Bayesian modeling reveals metabolite-dependent ultrasensitivity in the cyanobacterial circadian clock.

Mathematical models can enable a predictive understanding of mechanism in cell biology by quantitatively describing complex networks of interactions, but such models are often poorly constrained by available data. Owing to its relative biochemical simplicity, the core circadian oscillator in Synechococcus elongatus has become a prototypical system for studying how collective dynamics emerge from molecular interactions. The oscillator consists of only three proteins, KaiA, KaiB, and KaiC, and near-24-h cycles of KaiC phosphorylation can be reconstituted in vitro. Here, we formulate a molecularly detailed but mechanistically naive model of the KaiA-KaiC subsystem and fit it directly to experimental data within a Bayesian parameter estimation framework. Analysis of the fits consistently reveals an ultrasensitive response for KaiC phosphorylation as a function of KaiA concentration, which we confirm experimentally. This ultrasensitivity primarily results from the differential affinity of KaiA for competing nucleotide-bound states of KaiC. We argue that the ultrasensitive stimulus-response relation likely plays an important role in metabolic compensation by suppressing premature phosphorylation at nighttime.

Tissue Engineering for Musculoskeletal Regeneration and Disease Modeling.

Musculoskeletal injuries and associated conditions are the leading cause of physical disability worldwide. The concept of tissue engineering has opened up novel approaches to repair musculoskeletal defects in a fast and/or efficient manner. Biomaterials, cells, and signaling molecules constitute the tissue engineering triad. In the past 40 years, significant progress has been made in developing and optimizing all three components, but only a very limited number of technologies have been successfully translated into clinical applications. A major limiting factor of this barrier to translation is the insufficiency of two-dimensional cell cultures and traditional animal models in informing the safety and efficacy of in-human applications. In recent years, microphysiological systems, often referred to as organ or tissue chips, generated according to tissue engineering principles, have been proposed as the next-generation drug testing models. This chapter aims to first review the current tissue engineering-based approaches that are being applied to fabricate and develop the individual critical elements involved in musculoskeletal organ/tissue chips. We next highlight the general strategy of generating musculoskeletal tissue chips and their potential in future regenerative medicine research. Exemplary microphysiological systems mimicking musculoskeletal tissues are described. With sufficient physiological accuracy and relevance, the human cell-derived, three-dimensional, multi-tissue systems have been used to model a number of orthopedic disorders and to test new treatments. We anticipate that the novel emerging tissue chip technology will continually reshape and improve our understanding of human musculoskeletal pathophysiology, ultimately accelerating the development of advanced pharmaceutics and regenerative therapies.

Birth by caesarean section and educational achievement in adolescents.

BACKGROUND: Birth by caesarean section has been shown to alter the composition of the early infant gut microbiota and postulated to influence cognitive outcomes via the gut-brain axis. AIMS: To determine whether birth by caesarean section is associated with secondary school educational achievement. METHODS: Whole-population administrative data were used from anonymised individual level linkage of birth records to educational and health information from the New Zealand Integrated Data Infrastructure (IDI). Participants were 111 843 children born between 1 January 1996 and 31 December 1998 for whom mode of delivery information was available from International Classification of Diseases 9th edition codes in maternal records. The National Certificate of Educational Achievement (NCEA) is the main secondary school qualification undertaken by New Zealand students. Multivariable linear regression models were used to examine the association between mode of delivery and educational achievement. A family fixed effect analysis compared educational achievement outcomes in sibling pairs where one sibling was delivered by caesarean section and one delivered vaginally. RESULTS: After adjustment for potential confounders, there was no significant association between mode of delivery and achievement of university entrance (odds ratio = 0.98, 95% CI: 0.94-1.02). NCEA percentile scores were lower in caesarean born infants (Estimate = -0.37, 95% CI: -0.69 to -0.06)). However, in the fixed effect sibling analysis caesarean section was no longer significantly associated with NCEA percentile scores. CONCLUSIONS: We find that caesarean section is not related to educational outcomes, suggesting that even if the infant gut microbiota is altered in caesarean section, it does not appear to have a measurable impact on adolescent academic achievement.

Well-being and cultural identity for Maori: Knowledge of iwi (tribal) affiliations does not strongly relate to health and social service outcomes.

Research indicates that experiences in health and social services vary depending on identity. For Indigenous groups, identity and affiliation is complex. This paper explores ethnicity and knowledge of tribal (iwi) affiliations for Maori (the Indigenous peoples of Aotearoa New Zealand), and links this to health and social service outcomes in administrative data, the national Census, and Maori social survey data. While many initiatives have sought to connect Maori to iwi - where such knowledge has been severed by colonization - we find surprisingly few differences in data between those who named tribal affiliations and those who did not, across sole- and mixed-Maori ethnicity groups. Those who did not name an iwi were less likely to live in overcrowded homes, but were less likely to own that home, and more likely to be a smoker. Unsurprisingly, those who did not name tribal affiliations were less likely to find Maori culture as important, although many still did. These groups also had slightly less contact with social networks and support, plus felt lonelier. The results also point to sole-ethnic identification as Maori as a key marker of experiences of inequity and suggest that connections to tribal affiliations are more complicated than a binary of "connected" or "disconnected". However, in some indicator areas, affiliation differences should be followed up with future work. We argue these results give further weight to the need for good quality data and indicators designed with Maori populations in mind to measure and monitor inequity.

De novo distillation of thermodynamic affinity from deep learning regulatory sequence models of in vivo protein-DNA binding.

Transcription factors (TF) are proteins that bind DNA in a sequence-specific manner to regulate gene transcription. Despite their unique intrinsic sequence preferences, in vivo genomic occupancy profiles of TFs differ across cellular contexts. Hence, deciphering the sequence determinants of TF binding, both intrinsic and context-specific, is essential to understand gene regulation and the impact of regulatory, non-coding genetic variation. Biophysical models trained on in vitro TF binding assays can estimate intrinsic affinity landscapes and predict occupancy based on TF concentration and affinity. However, these models cannot adequately explain context-specific, in vivo binding profiles. Conversely, deep learning models, trained on in vivo TF binding assays, effectively predict and explain genomic occupancy profiles as a function of complex regulatory sequence syntax, albeit without a clear biophysical interpretation. To reconcile these complementary models of in vitro and in vivo TF binding, we developed Affinity Distillation (AD), a method that extracts thermodynamic affinities de-novo from deep learning models of TF chromatin immunoprecipitation (ChIP) experiments by marginalizing away the influence of genomic sequence context. Applied to neural networks modeling diverse classes of yeast and mammalian TFs, AD predicts energetic impacts of sequence variation within and surrounding motifs on TF binding as measured by diverse in vitro assays with superior dynamic range and accuracy compared to motif-based methods. Furthermore, AD can accurately discern affinities of TF paralogs. Our results highlight thermodynamic affinity as a key determinant of in vivo binding, suggest that deep learning models of in vivo binding implicitly learn high-resolution affinity landscapes, and show that these affinities can be successfully distilled using AD. This new biophysical interpretation of deep learning models enables high-throughput in silico experiments to explore the influence of sequence context and variation on both intrinsic affinity and in vivo occupancy.

Creation of a Knee Joint-on-a-Chip for Modeling Joint Diseases and Testing Drugs.

The high prevalence of debilitating joint diseases like osteoarthritis (OA) poses a high socioeconomic burden. Currently, the available drugs that target joint disorders are mostly palliative. The unmet need for effective disease-modifying OA drugs (DMOADs) has been primarily caused by the absence of appropriate models for studying the disease mechanisms and testing potential DMOADs. Herein, we describe the establishment of a miniature synovial joint-mimicking microphysiological system (miniJoint) comprising adipose, fibrous, and osteochondral tissue components derived from human mesenchymal stem cells (MSCs). To obtain the three-dimensional (3D) microtissues, MSCs were encapsulated in photocrosslinkable methacrylated gelatin before or following differentiation. The cell-laden tissue constructs were then integrated into a 3D-printed bioreactor, forming the miniJoint. Separate flows of osteogenic, fibrogenic, and adipogenic media were introduced to maintain the respective tissue phenotypes. A commonly shared stream was perfused through the cartilage, synovial, and adipose tissues to enable tissue crosstalk. This flow pattern allows the induction of perturbations in one or more of the tissue components for mechanistic studies. Furthermore, potential DMOADs can be tested via either "systemic administration" through all the medium streams or "intraarticular administration" by adding the drugs to only the shared "synovial fluid"-simulating flow. Thus, the miniJoint can serve as a versatile in vitro platform for efficiently studying disease mechanisms and testing drugs in personalized medicine.

A randomized trial of probiotic supplementation in nurses to reduce stress and viral illness.

Animal studies demonstrate how the gut microbiota influence psychological health and immunity to viral infections through their actions along multiple dynamic pathways in the body. Considerable interest exists in probiotics to reduce stress and illness symptoms through beneficial effects in the gut, but translating pre-clinical evidence from animal models into humans remains challenging. We conducted a large trial in nurses working during the 2020 COVID19 pandemic year to establish whether daily ingestion of the probiotic Lactobacillus rhamnosus HN001 reduced perceived stress and the number of days participants reported symptoms of a viral illness. Our results showed no significant difference in perceived stress or the average number of illness days between probiotic supplemented nurses and the placebo group. Stress and viral illness symptoms reduced during the study for all participants, a trajectory likely influenced by societal-level factors. The powerful effect of a well-managed public health response to the COVID19 pandemic and the elimination of COVID19 from the community in 2020 may have altered the trajectory of stress levels and reduced circulating viral infections making it difficult to detect any effect of probiotic supplementation. Our study highlights the challenge in controlling environmental factors in human trials.

Probiotics for Reduction of Examination Stress in Students (PRESS) study: A randomized, double-blind, placebo-controlled trial of the probiotic Lacticaseibacillus rhamnosus HN001.

BACKGROUND: Studies suggest that bioactive compounds such as probiotics may positively influence psychological health. This study aimed to determine whether supplementation with the probiotic Lacticaseibacillus rhamnosus HN001 reduced stress and improve psychological wellbeing in university students sitting examinations. METHODS: In this randomized, double-blind, placebo-controlled study, 483 undergraduate students received either the probiotic L. rhamnosus HN001, or placebo, daily during a university semester. Students completed measures of stress, anxiety, and psychological wellbeing at baseline and post-intervention before examinations. Mann Whitney U tests compared the change in psychological outcomes between groups. RESULTS: Of the 483 students, 391 (81.0%) completed the post-intervention questions. There was no significant difference between the probiotic and placebo supplemented groups in psychological health outcomes. The COVID19 pandemic restrictions may have influenced the typical trajectory of stress leading up to examinations. CONCLUSION: We found no evidence of significant benefit of probiotics on the psychological health of university students. These findings highlight the challenges of conducting probiotic trials in human populations where the potential for contextual factors such as COVID19 response, and participant adherence to the intervention may influence results.

Improvement in the psychological health of nurses working during the COVID-19 pandemic.

BACKGROUND: Nurses are a critical component of any healthcare system. The novel coronavirus pandemic has resulted in an increased workload for nurses and heightened stress. AIMS: To assess the psychological health over time of nurses working during the COVID-19 pandemic and to examine the factors associated with stress, anxiety, and psychological wellbeing. METHODS: Nurses enrolled in the study between 2 July and 26 August 2020 andcompleted questionnaires about stress, anxiety, and psychological wellbeing at baseline and at a second time point T2 12 weeks later. A paired sample t-test was used to examine whether changes in stress, anxiety, and psychological wellbeing were significantly different between baseline and T2. Linear regression models examined factors associated with psychological health outcomes. RESULTS: Of the 600 nurses initially enrolled, 484 (80.7%) completed psychological health measures at T2. Stress, anxiety, and poor psychological wellbeing scores were high at baseline. Unexpectedly, stress and psychological wellbeing significantly improved between baseline and T2, while anxiety levels increased. Younger nurses had higher baseline stress and anxiety scores. CONCLUSIONS: This study demonstrates the potential beneficial effect of effective public health management of the COVID-19 pandemic on nurses' stress and psychological wellbeing and highlights the importance of longitudinal research to understand psychological health in nurses.

Differences in the intrinsic chondrogenic potential of human mesenchymal stromal cells and iPSC-derived multipotent cells.

BACKGROUND: Human multipotent progenitor cells (hiMPCs) created from induced pluripotent stem cells (iPSCs) represent a new cell source for cartilage regeneration. In most studies, bone morphogenetic proteins (BMPs) are needed to enhance transforming growth factor-ß (TGFß)-induced hiMPC chondrogenesis. In contrast, TGFß alone is sufficient to result in robust chondrogenesis of human primary mesenchymal stromal cells (hMSCs). Currently, the mechanism underlying this difference between hiMPCs and hMSCs has not been fully understood. METHODS: In this study, we first tested different growth factors alone or in combination in stimulating hiMPC chondrogenesis, with a special focus on chondrocytic hypertrophy. The reparative capacity of hiMPCs-derived cartilage was assessed in an osteochondral defect model created in rats. hMSCs isolated from bone marrow were included in all studies as the control. Lastly, a mechanistic study was conducted to understand why hiMPCs and hMSCs behave differently in responding to TGFß. RESULTS: Chondrogenic medium supplemented with TGFß3 and BMP6 led to robust in vitro cartilage formation from hiMPCs with minimal hypertrophy. Cartilage tissue generated from this new method was resistant to osteogenic transition upon subcutaneous implantation and resulted in a hyaline cartilage-like regeneration in osteochondral defects in rats. Interestingly, TGFß3 induced phosphorylation of both Smad2/3 and Smad1/5 in hMSCs, but only activated Smad2/3 in hiMPCs. Supplementing BMP6 activated Smad1/5 and significantly enhanced TGFß's compacity in inducing hiMPC chondrogenesis. The chondro-promoting function of BMP6 was abolished by the treatment of a BMP pathway inhibitor. CONCLUSIONS: This study describes a robust method to generate chondrocytes from hiMPCs with low hypertrophy for hyaline cartilage repair, as well as elucidates the difference between hMSCs and hiMPCs in response to TGFß. Our results also indicated the importance of activating both Smad2/3 and Smad1/5 in the initiation of chondrogenesis.

Human Mesenchymal Stem Cell-Derived Miniature Joint System for Disease Modeling and Drug Testing.

Diseases of the knee joint such as osteoarthritis (OA) affect all joint elements. An in vitro human cell-derived microphysiological system capable of simulating intraarticular tissue crosstalk is desirable for studying etiologies/pathogenesis of joint diseases and testing potential therapeutics. Herein, a human mesenchymal stem cell-derived miniature joint system (miniJoint) is generated, in which engineered osteochondral complex, synovial-like fibrous tissue, and adipose tissue are integrated into a microfluidics-enabled bioreactor. This novel design facilitates different tissues communicating while still maintaining their respective phenotypes. The miniJoint exhibits physiologically relevant changes when exposed to interleukin-1ß mediated inflammation, which are similar to observations in joint diseases in humans. The potential of the miniJoint in predicting in vivo efficacy of drug treatment is confirmed by testing the "therapeutic effect" of the nonsteroidal anti-inflammatory drug, naproxen, as well as four other potential disease-modifying OA drugs. The data demonstrate that the miniJoint recapitulates complex tissue interactions, thus providing a robust organ chip model for the study of joint pathology and the development of novel therapeutic interventions.

Determination of pharmacy students' patient safety approach using the theory of planned behaviour: a mixed-method study.

OBJECTIVES: To investigate pharmacy students' attitudes, subjective norms, perceived behavioural control, intentions and their behaviour towards patient safety using a theory of planned behaviour framework. DESIGN: Mixed-methods research. SETTING: Private university in Malaysia. PARTICIPANTS: Pharmacy undergraduate students participated in the study. There were 18 students participated in the qualitative study and 272 students responded to the survey questionnaire. METHODS: A convergent parallel-mixed method design, involving a quantitative survey and qualitative focus group discussions was used among pharmacy students in a private university in Malaysia. Qualitative data of transcribed verbatim texts were then subjected to a thematic content analysis framework. Multiple correlations were undertaken using the quantitative data to examine how the dependent variable (self-reported knowledge) related to the independent variables (attitudes, behavioural intentions, subjective norms, perceived behavioural control. PRIMARY OUTCOME: Pharmacy students' attitudes, subjective norms, perceived behavioural control, behavioural intentions constructs led to their behaviour towards patient safety. SECONDARY OUTCOME: The quantitative study revealed that there was a moderate positive correlation between students' self-reported knowledge and attitudes (r=0.48, p=0.03). RESULTS: Pharmacy students' attitudes and perceived behavioural control constructs had positive correlations with pharmacy students' self-reported knowledge on patient safety. There was no correlation between students' self-reported knowledge and subjective norms (r=0.27, p=0.23). There was a weak positive correlation between students' self-reported knowledge and perceived behavioural control (r=0.39, p=0.04). There was no correlation between students' self-reported knowledge and behavioural intention (r=0.20, p=0.56). CONCLUSIONS: Theory of planned behaviour constructs such as attitudes, subjective norms, perceived behavioural control and behavioural intentions of pharmacy students, defined their behaviour towards patient safety. Pharmacy students' attitudes and perceived behavioural control constructs were correlated with their self-reported knowledge on patient safety.

Gait Variability and Relationships With Fear, Avoidance, and Pain in Adolescents With Chronic Pain.

OBJECTIVE: Some children with chronic pain struggle with fear of pain, avoidance behaviors, and associated disability; however, movement adaptations in the context of chronic pain in childhood is virtually unknown. Variability in adaptive movement responses previously observed between individuals might be largely explained by the presence of problematic psychological drivers (eg, fear, avoidance). The goals of this study were to quantify the variability of gait and examine relationships among pain, fear, avoidance, function (perceived and objective), and gait variability. METHODS: This study used a cross-sectional design. Eligible patients were between 8 and 17 years of age and had musculoskeletal, neuropathic, or headache pain that was not due to acute trauma (eg, active sprain) or any specific or systemic disease. Participants completed the Numeric Pain Rating Scale, Fear of Pain Questionnaire (FOPQ), Functional Disability Inventory, and 6-Minute Walk Test and received kinematic gait analysis. Relationships were analyzed among these measures, and the self-report and functional measures were examined to determine whether they predicted gait variability (GaitSD). RESULTS: The 16 participants who were evaluated (13.8 [SD = 2.2] years of age; 13 female) had high Numeric Pain Rating Scale scores (6.2 [SD = 2.1]), FOPQ-Fear scores (25.9 [SD = 12.1]), FOPQ-Avoidance scores (22.8 [SD = 10.2]), and Functional Disability Inventory scores (28.6 [SD = 9.4]) and low 6-Minute Walk Test distance (437.1 m [SD = 144.6]). Participants had greater GaitSD than age-predicted norms. Fear was related to self-selected GaitSD, and avoidance was related to both self-selected and standardized GaitSD. Avoidance predicted 43% and 47% of the variability in self-selected and standardized GaitSD, respectively. CONCLUSION: GaitSD was significantly related to both fear of pain and avoidance behaviors, suggesting the interplay of these psychological drivers with movement. FOPQ-Avoidance was robust in accounting for GaitSD. IMPACT: This study offers preliminary evidence in understanding movement adaptations associated with adolescents with chronic pain. They may lend to more directed interventions.

The relationship between income poverty and child hospitalisations in New Zealand: Evidence from longitudinal household panel data and Census data.

BACKGROUND: Very little high quality evidence exists on the causal relationship between income poverty and childhood health. We provide a comprehensive overview of the association between household income poverty and hospitalisations for children. METHODS: We used New Zealand's Integrated Data Infrastructure (IDI) to link income poverty data from the Survey of Family, Income and Employment (SoFIE; n = 21,759 households) and the 2013 New Zealand Census (n = 523,302 households) to publicly funded hospital records of children aged 0-17 (SoFIE: n = 39,459; Census, n = 986,901). Poverty was defined as equivalised household income below 60% of the median income, calculated both before and after housing costs, and using both self-reported and tax-recorded income. RESULTS: Correlations for the association between income poverty and hospitalisation were small (ranging from 0.02 to 0.05) and risk ratios were less than 1.35 for all but the rarest outcome-oral health hospitalisation. Weak or absent associations were apparent across age groups, waves of data collection, cumulative effects, and for estimates generated from fixed effects models and random effect models adjusted for age and ethnicity. Alternative measures of deprivation (area-level deprivation and material deprivation) showed stronger associations with hospitalisations (risk ratios ranged from 1.27-2.55) than income-based poverty measures. CONCLUSION: Income poverty is at best weakly associated with hospitalisation in childhood. Measures of deprivation may have a stronger association. Income measures alone may not be sufficient to capture the diversity of household economic circumstances when assessing the poverty-health relationship.

Graphene oxide-functionalized nanocomposites promote osteogenesis of human mesenchymal stem cells via enhancement of BMP-SMAD1/5 signaling pathway.

Biomaterials that can harness the intrinsic osteogenic potential of stem cells offer a promising strategy to accelerate bone regeneration and repair. Previously, we had used methacrylated gelatin (GelMA)-based scaffolds to achieve bone formation from human mesenchymal stem cells (hMSCs). In this study, we aimed to further enhance hMSC osteogenesis by incorporating graphene oxide (GO)-based nanosheets into GelMA. In vitro results showed high viability and metabolic activities in hMSCs encapsulated in the newly developed nanocomposites. Incorporation of GO markedly increased mineralization within hMSC-laden constructs, which was further increased by replacing GO with silica-coated graphene oxide (SiGO). Mechanistic analysis revealed that the nanosheet enhanced the production, retention, and biological activity of endogenous bone morphogenetic proteins (BMPs), resulting in robust osteogenesis in the absence of exogenous osteoinductive growth factors. Specifically, the osteoinductive effect of the nanosheets was abolished by inhibiting the BMP signaling pathway with LDN-193189 treatment. The bone formation potential of the technology was further tested in vivo using a mouse subcutaneous implantation model, where hMSCs-laden GO/GelMA and SiGO/GelMA samples resulted in bone volumes 108 and 385 times larger, respectively, than the GelMA control group. Taken together, these results demonstrate the biological activity and mechanism of action of GO-based nanosheets in augmenting the osteogenic capability of hMSCs, and highlights the potential of leveraging nanomaterials such as GO and SiGO for bone tissue engineering applications.

Avoid or engage? Outcomes of graded exposure in youth with chronic pain using a sequential replicated single-case randomized design.

Pain-related fear is typically associated with avoidance behavior and pain-related disability in youth with chronic pain. Youth with elevated pain-related fear have attenuated treatment responses; thus, targeted treatment is highly warranted. Evidence supporting graded in vivo exposure treatment (GET) for adults with chronic pain is considerable, but just emerging for youth. The current investigation represents the first sequential replicated and randomized single-case experimental phase design with multiple measures evaluating GET for youth with chronic pain, entitled GET Living. A cohort of 27 youth (81% female) with mixed chronic pain completed GET Living. For each participant, a no-treatment randomized baseline period was compared with GET Living and 3- and 6-month follow-ups. Daily changes in primary outcomes fear and avoidance and secondary outcomes pain catastrophizing, pain intensity, and pain acceptance were assessed using electronic diaries and subjected to descriptive and model-based inference analyses. Based on individual effect size calculations, a third of participants significantly improved by the end of treatment on fear, avoidance, and pain acceptance. By follow-up, over 80% of participants had improved across all primary and secondary outcomes. Model-based inference analysis results to examine the series of replicated cases were generally consistent. Improvements during GET Living was superior to the no-treatment randomized baseline period for avoidance, pain acceptance, and pain intensity, whereas fear and pain catastrophizing did not improve. All 5 outcomes emerged as significantly improved at 3- and 6-month follow-ups. The results of this replicated single-case experimental phase design support the effectiveness of graded exposure for youth with chronic pain and elevated pain-related fear avoidance.

Osteochondral Tissue Chip Derived From iPSCs: Modeling OA Pathologies and Testing Drugs.

Osteoarthritis (OA) is a chronic disease mainly characterized by degenerative changes in cartilage, but other joint elements such as bone are also affected. To date, there are no disease-modifying OA drugs (DMOADs), owing in part to a deficiency of current models in simulating OA pathologies and etiologies in humans. In this study, we aimed to develop microphysiological osteochondral (OC) tissue chips derived from human induced pluripotent stem cells (iPSCs) to model the pathologies of OA. We first induced iPSCs into mesenchymal progenitor cells (iMPCs) and optimized the chondro- and osteo-inductive conditions for iMPCs. Then iMPCs were encapsulated into photocrosslinked gelatin scaffolds and cultured within a dual-flow bioreactor, in which the top stream was chondrogenic medium and the bottom stream was osteogenic medium. After 28 days of differentiation, OC tissue chips were successfully generated and phenotypes were confirmed by real time RT-PCR and histology. To create an OA model, interleukin-1ß (IL-1ß) was used to challenge the cartilage component for 7 days. While under control conditions, the bone tissue promoted chondrogenesis and suppressed chondrocyte terminal differentiation of the overlying chondral tissue. Under conditions modeling OA, the bone tissue accelerated the degradation of chondral tissue which is likely via the production of catabolic and inflammatory cytokines. These findings suggest active functional crosstalk between the bone and cartilage tissue components in the OC tissue chip under both normal and pathologic conditions. Finally, a selective COX-2 inhibitor commonly prescribed drug for OA, Celecoxib, was shown to downregulate the expression of catabolic and proinflammatory cytokines in the OA model, demonstrating the utility of the OC tissue chip model for drug screening. In summary, the iPSC-derived OC tissue chip developed in this study represents a high-throughput platform applicable for modeling OA and for the screening and testing of candidate DMOADs.

Can studies of the second lumbrical interossei and its premotor potential reduce the number of tests for carpal tunnel syndrome?

The second lumbrical interossei latency difference test (2-LINT) is a frequently used test for diagnosing carpal tunnel syndrome (CTS). Recently, the premotor potential (2-LUMP) observed with 2-LINT was identified as a median sensory potential. 2-LINT recording therefore not only compares conduction across equidistant median and ulnar motor segments, but also registers median sensory conduction. In 52 CTS and 50 control hands, we tested whether motor and sensory data obtained with 2-LINT help to reduce the number of tests necessary to diagnose CTS. The combined sensitivity of 2-LINT derived parameters (2-LUMP latency, median second lumbrical to ulnar interossei latency difference, ulnar digit 5 sensory to 2-LUMP velocity, and ulnar interossei to 2-LUMP latency difference) was 89%, identical to that of combined non-2-LINT derived parameters (median digit 3 sensory velocity, ulnar digit 5 to median digit 3 sensory velocity difference, median abductor pollices brevis [APB] latency, median APB to ulnar abductor digiti minimi latency). The 2-LINT technique with its premotor potential may therefore help to reduce the number of nerve conduction tests commonly needed to investigate patients with suspected CTS.