Minimal Residual Disease in Myeloma: Application for Clinical Care and New Drug Registration.

The development of novel agents has transformed the treatment paradigm for multiple myeloma, with minimal residual disease (MRD) negativity now achievable across the entire disease spectrum. Bone marrow-based technologies to assess MRD, including approaches using next-generation flow and next-generation sequencing, have provided real-time clinical tools for the sensitive detection and monitoring of MRD in patients with multiple myeloma. Complementary liquid biopsy-based assays are now quickly progressing with some, such as mass spectrometry methods, being very close to clinical use, while others utilizing nucleic acid-based technologies are still developing and will prove important to further our understanding of the biology of MRD. On the regulatory front, multiple retrospective individual patient and clinical trial level meta-analyses have already shown and will continue to assess the potential of MRD as a surrogate for patient outcome. Given all this progress, it is not surprising that a number of clinicians are now considering using MRD to inform real-world clinical care of patients across the spectrum from smoldering myeloma to relapsed refractory multiple myeloma, with each disease setting presenting key challenges and questions that will need to be addressed through clinical trials. The pace of advances in targeted and immune therapies in multiple myeloma is unprecedented, and novel MRD-driven biomarker strategies are essential to accelerate innovative clinical trials leading to regulatory approval of novel treatments and continued improvement in patient outcomes.

Experiences of language barriers by homoeopathy student interns providing health services at the University of Johannesburg.

BACKGROUND: South Africa is a multilingual society, and therefore, the likelihood of healthcare providers (HCPs), including students training to be HCPs, encountering language barriers with patients is high. AIM: To explore and describe the experiences of homoeopathy student interns regarding language barriers in the delivery of health services and to provide guidance towards overcoming language barriers in homoeopathic practice at the University of Johannesburg (UJ). SETTING: The interviews and focus group discussions were conducted in English and at a private location that was convenient for the participants in Johannesburg, Gauteng. METHODS: This qualitative study used a phenomenological approach. Ten individual interviews were conducted with registered homoeopathy student interns (HSIs) from the UJ. The central question: 'What has your experience been regarding language barriers between you and your patients at the UJ Homoeopathy clinics?' was asked and responses were recorded and transcribed for later analysis. The interview results were presented to a focus group for discussion to validate findings that arose from the analysis and to provide an opportunity to add any insight, comment or recommendations that were not expressed in individual interviews and verification of emergent themes. RESULTS: Participants described how language barriers create challenges in understanding between patients and HSIs. Descriptions of the experiences of the intrapersonal and interpersonal effects that are associated with language barriers were provided. Participants also described the influence of language barriers on the various aspects of the health service process. Finally, participants described the mitigation of language barriers through various strategies. CONCLUSION: Participants reported their experiences of language barriers as challenging. Language barriers were found to adversely affect the various aspects of the health service process as well as the practitioner's personal feelings and the patient-practitioner relationship. Language acquisition and awareness modules introduced early on in the syllabus is a proposed solution to the mitigation of language barriers.

Resolution of calcinosis using bisphosphonates in overlap syndrome - a case report.

INTRODUCTION: Calcinosis cutis is a common complication of pediatric rheumatologic diseases. However, there is currently no consensus on first-line treatment. Bisphosphonates have been described as a successful treatment in several case studies, but most of these cases are limited to patients with isolated juvenile dermatomyositis or systemic sclerosis. Specifically, there are limited reports of their usefulness in treating overlap syndromes and mixed connective tissue disorders. CASE PRESENTATION: We describe the case of a 13 year-old girl with overlap syndrome with features of juvenile dermatomyositis and systemic lupus erythematosus. After 22 months of extensive immunosuppressive therapy, including monthly IVIG and Rituximab, she continued to have pain and weakness of the lower extremities. A CT scan was performed which showed significant multifocal soft tissue calcifications of the pelvis. She was started on treatment with oral alendronate with the goal of improving her calcinosis and improving her symptoms. After several months of therapy, our patient reported subjective improvement of her lower extremity pain and weakness, as well as complete resolution of abnormalities previously seen on physical examination. A repeat CT scan of the pelvis was performed after 11 months of therapy and demonstrated complete resolution of the previously seen calcinosis. CONCLUSIONS: We report the successful treatment of soft tissue calcinosis with oral bisphosphonates in a patient with juvenile dermatomyositis-systemic lupus erythematosus overlap syndrome. These results provide further evidence that bisphosphonates can be used successfully to treat calcinosis cutis in pediatric rheumatologic disorders. Additionally, the results provide new evidence that they can be used specifically in juvenile dermatomyositis-systemic lupus erythematosus overlap syndrome, which has not been previously reported.

healthcareCOVID: a national cross-sectional observational study identifying risk factors for developing suspected or confirmed COVID-19 in UK healthcare workers.

OBJECTIVE: To establish the prevalence, risk factors and implications of suspected or confirmed coronavirus disease 2019 (COVID-19) infection among healthcare workers in the United Kingdom (UK). DESIGN: Cross-sectional observational study. SETTING: UK-based primary and secondary care. PARTICIPANTS: Healthcare workers aged ≥18 years working between 1 February and 25 May 2020. MAIN OUTCOME MEASURES: A composite endpoint of laboratory-confirmed diagnosis of SARS-CoV-2, or self-isolation or hospitalisation due to suspected or confirmed COVID-19. RESULTS: Of 6,152 eligible responses, the composite endpoint was present in 1,806 (29.4%) healthcare workers, of whom 49 (0.8%) were hospitalised, 459 (7.5%) tested positive for SARS-CoV-2, and 1,776 (28.9%) reported self-isolation. Overall, between 11,870 and 21,158 days of self-isolation were required by the cohort, equalling approximately 71 to 127 working days lost per 1,000 working days. The strongest risk factor associated with the presence of the primary composite endpoint was increasing frequency of contact with suspected or confirmed COVID-19 cases without adequate personal protective equipment (PPE): 'Never' (reference), 'Rarely' (adjusted odds ratio 1.06, (95% confidence interval: [0.87-1.29])), 'Sometimes' (1.7 [1.37-2.10]), 'Often' (1.84 [1.28-2.63]), 'Always' (2.93, [1.75-5.06]). Additionally, several comorbidities (cancer, respiratory disease, and obesity); working in a 'doctors' role; using public transportation for work; regular contact with suspected or confirmed COVID-19 patients; and lack of PPE were also associated with the presence of the primary endpoint. A total of 1,382 (22.5%) healthcare workers reported lacking access to PPE items while having clinical contact with suspected or confirmed COVID-19 cases. CONCLUSIONS: Suspected or confirmed COVID-19 was more common in healthcare workers than in the general population and is associated with significant workforce implications. Risk factors included inadequate PPE, which was reported by nearly a quarter of healthcare workers. Governments and policymakers must ensure adequate PPE is available as well as developing strategies to mitigate risk for high-risk healthcare workers during future COVID-19 waves.

Patient-reported outcomes for ambulatory surgery.

PURPOSE OF REVIEW: To discuss the importance of validated tools that measure patient-reported outcomes and their use in ambulatory surgery. RECENT FINDINGS: Sustained increases in ambulatory surgical care reflect advances in surgical techniques and perioperative anaesthetic care. Use of patient-reported outcomes allows identification of minor adverse events that are more common in this population compared with traditional endpoints such as mortality. Variability in reported outcomes restricts research potential and limits the ability to benchmark providers. The standardized endpoints in perioperative medicine initiative's recommendations on patient-reported outcomes and patient comfort measures are relevant to evaluating ambulatory care. Combining validated generic and disease-specific patient-reported outcome measures (PROMs) examines the widest spectrum of outcomes. Technological advances can be used to facilitate outcome measurement in ambulatory surgery with digital integration optimizing accurate real-time data collection. Telephone or web-based applications for reviewing ambulatory patients were found to be acceptable in multiple international settings and should be harnessed to allow remote follow-up. SUMMARY: Use of validated tools to measure patient-reported outcomes allows internal and external quality comparison. Tools can be combined to measure objective outcomes and patient satisfaction. These are both key factors in driving forward improvements in perioperative ambulatory surgical care.

Effects of Non-nutritive Sweeteners on Sweet Taste Processing and Neuroendocrine Regulation of Eating Behavior.

PURPOSE OF REVIEW: Non-nutritive sweeteners (NNS) are increasingly used as a replacement for nutritive sugars as means to quench the desire for "sweets" while contributing few or no dietary calories. However, there is concern that NNS may uncouple the evolved relationship between sweet taste and post-ingestive neuroendocrine signaling. In this review, we examine the effects of NNS exposure on neural and peripheral systems in humans. RECENT FINDINGS: NNS exposure during early development may influence sweet taste preferences, and NNS consumption might increase motivation for sweet foods. Neuroimaging studies provide evidence that NNS elicit differential neuronal responsivity in areas related to reward and satiation, compared with caloric sweeteners. Findings are heterogenous regarding whether NNS affect physiological responses. Additional studies are warranted regarding the consequences of NNS on metabolic outcomes and neuroendocrine pathways. Given the widespread popularity of NNS, future studies are essential to establish their role in long-term health.

Perceived effectiveness of complementary medicine by mothers of infants with colic in Gauteng.

BACKGROUND: Infantile colic is a self-limiting condition, characterised by spasmodic, excessive and inconsolable crying without apparent cause. Although common, there is no widely accepted conventional treatment approach for colic. Complementary medicine is often promoted as an alternative therapeutic option for infantile colic; however, there is limited research available on its use, safety and effectiveness. AIM: The aim of this study was to determine the perceived effectiveness of complementary medicine by mothers of infants with colic by means of the Infantile Colic Questionnaire. SETTING: Mothers of infants who had colic were recruited from complementary medicine pharmacies, schools, baby clinics and various businesses in Gauteng, South Africa. METHODS: A quantitative-descriptive design was used whereby data was collected through a randomised, cross-sectional questionnaire. The research sample consisted of 152 participants (mothers), aged between 18 and 45 years, with one or more children who suffered from symptoms of infantile colic, who had used complementary medicine as a form of treatment. RESULTS: Results indicated that most participants made use of both complementary and conventional medicines for their infant's colic; the most commonly used complementary medicine products were homeopathic remedies, probiotics and herbal medicines. Some participants were, however, unfamiliar with the term 'complementary medicine', indicating a need for further patient education. CONCLUSIONS: The participants perceived complementary medicines as safe and effective forms of treatment for infantile colic. However, further, larger scale studies should be conducted to validate this finding.

Suppression and resolution of autoimmune arthritis by rhesus θ-defensin-1, an immunomodulatory macrocyclic peptide.

θ-defensins constitute a family of macrocyclic peptides expressed exclusively in Old World monkeys. The peptides are pleiotropic effectors of innate immunity, possessing broad spectrum antimicrobial activities and immunoregulatory properties. Here we report that rhesus θ-defensin 1 (RTD-1) is highly effective in arresting and reversing joint disease in a rodent model of rheumatoid arthritis (RA). Parenteral RTD-1 treatment of DA/OlaHsd rats with established pristane-induced arthritis (PIA) rapidly suppressed joint disease progression, restored limb mobility, and preserved normal joint architecture. RTD-1 significantly reduced joint IL-1ß levels compared with controls. RTD-1 dose-dependently inhibited fibroblast-like synoviocyte (FLS) invasiveness and FLS IL-6 production. Consistent with the inhibition of FLS invasiveness, RTD-1 was a potent inhibitor of arthritogenic proteases including ADAMs 17 and 10 which activate TNFα, and inhibited matrix metalloproteases, and cathepsin K. RTD-1 was non-toxic, non-immunogenic, and effective when administered as infrequently as once every five days. Thus θ-defensins, which are absent in humans, have potential as retroevolutionary biologics for the treatment of RA.

In vivo dosimetry for total body irradiation: five-year results and technique comparison.

The aim of this work is to establish if the new CT-based total body irradiation (TBI) planning techniques used at University College London Hospital (UCLH) and Royal Free Hospital (RFH) are comparable to the previous technique at the Middlesex Hospital (MXH) by analyzing predicted and measured diode results. TBI aims to deliver a homogeneous dose to the entire body, typically using extended SSD fields with beam modulation to limit doses to organs at risk. In vivo dosimetry is used to verify the accuracy of delivered doses. In 2005, when the Middlesex Hospital was decommissioned and merged with UCLH, both UCLH and the RFH introduced updated CT-planned TBI techniques, based on the old MXH technique. More CT slices and in vivo measurement points were used by both; UCLH introduced a beam modulation technique using MLC segments, while RFH updated to a combination of lead compensators and bolus. Semiconductor diodes were used to measure entrance and exit doses in several anatomical locations along the entire body. Diode results from both centers for over five years of treatments were analyzed and compared to the previous MXH technique for accuracy and precision of delivered doses. The most stable location was the field center with standard deviations of 4.1% (MXH), 3.7% (UCLH), and 1.7% (RFH). The least stable position was the ankles. Mean variation with fraction number was within 1.5% for all three techniques. In vivo dosimetry can be used to verify complex modulated CT-planned TBI, and demonstrate improvements and limitations in techniques. The results show that the new UCLH technique is no worse than the previous MXH one and comparable to the current RFH technique.

Shared quality data are associated with increased protamine use and reduced bleeding complications after carotid endarterectomy in the Vascular Study Group of New England.

OBJECTIVE: The goal of this study was to evaluate whether protamine usage after carotid endarterectomy (CEA) increased within the Vascular Study Group of New England (VSGNE) in response to studies indicating that protamine reduces bleeding complications associated with CEA without increasing the risk of stroke. METHODS: We reviewed 10,059 CEAs, excluding concomitant coronary bypass, performed within the VSGNE from January 2003 to July 2012. Protamine use and reoperation for bleeding were evaluated monthly using statistical process control. Twelve centers and 77 surgeons entering the VSGNE between 2003 and 2008 were classified as original participants, and 14 centers and 60 surgeons joining after May 2009 were considered new. Protamine use for surgeons was categorized as rare (<10%), selective (10%-80%), or routine (>80%). Outcome measures were in-hospital reoperation for bleeding, postoperative myocardial infarction (POMI), and stroke or death. RESULTS: Two significant increases occurred in protamine use for all VSGNE centers over time. From 2003 to 2007, the protamine rate remained stable at 43%. In 2008, protamine usage increased to 52% (P < .01), coincident with new centers joining the VSGNE. Protamine usage then increased to 62% in 2010 (P < .01), shortly after the presentations of the data showing a benefit of protamine. This effect was due to 10 surgeons in the original VSGNE centers who increased their usage of protamine: six surgeons from rare use to selective use and four surgeons to routine use. Reoperation for bleeding was reduced by 0.84% (relative risk reduction, 57.2%) in patients who received protamine (0.6% vs 1.44%; P < .001). There were no differences in POMI (1.1% vs 1.09%) or stroke or death (1.1% vs 1.03%) between protamine treated and untreated patients, respectively. Reoperation for bleeding was decreased for surgeons who used protamine routinely (0.5%; P < .001) compared with selective (1.4%) and rare users (1.5%) of protamine. There were no differences in POMI (0.9%, 1.2%, 1.1%; P = .720) and stroke or death rates (1.0%, 1.2%, 1.0%; P = .656) for rare, selective, and routine users of protamine. CONCLUSIONS: Protamine use increased over time by VSGNE surgeons, most significantly after the presentations of VSGNE-derived data showing the benefit of protamine, and was associated with a decrease in reoperation for bleeding. Improvements in processes of care and outcomes can be achieved in regional quality groups by sharing safety and efficacy data.

Combinatorial mRNA binding by AUF1 and Argonaute 2 controls decay of selected target mRNAs.

The RNA-binding protein AUF1 binds AU-rich elements in 3'-untranslated regions to regulate mRNA degradation and/or translation. Many of these mRNAs are predicted microRNA targets as well. An emerging theme in post-transcriptional control of gene expression is that RNA-binding proteins and microRNAs co-regulate mRNAs. Recent experiments and bioinformatic analyses suggest this type of co-regulation may be widespread across the transcriptome. Here, we identified mRNA targets of AUF1 from a complex pool of cellular mRNAs and examined a subset of these mRNAs to explore the links between RNA binding and mRNA degradation for both AUF1 and Argonaute 2 (AGO2), which is an essential effector of microRNA-induced gene silencing. Depending on the specific mRNA examined, AUF1 and AGO2 binding is proportional/cooperative, reciprocal/competitive or independent. For most mRNAs in which AUF1 affects their decay rates, mRNA degradation requires AGO2. Thus, AUF1 and AGO2 present mRNA-specific allosteric binding relationships for co-regulation of mRNA degradation.

Use of a postoperative insulin protocol decreases wound infection in diabetics undergoing lower extremity bypass.

OBJECTIVE: Strict glucose control in patients undergoing coronary bypass grafting has been shown to decrease infectious complications, arrhythmias, and mortality. Our objective was to determine if strict glucose control reduced morbidity after lower extremity bypass (LEB). METHODS: A prospective pilot study at a single institution within the Vascular Study Group of New England was conducted from January 2009 to December 2010. Patients with diabetes and without undergoing LEB were placed on an intravenous (IV) insulin infusion for 3 days after surgery with titration of blood glucose from 80 to 150 mg/dL. The IV insulin study group (n = 104) was compared to a historic control group (n = 189) that received standard insulin treatment from the preceding 3 years. The Fisher exact test, t-tests, Wilcoxon rank-sum tests, χ(2), and logistic regression analyses were used to compare in-hospital morbidity. Stratified analyses were conducted to determine if findings differed based on the presence or absence of diabetes. RESULTS: There was no difference in postoperative complications between the two groups with regard to graft infection, myocardial infarction, dysrhythmia, primary patency at discharge, or mortality. Patients in the IV insulin group had significantly fewer in-hospital wound infections (4% vs 11%; odds ratio [OR], 0.32; 95% confidence interval [CI], 0.11-0.96; P = .047). This association strengthened after adjusting for potentially confounding baseline differences in gender, body mass index, and smoking status (adjusted OR, 0.22; 95% CI, 0.05-0.84; P = .03). When stratified by presence of diabetes, wound infections were decreased in the IV insulin group (0/44 [0%] vs 9/90 [10%]; P = .03). In patients without diabetes treated with IV insulin, there was no significant difference in wound infections (7% vs 12%; P = .42). CONCLUSIONS: Strict glucose control with a postoperative insulin infusion protocol significantly decreased the incidence of postoperative in-hospital wound infection in the diabetic population. These previously unreported findings from this single-institution prospective study warrant further investigation.

Increased sensitivity to testicular toxicity of transplacental benzo[a]pyrene exposure in male glutamate cysteine ligase modifier subunit knockout (Gclm-/-) mice.

Polycyclic aromatic hydrocarbons (PAHs), like benzo[a]pyrene (BaP), are ubiquitous environmental pollutants formed by the incomplete combustion of organic materials. The tripeptide glutathione (GSH) is a major antioxidant and is important in detoxification of PAH metabolites. Mice null for the modifier subunit of glutamate cysteine ligase (Gclm), the rate-limiting enzyme in GSH synthesis, have decreased GSH concentrations. We investigated the effects of Gclm deletion alone on male fertility and spermatogenesis and its effect on the sensitivity of male embryos to the transplacental testicular toxicity of BaP. Gclm-/- males had dramatically decreased testicular and epididymal GCL enzymatic activity and total GSH concentrations compared with Gclm+/+ littermates. Ratios of reduced to oxidized GSH were significantly increased in Gclm-/- testes. GSH reductase enzymatic activity was increased in Gclm-/- epididymides. We observed no changes in fertility, testicular weights, testicular sperm head counts, or testicular histology and subtle changes in cauda epididymal sperm counts, motility, and morphology in Gclm-/- compared with Gclm+/+ males. Prenatal exposure to BaP from gestational day 7 to 16 was dose dependently associated with significantly decreased testicular and epididymal weights, testicular and epididymal sperm counts, and with vacuolated seminiferous tubules at 10 weeks of age. Gclm-/- males exposed prenatally to BaP had greater decreases in testicular weights, testicular sperm head counts, epididymal sperm counts, and epididymal sperm motility than Gclm+/+ littermates. These results show no effects of Gclm deletion alone on male fertility and testicular spermatogenesis and subtle epididymal effects but support increased sensitivity of Gclm-/- males to the transplacental testicular toxicity of BaP.

Aminopiperidine-fused imidazoles as dipeptidyl peptidase-IV inhibitors.

A new series of DPP-4 inhibitors derived from piperidine-fused benzimidazoles and imidazopyridines is described. Optimization of this class of DPP-4 inhibitors led to the discovery of imidazopyridine 34. The potency, selectivity, cross-species DMPK profiles, and in vivo efficacy of 34 is reported.

Discovery of new binding elements in DPP-4 inhibition and their applications in novel DPP-4 inhibitor design.

Probing with tool molecules, and by modeling and X-ray crystallography the binding modes of two structurally distinct series of DPP-4 inhibitors led to the discovery of a rare aromatic fluorine H-bond and the spatial requirement for better biaryl binding in the DPP-4 enzyme active site. These newly found binding elements were successfully incorporated into novel DPP-4 inhibitors.

Fluoroolefins as amide bond mimics in dipeptidyl peptidase IV inhibitors.

The synthesis, selectivity, rat pharmacokinetic profile, and drug metabolism profiles of a series of potent fluoroolefin-derived DPP-4 inhibitors (4) are reported. A radiolabeled fluoroolefin 33 was shown to possess a high propensity to form reactive metabolites, thus revealing a potential liability for this class of DPP-4 inhibitors.

Imidazopiperidine amides as dipeptidyl peptidase IV inhibitors for the treatment of diabetes.

A series of substituted imidazopiperidine amides has been prepared and evaluated for inhibition of dipeptidyl peptidase IV (DPP-4). Substitution at the 1- and 3-positions produced increased selectivity for DPP-4 relative to DPP-8 and DPP-9. Compounds in this series had IC(50) values as low as 5.8 nM for inhibition of DPP-4.