Functional MRI Readouts From BOLD and Diffusion Measurements Differentially Respond to Optogenetic Activation and Tissue Heating

Functional blood-oxygenation-level-dependent (BOLD) MRI provides a brain-wide readout that depends on the hemodynamic response to neuronal activity. Diffusion fMRI has been proposed as an alternative to BOLD fMRI and has been postulated to directly rely on neuronal activity. These complementary functional readouts are versatile tools to be combined with optogenetic stimulation to investigate networks of the brain. The cell-specificity and temporal precision of optogenetic manipulations promise to enable further investigation of the origin of fMRI signals. The signal characteristics of the diffusion fMRI readout vice versa may better resolve network effects of optogenetic stimulation. However, the light application needed for optogenetic stimulation is accompanied by heat deposition within the tissue. As both diffusion and BOLD are sensitive to temperature changes, light application can lead to apparent activations confounding the interpretation of fMRI data. The degree of tissue heating, the appearance of apparent activation in different fMRI sequences and the origin of these phenomena are not well understood. Here, we disentangled apparent activations in BOLD and diffusion measurements in rats from physiological activation upon sensory or optogenetic stimulation. Both, BOLD and diffusion fMRI revealed similar signal shapes upon sensory stimulation that differed clearly from those upon heating. Apparent activations induced by high-intensity light application were dominated by T2∗-effects and resulted in mainly negative signal changes. We estimated that even low-intensity light application used for optogenetic stimulation reduces the BOLD response close to the fiber by up to 0.4%. The diffusion fMRI signal contained T2, T2∗ and diffusion components. The apparent diffusion coefficient, which reflects the isolated diffusion component, showed negative changes upon both optogenetic and electric forepaw stimulation. In contrast, positive changes were detected upon high-intensity light application and thus ruled out heating as a major contributor to the diffusion fMRI signal

The effects of a varus unloader brace for lateral tibiofemoral osteoarthritis and valgus malalignment after anterior cruciate ligament reconstruction: A single case study

We investigated the immediate effects of a varus knee brace on knee symptoms and knee-joint biomechanics in an individual with predominant lateral tibiofemoral joint osteoarthritis (TFJOA) and valgus malalignment after anterior cruciate ligament (ACL) reconstruction. A varus unloader brace was prescribed to a 48-year-old male with predominant lateral radiographic and symptomatic TFJOA and valgus malalignment eight-years following ACL reconstruction. During a step-down task, the participant rated knee pain, task-difficulty, knee-stability and knee-confidence on four separate visual analogue scales. Quantitative gait analysis was conducted during self-selected walking trials under three test conditions in a randomized order: (i) no brace; (ii) brace without frontal plane adjustment (no varus re-alignment); and (ii) brace with frontal plane adjustment (varus re-alignment). Post-processing of gait data involved calculation of knee kinematics and net joint moments for the reconstructed limb. The participant reported improved pain (3%), task difficulty (41%), stability (46%) and confidence (49%) when performing the step-down task with the brace. The varus brace resulted in immediate reductions in knee abduction angle (24%) and internal rotation angle (56%), and increased knee adduction moment (18%). These findings provide preliminary evidence for potentially beneficial effects of bracing on knee-symptoms and biomechanics in individuals with lateral TFJOA after reconstruction

Exercise, education, manual-therapy and taping compared to education for patellofemoral osteoarthritis: a blinded, randomised clinical trial

Objective: Patellofemoral joint osteoarthritis (PFJ OA) contributes considerably to knee OA symptoms. This study aimed to determine the efficacy of a PFJ-targeted exercise, education manual-therapy and taping program compared to OA education alone, in participants with PFJ OA. Methods: A randomised, participant-blinded and assessor-blinded clinical trial was conducted in primary-care physiotherapy. 92 people aged ≥40 years with symptomatic and radiographic PFJ OA participated. Physiotherapists delivered the PFJ-targeted exercise, education, manual-therapy and taping program, or the OA-education (control condition) in eight sessions over 12 weeks.Primary outcomes at 3-month (primary) and 9-month follow-up: (1) patient-perceived global rating of change (2) pain visual analogue scale (VAS) (100 mm); and (3) activities of daily living (ADL) subscale of the Knee injury and Osteoarthritis Outcome Score (KOOS). Results: 81 people (88%) completed the 3-month follow-up and data analysed on an intention-to-treat basis. Between-group baseline similarity for participant characteristics was observed. The exercise, education, manual-therapy and taping program resulted in more people reporting much improvement (20/44) than the OA-education group (5/48) (number needed to treat 3 (95% confidence interval (CI) 2 to 5)) and greater pain reduction (mean difference: -15.2 mm, 95% CI -27.0 to -3.4). No significant effects on ADL were observed (5.8; 95% CI -0.6 to 12.1). At 9 months there were no significant effects for self-report of improvement, pain (-10.5 mm, 95% CI -22.7 to 1.8) or ADL (3.0, 95% CI -3.7 to 9.7). Conclusion: Exercise, education, manual-therapy and taping can be recommended to improve short-term patient rating of change and pain severity. However over 9-months, both options were equivalent. Trial registration: Australian New Zealand Clinical Trials Registry (ACTRN12608000288325): https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=82878

Altered hip muscle forces during gait in people with patellofemoral osteoarthritis

Objectives: The study aimed to (1) assess whether higher vasti (VASTI), gluteus medius (GMED), gluteus maximus (GMAX) and gluteus minimus (GMIN) forces are associated with participant characteristics (lower age, male gender) and clinical characteristics (lower radiographic disease severity, lower symptom severity and higher walking speed); and (2) determine whether hip and knee muscle forces are lower in people with patellofemoral joint (PFJ) osteoarthritis (OA) compared to those without PFJ OA. Design: Sixty participants with PFJ OA and 18 (asymptomatic, no radiographic OA) controls ≥40 years were recruited from the community or via referrals. A three-dimensional musculoskeletal model was used in conjunction with optimisation theory to calculate lower-limb muscle forces during walking. Associations of peak muscle forces with participant and clinical characteristics were conducted using Pearson's r or independent t-tests and between-group comparisons of mean peak muscle forces performed with walking speed as a covariate. Results: Peak muscle forces were not significantly associated with participant, symptomatic or radiographic-specific characteristics. Faster walking speed was associated with higher VASTI muscle force in the PFJ OA (r = 0.495; P < 0.001) and control groups (r = 0.727; P = 0.001) and higher GMAX muscle force (r = 0.593; P = 0.009) in the control group only. Individuals with PFJ OA (N = 60) walked with lower GMED and GMIN muscle forces than controls (N = 18): GMED, mean difference 0.15 [95% confidence interval (CI): 0.01 to 0.29] body weight (BW); GMIN, 0.03 [0.01 to 0.06] BW. No between-group differences were observed in VASTI or GMAX muscle force: VASTI, 0.10 [-0.11 to 0.31] BW; GMAX, 0.01 [-0.11 to 0.09] BW. Conclusion: Individuals with PFJ OA ambulate with lower peak hip abductor muscle forces than their healthy counterparts

Prognostic implications of p16 and HPV discordance in oropharyngeal cancer (HNCIG-EPIC-OPC): a multicentre, multinational, individual patient data analysis

Background: p16INK4a (p16) immunohistochemistry is the most widely used biomarker assay for inferring HPV causation in oropharyngeal cancer in clinical and trial settings. However, discordance exists between p16 and HPV DNA or RNA status in some patients with oropharyngeal cancer. We aimed to clearly quantify the extent of discordance, and its prognostic implications. Methods: In this multicentre, multinational individual patient data analysis, we did a literature search in PubMed and Cochrane database for systematic reviews and original studies published in English between Jan 1, 1970, and Sept 30, 2022. We included retrospective series and prospective cohorts of consecutively recruited patients previously analysed in individual studies with minimum cohort size of 100 patients with primary squamous cell carcinoma of the oropharynx. Patient inclusion criteria were diagnosis with a primary squamous cell carcinoma of oropharyngeal cancer; data on p16 immunohistochemistry and on HPV testing; information on age, sex, tobacco, and alcohol use; staging by TNM 7th edition; information on treatments received; and data on clinical outcomes and follow-up (date of last follow-up if alive, date of recurrence or metastasis, and date and cause of death). There were no limits on age or performance status. The primary outcomes were the proportion of patients of the overall cohort who showed the different p16 and HPV result combinations, as well as 5-year overall survival and 5-year disease-free survival. Patients with recurrent or metastatic disease or who were treated palliatively were excluded from overall survival and disease-free survival analyses. Multivariable analysis models were used to calculate adjusted hazard ratios (aHR) for different p16 and HPV testing methods for overall survival, adjusted for prespecified confounding factors. Findings: Our search returned 13 eligible studies that provided individual data for 13 cohorts of patients with oropharyngeal cancer from the UK, Canada, Denmark, Sweden, France, Germany, the Netherlands, Switzerland, and Spain. 7895 patients with oropharyngeal cancer were assessed for eligibility. 241 were excluded before analysis, and 7654 were eligible for p16 and HPV analysis. 5714 (74·7%) of 7654 patients were male and 1940 (25·3%) were female. Ethnicity data were not reported. 3805 patients were p16-positive, 415 (10·9%) of whom were HPV-negative. This proportion differed significantly by geographical region and was highest in the areas with lowest HPV-attributable fractions (r=–0·744, p=0·0035). The proportion of patients with p16+/HPV– oropharyngeal cancer was highest in subsites outside the tonsil and base of tongue (29·7% vs 9·0%, p<0·0001). 5-year overall survival was 81·1% (95% CI 79·5–82·7) for p16+/HPV+, 40·4% (38·6–42·4) for p16–/HPV–, 53·2% (46·6–60·8) for p16–/HPV+, and 54·7% (49·2–60·9) for p16+/HPV–. 5-year disease-free survival was 84·3% (95% CI 82·9–85·7) for p16+/HPV+, 60·8% (58·8–62·9) for p16–/HPV–; 71·1% (64·7–78·2) for p16–/HPV+, and 67·9% (62·5–73·7) for p16+/HPV–. Results were similar across all European sub-regions, but there were insufficient numbers of discordant patients from North America to draw conclusions in this cohort. Interpretation: Patients with discordant oropharyngeal cancer (p16–/HPV+ or p16+/HPV–) had a significantly worse prognosis than patients with p16+/HPV+ oropharyngeal cancer, and a significantly better prognosis than patients with p16–/HPV– oropharyngeal cancer. Along with routine p16 immunohistochemistry, HPV testing should be mandated for clinical trials for all patients (or at least following a positive p16 test), and is recommended where HPV status might influence patient care, especially in areas with low HPV-attributable fractions

Prognostic implications of p16 and HPV discordance in oropharyngeal cancer (HNCIG-EPIC-OPC): a multicentre, multinational, individual patient data analysis

Background p16(INK4a) (p16) immunohistochemistry is the most widely used biomarker assay for inferring HPV causation in oropharyngeal cancer in clinical and trial settings. However, discordance exists between p16 and HPV DNA or RNA status in some patients with oropharyngeal cancer. We aimed to clearly quantify the extent of discordance, and its prognostic implications. Methods In this multicentre, multinational individual patient data analysis, we did a literature search in PubMed and Cochrane database for systematic reviews and original studies published in English between Jan 1, 1970, and Sept 30, 2022. We included retrospective series and prospective cohorts of consecutively recruited patients previously analysed in individual studies with minimum cohort size of 100 patients with primary squamous cell carcinoma of the oropharynx. Patient inclusion criteria were diagnosis with a primary squamous cell carcinoma of oropharyngeal cancer; data on p16 immunohistochemistry and on HPV testing; information on age, sex, tobacco, and alcohol use; staging by TNM 7th edition; information on treatments received; and data on clinical outcomes and follow-up (date of last follow-up if alive, date of recurrence or metastasis, and date and cause of death). There were no limits on age or performance status. The primary outcomes were the proportion of patients of the overall cohort who showed the different p16 and HPV result combinations, as well as 5-year overall survival and 5-year disease-free survival. Patients with recurrent or metastatic disease or who were treated palliatively were excluded from overall survival and disease-free survival analyses. Multivariable analysis models were used to calculate adjusted hazard ratios (aHR) for different p16 and HPV testing methods for overall survival, adjusted for prespecified confounding factors. Findings Our search returned 13 eligible studies that provided individual data for 13 cohorts of patients with oropharyngeal cancer from the UK, Canada, Denmark, Sweden, France, Germany, the Netherlands, Switzerland, and Spain. 7895 patients with oropharyngeal cancer were assessed for eligibility. 241 were excluded before analysis, and 7654 were eligible for p16 and HPV analysis. 5714 (74middot7%) of 7654 patients were male and 1940 (25middot3%) were female. Ethnicity data were not reported. 3805 patients were p16-positive, 415 (10middot9%) of whom were HPV-negative. This proportion differed significantly by geographical region and was highest in the areas with lowest HPV-attributable fractions (r=-0middot744, p=0middot0035). The proportion of patients with p16+/HPV- oropharyngeal cancer was highest in subsites outside the tonsil and base of tongue (29middot7% vs 9middot0%, p<0middot0001). 5-year overall survival was 81middot1% (95% CI 79middot5-82middot7) for p16+/HPV+, 40middot4% (38middot6-42middot4) for p16-/HPV-, 53middot2% (46middot6-60middot8) for p16-/HPV+, and 54middot7% (49middot2-60middot9) for p16+/HPV-. 5-year disease-free survival was 84middot3% (95% CI 82middot9-85middot7) for p16+/HPV+, 60middot8% (58middot8-62middot9) for p16-/HPV-; 71middot1% (64middot7-78middot2) for p16-/HPV+, and 67middot9% (62middot5-73middot7) for p16+/HPV-. Results were similar across all European sub-regions, but there were insufficient numbers of discordant patients from North America to draw conclusions in this cohort. Interpretation Patients with discordant oropharyngeal cancer (p16-/HPV+ or p16+/HPV-) had a significantly worse prognosis than patients with p16+/HPV+ oropharyngeal cancer, and a significantly better prognosis than patients with p16-/HPV- oropharyngeal cancer. Along with routine p16 immunohistochemistry, HPV testing should be mandated for clinical trials for all patients (or at least following a positive p16 test), and is recommended where HPV status might influence patient care, especially in areas with low HPV-attributable fractions. Copyright (c) 2023 The Author(s). Published by Elsevier Ltd