Report of the international conference on next generation sequencing for adventitious virus detection in biologicals.

A fundamental aspect of biological product safety is to assure absence of adventitious agents in the final product. Next-generation or high-throughput sequencing (NGS/HTS) has recently demonstrated detection of viruses that were previously missed using the recommended routine assays for adventitious agent testing of biological products. This meeting was co-organized by the International Alliance for Biological Standardization (IABS) and the U.S. Food and Drug Administration (FDA) to assess the current status and discuss the readiness of NGS for adventitious virus detection in biologics. The presentations included efforts for standardization, case studies on applications in biologics, comparison with routine virus detection assays, and current regulatory thinking. Participants identified the need for standard reference reagents, well-annotated databases, large data storage and transfer capacity, personnel with relevant expertise, particularly in bioinformatics; and harmonization of international regulations for testing biologic products and reagents used for their manufacturing. We hope this meeting summary will be of value to regulators and industry for considerations of NGS applications for adventitious virus detection in biologics.

Vitamin B12 deficiency-induced neuropathy secondary to prolonged recreational use of nitrous oxide.

A 24-year-old female, otherwise healthy, presented to the Emergency Department (ED) with difficulty walking and bilateral leg pain. The patient was a recreational nitrous oxide (NO2) user, also known as "whippets" or simply nitrous. Neurologic examination demonstrated an unsteady gait and positive Romberg sign along with normal deep tendon reflexes and normal muscle strength in upper and lower extremities. Laboratory results demonstrated macrocytic erythropoiesis, reduced B12, elevated homocysteine, and elevated methylmalonic acid. Outpatient MRI later demonstrated degeneration of the posterior spinal column. The patient was empirically treated in the ED with intramuscular B12 and admitted to the evaluation unit for pain control and Physical Therapy (PT) evaluation. Emergency Medicine (EM) physicians should be aware of this condition because NO2 is used both recreationally and in medicine. With the popularity of recreational nitrous oxide, many emergency patients have experience with this drug. As in our case report, the toxic effects can be profound and mimic other emergent conditions like stroke. Emergency physicians should have a higher index of suspicion for the toxic effects of this common drug. Elderly, vegetarians and patients with Irritable Bowel Disease are at higher risk and may even experience toxicity from nitrous oxide used therapeutically during routine anesthesia.

The addition of manipulation to an extension-oriented intervention for a patient with chronic LBP.

OBJECTIVE AND IMPORTANCE: There is a paucity of research investigating the combined interventions of direction-specific lumbar exercise and manipulation for individuals with low back pain (LBP) who exhibit centralization or a directional preference. The purpose of this report was to describe the management and outcomes of a patient with chronic LBP who met two categories of the revised treatment based classification (TBC) approach initially described by Delitto and colleagues. CLINICAL PRESENTATION: A 55-year-old female with a 15-year history of right LBP/leg pain demonstrated centralization of symptoms with repeated extension and met four out of five criteria on the clinical prediction rule for thrust manipulation. INTERVENTIONS: The patient was treated for seven physical therapy sessions, once a week for seven weeks. Lumbar thrust manipulation and extension-oriented interventions were combined throughout the course of care. The patient experienced a decrease on the modified Oswestry disability index score from 26 to 8%, an increase in the patient-specific functional scale score from 5.6 to 9.4, and patient-report of full return to pain-free activity at discharge. CONCLUSION: A patient with chronic LBP reported a clinically meaningful improvement after seven visits of manipulation and extension-oriented interventions. Further research should compare the effectiveness of combining interventions for individuals who meet the two TBC groups of manipulation and extension-specific exercise compared with performing either intervention alone.

Only 1% of Total Knee Arthroplasty Clinical Trials Report Patient Opioid Use Before or After Surgery: A Systematic Review.

OBJECTIVES: Many clinical trials report significant improvements in osteoarthritis-related pain and function after total knee arthroplasty (TKA). Opioids are commonly prescribed for pain management of knee osteoarthritis and also perioperative pain after surgery. The extent of persistent opioid use after TKA is unknown. Because up to 20% of individuals have poor outcomes after TKA and prior opioid use is a risk factor for future opioid use, treatment effects from TKA clinical trials would be better understood by assessing opioid use data from trial participants. The purpose of this review was to determine the proportion of participants in TKA trials with opioid use before surgery and persistent use after surgery and how well clinical trials capture and report these variables. MATERIALS AND METHODS: A systematic review of the literature (5 databases: CINAHL Cochrane CENTRAL, Embase, PubMed, and Web of Science) was conducted to assess the reporting of opioid use in TKA clinical trials. All opioid use was extracted, both prior and postoperatively. Long-term opioid use was determined using 4 different contemporary definitions to increase the sensitivity of the assessment. RESULTS: The search produced 24,252 titles and abstracts, and 324 met the final inclusion criteria. Only 4 of the 324 trials (1.2%) reported any type of opioid use; 1 identified prior opioid use, and none reported long-term opioid use after surgery. Only 1% of TKA clinical trials in the past 15 years reported any opioid use. DISCUSSION: Based on available research, it is not possible to determine if TKA is effective in reducing reliance on opioids for pain management. It also highlights the need to better track and report prior and long-term opioid use as a core outcome in future TKA trials.

Post-licensure evaluation of vaccine safety: current status and future directions. Symposium organised by the International Alliance for Biological Standardization (IABS) in Barcelona, Spain, 27-28 April 2011.

Adverse events following immunization, while rare, unfortunately do occur. And when they do, the public's faith in vaccines waves. It's a known fact, for example, that vaccine safety concerns are among the most important factors contributing to parents refusing vaccination for their children. How best, then, to tackle these concerns and increase public confidence in the vaccine safety system? In an effort to contribute to identifying the right mechanisms, the International Alliance for Biological Standardization organized an international symposium on "Post-Licensure Evaluation of Vaccine Safety" in Barcelona in early Spring. Delegates from 24 countries took a close look at the current status of this challenging problem and identified several practical measures which could help address the situation. They suggested an integrated vaccine safety program to be in place in all countries and standardized so that information and data can be exchanged on a routine basis. Another proposal was to put in place simple measures such as the use of bar codes on vaccine vials.

When Treating Coexisting Low Back Pain and Hip Impairments, Focus on the Back: Adding Specific Hip Treatment Does Not Yield Additional Benefits-A Randomized Controlled Trial.

OBJECTIVE: To determine whether adding hip treatment to usual care for low back pain (LBP) improved disability and pain in individuals with LBP and a concurrent hip impairment. DESIGN: Randomized controlled trial. METHODS: Seventy-six participants (age, 18 years or older; Oswestry Disability Index, 20% or greater; numeric pain-rating scale, 2 or more points) with LBP and a concurrent hip impairment were randomly assigned to a group that received treatment to the lumbar spine only (LBO group) (n = 39) or to one that received both lumbar spine and hip treatments (LBH group) (n = 37). The individual treating clinicians decided which specific low back treatments to administer to the LBO group. Treatments aimed at the hip (LBH group) included manual therapy, exercise, and education, selected by the therapist from a predetermined set of treatments. Primary outcomes were disability and pain, measured by the Oswestry Disability Index and the numeric pain-rating scale, respectively, at baseline, 2 weeks, discharge, 6 months, and 12 months. The secondary outcomes were fear-avoidance beliefs (work and physical activity subscales of the Fear-Avoidance Beliefs Questionnaire), global rating of change, the Patient Acceptable Symptom State, and physical activity level. We used mixed-model 2-by-3 analyses of variance to examine group-by-time interaction effects (intention-to-treat analysis). RESULTS: Data were available for 68 patients at discharge (LBH group, n = 33; LBO group, n = 35) and 48 at 12 months (n = 24 for both groups). There were no between-group differences in disability at discharge (-5.0; 95% confidence interval [CI]: -10.9, 0.89; P = .09), 12 months (-1.0; 95% CI: -4.44, 2.35; P = .54), and all other time points. There were no between-group differences in pain at discharge (-0.2; 95% CI: -1.03, 0.53; P = .53), 12 months (0.1; 95% CI: -0.53, 0.72; P = .76), and all other time points. There were no between-group differences in secondary outcomes, except for higher Fear-Avoidance Beliefs Questionnaire (work subscale) scores in the LBH group at 2 weeks (-3.35; 95% CI: -6.58, -0.11; P = .04) and discharge (-3.45; 95% CI: - 6.30, -0.61; P = .02). CONCLUSION: Adding treatments aimed at the hip to usual low back physical therapy did not provide additional short- or long-term benefits in reducing disability and pain in individuals with LBP and a concurrent hip impairment. Clinicians may not need to include hip treatments to achieve reductions in low back disability and pain in individuals with LBP and a concurrent hip impairment. J Orthop Sports Phys Ther 2021;51(12):581-601. Epub 16 Nov 2021. 2021. doi:10.2519/jospt.2021.10593.

Validation of the safety of MDCK cells as a substrate for the production of a cell-derived influenza vaccine.

Cell culture-based production methods may assist in meeting increasing demand for seasonal influenza vaccines and developing production flexibility required for addressing influenza pandemics. MDCK-33016PF cells are used in propagation of a cell-based seasonal influenza vaccine (Optaflu); but, like most continuous cell lines, can grow in immunocompromised mice to produce tumors. It is, therefore, essential that no residual cells remain within the vaccine, that cell lysates or DNA are not oncogenic, and that the cell substrate does not contain oncogenic viruses or oncogenic DNA. Multiple, redundant processes ensure the safety of influenza vaccines produced in MDCK-33016PF cells. The probability of a residual cell being present in a dose of vaccine is approximately 1 in 10(34). Residual MDCK-DNA is < or =10 ng per dose and the ss-propiolactone used to inactivate influenza virus results in reduction of detectable DNA to less than 200 base pairs (bp). Degenerate PCR and specific PCR confirm exclusion of oncogenic viruses. The manufacturing process has been validated for its capacity to remove and inactivate viruses. We conclude that the theoretical risks arising from manufacturing seasonal influenza vaccine using MDCK-33016PF cells are reduced to levels that are effectively zero by the multiple, orthogonal processes used during production.

Mode of action of adjuvants: implications for vaccine safety and design.

For decades, the search for new vaccine adjuvants has been largely empirical. A series of new adjuvants and related formulations are now emerging that are acting through identified immunological mechanisms. Understanding adjuvant mechanism of action is crucial for vaccine design, since this allows for directing immune responses towards efficacious disease-specific effector mechanisms and appropriate memory. It is also of great importance to build new paradigms for assessing adjuvant safety at development stages and at regulatory level. This report reflects the conclusions of a group of scientists from academia, regulatory agencies and industry who attended a conference, organized by the International Association for Biologicals (IABS), on the mode of action of adjuvants on 29-30 April 2010 in Bethesda, Maryland, USA, particularly focusing on how understanding adjuvants mode of action can impact on the assessment of vaccine safety and help to develop target-specific vaccines. More information on the conference output can be found on the IABS website, http://www.iabs.org/.

Minimal physical therapy utilization compared with higher physical therapy utilization for patients with low back pain: a systematic review.

Aim: Currently there is a large and perhaps unwarranted variation regarding physical therapy utilization for individuals with low back pain (LBP).  The purpose of this systematic review was to compare the effects of minimal physical therapy utilization/education (two visits or less) versus typical physical therapy utilization (three visits or more) on patient-important outcomes for patients with LBP. Methods: Two independent reviewers searched Cochrane, Medline, CINAHL, Web of Science, and PEDro from database inception until March 2017. Eligible studies used a randomized design, included subjects with LBP, and compared minimal versus higher utilization. The GRADE approach was used to provide an overall level of evidence regarding utilization. Eight articles (1153 individual subjects) met the inclusion criteria. Effect sizes for each outcome measure were calculated using Hedge's g and were adjusted for baseline values at each time period. Findings: When compared with minimal utilization, higher utilization demonstrated no significant differences on pain, disability, or quality of life at the 1-year follow-up. However, two of the three studies that analyzed cost-effectiveness found higher utilization to be more cost-effective at 1-year follow-up. Moreover, there was insufficient evidence available to investigate patient subgroups (acuity, risk for chronicity), multiple levels of utilization dosage (low, typical, and high), or intervention type. Conclusions: This review identifies the need for further research on the dosage of physical therapy among various subgroups of patients with LBP. While higher utilization may not result in significant improvements in patient-important outcomes, it may be more cost-effective for patients with chronic or complex LBP conditions when compared to minimal utilization.

Basic principles of stability.

An understanding of the principles of degradation, as well as the statistical tools for measuring product stability, is essential to management of product quality. Key to this is management of vaccine potency. Vaccine shelf life is best managed through determination of a minimum potency release requirement, which helps assure adequate potency throughout expiry. Use of statistical tools such a least squares regression analysis should be employed to model potency decay. The use of such tools provides incentive to properly design vaccine stability studies, while holding stability measurements to specification presents a disincentive for collecting valuable data. The laws of kinetics such as Arrhenius behavior help practitioners design effective accelerated stability programs, which can be utilized to manage stability after a process change. Design of stability studies should be carefully considered, with an eye to minimizing the variability of the stability parameter. In the case of measuring the degradation rate, testing at the beginning and the end of the study improves the precision of this estimate. Additional design considerations such as bracketing and matrixing improve the efficiency of stability evaluation of vaccines.

NMR Assays for Estimating the O-Acetyl Content of Meningococcal Polysaccharide Serogroup A in Quadrivalent Conjugate Vaccine Formulation.

The use of multivalent glycoconjugate vaccines has dramatically contributed to reduce the incidence of meningococcal infectious disease. The advanced structural characterization of polysaccharide conjugates leads to enhancements in the quality and control of the products. Here, we report a novel nuclear magnetic resonance (NMR) method to confirm the identity and structural conformity (e.g., O-acetyl content) of saccharide antigens that comprise a licensed tetravalent meningococcal serogroups A, C, W, and Y vaccine. For the first time, the NMR methodology is applied on a formulation (licensed vaccine) containing a large excess of excipient (i.e., sucrose) without analytical sample pretreatment. This work confirms the applicability of a rapid and easy NMR assay on a multivalent conjugate vaccine, which might be extended to other combination vaccines that are already licensed or in clinical development.

Correction to "NMR Assays for Estimating the O-Acetyl Content of Meningococcal Polysaccharide Serogroup A in Quadrivalent Conjugate Vaccine Formulation".

[This corrects the article DOI: 10.1021/acsomega.9b01678.].

Timing of Physical Therapy Initiation for Nonsurgical Management of Musculoskeletal Disorders and Effects on Patient Outcomes: A Systematic Review.

STUDY DESIGN: Systematic review. BACKGROUND: Current US practice guidelines suggest an initial "wait-and-see" approach following onset of musculoskeletal pain, particularly for spinal pain. Several studies suggest that early, compared with delayed, initiation of physical therapy for musculoskeletal conditions may decrease health costs and improve outcomes. OBJECTIVE: To compare early and delayed initiation of physical therapy for individuals with musculoskeletal conditions and to assess effects on patient-important outcomes and cost. METHODS: MEDLINE (Ovid), CINAHL (EBSCO), Web of Science, and PEDro were the data sources. We included studies that compared early and delayed initiation of physical therapy for patients with musculoskeletal disorders. Studies in which early and delayed interventions differed were excluded. Two independent reviewers extracted study characteristics and outcomes, and determined eligibility and quality through consensus with a third reviewer. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used in summary conclusions. Standardized effect sizes (d) and odds ratios were calculated to assess the effect strength of early versus delayed physical therapy for each included study. RESULTS: Of the 3855 articles initially screened, 14 studies were included. The majority of articles studied low back pain (only 2 articles studied cervical pain). For spinal pain, there was low-quality evidence that early versus delayed physical therapy was associated with decreased cost and decreased frequency of opioid prescriptions, advanced imaging, and surgeries without compromising patient-important outcomes. One subgroup analyzed showed improved function/disability with early physical therapy in an occupational health setting. CONCLUSION: Although there were consistent results across studies favoring early physical therapy for decreased cost and medical utilization, quality was limited. Preliminary evidence suggests that early physical therapy may decrease cost without compromising outcomes. The primary limitation of the current research on this topic is in study design. Additional high-quality research involving prospective randomized designs and economic impact analyses is required to further investigate the outcomes associated with early initiation of physical therapy. LEVEL OF EVIDENCE: Therapy, level 1a.

Implications of Dynamic Occupancy, Binding Kinetics, and Channel Gating Kinetics for hERG Blocker Safety Assessment and Mitigation.

Blockade of the hERG potassium channel prolongs the ventricular action potential (AP) and QT interval, and triggers early after depolarizations (EADs) and torsade de pointes (TdP) arrhythmia. Opinions differ as to the causal relationship between hERG blockade and TdP, the relative weighting of other contributing factors, definitive metrics of preclinical proarrhythmicity, and the true safety margin in humans. Here, we have used in silico techniques to characterize the effects of channel gating and binding kinetics on hERG occupancy, and of blockade on the human ventricular AP. Gating effects differ for compounds that are sterically compatible with closed channels (becoming trapped in deactivated channels) versus those that are incompatible with the closed/closing state, and expelled during deactivation. Occupancies of trappable blockers build to equilibrium levels, whereas those of non-trappable blockers build and decay during each AP cycle. Occupancies of ~83% (non-trappable) versus ~63% (trappable) of open/inactive channels caused EADs in our AP simulations. Overall, we conclude that hERG occupancy at therapeutic exposure levels may be tolerated for nontrappable, but not trappable blockers capable of building to the proarrhythmic occupancy level. Furthermore, the widely used Redfern safety index may be biased toward trappable blockers, overestimating the exposure-IC50 separation in nontrappable cases.

Prediction of intestinal permeability.

This review focuses on computational methods for the prediction of passive intestinal permeability. Existing computational models are surveyed and assessed in terms of descriptors, model type/complexity, speed of computation, predictive performance, and interpretability. Challenges to the successful computational prediction of intestinal permeability, i.e. data quantity, measurement imprecision, confounding factors such as solubility, metabolism, or active efflux, and the need for robust statistical methods, are also discussed.

Guiding molecules towards drug-likeness.

This review discusses computational methods for the prediction of drug-likeness. The coverage of published works include the assessment of historical practices of lead generation and optimization, surveys of the properties of known drugs and their constituent fragments and scaffolds, methods for delineating drug space, optimization techniques for simultaneously enhancing multiple properties and drug-like characteristics, similarity metrics and the application of more advanced pattern recognition algorithms for the prediction of drug-likeness. Areas which could be improved in this field are the scope of the datasets used to build models, the chemical interpretability of models, the use of multivariate optimization methods for drug design and the application of underappreciated statistical methods proven to work in other fields.

In silico prediction of drug safety: despite progress there is abundant room for improvement.

Predictive models for drug safety are crucial for helping to avoid costly late-stage failures. We review recent work on models for genotoxicity, liver toxicity, CYP450 inhibition and cardiotoxicity. These models have improved somewhat in recent years, and research has expanded into new frontiers, such as the prediction of liver toxicity. However, much more needs to be done.:

A treatment-based classification approach to examination and intervention of lumbar disorders.

CONTEXT: Low back injuries are a common occurrence in athletes and often result in missed competition and practice time. The examination of athletes with low back pain commonly involves diagnostic imaging, which rarely guides the clinician in selecting the appropriate interventions. DATA ACQUISITION: All years of PubMed, CINAHL, PEDro, and SPORTDiscus were searched in December 2010. Keywords included treatment based classification and lumbar with the following terms: rehabilitation, treatment, athlete, low back pain, sports, and outcomes. RESULTS: A treatment-based classification approach is preferred for the management of the athlete with low back pain. The treatment-based classification approach involves 3 steps. First is to screen the patient for potentially serious conditions that are not appropriate for conservative management. Second is staging the athlete (based on current disability ratings and ability to perform functional activities). Finally, treatment interventions are selected on the basis of the athlete's signs and symptoms. CONCLUSION: The treatment-based classification scheme provides the clinician with a reliable algorithm for matching an athlete's symptom presentation to the optimal intervention, potentially reducing participation loss. Managing individuals with low back pain using a treatment-based classification approach significantly reduces disability and pain compared with current clinical practice guideline standards.