.8-10.9] mo). The most common drug-related adverse events were diarrhea (75 %), paronychia (69 %), and rash (69 %) in part A and diarrhea (31 %), rash (19 %), paronychia (19 %), and fatigue (19 %) in part B.

CONCLUSIONS: There were no new safety issues; xentuzumab and afatinib could be safely coadministered. Nevertheless, the combination revealed only modest activity in patients with EGFR mutation-positive, T790M-negative NSCLC after progression on afatinib.

PMID:34590052 | PMC:PMC8474216 | DOI:10.1016/j.jtocrr.2021.100206

Drug Ther Bull. 2021 Oct;59(10):150-151. doi: 10.1136/dtb.2021.000040.

ABSTRACT

Commentary on: Maron DJ, Hochman JS, Reynolds HR, et al Initial Invasive or Conservative Strategy for Stable Coronary Disease. N Engl J Med 2020;382:1395-1407.Series co-ordinator: Dr Teck Khong, DTB Associate Editor Clinical Pharmacology, St George's, University of London, UK.

PMID:34588183 | DOI:10.1136/dtb.2021.000040

J Mater Chem B. 2021 Sep 29. doi: 10.1039/d1tb01619a. Online ahead of print.

ABSTRACT

HER2+ breast cancer is highly aggressive and proliferative even after multiple chemotherapy regimens. At present, the available clinical treatment duration of chemotherapeutic agents is limited by severe toxicity to noncancerous tissues, which are attributed to insufficient targeting. Here, we designed an active-targeted and pH-responsive liposome to improve the treatment. The ideas were as follows: (1) using liposome as a nano-delivery system for HER2 inhibitor (lapatinib; LAP) to reduce the toxicity; (2) modifying the capsule with T7 peptide for specific targeted delivery to the tumor cells, and (3) enabling the capsule with the pH-sensitive ability and triggering sustained drug release at extracellular weakly acidic microenvironment to emerge toxicity in tumors and to improve curative effects. It was found that T7 peptide-modified pH-sensitive liposome (T7-LP) was more effective and safer than free drug and unmodified liposome, and reduced drug-induced side effects and noncancerous toxicity. These results support the application potential of T7-LP in improving the efficacy of LAP in HER2+ breast cancer treatment. It might be a novel LAP formulation as a clinical agent.

PMID:34585713 | DOI:10.1039/d1tb01619a

J Gynecol Obstet Hum Reprod. 2021 Sep 25:102235. doi: 10.1016/j.jogoh.2021.102235. Online ahead of print.

ABSTRACT

AIM: To conduct a systematic review and meta-analysis of all randomized controlled trials (RCTs) that examined the maternal and neonatal outcomes of misoprostol+isosorbide mononitrate (ISMN) versus misoprostol alone (control) in promoting cervical ripening during labor induction.

METHODS: We searched five databases from inception until 05-May-2021. We assessed risk of bias of RCTs, meta-analyzed 23 endpoints, and pooled them as mean difference or risk ratio with 95% confidence interval.

RESULTS: Overall, five RCTs met the inclusion criteria, comprising 850 patients (426 and 424 patients were allocated to misoprostol+ISMN and misoprostol group, respectively). Overall, the RCTs had a low risk of bias. Pertaining to maternal delivery-related outcomes, there was no significant difference between both groups regarding the mean interval from drug administration to delivery, rate of vaginal delivery, rate of cesarean section delivery, and rate of need for oxytocin augmentation. Pertaining to maternal drug-related side effects, the rate of maternal headache was significantly higher in disfavor of the misoprostol+ISMN compared with misoprostol alone. However, the rates of maternal nausea, hypotension, flushing, palpitation, dizziness, postpartum hemorrhage, and uterine tachysystole did not differ between both groups. Pertaining to neonatal outcomes, there was no significant difference between both groups regarding rates of NICU admission, meconium-stained amniotic fluid, and Apgar score <7 at five minutes.

CONCLUSION: Compared with misoprostol alone, co-administration of misoprostol+ISMN did not correlate with superior maternal delivery-related outcomes. The rate of maternal headache was significantly higher in disfavor of the misoprostol+ISMN group. There was no significant difference between both groups regarding neonatal endpoints.

PMID:34583026 | DOI:10.1016/j.jogoh.2021.102235

J Infect Chemother. 2021 Sep 20:S1341-321X(21)00259-2. doi: 10.1016/j.jiac.2021.09.010. Online ahead of print.

ABSTRACT

A 60-year-old man presented with dyspnea four days after the second dose of the coronavirus disease (COVID-19) vaccine. Imaging revealed extensive ground-glass opacification. Blood tests were notable for elevated KL-6 levels. Bronchoalveolar lavage fluid analysis showed increased lymphocyte-dominant inflammatory cells and decreased CD4/CD8 ratio. These findings were consistent with the diagnosis of drug-induced interstitial lung disease (DIILD). To the best of our knowledge, this has never been reported in previous literature. Treatment with glucocorticoids relieved his symptoms. This paper highlights that although extremely rare, COVID-19 vaccine could cause DIILD, and early diagnosis and treatment are crucial to improve patient outcomes.

PMID:34580010 | DOI:10.1016/j.jiac.2021.09.010

Medicina (Kaunas). 2021 Aug 31;57(9):914. doi: 10.3390/medicina57090914.

ABSTRACT

Background and Objectives: Treatment for elderly (aged ≥75 years) patients with rheumatoid arthritis (RA) is important because they usually have several complications and organ dysfunction and are more susceptible to drug-related adverse events. Abatacept (ABT) treatment is relatively safe in elderly RA patients; however, the real-world data of efficacy and long-term retention of ABT is sparse in such patients. This study aimed to investigate the clinical efficacy and long-term retention rates of ABT in elderly Japanese RA patients. Materials and Methods: This 10-year retrospective observational cohort study was performed in two centers in Fukushima, Japan. We reviewed the clinical features of elderly RA patients who received ABT and investigated the differences in retention rates with concomitant administration of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Results: The clinical characteristics of younger (<75 years old, 39 cases) and elderly (≥75 years old, 20 cases) RA patients were generally similar. Although the efficacy was also similar, the concomitant administration of csDMARDs with ABT differed between the two groups. Younger patients significantly decreased methotrexate (MTX) administration than elderly patients (p < 0.01), and elderly patients significantly received tacrolimus (TAC) (p < 0.01) or salazosulfapyridine (SASP; p = 0.01) than younger patients. The overall retention and infection-free survival rates were similar between the two groups. Conclusion: Elderly RA patients showed sustained retention rates compared to younger RA patients. TAC and SASP can help to maintain sustained retention rates in elderly RA patients.

PMID:34577837 | DOI:10.3390/medicina57090914

Pharmaceuticals (Basel). 2021 Aug 29;14(9):873. doi: 10.3390/ph14090873.

ABSTRACT

mRNA-based COVID-19 vaccines such as BNT162b2 have recently been a target of anti-vaccination campaigns due to their novelty in the healthcare industry; nevertheless, these vaccines have exhibited excellent results in terms of efficacy and safety. As a consequence, they acquired the first approvals from drug regulators and were deployed at a large scale among priority groups, including healthcare workers. This phase IV study was designed as a nationwide cross-sectional survey to evaluate the post-vaccination side effects among healthcare workers in Slovakia. The study used a validated self-administered questionnaire that inquired about participants' demographic information, medical anamneses, COVID-19-related anamnesis, and local, systemic, oral, and skin-related side effects following receiving the BNT162b2 vaccine. A total of 522 participants were included in this study, of whom 77% were females, 55.7% were aged between 31 and 54 years, and 41.6% were from Banska Bystrica. Most of the participants (91.6%) reported at least one side effect. Injection site pain (85.2%) was the most common local side effect, while fatigue (54.2%), headache (34.3%), muscle pain (28.4%), and chills (26.4%) were the most common systemic side effects. The reported side effects were of a mild nature (99.6%) that did not require medical attention and a short duration, as most of them (90.4%) were resolved within three days. Females and young adults were more likely to report post-vaccination side effects; such a finding is also consistent with what was previously reported by other phase IV studies worldwide. The role of chronic illnesses and medical treatments in post-vaccination side effect incidence and intensity requires further robust investigation among large population groups.

PMID:34577573 | DOI:10.3390/ph14090873

Cancers (Basel). 2021 Sep 21;13(18):4731. doi: 10.3390/cancers13184731.

ABSTRACT

Despite multimodal treatment with surgery and radiochemotherapy, the prognosis of glioblastoma remains poor, and practically all glioblastomas relapse. To date, no standard treatment exists for recurrent glioblastoma patients and traditional therapies have showed limited efficacy. Regorafenib is an oral multi-targeted tyrosine kinase inhibitor showing encouraging benefits in recurrent GBM patients enrolled in the REGOMA trial. We performed a large study to investigate clinical outcomes and the safety of regorafenib in a real-life population of recurrent glioblastoma patients. Patients receiving regorafenib outside clinical trials at the Veneto Institute of Oncology were retrospectively reviewed. The major inclusion criteria were: histologically confirmed diagnosis of glioblastoma, prior first line therapy according to "Stupp protocol", Eastern Cooperative Oncology Group (ECOG) performance status score ≤1. According to the original schedule, patients received regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle. The primary endpoints of the study were overall survival and safety. A total of 54 consecutive patients were enrolled. The median age was 56, MGMT methylated status was found in 28 out of 53 available patients (52.8%), IDH mutation in 5 (9.3%) and 22 patients were receiving steroids at baseline. The median overall survival was 10.2 months (95% CI, 6.4-13.9), the OS-12 was 43%. Age, MGMT methylation status and steroid use at baseline were not statistically significant on a multivariate analysis for OS. Patients reporting a disease control as best response to regorafenib demonstrated a significant longer survival (24.8 months vs. 6.2 months for patients with progressive disease, p = 0.0001). Grade 3 drug-related adverse events occurred in 10 patients (18%); 1 patient (2%) reported a grade 4 adverse event (rash maculo-papular). No death was considered to be drug-related. This study reported the first large "real-life" experience of regorafenib in recurrent glioblastoma. Overall, our results are close to the ones reported in the previous phase 2 study, despite the fact that we had a longer survival. We showed the encouraging activity and tolerability of this treatment in recurrent glioblastoma patients when used as a second-line treatment.

PMID:34572958 | DOI:10.3390/cancers13184731

Toxins (Basel). 2021 Sep 10;13(9):641. doi: 10.3390/toxins13090641.

ABSTRACT

Human botulism can be caused by botulinum neurotoxin (BoNT) serotypes A to G. Here, we present an antibody-based antitoxin composed of four human monoclonal antibodies (mAbs) against BoNT/C, BoNT/D, and their mosaic toxins. This work built on our success in generating protective mAbs to BoNT /A, B and E serotypes. We generated mAbs from human immune single-chain Fv (scFv) yeast-display libraries and isolated scFvs with high affinity for BoNT/C, BoNT/CD, BoNT/DC and BoNT/D serotypes. We identified four mAbs that bound non-overlapping epitopes on multiple serotypes and mosaic BoNTs. Three of the mAbs underwent molecular evolution to increase affinity. A four-mAb combination provided high-affinity binding and BoNT neutralization of both serotypes and their mosaic toxins. The mAbs have potential utility as therapeutics and as diagnostics capable of recognizing and neutralizing BoNT/C and BoNT/D serotypes and their mosaic toxins. A derivative of the four-antibody combination (NTM-1634) completed a Phase 1 clinical trial (Snow et al., Antimicrobial Agents and Chemotherapy, 2019) with no drug-related serious adverse events.

PMID:34564645 | DOI:10.3390/toxins13090641

J Antimicrob Chemother. 2021 Sep 25:dkab359. doi: 10.1093/jac/dkab359. Online ahead of print.

ABSTRACT

OBJECTIVES: Potential interactions between CYP3A4 inhibitors and γ-hydroxybutyric acid (GHB) have been suggested as a possible explanation for cases of GHB overdose in recent years among people living with HIV engaged in chemsex. Our objective was to assess the effect of cobicistat on the pharmacokinetics of GHB.

METHODS: Fifteen healthy adults were enrolled in this randomized, double-blind, placebo-controlled, two-arm, crossover clinical trial. Participants underwent two 5 day treatment periods with at least a 1 week washout period between them. In each treatment period, participants received cobicistat (150 mg q24h orally) or matched placebo. On day 5 of each treatment period, participants were given a single oral dose of GHB (25 mg/kg). Plasma concentrations of GHB, subjective effects, blood pressure, heart rate and oxygen saturation were monitored for 5 h after dosing. GHB pharmacokinetic and pharmacodynamic parameters were calculated for each participant during each study period by non-compartmental analysis and were compared using linear mixed-effects models. The study was registered at https://www.clinicaltrialsregister.eu (Eudra-CT number 2019-002122-71) and at https://clinicaltrials.gov (NCT04322214).

RESULTS: Ten participants completed the two study periods. No drug-related adverse events that necessitated subject withdrawal or medical intervention occurred during the study. Compared with placebo, none of the primary pharmacokinetic parameters of GHB was substantially changed by the administration of GHB with cobicistat. Similarly, no differences regarding subjective or physiological effects were observed when GHB was administered alone or with cobicistat.

CONCLUSIONS: Neither pharmacokinetic nor pharmacodynamic drug-drug interactions between cobicistat and GHB were identified in this study.

PMID:34561695 | DOI:10.1093/jac/dkab359

Dermatol Clin. 2021 Oct;39(4):653-673. doi: 10.1016/j.det.2021.05.016. Epub 2021 May 31.

ABSTRACT

In 2021, we entered a new phase of the COVID-19 pandemic. As mass vaccinations are underway and more vaccines are approved, it is important to recognize cutaneous adverse events. We review the dermatologic manifestations of COVID-19 vaccines as reported in clinical trial data and summarize additional observational reports of skin reactions to COVID-19 vaccines. Early-onset local injection reactions were the most common cutaneous side effects observed in clinical trials; delayed injection reactions were the most common cutaneous side effect reported outside of clinical trials. Understanding the landscape of cutaneous manifestations to COVID-19 vaccines is key to providing appropriate vaccine guidance.

PMID:34556254 | PMC:PMC8165093 | DOI:10.1016/j.det.2021.05.016

Compr Physiol. 2021 Sep 23;11(4):1-31. doi: 10.1002/cphy.c210006.

ABSTRACT

We review the known physiological mechanisms underpinning all of pain processing, sleep regulation, and pharmacology of analgesics prescribed for chronic pain. In particular, we describe how commonly prescribed analgesics act in sleep-wake neural pathways, with potential unintended impact on sleep and/or wake function. Sleep disruption, whether pain- or drug-induced, negatively impacts quality of life, mental and physical health. In the context of chronic pain, poor sleep quality heightens pain sensitivity and may affect analgesic function, potentially resulting in further analgesic need. Clinicians already have to consider factors including efficacy, abuse potential, and likely side effects when making analgesic prescribing choices. We propose that analgesic-related sleep disruption should also be considered. The neurochemical mechanisms underlying the reciprocal relationship between pain and sleep are poorly understood, and studies investigating sleep in those with specific chronic pain conditions (including those with comorbidities) are lacking. We emphasize the importance of further work to clarify the effects (intended and unintended) of each analgesic class to inform personalized treatment decisions in patients with chronic pain. © 2021 American Physiological Society. Compr Physiol 11:1-31, 2021.

PMID:34558668 | DOI:10.1002/cphy.c210006

Open Forum Infect Dis. 2021 Aug 25;8(9):ofab439. doi: 10.1093/ofid/ofab439. eCollection 2021 Sep.

ABSTRACT

BACKGROUND: In the Long-Acting Antiretroviral Treatment Enabling Trial 2 (LATTE-2) phase 2b study, long-acting (LA) injectable cabotegravir + rilpivirine dosed every 8 weeks (Q8W) or every 4 weeks (Q4W) demonstrated comparable efficacy with daily oral antiretroviral therapy (ART) through 96 weeks in ART-naive adults with human immunodeficiency virus type 1 (HIV-1). Here we report efficacy, tolerability, and safety of cabotegravir + rilpivirine LA over approximately 5 years.

METHODS: After 20 weeks of oral cabotegravir + abacavir/lamivudine, participants were randomized to cabotegravir + rilpivirine LA Q8W or Q4W or continue oral ART through the 96-week maintenance period. In the extension period through week 256, participants continued their current LA regimen (randomized Q8W/Q4W groups) or switched from oral ART to Q8W or Q4W LA therapy (extension-switch groups). Endpoints assessed included proportion of participants with HIV-1 RNA <50 copies/mL (Snapshot algorithm) and adverse events (AEs).

RESULTS: At week 256, 186 of 230 (81%) participants in randomized Q8W/Q4W groups and 41 of 44 (93%) participants in extension-switch groups had HIV-1 RNA <50 copies/mL. No protocol-defined virologic failures occurred after week 48. Injection wsite reactions infrequently resulted in discontinuation (4 [2%] and 1 [2%] participants in randomized Q8W/Q4W and extension-switch groups, respectively). Three participants in randomized Q8W/Q4W groups experienced drug-related serious AEs, including 1 fatal serious AE (Q4W group); none occurred in extension-switch groups. Of 25 participants with AEs leading to withdrawal, 20 were in the randomized Q4W group; no AE leading to withdrawal occurred in >1 participant.

CONCLUSIONS: Cabotegravir + rilpivirine LA exhibited long-term efficacy and tolerability, demonstrating its durability as maintenance therapy for HIV-1 infection.Clinical Trials Registration. NCT02120352.

PMID:34557563 | PMC:PMC8454521 | DOI:10.1093/ofid/ofab439

Eur J Endocrinol. 2021 Jun;184(6):857-865. doi: 10.1530/eje-20-1362. Epub 2021 May 10.

ABSTRACT

OBJECTIVE: Obese and overweight body mass index (BMI) categories have been associated with increased immune-related adverse events (irAEs) in patients with cancer receiving immune checkpoint inhibitors (ICIs); however, the impact of being overweight in conjunction with related metabolic syndrome-associated factors on irAEs have not been investigated. We aimed to evaluate the impact of overweight and obese BMI according to metabolic disease burden on the development of irAEs.

DESIGN AND METHODS: We conducted a retrospective observational study of patients receiving ICIs at a cancer center. Our main study outcome was development of ≥grade 2 (moderate) irAEs. Our main predictor was weight/metabolic disease risk category: (1) normal weight (BMI 18.5-24.9 kg/m2)/low metabolic risk (<2 metabolic diseases [diabetes, dyslipidemia, hypertension]), (2) normal weight/high metabolic risk (≥2 metabolic diseases), (3) overweight (BMI ≥25 kg/m2)/low metabolic risk, and (4) overweight/high metabolic risk.

RESULTS: Of 411 patients in our cohort, 374 were eligible for analysis. Overall, 111 (30%) patients developed ≥grade 2 irAEs. In Cox analysis, overweight/low metabolic risk was significantly associated with ≥grade 2 irAEs (hazard ratio [HR]: 2.0, 95% confidence interval [95% CI]: 1.2-3.4) when compared to normal weight/low metabolic risk, while overweight/high metabolic risk (HR: 1.3, 95% CI: 0.7-2.2) and normal weight/high metabolic risk (HR: 1.5, 95% CI: 0.7-3.0) were not.

CONCLUSIONS: Overweight patients with fewer metabolic comorbidities were at increased risk for irAEs. This study provides an important insight that BMI should be evaluated in the context of associated metabolic comorbidities in assessing risk of irAE development and ICI immune response.

PMID:34552304 | PMC:PMC8451971 | DOI:10.1530/eje-20-1362