Search

Fabíola Costa,1 Dora Janela,1 Maria Molinos,1 Robert G Moulder,2 Jorge Lains,3,4 Virgílio Bento,1 Justin Scheer,5 Vijay Yanamadala,1,6,7 Fernando Dias Correia,1,8 Steven P Cohen9,10 1SWORD Health, Inc, Clinical Research, Draper, UT, USA; 2Institute for Cognitive Science, University of Colorado Boulder, Boulder, CO, USA; 3Rovisco Pais Medical and Rehabilitation Centre, Tocha, Portugal; 4Faculty of Medicine, Coimbra University, Coimbra, Portugal; 5Department of Neurological Surgery, University of California, San Francisco, CA, USA; 6Department of Surgery, Quinnipiac University Frank H. Netter School of Medicine, Hamden, CT, USA; 7Department of Neurosurgery, Hartford Healthcare Medical Group, Westport, CT, USA; 8Neurology Department, Centro Hospitalar e Universitário do Porto, Porto, Portugal; 9Departments of Anesthesiology & Critical Care Medicine, Physical Medicine and Rehabilitation, Neurology, and Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA; 10Departments of Anesthesiology and Physical Medicine and Rehabilitation and Anesthesiology, Uniformed Services University of the Health Sciences, Bethesda, MD, USACorrespondence: Fernando Dias Correia, 65 E Wadsworth Park Dr Ste 230, Draper, UT, 84020, USA, Tel +1 385-308-8034, Fax +1 801-206-3433, Email fcorreia@swordhealth.comBackground: Low back pain (LBP) has a lifetime prevalence of 70– 80%. Access to timely and personalized, evidence-based care is key to prevent chronic progression. Digital solutions may ease accessibility to treatment while reducing healthcare-related costs.Purpose: We aim to report the results of a fully remote digital care program (DCP) for acute LBP.Patients and Methods: This was an interventional, single-arm, cohort study of patients with acute LBP who received a DCP. Primary outcome was the mean change in disability (Oswestry Disability Index – ODI) after 12 weeks. Secondary outcomes included change in pain (NPRS), analgesic consumption, surgery likelihood, depression (PHQ-9), anxiety (GAD-7), fear-avoidance beliefs (FABQ-PA), work productivity (WPAI) and engagement.Results: A total of 406 patients were enrolled in the program and of those, 332 (81.8%) completed the intervention. A significant disability reduction of 55.1% (14.93, 95% CI 13.95; 15.91) was observed, corresponding to a 76.1% responder rate (30% cut-off). Disability reduction was accompanied by significant improvements in pain (61.0%), depression (55.4%), anxiety (59.5%), productivity (65.6%), fear-avoidance beliefs (46.3%), intent to pursue surgery (59.1%), and analgesic consumption (from 35.7% at baseline to 10.8% at program end). DCP-related patient satisfaction score was 8.7/10.0 (SD 1.4).Conclusion: This study demonstrated the utility of a multimodal DCP for patients with acute LBP. Very high adherence rates and patient satisfaction were observed, alongside significant reductions in all assessed outcomes, consistent with the growing body of evidence supporting the management of acute LBP with DCPs.Keywords: physical therapy, telerehabilitation, digital therapy, eHealth, musculoskeletal conditions

Dora Janela,1 Fabíola Costa,1 Maria Molinos,1 Robert G Moulder,2 Jorge Lains,3,4 Gerard E Francisco,5 Virgílio Bento,1 Steven P Cohen,6,7 Fernando Dias Correia1,8 1SWORD Health Technologies, Inc, Clinical Validation, Draper, UT, USA; 2Institute for Cognitive Science, University of Colorado Boulder, Boulder, CO, USA; 3Rovisco Pais Medical and Rehabilitation Centre, Tocha, Portugal; 4Faculty of Medicine, Coimbra University, Coimbra, Portugal; 5Department of Physical Medicine and Rehabilitation, The University of Texas Health Science Center McGovern Medical School, and TIRR Memorial Hermann, Houston, TX, USA; 6Departments of Anesthesiology & Critical Care Medicine, Physical Medicine and Rehabilitation, Neurology, and Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA; 7Departments of Anesthesiology and Physical Medicine and Rehabilitation and Anesthesiology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA; 8Neurology Department, Centro Hospitalar e Universitário do Porto, Porto, PortugalCorrespondence: Fernando Dias CorreiaSWORD Health Technologies, Inc, Clinical Validation, 65 E Wadsworth Park Dr Ste 230, Draper, UT, 84020, USATel +1 385-308-8034Fax +1 801-206-3433Email fcorreia@swordhealth.comBackground: Chronic shoulder pain (SP) is responsible for significant morbidity, decreased quality of life and impaired work ability, resulting in high socioeconomic burden. Successful SP management is dependent on adherence and compliance with effective evidence-based interventions. Digital solutions may improve accessibility to such treatments, increasing convenience, while reducing healthcare-related costs.Purpose: Present the results of a fully remote digital care program (DCP) for chronic SP.Patients and Methods: Interventional, single-arm, cohort study of individuals with chronic SP applying for a digital care program. Primary outcome was the mean change between baseline and 12 weeks on the Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) questionnaire. Secondary outcomes were change in pain (NPRS), analgesic consumption, intention to undergo surgery, anxiety (GAD-7), depression (PHQ-9), fear-avoidance beliefs (FABQ-PA), work productivity (WPAI) and engagement.Results: From 296 patients at program start, 234 (79.1%) completed the intervention. Changes in QuickDASH between baseline and end-of-program were both statistically (p < 0.001) and clinically significant, with a mean reduction of 51.6% (mean − 13.45 points, 95% CI: 11.99; 14.92). Marked reductions were also observed in all secondary outcomes: 54.8% in NPRS, 44.1% ceased analgesics consumption, 55.5% in surgery intent, 37.7% in FABQ-PA, 50.3% in anxiety, 63.6% in depression and 66.5% in WPAI overall. Higher engagement was associated with higher improvements in disability. Mean patient satisfaction score was 8.7/10.0 (SD 1.6).Conclusion: This is the first real-world cohort study reporting the results of a multimodal remote digital approach for chronic SP rehabilitation. High completion and engagement rates were observed, which were associated with clinically significant improvement in all health-related outcomes, as well as marked productivity recovery. These promising results support the potential of digital modalities to address the global burden of chronic musculoskeletal pain.Keywords: chronic pain, physical therapy, telerehabilitation, digital therapeutic, eHealth

David E Jamison,1,2 Steven P Cohen1–6 1Department of Anesthesiology, Walter Reed National Military Medical Center (WRNMMC), Bethesda, MD, USA; 2Department of Anesthesiology, Uniformed Services University of Health Sciences (USUHS), Bethesda, MD, USA; 3Department of Anesthesiology and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA; 4Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA; 5Department of Physical Medicine and Rehabilitation, Johns Hopkins School of Medicine, Baltimore, MD, USA; 6Department of Physical Medicine and Rehabilitation, USUHS, Bethesda, MD, USA Background: The use of radiofrequency ablation (RFA) procedures to treat chronic knee pain has surged in the past decade, though many questions remain regarding anatomical targets, selection criteria, and evidence for effectiveness. Methods: A comprehensive literature review was performed on anatomy, selection criteria, technical parameters, results of clinical studies, and complications. Databases searched included MEDLINE and Google Scholar, with all types of clinical and preclinical studies considered. Results: We identified nine relevant clinical trials, which included 592 patients, evaluating knee RFA for osteoarthritis and persistent postsurgical pain. These included one randomized, placebo-controlled trial, one randomized controlled trial evaluating RFA as add-on therapy, four comparative-effectiveness studies, two randomized trials comparing different techniques and treatment paradigms, and one non-randomized, controlled trial. The results of these studies demonstrate significant benefit for both reduction and functional improvement lasting between 3 and 12 months, with questionable utility for prognostic blocks. There was considerable variation in the described neuroanatomy, neural targets, radiofrequency technique, and selection criteria. Conclusion: RFA of the knee appears to be a viable and effective treatment option, providing significant benefit to well-selected patients lasting at least 3 months. More research is needed to better identify neural targets, refine selection criteria to include the use of prognostic blocks, optimize treatment parameters, and better elucidate relative effectiveness compared to other treatments. Keywords: Knee pain, osteoarthritis, radiofrequency, ablation, denervation, genicular nerve

David S Chang,1 Eugene Hsu,2 Daniel G Hottinger,1 Steven P Cohen1,3–5 1Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 2Clinical Excellence Research Center, Stanford University School of Medicine, Stanford, CA, 3Department of Anesthesiology, 4Department of Physical Medicine and Rehabilitation, Uniformed Services University of the Health Sciences, Bethesda 5Department of Physical Medicine and Rehabilitation, Johns Hopkins University School of Medicine, Baltimore, MD, USA Abstract: There continues to be an unmet need for safe and effective pain medications. Opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) dominate the clinical landscape despite limited effectiveness and considerable side-effect profiles. Although significant advancements have identified myriad potential pain targets over the past several decades, the majority of new pain pharmacotherapies have failed to come to market. The discovery of nerve growth factor (NGF) and its interaction with tropomyosin receptor kinase A (trkA) have been well characterized as important mediators of pain initiation and maintenance, and pharmacotherapies targeting this pathway have the potential to be considered promising methods in the treatment of a variety of nociceptive and neuropathic pain conditions. Several methodologic approaches, including sequestration of free NGF, prevention of NGF binding and trkA activation, and inhibition of trkA function, have been investigated in the development of new pharmacotherapies. Among these, NGF-sequestering antibodies have exhibited the most promise in clinical trials. However, in 2010, reports of rapid joint destruction leading to joint replacement prompted the Food and Drug Administration (FDA) to place a hold on all clinical trials involving anti-NGF antibodies. Although the FDA has since lifted this hold and a number of new trials are under way, the long-term efficacy and safety profile of anti-NGF antibodies are yet to be established. Keywords: nociceptive pain, neuropathic pain, drug discovery, tanezumab, fulranumab, fasinumab

Eugene Hsu,1 Steven P Cohen21Johns Hopkins School of Medicine, Baltimore, MD, USA; 2Johns Hopkins School of Medicine and Uniformed Services, University of the Health Sciences, Bethesda, MD, USAAbstract: Postamputation pain (PAP) is highly prevalent after limb amputation but remains an extremely challenging pain condition to treat. A large part of its intractability stems from the myriad pathophysiological mechanisms. A state-of-art understanding of the pathophysiologic basis underlying postamputation phenomena can be broadly categorized in terms of supraspinal, spinal, and peripheral mechanisms. Supraspinal mechanisms involve somatosensory cortical reorganization of the area representing the deafferentated limb and are predominant in phantom limb pain and phantom sensations. Spinal reorganization in the dorsal horn occurs after deafferentation from a peripheral nerve injury. Peripherally, axonal nerve damage initiates inflammation, regenerative sprouting, and increased "ectopic" afferent input which is thought by many to be the predominant mechanism involved in residual limb pain or neuroma pain, but may also contribute to phantom phenomena. To optimize treatment outcomes, therapy should be individually tailored and mechanism based. Treatment modalities include injection therapy, pharmacotherapy, complementary and alternative therapy, surgical therapy, and interventions aimed at prevention. Unfortunately, there is a lack of high quality clinical trials to support most of these treatments. Most of the randomized controlled trials in PAP have evaluated medications, with a trend for short-term efficacy noted for ketamine and opioids. Evidence for peripheral injection therapy with botulinum toxin and pulsed radiofrequency for residual limb pain is limited to very small trials and case series. Mirror therapy is a safe and cost-effective alternative treatment modality for PAP. Neuromodulation using implanted motor cortex stimulation has shown a trend toward effectiveness for refractory phantom limb pain, though the evidence is largely anecdotal. Studies that aim to prevent PAP using epidural and perineural catheters have yielded inconsistent results, though there may be some benefit for epidural prevention when the infusions are started more than 24 hours preoperatively and compared with nonoptimized alternatives. Further investigation into the mechanisms responsible for and the factors associated with the development of PAP is needed to provide an evidence-based foundation to guide current and future treatment approaches.Keywords: phantom pain, stump pain, residual limb pain

Postamputation pain (PAP) affects over 60% of major limb amputees. One of the main challenges in treating PAP is the difficulty involved in identifying pain mechanism(s), which pertains to both residual limb pain (RLP) and phantom limb pain (PLP). In this study, sympathetic blocks were performed on 17 major limb amputees refractory to treatment, including 2 placebo-controlled blocks done for bilateral amputations. One hour postinjection, mean RLP scores at rest declined from 5.2 (SD 2.8) to 2.8 (SD 2.6) (P = .0002), and PLP decreased from 5.3 (SD 3.1) to 2.3 (SD 2.1) (P = .0009). By 1 week, mean pain scores for RLP and PLP were 4.3 (SD 2.9) and 4.2 (SD 3.0), respectively. Overall, 8 of 16 (50%) patients experienced >=50% reduction in RLP 1-hour postinjection, with the beneficial effects being maintained at 1 and 8 weeks in 4 and 1 patient(s), respectively. For PLP, 8 of 15 (53%) patients obtained >=50% decrease in pain 1-hour postblock, with these numbers decreasing to 2 patients at both 1 and 8 weeks. In the 2 bilateral amputees who received controlled injections, mean PLP and RLP at rest scores went from 4.0 and 3.3 to 4.0 and 2.5 1-hour postblock, respectively, on the placebo side. On the treatment side, mean PLP and RLP scores decreased from 7.5 and 6.5, respectively, to 0. PERSPECTIVE: The results of this study suggest that sympathetic mechanisms play a role in PLP and to a lesser extent, RLP, but that blocks confer long-term benefits in only a small percentage of patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: Medical errors exact an inordinate toll on healthcare costs. One of the most publicized and analyzed type of medical error is wrong-site surgery. Yet, despite the burgeoning number of procedures performed, no literature exists on wrong-site pain management injections. The purpose of this study was to estimate the relative incidence and determine the causes of wrong-site pain management procedures. METHODS: Quality improvement records were examined during a 2-yr period from four civilian academic teaching hospitals, three military treatment facilities, and three private practices, for 'sentinel' events involving wrong-site pain management procedures. A total of 13 cases (incidence 0.027%; 95% CI 0.01-0.05%) were identified from approximately 48,941 collective procedures of which 52.4% were deemed to be 'at risk' for the occurrence. Root cause analyses were then conducted to determine the origin of each error. RESULTS: The 13 cases included five wrong-side transforaminal epidural steroid injections, six other wrong-side injections, and two wrong-level minimally invasive surgical procedures. In only one case was the 'universal protocol' completely followed, and in nine procedures, multiple lapses occurred in protocol. Three patients had bilateral pathology, and in seven cases, the patient knew at the time that the wrong side was being injected. In no instance did any technical, legal, or professional consequences ensue from the error. CONCLUSIONS: Wrong-site nerve blocks occur more frequently in pain management centers than has previously been acknowledged. Adaptation of the universal protocol to nerve blocks and strict adherence to widely accepted guidelines may prevent wrong-site interventional pain procedures. [ABSTRACT FROM AUTHOR]

BACKGROUND: Recent evidence implicates the inflammatory cytokine tumor necrosis factor as a major cause of radiculopathy. Yet, whereas open-label studies with systemically delivered tumor necrosis factor inhibitors have yielded positive results, a placebo-controlled study failed to demonstrate efficacy. One variable that may have contributed to poor outcomes is low drug levels at the site of nerve inflammation. To date, no studies have evaluated the efficacy or safety of epidurally administered anti-tumor necrosis factor agents. METHODS: A double-blind, placebo-controlled, dose-response study was conducted to evaluate an epidural tumor necrosis factor inhibitor. Twenty-four patients with subacute lumbosacral radiculopathy were randomly assigned to receive two transforaminal epidural injections of 2, 4, or 6 mg of entanercept 2 weeks apart in successive groups of eight. In each group, two patients received epidural saline. A parallel epidural canine safety study was conducted using the same injection doses and paradigm as in the clinical study. RESULTS: The animal and human safety studies revealed no behavioral, neurologic, or histologic evidence of drug-related toxicity. In the clinical arm, significant improvements in leg and back pain were collectively noted for the etanercept-treated patients, but not for the saline group, one month after treatment. One patient in the saline group (17%), six patients in the 2-mg group (100%), and four patients each in the 4-mg and 6-mg groups (67%) reported at least 50% reduction in leg pain and a positive global perceived effect one month after treatment. Six months after treatment, the beneficial effects persisted in all but one patient. CONCLUSION: Epidural entanercept holds promise as a treatment for lumbosacral radiculopathy. [ABSTRACT FROM AUTHOR]

Background: Sacroiliac joint pain is a challenging condition accounting for approximately 20% of cases of chronic low back pain. Currently, there are no effective long-term treatment options for sacroiliac joint pain.Methods: A randomized placebo-controlled study was conducted in 28 patients with injection-diagnosed sacroiliac joint pain. Fourteen patients received L4-L5 primary dorsal rami and S1-S3 lateral branch radiofrequency denervation using cooling-probe technology after a local anesthetic block, and 14 patients received the local anesthetic block followed by placebo denervation. Patients who did not respond to placebo injections crossed over and were treated with radiofrequency denervation using conventional technology.Results: One, 3, and 6 months after the procedure, 11 (79%), 9 (64%), and 8 (57%) radiofrequency-treated patients experienced pain relief of 50% or greater and significant functional improvement. In contrast, only 2 patients (14%) in the placebo group experienced significant improvement at their 1-month follow-up, and none experienced benefit 3 months after the procedure. In the crossover group (n = 11), 7 (64%), 6 (55%), and 4 (36%) experienced improvement 1, 3, and 6 months after the procedure. One year after treatment, only 2 patients (14%) in the treatment group continued to demonstrate persistent pain relief.Conclusions: These results provide preliminary evidence that L4 and L5 primary dorsal rami and S1-S3 lateral branch radiofrequency denervation may provide intermediate-term pain relief and functional benefit in selected patients with suspected sacroiliac joint pain. Larger studies are needed to confirm these results and to determine the optimal candidates and treatment parameters for this poorly understood disorder. [ABSTRACT FROM AUTHOR]

Objective: To determine variables associated with difficult clinical encounters., Patients and Methods: This was a cross-sectional study of 428 new patients evaluated from 2022 to 2023. Demographic, clinical, social (eg, missed appointments, prior felony conviction, prior pain physicians, medical assistance) and visit-related (eg, visit took longer than expected, difficulty communicating) information was recorded, supplemented by in-person history gathered by the trainee and attending whose demographic data were also recorded. Physicians independently rated the "difficulty" of the encounter on a 6-point Likert scale from 1 = very easy/pleasant, 2 = easy/pleasant, 3 = neutral/average, 4 = difficult, 5 = very difficult, to 6 = extremely difficult. A difficult encounter was a combined trainee and attending rating of one IQR above the median of 2.0±1.75., Results: Among 428 participants, mean ± SD age was 54.2±15.8 years and 261 (61.0%) were female. Attending gender, gender concordance, race and racial concordance, and years of physician experience were not associated with difficulty. In multivariable analysis, requesting opioids (P=.001), lengthier than expected visit (P<.001), hostile/demanding behavior (P=.003), refusal to try recommended treatment (P=.002), unrealistic expectations (P<0.001), and difficulty communicating (P=.02) were associated with difficult encounters., Conclusion: Most variables associated with physician impressions of difficult encounters were visit-related, suggesting some patient-related factors (eg, prior substance abuse, translator requirement) may be less relevant in pain patients. Future research should evaluate interventions designed to decrease the difficulty of encounters and determine their effect on patients and physicians., (Published by Elsevier Inc.)

Background: Race/ethnicity and gender concordance between patients and providers is a potential strategy to improve health care interventions. In digital health, where human interactions occur both synchronously and asynchronously, the effect of concordance between patients and providers is unknown., Objective: This study aimed to evaluate the impact of race/ethnicity or gender concordance between patients and physical therapists (PTs) in engagement and the clinical outcomes following a digital care program (DCP) in patients with musculoskeletal (MSK) conditions., Methods: This secondary analysis of 2 prospective longitudinal studies (originally focused on assessing the acceptance, engagement, and clinical outcomes after a remote DCP) examined the impact of both race/ethnicity concordance and gender concordance between patients and PTs on outcomes for a digital intervention for MSK conditions. Outcomes included engagement (measured by the completion rate and communication, assessed by text interactions), satisfaction, and clinical outcomes (response rate, ie, percentage of patients achieving at least a minimal clinically important change in pain, measured by the Numerical Pain Rating Scale [NPRS]; anxiety, measured by the Generalized Anxiety Disorder 7-item scale [GAD-7]; depression, measured by the Patient Health Questionnaire 9-item [PHQ-9]; and daily activity impairment, measured by the Work Productivity and Activity Impairment [WPAI] questionnaire)., Results: Of 71,201 patients, 63.9% (n=45,507) were matched with their PT in terms of race/ethnicity, while 61.2% (n=43,560) were matched for gender. Concordant dyads showed a higher completion rate among White (adjusted odds ratio [aOR] 1.11, 95% CI 1.05-1.19, P<.001) and Hispanic (aOR 1.27, 95% CI 1.08-1.54, P=.009) groups, as well as women (aOR 1.10, 95% CI 1.06-1.18, P<.001), when compared to discordant dyads. High and similar levels of interaction between patients and PTs were observed across race/ethnicity and gender dyads, except for Asian concordant dyads (adjusted β coefficient 5.32, 95% CI 3.28-7.36, P<.001). Concordance did not affect satisfaction, with high values (>8.52, 95% CI 8.27-8.77) reported across all dyads. Response rates for pain, anxiety, and daily activity impairment were unaffected by race/ethnicity concordance. An exception was observed for depression, with White patients reporting a higher response rate when matched with PTs from other races/ethnicities (aOR 1.20, 95% CI 1.02-1.39, P=.02). In terms of gender, men had a slightly higher pain response rate in discordant dyads (aOR 1.08, 95% CI 1.01-1.15, P=.03) and a higher depression response rate in concordant dyads (aOR 1.23, 95% CI 1.05-1.47, P=.01)., Conclusions: Race/ethnicity and gender concordance between patients and PTs does not translate into higher satisfaction or improvement for most clinical outcomes, aside from a positive effect on treatment completion. These results highlight the importance of other PT characteristics, in addition to race/ethnicity or gender concordance, suggesting the potential benefit of experience, languages spoken, and cultural safety training as ways to optimize care., Trial Registration: ClinicalTrials.gov NCT04092946, NCT05417685; https://clinicaltrials.gov/study/NCT05417685, https://clinicaltrials.gov/study/NCT04092946., (©Anabela C Areias, Dora Janela, Maria Molinos, Virgílio Bento, Carolina Moreira, Vijay Yanamadala, Steven P Cohen, Fernando Dias Correia, Fabíola Costa. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 29.10.2024.)

Here, we report a hybrid genome of Marasmius tenuissimus strain MS-2, a cacao thread blight disease causing isolate that was collected from cacao leaves in Tafo, Eastern region, Ghana. The final assembly consists of 2,083 contigs spanning 69,843,039 bp, with 49.21% GC content, 92.6% BUSCO completeness, and scaffold N50 186,871., Competing Interests: The authors declare no conflict of interest.

Introduction: The acute respiratory distress syndrome (ARDS) is a common complication of severe COVID-19 and contributes to patient morbidity and mortality. ARDS is a heterogeneous syndrome caused by various insults, and results in acute hypoxemic respiratory failure. Patients with ARDS from COVID-19 may represent a subgroup of ARDS patients with distinct molecular profiles that drive disease outcomes. Here, we hypothesized that longitudinal transcriptomic analysis may identify distinct dynamic pathobiological pathways during COVID-19 ARDS., Methods: We identified a patient cohort from an existing ICU biorepository and established three groups for comparison: 1) patients with COVID-19 ARDS that survived hospitalization (COVID survivors, n = 4), 2) patients with COVID-19 ARDS that did not survive hospitalization (COVID non-survivors, n = 5), and 3) patients with ARDS from other causes as a control group (ARDS controls, n = 4). RNA was isolated from peripheral blood mononuclear cells (PBMCs) at 4 time points (Days 1, 3, 7, and 10 following ICU admission) and analyzed by bulk RNA sequencing., Results: We first compared transcriptomes between groups at individual timepoints and observed significant heterogeneity in differentially expressed genes (DEGs). Next, we utilized the likelihood ratio test to identify genes that exhibit different patterns of change over time between the 3 groups and identified 341 DEGs across time, including hemoglobin subunit alpha 2 ( HBA1, HBA2 ), hemoglobin subunit beta ( HBB ), von Willebrand factor C and EGF domains ( VWCE ), and carbonic anhydrase 1 ( CA1 ), which all demonstrated persistent upregulation in the COVID non-survivors compared to COVID survivors. Of the 341 DEGs, 314 demonstrated a similar pattern of persistent increased gene expression in COVID non-survivors compared to survivors, associated with canonical pathways of iron homeostasis signaling, erythrocyte interaction with oxygen and carbon dioxide, erythropoietin signaling, heme biosynthesis, metabolism of porphyrins, and iron uptake and transport., Discussion: These findings describe significant differences in gene regulation during patient ICU course between survivors and non-survivors of COVID-19 ARDS. We identified multiple pathways that suggest heme and red blood cell metabolism contribute to disease outcomes. This approach is generalizable to larger cohorts and supports an approach of longitudinal sampling in ARDS molecular profiling studies, which may identify novel targetable pathways of injury and resolution., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Eltobgy, Johns, Farkas, Leuenberger, Cohen, Ho, Karow, Swoope, Pannu, Horowitz, Mallampalli, Englert and Bednash.)

Background: The use of sedation during interventional procedures has continued to rise resulting in increased costs, complications and reduced validity during diagnostic injections, prompting a search for alternatives. Virtual reality (VR) has been shown to reduce pain and anxiety during painful procedures, but no studies have compared it to a control and active comparator for a pain-alleviating procedure. The main objective of this study was to determine whether VR reduces procedure-related pain and other outcomes for epidural steroid injections (ESI)., Methods: A randomized controlled trial was conducted in 146 patients undergoing an ESI at 6 hospitals in Thailand and the United States. Patients were allocated to receive immersive VR with local anesthetic, sedation with midazolam and fentanyl plus local anesthetic, or local anesthetic alone. The primary outcome was procedure-related pain recorded on a 0-10 scale. Other immediate-term outcome measures were pain from a standardized subcutaneous skin wheal, procedure-related anxiety, ability to communicate, satisfaction, and time to discharge. Intermediate-term outcome measures at 4 weeks included back and leg pain scores, function, and success defined as a ≥2-point decrease in average leg pain coupled with a score ≥5/7 on a Patient Global Impression of Change scale., Findings: Procedure-related pain scores with both VR (mean 3.7 (SD 2.5)) and sedation (mean 3.2 (SD 3.0)) were lower compared to control (mean 5.2 (SD 3.1); mean differences -1.5 (-2.7, -0.4) and -2.1 (-3.3, -0.9), respectively), but VR and sedation scores did not significantly differ (mean difference 0.5 (-0.6, 1.7)). Among secondary outcomes, communication was decreased in the sedation group (mean 3.7 (SD 0.9)) compared to the VR group (mean 4.1 (SD 0.5); mean difference 0.4 (0.1, 0.6)), but neither VR nor sedation was different than control. The trends favoring sedation and VR over control for procedure-related anxiety and satisfaction were not statistically significant. Post-procedural recovery time was longer for the sedation group compared to both VR and control groups. There were no meaningful intermediate-term differences between groups except that medication reduction was lowest in the control group., Interpretation: VR provides comparable benefit to sedation for procedure-related pain, anxiety and satisfaction, but with fewer side effects, superior communication and a shorter recovery period., Funding: Funded in part by grants from MIRROR, Uniformed Services University of the Health Sciences, U.S. Dept. of Defense, grant # HU00011920011. Equipment was provided by Harvard MedTech, Las Vegas, NV., Competing Interests: SPC is a consultant for Avanos, SPR Therapeutics, Persica, Scilex and SWORD, and has previously served as a consultant for Relieviate and Clearing in the past 3 years. The views expressed in this manuscript are those of the authors and do not reflect the official policy of the Uniformed Services University, the Departments of Army and Navy, Department of Defense, the Department of Veterans Affairs, or the U.S. Government. The identification of specific products or scientific instrumentation is considered an integral part of the scientific endeavor and does not constitute endorsement or implied endorsement on the part of the authors, DoD, or any component agency.

Theobroma cacao, the chocolate tree, is indigenous to the Amazon basin, the greatest biodiversity hotspot on earth. Recent advancement in plant genomics highlights the importance of de novo sequencing of multiple reference genomes to capture the genome diversity present in different cacao populations. In this study, three high-quality chromosome-level genomes of wild cacao were constructed, de novo assembled with HiFi long reads sequencing, and scaffolded using a reference-free strategy. These genomes represent the three most important genetic clusters of cacao trees from the Upper Amazon region. The three wild cacao genomes were compared with two reference genomes of domesticated cacao. The five cacao genetic clusters were inferred to have diverged in the early and middle Pleistocene period, approximately 1.83-0.69 million years ago. The results shown here serve as an example of understanding how the Amazonian biodiversity was developed. The three wild cacao genomes provide valuable resources for studying genetic diversity and advancing genetic improvement of this species., (© 2024. The Author(s).)

Pain that accompanies deafferentation is one of the most mysterious and misunderstood medical conditions. Prevalence rates for the assorted conditions vary considerably but the most reliable estimates are greater than 50% for strokes involving the somatosensory system, brachial plexus avulsions, spinal cord injury, and limb amputation, with controversy surrounding the mechanistic contributions of deafferentation to ensuing neuropathic pain syndromes. Deafferentation pain has also been described for loss of other body parts (e.g., eyes and breasts) and may contribute to between 10% and upwards of 30% of neuropathic symptoms in peripheral neuropathies. There is no pathognomonic test or sign to identify deafferentation pain, and part of the controversy surrounding it stems from the prodigious challenges in differentiating cause and effect. For example, it is unknown whether cortical reorganization causes pain or is a byproduct of pathoanatomical changes accompanying injury, including pain. Similarly, ascertaining whether deafferentation contributes to neuropathic pain, or whether concomitant injury to nerve fibers transmitting pain and touch sensation leads to a deafferentation-like phenotype can be clinically difficult, although a detailed neurologic examination, functional imaging, and psychophysical tests may provide clues. Due in part to the concurrent morbidities, the physical, psychologic, and by extension socioeconomic costs of disorders associated with deafferentation are higher than for other chronic pain conditions. Treatment is symptom-based, with evidence supporting first-line antineuropathic medications such as gabapentinoids and antidepressants. Studies examining noninvasive neuromodulation and virtual reality have yielded mixed results., (Copyright © 2024 American Society of Anesthesiologists. All Rights Reserved.)

Background: There are few efficacious treatments for mechanical neck pain, with controlled trials suggesting efficacy for muscle relaxants and topical nonsteroidal anti-inflammatory drugs. Although studies evaluating topical lidocaine for back pain have been disappointing, the more superficial location of the cervical musculature suggests a possible role for topical local anesthetics., Methods: This study was a randomized, double-blind, placebo-controlled crossover trial performed at four U.S. military, Veterans Administration, academic, and private practice sites, in which 76 patients were randomized to receive either placebo followed by lidocaine patch for 4-week intervals (group 1) or a lidocaine-then-placebo patch sequence. The primary outcome measure was mean reduction in average neck pain, with a positive categorical outcome designated as a reduction of at least 2 points in average neck pain coupled with at least a 5-point score of 7 points on the Patient Global Impression of Change scale at the 4-week endpoint., Results: For the primary outcome, the median reduction in average neck pain score was -1.0 (interquartile range, -2.0, 0.0) for the lidocaine phase versus -0.5 (interquartile range, -2.0, 0.0) for placebo treatment (P = 0.17). During lidocaine treatment, 27.7% of patients experienced a positive outcome versus 14.9% during the placebo phase (P = 0.073). There were no significant differences between treatments for secondary outcomes, although a carryover effect on pain pressure threshold was observed for the lidocaine phase (P = 0.015). A total of 27.5% of patients in the lidocaine group and 20.5% in the placebo group experienced minor reactions, the most common of which was pruritis (P = 0.36)., Conclusions: The differences favoring lidocaine were small and nonsignificant, but the trend toward superiority of lidocaine suggests more aggressive phenotyping and applying formulations with greater penetrance may provide clinically meaningful benefit.

The oomycete Phytophthora palmivora infects the fruit of cacao trees (Theobroma cacao) causing black pod rot and reducing yields. Cacao genotypes vary in their resistance levels to P. palmivora, yet our understanding of how cacao fruit respond to the pathogen at the molecular level during disease establishment is limited. To address this issue, disease development and RNA-Seq studies were conducted on pods of seven cacao genotypes (ICS1, WFT, Gu133, Spa9, CCN51, Sca6 and Pound7) to better understand their reactions to the post-penetration stage of P. palmivora infection. The pod tissue-P. palmivora pathogen assay resulted in the genotypes being classified as susceptible (ICS1, WFT, Gu133 and Spa9) or resistant (CCN51, Sca6 and Pound7). The number of differentially expressed genes (DEGs) ranged from 1625 to 6957 depending on genotype. A custom gene correlation approach identified 34 correlation groups. De novo motif analysis was conducted on upstream promoter sequences of differentially expressed genes, identifying 76 novel motifs, 31 of which were over-represented in the upstream sequences of correlation groups and associated with gene ontology terms related to oxidative stress response, defense against fungal pathogens, general metabolism and cell function. Genes in one correlation group (Group 6) were strongly induced in all genotypes and enriched in genes annotated with defense-responsive terms. Expression pattern profiling revealed that genes in Group 6 were induced to higher levels in the resistant genotypes. An additional analysis allowed the identification of 17 candidate cis-regulatory modules likely to be involved in cacao defense against P. palmivora. This study is a comprehensive exploration of the cacao pod transcriptional response to P. palmivora spread after infection. We identified cacao genes, promoter motifs, and promoter motif combinations associated with post-penetration resistance to P. palmivora in cacao pods and provide this information as a resource to support future and ongoing efforts to breed P. palmivora-resistant cacao., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Digital interventions have emerged as a solution for time and geographical barriers, however, their potential to target other social determinants of health is largely unexplored. In this post-hoc analysis, we report the impact of social deprivation on engagement and clinical outcomes after a completely remote multimodal musculoskeletal (MSK) digital care program managed by a culturally-sensitive clinical team. Patients were stratified in five categories according to their social deprivation index, and cross-referenced with their race/ethnicity, rurality and distance to healthcare facilities. From a total of 12,062 patients from all U.S. states, 8569 completed the program. Higher social deprivation was associated with greater baseline disease burden. We observed that all categories reported pain improvements (ranging from -2.0 95%CI -2.1, -1.9 to -2.1 95%CI -2.3, -1.9, p < 0.001) without intergroup differences in mean changes or responder rates (from 59.9% (420/701) to 66.6% (780/1172), p = 0.067), alongside reduction in analgesic consumption. We observed significant improvements in mental health and productivity across all categories, with productivity and non-work-related functional recovery being greater within the most deprived group. Engagement was high but varied slightly across categories. Together these findings highlight the importance of a patient-centered digital care program as a tool to address health inequities in musculoskeletal pain management. The idea of investigating social deprivation within a digital program provides a foundation for future work in this field to identify areas of improvement., (© 2023. Springer Nature Limited.)

The basidiomycete Moniliophthora roreri causes frosty pod rot of cacao (Theobroma cacao) in the western hemisphere. Moniliophthora roreri is considered asexual and haploid throughout its hemibiotrophic life cycle. To understand the processes driving genome modification, using long-read sequencing technology, we sequenced and assembled 5 high-quality M. roreri genomes out of a collection of 99 isolates collected throughout the pathogen's range. We obtained chromosome-scale assemblies composed of 11 scaffolds. We used short-read technology to sequence the genomes of 22 similarly chosen isolates. Alignments among the 5 reference assemblies revealed inversions, translocations, and duplications between and within scaffolds. Isolates at the front of the pathogens' expanding range tend to share lineage-specific structural variants, as confirmed by short-read sequencing. We identified, for the first time, 3 new mating type A locus alleles (5 in total) and 1 new potential mating type B locus allele (3 in total). Currently, only 2 mating type combinations, A1B1 and A2B2, are known to exist outside of Colombia. A systematic survey of the M. roreri transcriptome across 2 isolates identified an expanded candidate effector pool and provided evidence that effector candidate genes unique to the Moniliophthoras are preferentially expressed during the biotrophic phase of disease. Notably, M. roreri isolates in Costa Rica carry a chromosome segment duplication that has doubled the associated gene complement and includes secreted proteins and candidate effectors. Clonal reproduction of the haploid M. roreri genome has allowed lineages with unique genome structures and compositions to dominate as it expands its range, displaying a significant founder effect., Competing Interests: Conflicts of interest The author(s) declare no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Genetics Society of America.)

Background: Chronic shoulder pain (CSP) is a common condition with various etiologies, including rotator cuff disorders, adhesive capsulitis, shoulder instability, and shoulder arthritis. It is associated with substantial disability and psychological distress, resulting in poor productivity and quality of life. Physical therapy constitutes the mainstay treatment for CSP, but several barriers exist in accessing care. In recent years, telerehabilitation has gained momentum as a potential solution to overcome such barriers. It has shown numerous benefits, including improving access and convenience, promoting patient adherence, and reducing costs. However, to date, no previous randomized controlled trial has compared fully remote digital physical therapy to in-person rehabilitation for nonoperative CSP., Objective: The aim of this study is to compare clinical outcomes between digital physical therapy and conventional in-person physical therapy in patients with CSP., Methods: We conducted a single-center, parallel-group, randomized controlled trial involving 82 patients with CSP referred for outpatient physical therapy. Participants were randomized into digital or conventional physical therapy (8-week interventions). The digital intervention consisted of home exercise, education, and cognitive behavioral therapy (CBT), using a device with movement digitalization for biofeedback and asynchronous physical therapist monitoring through a cloud-based portal. The conventional group received in-person physical therapy, including exercises, manual therapy, education, and CBT. The primary outcome was the change (baseline to 8 weeks) in function and symptoms using the short-form of Disabilities of the Arm, Shoulder, and Hand questionnaire. Secondary outcome measures included self-reported pain, surgery intent, analgesic intake, mental health, engagement, and satisfaction. All questionnaires were delivered electronically., Results: A total of 90 participants were randomized into digital or conventional physical therapy, with 82 receiving the allocated intervention. Both groups experienced significant improvements in function measured by the short-form of the Disabilities of the Arm, Shoulder, and Hand questionnaire, with no differences between groups (-1.8, 95% CI -13.5 to 9.8; P=.75). For secondary outcomes, no differences were observed in surgery intent, analgesic intake, and mental health or worst pain. Higher reductions were observed in average and least pain in the conventional group, which, given the small effect sizes (least pain 0.15 and average pain 0.16), are unlikely to be clinically meaningful. High adherence and satisfaction were observed in both groups, with no adverse events., Conclusions: This study shows that fully remote digital programs can be viable care delivery models for CSP given their scalability and effectiveness, assessed through comparison with high-dosage in-person rehabilitation., Trial Registration: ClinicalTrials.gov (NCT04636528); https://clinicaltrials.gov/study/NCT04636528., (©Sang S Pak, Dora Janela, Nina Freitas, Fabíola Costa, Robert Moulder, Maria Molinos, Anabela C Areias, Virgílio Bento, Steven P Cohen, Vijay Yanamadala, Richard B Souza, Fernando Dias Correia. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 18.08.2023.)

Background: Aging is closely associated with an increased prevalence of musculoskeletal conditions. Digital musculoskeletal care interventions emerged to deliver timely and proper rehabilitation; however, older adults frequently face specific barriers and concerns with digital care programs (DCPs)., Objective: This study aims to investigate whether known barriers and concerns of older adults impacted their participation in or engagement with a DCP or the observed clinical outcomes in comparison with younger individuals., Methods: We conducted a secondary analysis of a single-arm investigation assessing the recovery of patients with musculoskeletal conditions following a DCP for up to 12 weeks. Patients were categorized according to age: ≤44 years old (young adults), 45-64 years old (middle-aged adults), and ≥65 years old (older adults). DCP access and engagement were evaluated by assessing starting proportions, completion rates, ability to perform exercises autonomously, assistance requests, communication with their physical therapist, and program satisfaction. Clinical outcomes included change between baseline and program end for pain (including response rate to a minimal clinically important difference of 30%), analgesic usage, mental health, work productivity, and non-work-related activity impairment., Results: Of 16,229 patients, 12,082 started the program: 38.3% (n=4629) were young adults, 55.7% (n=6726) were middle-aged adults, and 6% (n=727) were older adults. Older patients were more likely to start the intervention and to complete the program compared to young adults (odds ratio [OR] 1.72, 95% CI 1.45-2.06; P<.001 and OR 2.40, 95% CI 1.97-2.92; P<.001, respectively) and middle-aged adults (OR 1.22, 95% CI 1.03-1.45; P=.03 and OR 1.38, 95% CI 1.14-1.68; P=.001, respectively). Whereas older patients requested more technical assistance and exhibited a slower learning curve in exercise performance, their engagement was higher, as reflected by higher adherence to both exercise and education pieces. Older patients interacted more with the physical therapist (mean 12.6, SD 18.4 vs mean 10.7, SD 14.7 of young adults) and showed higher satisfaction scores (mean 8.7, SD 1.9). Significant improvements were observed in all clinical outcomes and were similar between groups, including pain response rates (young adults: 949/1516, 62.6%; middle-aged adults: 1848/2834, 65.2%; and older adults: 241/387, 62.3%; P=.17)., Conclusions: Older adults showed high adherence, engagement, and satisfaction with the DCP, which were greater than in their younger counterparts, together with significant clinical improvements in all studied outcomes. This suggests DCPs can successfully address and overcome some of the barriers surrounding the participation and adequacy of digital models in the older adult population., (©Anabela C Areias, Dora Janela, Maria Molinos, Robert G Moulder, Virgílio Bento, Vijay Yanamadala, Steven P Cohen, Fernando Dias Correia, Fabíola Costa. Originally published in JMIR Rehabilitation and Assistive Technology (https://rehab.jmir.org), 15.08.2023.)

Background: Because of the high initial cost of intrathecal drug delivery (ITDD) therapy, this study investigated the cost-effectiveness and cost-utility of ITDD therapy in refractory cancer pain management in Thailand over the past 10 years., Methods: The retrospective study was conducted in patients with cancer pain who underwent ITDD therapy from January 2011 to 2021 at three university hospitals. Clinical outcomes included the numerical rating scale (NRS), Palliative Performance Scale, and the EQ-5D. The direct medical and nonmedical as well as indirect costs were also recorded. Cost-effectiveness and cost-utility analyses were performed comparing ITDD therapy with conventional therapy (extrapolated from costs of the same patient before ITDD therapy) from a societally oriented economic evaluation., Results: Twenty patients (F:M: 10:10) aged 60 ± 15 years who underwent implantation of an intrathecal percutaneous port (IT port; n = 15) or programmable intrathecal pump (IT pump; n = 5) were included. The median survival time was 78 (interquartile range = 121-54) days after ITDD therapy. At 2-month follow-up, the incremental cost-effectiveness ratio (ICER)/pain reduction of an IT port (US$2065.36 (CA$2829.54)/2-point NRS reduction/lifetime) was lower than for patients with an IT pump (US$5479.26 (CA$7506.58)/2-point NRS reduction/lifetime) compared with continued conventional therapy. The ICER/quality-adjusted life years (QALYs) gained for an IT port compared with conventional treatment was US$93,999.31(CA$128,799.06)/QALY gained, which is above the cost-effectiveness threshold for Thailand., Conclusion: The cost-effectiveness and cost-utility of IT port therapy for cancer pain was high relative to the cost of living in Thailand, above the cost-effectiveness threshold. Prospective cost analysis studies enrolling more patients with diverse cancers that investigate the benefit of early ITDD therapy with devices over a range of prices are warranted., Competing Interests: No potential conflict of interest was reported by the authors., (© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Low back pain (LBP) is the world's leading cause of years lived with disability. Digital exercise-based interventions have shown great potential in the management of musculoskeletal conditions, promoting access and easing the economic burden. However, evidence of their effectiveness for chronic LBP (CLBP) management compared to in-person physiotherapy has yet to be unequivocally established. This randomized controlled trial (RCT) aims to compare the clinical outcomes of patients with CLBP following a digital intervention versus evidence-based in-person physiotherapy. Our results demonstrate that patient satisfaction and adherence were high and similar between groups, although a significantly lower dropout rate is observed in the digital group (11/70, 15.7% versus 24/70, 34.3% in the conventional group; P = 0.019). Both groups experience significant improvements in disability (primary outcome), with no differences between groups in change from baseline (median difference: -0.55, 95% CI: -2.42 to 5.81, P = 0.412) or program-end scores (-1.05, 95% CI: -4.14 to 6.37; P = 0.671). Likewise, no significant differences between groups are found for secondary outcomes (namely pain, anxiety, depression, and overall productivity impairment). This RCT demonstrates that a remote digital intervention for CLBP can promote the same levels of recovery as evidence-based in-person physiotherapy, being a potential avenue to ease the burden of CLBP., (© 2023. The Author(s).)

There is increasing evidence that the relationship between chronic pain and infections is complex and intertwined. Bacterial and viral infections can cause pain through numerous mechanisms such as direct tissue damage and inflammation, the induction of excessive immunologic activity, and the development of peripheral or central sensitization. Treating infections might relieve pain by attenuating these processes, but a growing body of literature suggests that some antimicrobial therapies confer analgesic effects, including for nociceptive and neuropathic pain symptoms, and affective components of pain. The analgesic mechanisms of antimicrobials are indirect, but might be conceptualized into two broad categories: 1) the reduction of the infectious burden and associated pro-inflammatory processes; and 2) the inhibition of signaling processes (e.g., enzymatic and cytokine activity) necessary for nociception and maladaptive neuroplastic changes via off-target effects (unintended binding sites). For the former, there is evidence that symptoms of chronic low back pain (when associated with Modic type 1 changes), irritable bowel syndrome, inflammatory bowel disease, chronic pelvic pain, and functional dyspepsia might be improved after antibiotic treatment, though significant questions remain regarding specific regimens and dose, and which subpopulations are most likely to benefit. For the latter, there is evidence that several antimicrobial classes and medications exert analgesic effects independent of their reduction of infectious burden, and these include cephalosporins, ribavirin, chloroquine derivatives, rapalogues, minocycline, dapsone, and piscidin-1. This article aims to comprehensively review the existing literature for antimicrobial agents that have demonstrated analgesic efficacy in preclinical or clinical studies.

The discovery and development of antimicrobial therapies represents one of the most significant advancements in modern medicine. Although the primary therapeutic intent of antimicrobials is to eliminate their target pathogens, several antimicrobials have been shown to provide analgesia as a secondary benefit. Antimicrobials have demonstrated analgesic effects in conditions that involve dysbiosis or potential subclinical infection ( e.g . , chronic low back pain with Modic type 1 changes; chronic prostatitis/chronic pelvic pain; irritable bowel syndrome; inflammatory bowel disease; functional gastrointestinal disorders/dyspepsia; myalgic encephalomyelitis/chronic fatigue syndrome), and might even prevent the chronification of pain after acute infections that are associated with excessive systemic inflammation ( e.g . , post COVID-19 condition/long Covid, rheumatic fever). Clinical studies often assess the analgesic effects of antimicrobial therapies in an observational manner, without the ability to identify causative relationships, and significant gaps in the understanding remain regarding the analgesic potential of antimicrobials. Numerous interrelated patient-specific, antimicrobial-specific, and disease-specific factors altogether contribute to the perception and experience of pain, and each of these requires further study. Given worldwide concerns regarding antimicrobial resistance, antimicrobials must continue to be used judiciously and are unlikely to be repurposed as primary analgesic medications. However, when equipoise exists among several antimicrobial treatment options, the potential analgesic benefits of certain antimicrobial agents might be a valuable aspect to consider in clinical decision-making. This article (the second in a two-part series) aims to comprehensively review the evidence on the prevention and treatment of chronic pain using antimicrobial therapies and suggest a framework for future studies on this topic.

Background: Musculoskeletal conditions are the leading cause of disability worldwide. Telerehabilitation may be a viable option in the management of these conditions, facilitating access and patient adherence. Nevertheless, the impact of biofeedback-assisted asynchronous telerehabilitation remains unknown., Objective: To systematically review and assess the effectiveness of exercise-based asynchronous biofeedback-assisted telerehabilitation on pain and function in individuals with musculoskeletal conditions., Methods: This systematic review followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The search was conducted using three databases: PubMed, Scopus, and PEDro. Study criteria included articles written in English and published from January 2017 to August 2022, reporting interventional trials evaluating exercise-based asynchronous telerehabilitation using biofeedback in adults with musculoskeletal disorders. The risks of bias and certainty of evidence were appraised using the Cochrane tool and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE), respectively. The results are narratively summarized, and the effect sizes of the main outcomes were calculated., Results: Fourteen trials were included: 10 using motion tracker technology ( N  = 1284) and four with camera-based biofeedback ( N  = 467). Telerehabilitation with motion trackers yields at least similar improvements in pain and function in people with musculoskeletal conditions (effect sizes: 0.19-1.45; low certainty of evidence). Uncertain evidence exists for the effectiveness of camera-based telerehabilitation (effect sizes: 0.11-0.13; very low evidence). No study found superior results in a control group., Conclusions: Asynchronous telerehabilitation may be an option in the management of musculoskeletal conditions. Considering its potential for scalability and access democratization, additional high-quality research is needed to address long-term outcomes, comparativeness, and cost-effectiveness and identify treatment responders., (© The Author(s) 2023.)

Xanthomonas euvesicatoria and X. vesicatoria are two economically important causal agents of bacterial spot (BS) of tomato and pepper. Management of BS in the field requires rapid and accurate detection. Therefore, this work aimed to develop a pipeline to design a simple, fast, and reliable assay for the detection of X. euvesicatoria and X. vesicatoria by loop-mediated isothermal amplification. In total, 109 publicly available whole genomic sequences of 24 different species of bacterial pathogens were used to design primers that would amplify the DNA of the two target species. Laboratory testing of the assay was performed on pure bacterial cultures and artificially infected plants, and amplification was conducted with both a sophisticated laboratory instrument and a simple mobile platform. The testing of the assay confirmed its specificity with a sensitivity reaching 1 pg µl -1 for both pathogens with an assay duration of 40 min on a mobile detection platform. Our diagnostics development pipeline enables the easy and fast design of a reliable detection assay in the genomics age. By validating the pipeline with X. euvesicatoria and X. vesicatoria pathogens, we have simultaneously developed an assay with high specificity, sensitivity, and speed, which will allow it to be deployed, contributing to successful management of BS., Competing Interests: The author(s) declare no conflict of interest.

Objective: To determine the association between cervical nonorganic pain signs and epidural corticosteroid injection outcomes and coexisting pain and psychiatric conditions., Patients and Methods: Seventy-eight patients with cervical radiculopathy who received epidural corticosteroid injection were observed to determine the effects that nonorganic signs have on treatment outcome. A positive outcome was a decrease of 2 or more points in average arm pain, coupled with a score of 5 on a 7-point Patient Global Impression of Change scale 4 weeks after treatment. Nine tests in 5 categories (abnormal tenderness, regional disturbances deviating from normal anatomy, overreaction, discrepancies in examination findings with distraction, and pain during sham stimulation) were modified from previous studies and standardized. Other variables examined for their association with nonorganic signs and outcomes included disease burden, psychopathology, coexisting pain conditions, and somatization., Results: Of the 78 patients, 29% (n=23) had no nonorganic signs, 21% (n=16) had signs in 1 category, 10% (n=8) had signs in 2 categories, 21% (n=16) had signs in 3 categories, 10% (n=8) had signs in 4 categories, and 9% (n=7) had signs in 5 categories. The most common nonorganic sign was superficial tenderness (44%; n=34). Mean number of positive nonorganic categories was higher in individuals with negative treatment outcomes (2.5±1.8; 95% CI, 2.0 to 3.1) compared with those with positive outcomes (1.1±1.3; 95% CI, 0.7 to 1.5; P=.0002). Negative treatment outcomes were most strongly associated with regional disturbances and overreaction. Positive associations were noted between nonorganic signs and multiple pain (P=.011) and multiple psychiatric (P=.028) conditions., Conclusion: Cervical nonorganic signs correlate with treatment outcome, pain, and psychiatric comorbidities. Screening for these signs and psychiatric symptoms may improve treatment outcomes., Trial Registration: ClinicalTrials.gov identifier: NCT04320836., (Copyright © 2022 Mayo Foundation for Medical Education and Research. All rights reserved.)

Background: The accuracy of diagnostic tests available in primary care to identify the disc, sacroiliac joint, and facet joint as the source of low back pain is uncertain., Methods: Systematic review of diagnostic tests available in primary care. MEDLINE, CINAHL, and EMBASE were searched between March 2006 and 25th January 2023. Pairs of reviewers independently screened all studies, extracted data, and assessed risk of bias using QUADAS-2. Pooling was performed for homogenous studies. Positive likelihood ratios (+LR) ≥2 and negative likelihood ratios (-LR) ≤0.5 were considered informative. This review is registered with PROSPERO (CRD42020169828)., Findings: We included 62 studies: 35 investigated the disc, 14 the facet joint, 11 the sacroiliac joint, and 2 investigated all three structures in patients with persistent low back pain. For risk of bias, the domain 'reference standard' scored worst, however approximately half the studies were of low risk of bias for every other domain. For the disc, pooling demonstrated MRI findings of disc degeneration and annular fissure resulted in informative +LRs: 2.53 (95% CI: 1.57-4.07) and 2.88 (95% CI: 2.02-4.10) and -LRs: 0.15 (95% CI: 0.09-0.24) and 0.24 (95% CI: 0.10-0.55) respectively. Pooled results for Modic type 1, Modic type 2, and HIZ on MRI, and centralisation phenomenon yielded informative +LRs: 10.00 (95% CI: 4.20-23.82), 8.03 (95% CI: 3.23-19.97), 3.10 (95% CI: 2.27-4.25), and 3.06 (95% CI: 1.44-6.50) respectively, but uninformative -LRs: 0.84 (95% CI: 0.74-0.96), 0.88 (95% CI: 0.80-0.96), 0.61 (95% CI: 0.48-0.77), and 0.66 (95% CI: 0.52-0.84) respectively. For the facet joint, pooling demonstrated facet joint uptake on SPECT resulted in informative +LRs: 2.80 (95% CI: 1.82-4.31) and -LRs: 0.44 (95% CI: 0.25-0.77). For the sacroiliac joint, a combination of pain provocation tests and absence of midline low back pain resulted in informative +LRs of 2.41 (95% CI: 1.89-3.07) and 2.44 (95% CI: 1.50-3.98) and -LRs of 0.35 (95% CI: 0.12-1.01) and 0.31 (95% CI: 0.21-0.47) respectively. Radionuclide imaging yielded an informative +LR 7.33 (95% CI: 1.42-37.80) but an uninformative -LR 0.74 (95% CI: 0.41-1.34)., Interpretation: There are informative diagnostic tests for the disc, sacroiliac joint, and facet joint (only one test). The evidence suggests a diagnosis may be possible for some patients with low back pain, potentially guiding targeted and specific treatment approaches., Funding: There was no funding for this study., Competing Interests: We (author team) declare no competing interests., (© 2023 The Author(s).)

Background: Chronic low back pain (CLBP) is often associated with clinical evidence of central nervous system sensitization and finding a clear source of nociceptive input can be challenging. Conventional therapies targeting peripheral spinal pain structures can fail to address centrally-mediated, underlying causes of pain. Sixty-day percutaneous peripheral nerve stimulation (PNS) applied to the lumbar medial branch nerves is a non-surgical, non-opioid treatment that may restore the balance of peripheral inputs to the central nervous system and reverse maladaptive changes in central pain processing. As a minimally invasive, non-destructive treatment, percutaneous PNS was designed to be used earlier in the treatment continuum than radiofrequency ablation or permanently-implanted neurostimulation systems., Objective: The objective of this clinical trial was to characterize the durability of responses to medial branch PNS in a prospective multicenter case series study of CLBP patients recalcitrant to multiple non-surgical treatments., Design: Prospective, multicenter clinical trial., Population: Adults with CLBP without radicular leg pain who had previously failed multiple types of conventional treatments., Intervention: Sixty-day percutaneous PNS applied to the lumbar medial branch nerves., Methods: Percutaneous PNS leads were implanted under image guidance (ultrasound and/or fluoroscopy) and treatment was applied for up to 60 days, after which the leads were removed. Participants were followed through 14 months (12 months after the 2-month PNS treatment). Prospectively-defined endpoints included assessments of pain intensity, disability, pain interference, health-related quality of life, depression, and patient global impression of change., Results: Treatment of CLBP with 60-day percutaneous PNS treatment produced clinically meaningful improvements in average pain intensity, disability, and/or pain interference for a majority of participants through the entire 14 month follow up period without requiring permanent system implantation. The proportion of participants experiencing clinically meaningful improvement in at least one outcome (pain intensiy, disability, pain interference) with PNS was 91% after 2 months, 79% at 5 months, 73% at 8 months, 75% at 11 months, and 77% at 14 months. There were no serious or unanticipated study-related adverse events., Conclusion: This prospective multicenter clinical trial demonstrates the clinical utility of percutaneous PNS when applied to the medial branch nerves for the treatment of chronic low back pain recalcitrant to non-surgical treatments. Given the minimally invasive nature of percutaneous PNS and the significant benefits experienced by participants, percutaneous PNS provides a safe and effective first-line neuromodulation treatment for patients with CLBP that may obviate the need for neuroablative procedures or permanent neurostimulation system implantation., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Christopher Gilmore, Mehul Desai, Sean Li, Michael DePalma, Timothy Deer, and Steven Cohen reports financial support was provided by SPR Therapeutics Inc. Christopher Gilmore, Mehul Desai, Sean Li, Michael DePalma, Timothy Deer, and Steven Cohen reports a relationship with SPR Therapeutics Inc that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Joseph Boggs and Meredith McGee has patent issued to SPR Therapeutics, Inc. Drs Gilmore, Desai, Hopkins, Li, DePalma, and Deer are physician investigators with clinical research sponsored by SPR Therapeutics. Drs Gilmore, Desai, Li, Deer, and Cohen are consultants for SPR, and Drs Desai and Deer have equity ownership in SPR Therapeutics. Drs McGee and Boggs are employees of SPR Therapeutics with equity ownership., (© 2023 The Authors.)

Background: Postamputation phantom pain is notoriously persistent with few validated treatments. Cryoneurolysis involves the application of low temperatures to reversibly ablate peripheral nerves. The authors tested the hypothesis that a single cryoneurolysis treatment would decrease phantom pain 4 months later., Methods: The authors enrolled patients with a lower-limb amputation and established phantom pain. Each received a single-injection femoral and sciatic nerve block with lidocaine and was subsequently randomized to receive either ultrasound-guided percutaneous cryoneurolysis or sham treatment at these same locations. The primary outcome was the change in average phantom pain intensity between baseline and 4 months as measured with a numeric rating scale (0 to 10), after which an optional crossover treatment was offered. Investigators, participants, and clinical staff were masked to treatment group assignment with the exception of the treating physician performing the cryoneurolysis, who had no subsequent participant interaction., Results: Pretreatment phantom pain scores were similar in both groups, with a median [quartiles] of 5.0 [4.0, 6.0] for active treatment and 5.0 [4.0, 7.0] for sham. After 4 months, pain intensity decreased by 0.5 [-0.5, 3.0] in patients given cryoneurolysis (n = 71) versus 0 [0, 3] in patients given sham (n = 73), with an estimated difference (95% CI) of -0.1 (-1.0 to 0.7), P = 0.759. Following their statistical gatekeeping protocol, the authors did not make inferences or draw conclusions on secondary endpoints. One serious adverse event occurred after a protocol deviation in which a femoral nerve cryolesion was induced just below the inguinal ligament-instead of the sensory-only saphenous nerve-which resulted in quadriceps weakness, and possibly a fall and clavicle fracture., Conclusions: Percutaneous cryoneurolysis did not decrease chronic lower extremity phantom limb pain 4 months after treatment. However, these results were based upon the authors' specific study protocol, and since the optimal cryoneurolysis treatment parameters such as freeze duration and anatomic treatment location remain unknown, further research is warranted., (Copyright © 2022, the American Society of Anesthesiologists. All Rights Reserved.)

Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background: Musculoskeletal (MSK) pain disproportionately affects people from different ethnic backgrounds through higher burden and less access to care. Digital care programs (DCPs) can improve access and help reduce inequities. However, the outcomes of such programs based on race and ethnicity have yet to be studied., Objective: We aimed to assess the impact of race and ethnicity on engagement and outcomes in a multimodal DCP for MSK pain., Methods: This was an ad hoc analysis of an ongoing decentralized single-arm investigation into engagement and clinical-related outcomes after a multimodal DCP in patients with MSK conditions. Patients were stratified by self-reported racial and ethnic group, and their engagement and outcome changes between baseline and 12 weeks were compared using latent growth curve analysis. Outcomes included program engagement (number of sessions), self-reported pain scores, likelihood of surgery, Generalized Anxiety Disorder 7-item scale, Patient Health Questionnaire 9-item, and Work Productivity and Activity Impairment. A minimum clinically important difference (MCID) of 30% was calculated for pain, and multivariable logistic regression was performed to evaluate race as an independent predictor of meeting the MCID., Results: A total of 6949 patients completed the program: 65.5% (4554/6949) of them were non-Hispanic White, 10.8% (749/6949) were Black, 9.7% (673/6949) were Asian, 9.2% (636/6949) were Hispanic, and 4.8% (337/6949) were of other racial or ethnic backgrounds. The population studied was diverse and followed the proportions of the US population. All groups reported high engagement and satisfaction, with Hispanic and Black patients ranking first among satisfaction despite lower engagement. Black patients had a higher likelihood to drop out (odds ratio [OR] 1.19, 95% CI 1.01-1.40, P=.04) than non-Hispanic White patients. Hispanic and Black patients reported the highest level of pain, surgical intent, work productivity, and impairment in activities of daily living at baseline. All race groups showed a significant improvement in all outcomes, with Black and Hispanic patients reporting the greatest improvements in clinical outcomes. Hispanic patients also had the highest response rate for pain (75.8%) and a higher OR of meeting the pain MCID (OR 1.74, 95% CI 1.24-2.45, P=.001), when compared with non-Hispanic White patients, independent of age, BMI, sex, therapy type, education level, and employment status. No differences in mental health outcomes were found between race and ethnic groups., Conclusions: This study advocates for the utility of a DCP in improving access to MSK care and promoting health equity. Engagement and satisfaction rates were high in all the groups. Black and Hispanic patients had higher MSK burden at baseline and lower engagement but also reported higher improvements, with Hispanic patients presenting a higher likelihood of pain improvement., (©Justin Scheer, Fabíola Costa, Maria Molinos, Anabela Areias, Dora Janela, Robert G Moulder, Jorge Lains, Virgílio Bento, Vijay Yanamadala, Steven P Cohen, Fernando Dias Correia. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 31.10.2022.)

Tea is a steeped beverage made from the leaves of Camellia sinensis . Globally, this healthy, caffeine-containing drink is one of the most widely consumed beverages. At least 50 countries produce tea and most of the production information and tea research is derived from international sources. Here, we discuss information related to tea production, genetics, and chemistry as well as production issues that affect or are likely to affect emerging tea production and research in the United States. With this review, we relay current knowledge on tea production, threats to tea production, and solutions to production problems to inform this emerging market in the United States., Competing Interests: The authors declare that this review was written in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 D’Auria, Cohen, Leung, Glockzin, Glockzin, Gervay-Hague, Zhang and Meinhardt.)