Fundamentals of osteoarthritis. Rehabilitation: Exercise, diet, biomechanics, and physical therapist-delivered interventions.

Insights related to the pathogenesis of osteoarthritis (OA) have informed rehabilitative treatments that aim to mitigate the influence of several known impairments and risk factors for OA, with the goal to improve pain, function, and quality of life. The purpose of this invited narrative review is to provide fundamental knowledge to non-specialists about exercise and education, diet, biomechanical interventions, and other physical therapist-delivered treatments. In addition to summarizing the rationale for common rehabilitative therapies, we provide a synthesis of current core recommendations. Robust evidence based on randomized clinical trials supports exercise with education and diet as core treatments for OA. Structured, supervised exercise therapy is advised. The mode of exercise may vary but should be individualized. The dose should be based on an initial assessment, the desired physiological changes, and progressed when appropriate. Diet combined with exercise is strongly recommended and studies demonstrate a dose-response relationship between the magnitude of weight loss and symptom improvement. Recent evidence suggests the use of technology to remotely deliver exercise, diet and education interventions is cost-effective. Although several studies support the mechanisms for biomechanical interventions (e.g., bracing, shoe inserts) and physical therapist-delivered (passive) treatments (e.g., manual therapy, electrotherapeutic modalities) fewer rigorous randomized trials support their clinical use; these therapies are sometimes recommended as adjuncts to core treatments. The mechanisms of action for all rehabilitative interventions include contextual factors such as attention and placebo effects. These effects can challenge our interpretation of treatment efficacy from clinical trials, yet also provide opportunities to maximize patient outcomes in clinical practice. When evaluating rehabilitative interventions, the field may benefit from increased emphasis on research that considers contextual factors while evaluating mechanistic, longer-term, clinically-important and policy-relevant outcome measures.

Single cell multi-omics characterise discrete human tendon cells populations that persist in vitro and on fibrous scaffolds.

Chronic tendinopathy represents a growing healthcare burden in the ageing global population. Curative therapies remain elusive as the mechanisms that underlie chronic inflammation in tendon disease remain unclear. Identifying and isolating key pathogenic and reparative cells is essential in developing precision therapies and implantable materials for improved tendon healing. Multiple discrete human tendon cell populations have been previously described ex vivo. To determine if these populations persist in vitro, healthy human hamstring tenocytes were cultured for 8 d on either tissue culture plastic or aligned electrospun fibres of absorbable polydioxanone. Novel single-cell surface proteomics combined with unbiased single-cell transcriptomics (CITE-Seq) was used to identify discrete tenocyte populations. 6 cell populations were found, 4 of which shared key gene expression determinants with ex vivo human cell clusters: PTX3_PAPPA, POSTN_SCX, DCN_LUM and ITGA7_NES. Surface proteomics found that PTX3_PAPPA cells were CD10+CD26+CD54+. ITGA7_NES cells were CD146+ and POSTN_SCX cells were CD90+CD95+CD10+. Culture on the aligned electrospun fibres favoured 3 cell subtypes (DCN_LUM, POSTN_SCX and PTX3_ PAPPA), promoting high expression of tendon-matrix-associated genes and upregulating gene sets enriched for TNF-a and IL-6/STAT3 signalling. Discrete human tendon cell subpopulations persisted in in vitro culture and could be recognised by specific gene and surface-protein signatures. Aligned polydioxanone fibres promoted the survival of 3 clusters, including pro-inflammatory PTX3-expressing CD10+CD26+CD54+ cells found in chronic tendon disease. These results improved the understanding of preferred culture conditions for different tenocyte subpopulations and informed the development of in vitro models of tendon disease.

Item-specific encoding reduces false recognition of homograph and implicit mediated critical lures.

We evaluated the effects of item-specific and relational encoding instructions on false recognition for critical lures that originated from homograph and mediated study lists. Homograph lists contained list items that were taken from two meanings of the same critical lure (e.g., autumn, trip, harvest, stumble; for fall) which disrupted thematic/gist consistency of the list. Mediated lists contained unrelated list items (e.g., slippery, spicy, vent, sleigh) that were indirectly related to a critical lure (e.g., cold), through a set of non-presented mediators (e.g., wet, hot, air, snow), and had no thematic/gist consistency. In two experiments, item-specific and relational encoding improved correct recognition relative to a read-only control task, but only item-specific encoding reduced false recognition of critical lures. Signal-detection analyses indicated that the item-specific reduction increased test-based monitoring. The item-specific reduction for homograph and mediated critical lures is consistent with the activation-monitoring framework given gist-based processes are reduced or eliminated on these list types.

Fetal lung transcriptome patterns in an ex vivo compression model of diaphragmatic hernia.

BACKGROUND: The purpose of this study was to employ a novel ex vivo lung model of congenital diaphragmatic hernia (CDH) to determine how a mechanical compression affects early pulmonary development. METHODS: Day-15 whole fetal rat lungs (n = 6-12/group) from nitrofen-exposed and normal (vehicle only) dams were explanted and cultured ex vivo in compression microdevices (0.2 or 0.4 kPa) for 16 h to mimic physiologic compression forces that occur in CDH in vivo. Lungs were evaluated with significance set at P < 0.05. RESULTS: Nitrofen-exposed lungs were hypoplastic and expressed lower levels of surfactant protein C at baseline. Although compression alone did not alter the α-smooth muscle actin (ACTA2) expression in normal lungs, nitrofen-exposed lungs had significantly increased ACTA2 transcripts (0.2 kPa: 2.04 ± 0.15; 0.4 kPa: 2.22 ± 0.11; both P < 0.001). Nitrofen-exposed lungs also showed further reductions in surfactant protein C expression at 0.2 and 0.4 kPa (0.53 ± 0.04, P < 0.01; 0.69 ± 0.23, P < 0.001; respectively). Whereas normal lungs exposed to 0.2 and 0.4 kPa showed significant increases in periostin (POSTN), a mechanical stress-response molecule (1.79 ± 0.10 and 2.12 ± 0.39, respectively; both P < 0.001), nitrofen-exposed lungs had a significant decrease in POSTN expression (0.4 kPa: 0.67 ± 0.15, P < 0.001), which was confirmed by immunohistochemistry. CONCLUSIONS: Collectively, these pilot data in a model of CDH lung hypoplasia suggest a primary aberration in response to mechanical stress within the nitrofen lung, characterized by an upregulation of ACTA2 and a downregulation in SPFTC and POSTN. This ex vivo compression system may serve as a novel research platform to better understand the mechanobiology and complex regulation of matricellular dynamics during CDH fetal lung development.

Priming of the Respiratory Tract with Immunobiotic Lactobacillus plantarum Limits Infection of Alveolar Macrophages with Recombinant Pneumonia Virus of Mice (rK2-PVM).

UNLABELLED: Pneumonia virus of mice (PVM) is a natural rodent pathogen that replicates in bronchial epithelial cells and reproduces many clinical and pathological features of the more severe forms of disease associated with human respiratory syncytial virus. In order to track virus-target cell interactions during acute infection in vivo, we developed rK2-PVM, bacterial artificial chromosome-based recombinant PVM strain J3666 that incorporates the fluorescent tag monomeric Katushka 2 (mKATE2). The rK2-PVM pathogen promotes lethal infection in BALB/c mice and elicits characteristic cytokine production and leukocyte recruitment to the lung parenchyma. Using recombinant virus, we demonstrate for the first time PVM infection of both dendritic cells (DCs; CD11c(+) major histocompatibility complex class II(+)) and alveolar macrophages (AMs; CD11c(+) sialic acid-binding immunoglobulin-like lectin F(+)) in vivo and likewise detect mKATE2(+) DCs in mediastinal lymph nodes from infected mice. AMs support both active virus replication and production of infectious virions. Furthermore, we report that priming of the respiratory tract with immunobiotic Lactobacillus plantarum, a regimen that results in protection against the lethal inflammatory sequelae of acute respiratory virus infection, resulted in differential recruitment of neutrophils, DCs, and lymphocytes to the lungs in response to rK2-PVM and a reduction from ∼ 40% to <10% mKATE2(+) AMs in association with a 2-log drop in the release of infectious virions. In contrast, AMs from L. plantarum-primed mice challenged with virus ex vivo exhibited no differential susceptibility to rK2-PVM. Although the mechanisms underlying Lactobacillus-mediated viral suppression remain to be fully elucidated, this study provides insight into the cellular basis of this response. IMPORTANCE: Pneumonia virus of mice (PVM) is a natural mouse pathogen that serves as a model for severe human respiratory syncytial virus disease. We have developed a fully functional recombinant PVM strain with a fluorescent reporter protein (rK2-PVM) that permits us to track infection of target cells in vivo. With rK2-PVM, we demonstrate infection of leukocytes in the lung, notably, dendritic cells and alveolar macrophages. Alveolar macrophages undergo productive infection and release infectious virions. We have shown previously that administration of immunobiotic Lactobacillus directly to the respiratory mucosa protects mice from the lethal sequelae of PVM infection in association with profound suppression of the virus-induced inflammatory response. We show here that Lactobacillus administration also limits infection of leukocytes in vivo and results in diminished release of infectious virions from alveolar macrophages. This is the first study to provide insight into the cellular basis of the antiviral impact of immunobiotic L. plantarum.

Resorbable electrospun polydioxanone fibres modify the behaviour of cells from both healthy and diseased human tendons.

Chronic tendinopathy in an active and ageing population represents an increasing burden to healthcare systems. Rotator cuff tendinopathy alone accounts for approximately 70 % of all shoulder pain. Tendinopathic tissue has a disorganised extracellular matrix, altered vasculature, and infiltration of fibroblasts and inflammatory cells. This altered biology may contribute to the limited success of surgical repair strategies. Electrospun resorbable scaffolds can potentially enhance endogenous repair mechanisms by influencing the tissue microenvironment. Polydioxanone (PDO) has an established safety profile in patients. We compared the response of healthy and diseased human tendon cells to electrospun PDO fibres using live cell imaging, proliferation, flow cytometry, and gene expression studies. Within 4 h of initial contact with electrospun PDO, healthy tendon cells underwent a marked transformation; elongating along the fibres in a fibre density dependent manner. Diseased tendon cells initially responded at a slower rate, but ultimately underwent a similar morphological change. Electrospun fibres increased the proliferation rate of diseased tendon cells and increased the ratio of type I:IIIcollagenmRNA expression. Flow cytometry revealed decreased expression of CD106, a marker of mesenchymal stem cells, and increased expression of CD10 on healthy versus diseased tendon cells. PDO electrospun scaffolds further promoted CD106negCD10pos expression of healthy tendon cells. Despite their behavioural differences, both healthy and diseased human tendon cells responded to electrospun PDO fibres. This encourages further work establishing their efficacy in augmenting surgical repair of diseased tendons.

Are the Effects of Resistance Exercise on Pain and Function in Knee and Hip Osteoarthritis Dependent on Exercise Volume, Duration, and Adherence? A Systematic Review and Meta-Analysis.

OBJECTIVE: The purpose of this study was to determine dose parameters for resistance exercise associated with improvements in pain and physical function in knee and hip osteoarthritis (OA) and whether these improvements were related to adherence. METHODS: We searched six databases, from inception to January 28, 2023, for randomized controlled trials comparing land-based, resistance exercise-only interventions with no intervention, or any other intervention. There were four subgroups of intervention duration: 0 to <3 months, 3 to 6 months, >6 to <12 months, ≥12 months. The between-group effect was calculated for immediate postintervention pain and physical function (activities of daily living [ADL] and sports/recreation [SPORT]). RESULTS: For both knee and hip, data from 280 studies showed moderate benefit for pain, physical function ADL, and physical function SPORT in favor of interventions 3 to 6 months. For the knee, there was also a moderate benefit for physical function ADL in favor of interventions >6 to <12 months. From 151 knee and hip studies that provided total exercise volume data (frequency, time, duration), there was no association between volume with the effect size for pain and physical function. A total of 74 studies (69 knee, 5 hip) reported usable adherence data. There was no association between adherence with the effect size for pain and physical function. CONCLUSION: In knee and hip OA, resistance exercise interventions 3 to 6 months (and for the knee >6 to <12 months) duration improve pain and physical function. Improvements do not depend on exercise volume or adherence, suggesting exercise does not require rigid adherence to a specific dose.

The relationship between muscle capacity utilization during gait and pain in people with symptomatic knee osteoarthritis.

BACKGROUND: Muscle capacity utilization reflects the percentage of maximal knee extensor strength required to complete physical activities. RESEARCH QUESTION: Is pain associated with muscle capacity utilization during walking in older adults with knee osteoarthritis? Secondarily, is muscle capacity utilization in older adults with knee osteoarthritis sex-specific? METHODS: Twenty-three participants (15 females) with symptomatic knee OA completed this study [age 67 ( ± 8) years, body mass index 29.7 ( ± 3.9) kg/m2, gait speed during the Six Minute Walk test 1.25 ( ± 0.25) m/s]. Pain was measured using the Knee injury and Osteoarthritis Outcome Score. Muscle capacity utilization was quantified as the peak external knee flexor moment during level walking normalized to knee extensor maximum voluntary isometric contraction. The knee flexor moment was calculated from kinematic and kinetic data during barefoot level walking at a self-selected speed and at 1.1 m/s. Knee extensor maximum voluntary isometric contraction was measured on a dynamometer. Multiple linear regressions were used to determine the relationship between pain and muscle capacity utilization after adjusting for age, sex, body mass index, and gait speed. Independent sample t-tests examined sex differences. RESULTS: Pain was not associated with muscle capacity utilization during self-selected and standardized walking speeds (p = 0.38 and p = 0.36, respectively). Females did not require a greater muscle capacity utilization than males to complete gait at self-selected and standardized speeds (p = 0.28, and p = 0.40, respectively). SIGNIFICANCE: Muscle capacity utilization was not associated with pain during walking in people with knee osteoarthritis. Future work should explore more challenging activities of daily living in knee OA.

Manipulations of List Type in the DRM Paradigm: A Review of How Structural and Conceptual Similarity Affect False Memory.

The use of list-learning paradigms to explore false memory has revealed several critical findings about the contributions of similarity and relatedness in memory phenomena more broadly. Characterizing the nature of "similarity and relatedness" can inform researchers about factors contributing to memory distortions and about the underlying associative and semantic networks that support veridical memory. Similarity can be defined in terms of semantic properties (e.g., shared conceptual and taxonomic features), lexical/associative properties (e.g., shared connections in associative networks), or structural properties (e.g., shared orthographic or phonological features). By manipulating the type of list and its relationship to a non-studied critical item, we review the effects of these types of similarity on veridical and false memory. All forms of similarity reviewed here result in reliable error rates and the effects on veridical memory are variable. The results across a variety of paradigms and tests provide partial support for a number of theoretical explanations of false memory phenomena, but none of the theories readily account for all results.

Hydrogel and neural progenitor cell delivery supports organotypic fetal spinal cord development in an ex vivo model of prenatal spina bifida repair.

Studying how the fetal spinal cord regenerates in an ex vivo model of spina bifida repair may provide insights into the development of new tissue engineering treatment strategies to better optimize neurologic function in affected patients. Here, we developed hydrogel surgical patches designed for prenatal repair of myelomeningocele defects and demonstrated viability of both human and rat neural progenitor donor cells within this three-dimensional scaffold microenvironment. We then established an organotypic slice culture model using transverse lumbar spinal cord slices harvested from retinoic acid-exposed fetal rats to study the effect of fibrin hydrogel patches ex vivo. Based on histology, immunohistochemistry, gene expression, and enzyme-linked immunoabsorbent assays, these experiments demonstrate the biocompatibility of fibrin hydrogel patches on the fetal spinal cord and suggest this organotypic slice culture system as a useful platform for evaluating mechanisms of damage and repair in children with neural tube defects.

Strong independent associations between gait biomechanics and pain in patients with knee osteoarthritis.

We investigated the simple and multivariate associations between knee pain and gait biomechanics. 279 patients with medial knee osteoarthritis (OA) and discordant changes in pain between limbs after walking completed bilateral three-dimensional gait analysis. For each limb, patients rated their pain before and after a 6-min walk and the change in pain was recorded as an increase (≥1 points) or not (≤0 points). Among paired limbs, the simple and multivariate associations between an increase in pain and the external moments in each orthogonal plane were evaluated using conditional logistic regression. The analyses were then repeated for knee angles. Univariate analyses demonstrated associations in each plane that varied in both magnitude and direction, with larger associations for the knee moments [Odds Ratio (95% confidence interval) = first peak adduction moment: 2.80 (2.02, 3.88), second peak adduction moment: 2.36 (1.73, 3.24), adduction impulse: 6.65 (3.50, 12.62), flexion moment: 0.46 (0.36, 0.60), extension moment: 0.56 (0.44, 0.71), internal rotation moment: 7.54 (3.32, 17.13), external rotation moment: 0.001 (0.00, 0.04)]. Multivariate analyses with backward elimination resulted in a model including only the adduction impulse [5.35 (2.51, 11.42)], flexion moment [0.32 (0.22, 0.46)] and extension moment [0.28 (0.19, 0.42)]. The varus, flexion and extension angles were included in the final multivariate model for the knee angles. When between-person confounding is lessened by comparing limbs within patients, there are strong independent associations between knee pain and multiple external knee moments that vary in magnitude and direction. While controlling for other knee moments, a greater adduction impulse and lower flexion and extension moments were independently associated with greater odds of an increase in pain.

Improved Methods to Measure Outcomes After High Tibial Osteotomy.

Observational studies suggest high tibial osteotomy produces substantial improvements in knee loading and stability that can limit the progression of joint damage; decrease pain; improve function and quality of life; and delay the need for knee replacement surgery. It can be cost-effective in knee osteoarthritis. However, systematic reviews and clinical practice guidelines are unable to provide strong recommendations, because limited high-level evidence supports its therapeutic value versus other treatments. We describe findings suggesting it can improve outcomes important to knee joint structure and function, patient quality of life, and health care systems. Future clinical trials are warranted and required.

Association Between Knee Load and Pain: Within-Patient, Between-Knees, Case-Control Study in Patients With Knee Osteoarthritis.

OBJECTIVE: The association between knee loading and pain in patients with knee osteoarthritis is reported to be low and of questionable importance, but may be confounded by several factors that differ between patients. We aimed to elucidate the association between dynamic knee load and pain by minimizing confounding using a study design that was within the same patient, with knees discordant for pain. METHODS: A total of 265 patients with knees discordant for pain (530 knees) rated the pain in each knee before and after walking for 6 minutes, and then underwent 3-dimensional gait analysis. RESULTS: The peak knee adduction moment and knee adduction impulse (proxies for medial knee loading) were associated with increased pain (odds ratio [OR] 2.43 [95% confidence interval (95% CI) 1.77-3.33] and OR 6.62 [95% CI 3.46-12.7], respectively) and remained significant after controlling for radiographic disease severity. When split into quartiles, ORs indicated knees in the highest loading quartile had greater odds of experiencing increased pain with walking (OR 4.7 95% CI 2.3-9.5] for peak adduction moment; OR 9.0 [95% CI 4.0-20.1] for adduction impulse) compared to knees in the lowest loading quartile. CONCLUSION: When between-patient confounding is minimized, there is a strong association between medial knee load and increased knee pain during walking.

Variation in photosynthetic traits related to access to water in semiarid Australian woody species.

Low soil water content can limit photosynthesis by reducing stomatal conductance. Here, we explore relationships among traits pertaining to carbon uptake and pre-dawn leaf water potential (as an index of soil water availability) across eight species found in semiarid central Australia. We found that as pre-dawn leaf water potential declined, stomatal limitations to photosynthesis increased, as did foliar nitrogen, which enhanced photosynthesis. Nitrogen-fixing Acacia species had higher foliar nitrogen concentrations compared with non-nitrogen fixing species, although there was considerable variability of traits within the Acacia genus. From principal component analysis we found that the most dissimilar species was Acacia aptaneura Maslin&J.E.Reid compared with both Eucalyptus camaldulensis Dehnh. and Corymbia opaca. (D.J.Carr & S.G.M.Carr)K.D.Hill&L.A.S.Johnson, having both the largest foliar N content, equal largest leaf mass per area and experiencing the lowest pre-dawn water potential of all species. A. aptaneura has shallow roots and grows above a hardpan that excludes access to groundwater, in contrast to E. camaldulensis and C. opaca, which are known to access groundwater. We conclude that ecohydrological niche separation is an important factor driving the variability of within-biome traits related to carbon gain. These observations have important implications for global vegetation models, which are parameterised with many of the traits measured here, but are often limited by data availability.

Divergence in plant water-use strategies in semiarid woody species.

Partitioning of water resources amongst plant species within a single climate envelope is possible if the species differ in key hydraulic traits. We examined 11 bivariate trait relationships across nine woody species found in the Ti-Tree basin of central Australia. We found that species with limited access to soil moisture, evidenced by low pre-dawn leaf water potential, displayed anisohydric behaviour (e.g. large seasonal fluctuations in minimum leaf water potential), had greater sapwood density and lower osmotic potential at full turgor. Osmotic potential at full turgor was positively correlated with the leaf water potential at turgor loss, which was, in turn, positively correlated with the water potential at incipient stomatal closure. We also observed divergent behaviour in two species of Mulga, a complex of closely related Acacia species which range from tall shrubs to low trees and dominate large areas of arid and semiarid Australia. These Mulga species had much lower minimum leaf water potentials and lower specific leaf area compared with the other seven species. Finally, one species, Hakea macrocarpa A.Cunn ex.R.Br., had traits that may allow it to tolerate seasonal dryness (through possession of small specific leaf area and cavitation resistant xylem) despite exhibiting cellular water relations that were similar to groundwater-dependent species. We conclude that traits related to water transport and leaf water status differ across species that experience differences in soil water availability and that this enables a diversity of species to exist in this low rainfall environment.

Human Cardiomyocytes Prior to Birth by Integration-Free Reprogramming of Amniotic Fluid Cells.

: The establishment of an abundant source of autologous cardiac progenitor cells would represent a major advance toward eventual clinical translation of regenerative medicine strategies in children with prenatally diagnosed congenital heart disease. In support of this concept, we sought to examine whether functional, transgene-free human cardiomyocytes (CMs) with potential for patient-specific and autologous applications could be reliably generated following routine amniocentesis. Under institutional review board approval, amniotic fluid specimens (8-10 ml) at 20 weeks gestation were expanded and reprogrammed toward pluripotency using nonintegrating Sendai virus (SeV) expressing OCT4, SOX2, cMYC, and KLF4. Following exposure of these induced pluripotent stem cells to cardiogenic differentiation conditions, spontaneously beating amniotic fluid-derived cardiomyocytes (AF-CMs) were successfully generated with high efficiency. After 6 weeks, quantitative gene expression revealed a mixed population of differentiated atrial, ventricular, and nodal AF-CMs, as demonstrated by upregulation of multiple cardiac markers, including MYH6, MYL7, TNNT2, TTN, and HCN4, which were comparable to levels expressed by neonatal dermal fibroblast-derived CM controls. AF-CMs had a normal karyotype and demonstrated loss of NANOG, OCT4, and the SeV transgene. Functional characterization of SIRPA+ AF-CMs showed a higher spontaneous beat frequency in comparison with dermal fibroblast controls but revealed normal calcium transients and appropriate chronotropic responses after ß-adrenergic agonist stimulation. Taken together, these data suggest that somatic cells present within human amniotic fluid can be used to generate a highly scalable source of functional, transgene-free, autologous CMs before a child is born. This approach may be ideally suited for patients with prenatally diagnosed cardiac anomalies. SIGNIFICANCE: This study presents transgene-free human amniotic fluid-derived cardiomyocytes (AF-CMs) for potential therapy in tissue engineering and regenerative medicine applications. Using 8-10 ml of amniotic fluid harvested at 20 weeks gestation from normal pregnancies, a mixed population of atrial, ventricular, and nodal AF-CMs were reliably generated after Sendai virus reprogramming toward pluripotency. Functional characterization of purified populations of beating AF-CMs revealed normal calcium transients and appropriate chronotropic responses after ß-adrenergic agonist stimulation in comparison with dermal fibroblast controls. Because AF-CMs can be generated in fewer than 16 weeks, this approach may be ideally suited for eventual clinical translation at birth in children with prenatally diagnosed cardiac anomalies.

The roles of vaccination and amantadine prophylaxis in controlling an outbreak of influenza A (H3N2) in a nursing home.

An outbreak caused by influenza A/Philippines/2/82 (H3N2)-like viruses occurred in a partially vaccinated nursing home population in January 1985. During the first six days of the outbreak, 14 (25%) of 55 residents developed influenzalike illness. The risk of illness was most strongly associated with undetectable levels of antibody against the epidemic strain, with unvaccinated case-patients having more severe illnesses and a higher rate of hospitalization than vaccinated case-patients (5/8 vs 0/6). During the period of amantadine hydrochloride prophylaxis (100 mg/d) from days 7 to 35, only two (5%) of the remaining 41 residents became ill, even though 11 (27%) had no detectable antibody. Serum amantadine levels obtained on day 35 ranged from 117 to 737 ng/mL (mean 309 ng/mL), similar to therapeutic levels documented in younger adults who have taken the standard regimen of 200 mg/d; there were few clinically significant side effects. These findings illustrate the benefits of influenza vaccination and support the use of amantadine hydrochloride at a dosage of 100 mg daily for outbreak control among elderly persons.

Valgus bracing for knee osteoarthritis: a meta-analysis of randomized trials.

OBJECTIVE: To evaluate the effects of valgus knee bracing on pain and function, and compliance and complications, in patients with medial knee osteoarthritis (OA). METHODS: A meta-analysis of randomized controlled trials that compared changes in patient-reported pain and/or function in patients with medial knee OA was performed. Seven databases were searched from their inception to January 2014. Two reviewers independently determined study eligibility, rated risk of bias, and extracted data. Pooled estimates and 95% confidence intervals (95% CIs) for standardized mean differences (SMDs) for the improvement in pain (and function) were calculated. Event rates (proportions) were calculated for studies that reported complications. RESULTS: Six studies were included in the meta-analysis. Overall, there was a statistically significant difference favoring the valgus brace group for improvement in pain (SMD 0.33 [95% CI 0.13, 0.52], P = 0.001) and function (SMD 0.22 [95% CI 0.02, 0.41], P = 0.03). When compared to a control group that did not use an orthosis, the effect size was moderate for pain (SMD 0.56 [95% CI 0.03, 1.09], P = 0.04) and function (SMD 0.48 [95% CI 0.02, 0.95], P = 0.04). When compared to a control group that used a control orthosis, only a small, statistically significant effect for pain remained (SMD 0.33 [95% CI 0.08, 0.58], P = 0.01). Instructions for brace use varied considerably and compliance ranged from 45% to 100%. Up to 25% of patients reported minor complications with brace use. CONCLUSION: Meta-analysis of randomized trials suggests valgus bracing for medial knee OA results in small-to-moderate improvements in pain. Effect sizes vary based on study design and warrant future research.

Epidemiologic implications of changes in the influenza virus genome.

Among the molecular maneuvers that enable the influenza virus to survive are antigenic variation and functional alterations. Two kinds of minor antigenic variations, producing new strains within type A virus subtypes, have been discovered: antigenic drift, in which the amino acid sequences of the antigens are changed; and antigenic camouflage, in which the antigens are glycosylated. Both kinds of variation are caused by mutations in the viral genome. These mutations produce slightly changed antigens, which many existing antibodies cannot recognize. Major antigenic variations (so-called antigenic shift) are produced by gene reassortment. Two subtypes, coinfecting a host, can reassort their eight ribonucleoprotein gene segments into as many as 256 different combinations. Such recombinations can produce new viruses with the potential for transmission in humans, but whose surface antigens are completely unmatched by antibodies in the population, permitting a pandemic to occur. Functional changes, caused by mutations, alter the interactions between the virus and the host, including virus binding to host receptor sites and fusion of viral and host membranes. All these mechanisms allow the influenza virus to survive in humans, probably perpetually.

Genetic and antigenic analyses of influenza A (H1N1) viruses, 1986-1991.

Eighteen strains of human influenza A (H1N1) viruses isolated between August 1986 and January 1991 were analyzed in this study. Examination of the total viral genome of 12 strains by T1 mapping revealed that considerable genetic heterogeneity exists among these viruses. Partial sequencing of each of the non-HA RNA segments of 4 viruses having divergent T1 oligonucleotide maps indicated that only one was a reassortant virus that had genes from both the influenza A (H1N1) and (H3N2) subtypes. This reassortant obtained its PB2 gene from a virus of the H3N2 subtype and the other 7 RNA segments from an H1N1 parent. Sequencing studies of the HA1 domains of the hemagglutinin (HA) genes of these 18 strains revealed that although these viruses are antigenically similar to the reference strains A/Taiwan/1/86 and A/Singapore/6/86, 7 conserved amino acid substitutions that are shared by recently isolated H1N1 viruses have occurred in the main stream of evolution of the H1N1 subtype. Our data indicate that: (1) Genetic reassortment continues to contribute to genetic variability of H1N1 viruses. (2) Genetic variants of non-reassortant H1N1 viruses are co-circulating in the world. (3) The HA's of recent H1N1 viruses are related to those of the 1986 reference strains. (4) Although there has been little detectable antigenic variability, the HA genes of human epidemic influenza A (H1N1) viruses have continued to evolve at an evolutionary rate similar to that for the H1N1 and H3N2 viruses analyzed previously.