Targeting dorsal root ganglia for chemotherapy-induced peripheral neuropathy: from bench to bedside.

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating condition affecting an increasing number of cancer survivors worldwide. However, insights into its pathophysiology and availability of effective therapies remain lacking. Dorsal root ganglia (DRG) have been studied as a key component of chemotherapeutic drug toxicity and a potential therapeutic target for CIPN treatment. This comprehensive review aims to synthesize, summarize, and correlate the results of both preclinical and clinical studies relevant to the pathophysiology and management of CIPN in relation to the DRG. Design: Review. A thorough literature search was conducted using the terms 'dorsal root ganglion' and 'chemotherapy-induced peripheral neuropathy', along with appropriate variations. Searched databases included PubMed, EMBASE, Medline, Cochrane Library, Wiley Library, and Web of Science. Inclusion criteria targeted all English language, peer-reviewed original research from the inception of these databases to the present year. Review articles, book chapters, and other nonoriginal publications were excluded. Of 134 relevant studies identified, the majority were preclinical studies elucidating how various chemotherapeutic agents, especially taxanes, disrupt neurotransmission, inflammatory processes, and apoptotic pathways within sensory neurons of DRG. Not only do these effects correlate with the presentation of CIPN, but their disruption has also been shown to reduce CIPN symptoms in preclinical models. However, clinical studies addressing DRG interventions are very limited in number and scope at this time. These results reveal various pathways within DRG that may be effective targets for CIPN treatment. While limited, clinical studies do offer promise in the utility of DRG neuromodulation in managing painful CIPN. In the future, clinical trials are needed to assess interventions aimed at these neuronal and nonneuronal pathological targets to better treat this complex condition.

Surgical treatment of refractory low back pain using implanted BurstDR spinal cord stimulation (SCS) in a cohort of patients without options for corrective surgery: Findings and results from the DISTINCT study, a prospective randomized multi-center-controlled trial.

Background: Low back pain (LBP) is a highly prevalent, disabling condition affecting millions of people. Patients with an identifiable anatomic pain generator and resulting neuropathic lower extremity symptoms often undergo spine surgery, but many patients lack identifiable and/or surgically corrective pathology. Nonoperative treatment options often fail to provide sustained relief. Spinal cord stimulation (SCS) is sometimes used to treat these patients, but the lack of level 1 evidence limits its widespread use and insurance coverage. The DISTINCT RCT study evaluates the efficacy of passive recharge burst SCS compared to conventional medical treatment (CMM) in alleviating chronic, refractory axial low back pain. Methods: This prospective, multicenter, randomized, study with an optional 6-month crossover involved patients who were not candidates for lumbar spine surgery. The primary and secondary endpoints evaluated improvements in low back pain intensity (NRS), back pain-related disability (ODI), pain catastrophizing (PCS), and healthcare utilization. Patients were randomized to SCS therapy or CMM at 30 US study sites. Results: The SCS arm reported an 85.3% NRS responder rate (≥ 50% reduction) compared to 6.2% (5/81) in the CMM arm. After the 6M primary endpoint, SCS patients elected to remain on assigned therapy and 66.2% (49/74) of CMM patients chose to trial SCS (crossover). At the 12M follow-up, SCS and crossover patients reported 78.6% and 71.4% NRS responder rates. Secondary outcomes indicated significant improvements in ODI, PCS, and reduced healthcare utilization. Six serious adverse events were reported and resolved without sequelae. Conclusion: DISTINCT chronic low back pain patients with no indication for corrective surgery experienced a significant and sustained response to burst SCS therapy for up to 12 months. CMM patients who crossed over to the SCS arm reported profound improvements after 6 months. This data advocates for a timely consideration of SCS therapy in patients unresponsive to conservative therapy.

Efficacy and Safety of Pharmacological Treatment in Patients with Complex Regional Pain Syndrome: A Systematic Review and Meta-Analysis.

Complex regional pain syndrome (CRPS) is a disabling condition that usually affects the extremities after trauma or surgery. At present, there is no FDA-approved pharmacological treatment for patients with CRPS. We performed this systematic review and meta-analysis to evaluate the efficacy and safety of pharmacological therapies and determine the best strategy for CRPS. We searched the databases, including PubMed, Embase, Cochrane, Web of Science, Scopus, and ClinicalTrials.gov, for published eligible randomized controlled trials (RCTs) comparing pharmacological treatment with placebo in CRPS patients. Target patients were diagnosed with CRPS according to Budapest Criteria in 2012 or the 1994 consensus-based IASP CRPS criteria. Finally, 23 RCTs comprising 1029 patients were included. We used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to rate certainty (confidence in evidence and quality of evidence). Direct meta-analysis showed that using bisphosphonates (BPs) (mean difference [MD] -2.21, 95% CI -4.36--0.06, p = 0.04, moderate certainty) or ketamine (mean difference [MD] -0.78, 95% CI -1.51--0.05, p = 0.04, low certainty) could provide long-term (beyond one month) pain relief. However, there was no statistically significant difference in the efficacy of short-term pain relief. Ketamine (rank p = 0.55) and BPs (rank p = 0.61) appeared to be the best strategies for CRPS pain relief. Additionally, BPs (risk ratio [RR] = 1.86, 95% CI 1.34-2.57, p < 0.01, moderate certainty) and ketamine (risk ratio [RR] = 3.45, 95% CI 1.79-6.65, p < 0.01, moderate certainty) caused more adverse events, which were mild, and no special intervention was required. In summary, among pharmacological interventions, ketamine and bisphosphonate injection seemed to be the best treatment for CRPS without severe adverse events.

NMDA Receptors Regulate Oxidative Damage in Keratinocytes during Complex Regional Pain Syndrome in HaCaT Cells and Male Rats.

Complex regional pain syndrome (CRPS), a type of primary chronic pain, occurs following trauma or systemic disease and typically affects the limbs. CRPS-induced pain responses result in vascular, cutaneous, and autonomic nerve alterations, seriously impacting the quality of life of affected individuals. We previously identified the involvement of keratinocyte N-methyl-d-asparagic acid (NMDA) receptor subunit 2 B (NR2B) in both peripheral and central sensitizations in CRPS, although the mechanisms whereby NR2B functions following activation remain unclear. Using an in vivo male rat model of chronic post-ischemia pain (CPIP) and an in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) cell model, we discovered that oxidative injury occurs in rat keratinocytes and HaCaT cells, resulting in reduced cell viability, mitochondrial damage, oxidative damage of nucleotides, and increased apoptosis. In HaCaT cells, OGD/R induced increases in intracellular reactive oxygen species levels and disrupted the balance between oxidation and antioxidation by regulating a series of antioxidant genes. The activation of NMDA receptors via NMDA exacerbated these changes, whereas the inhibition of the NR2B subunit alleviated them. Co-administration of ifenprodil (an NR2B antagonist) and NMDA (an NMDA receptor agonist) during the reoxygenation stage did not result in any significant alterations. Furthermore, intraplantar injection of ifenprodil effectively reversed the altered gene expression that was observed in male CPIP rats, thereby revealing the potential mechanisms underlying the therapeutic effects of peripheral ifenprodil administration in CRPS. Collectively, our findings indicate that keratinocytes undergo oxidative injury in CRPS, with NMDA receptors playing regulatory roles.

An international study to explore the feasibility of collecting standardised outcome data for Complex Regional Pain Syndrome: recommendations for an international clinical research registry.

Introduction: Complex Regional Pain Syndrome (CRPS) is a persistent pain condition with low prevalence. Multi-centre collaborative research is needed to attain sufficient sample sizes for meaningful studies. This international observational study: (1) tested the feasibility and acceptability of collecting outcome data using an agreed core measurement set (2) tested and refined an electronic data management system to collect and manage the data. Methods: Adults with CRPS, meeting the Budapest diagnostic clinical criteria, were recruited to the study from 7 international research centres. After informed consent, a questionnaire comprising the core set outcome measures was completed: on paper at baseline (T1), and at 3 or 6 months (T2) using a paper or e-version. Participants and clinicians provided feedback on the data collection process. Clinicians completed the CRPS severity score at T1 and optionally, at T2. Ethical approval was obtained at each international centre. Results: Ninety-eight adults were recruited (female n=66; mean age 46.6 years, range 19-89), of whom 32% chose to receive the T2 questionnaire in an electronic format. Fifty-five participants completed both T1 and T2. Eighteen participants and nine clinicians provided feedback on their data collection experience. Conclusion: This study confirmed the questionnaire core outcome data are feasible and practicable to collect in clinical practice. The electronic data management system provided a robust means of collecting and managing the data across an international population. The findings have informed the final data collection tools and processes which will comprise the first international, clinical research registry and data bank for CRPS.

Nitrous oxide for the treatment of complex regional pain syndrome: a randomized blinded trial.

INTRODUCTION: Complex Regional Pain Syndrome (CRPS) is a debilitating neuropathic condition often refractory to conventional treatments. N-methyl-D-aspartate (NMDA) receptor antagonists have a well-established role in the development and modulation of chronic neuropathic pain. Nitrous oxide is widely used and generally safe anesthetic gas with NMDA receptor antagonist activity. We therefore tested the hypothesis that brief periods of nitrous oxide exposure reduce pain in patients with CRPS. METHODS: Patients with a diagnosis of CRPS were randomized to either 2 hours of nitrous oxide exposure on three alternating days (Nitrous Oxide) versus a placebo air/oxygen mixture (Air-Oxygen). Our primary outcome was patient-reported pain scores at 1 week and 1 month. Secondary and exploratory outcomes were physical and mental health (PRMOIS-29 v2 survey), specific neuropathic pain symptoms (McGill short-form questionnaire), and opioid consumption. RESULTS: 44 patients participated in the study; 20 were randomized to Nitrous Oxide and 24 were assigned to Air-Oxygen. Pain scores did not differ significantly, with the estimated difference in means (Nitrous Oxide-Air-Oxygen) of -0.57 (95% CI: -1.42 to 0.28) points, p=0.19. There were also no differences detected in secondary outcomes, with the estimated difference in mean Z-scores for physical health (Nitrous Oxide-Air-Oxygen) of 0.13 (95% CI: -0.16 to 0.43), mental health 0.087 (95% CI: -0.31 to 0.48), and Patient Global Impression of Change score -0.7 (95% CI: -1.85 to 0.46). CONCLUSIONS: Compared with air/oxygen, 2 hours of nitrous oxide/oxygen exposure for three sessions did not provide meaningful therapeutic potential for patients with chronic CRPS. Our results do not support using nitrous oxide for the treatment of CRPS.

Complement Receptor C3aR1 Contributes to Paclitaxel-Induced Peripheral Neuropathic Pain in Mice and Rats.

Cancer chemotherapy-induced neuropathic pain is a devastating pain syndrome without effective therapies. We previously reported that rats deficient in complement C3, the central component of complement activation cascade, showed a reduced degree of paclitaxel-induced mechanical allodynia (PIMA), suggesting that complement is integrally involved in the pathogenesis of this model. However, the underlying mechanism was unclear. Complement activation leads to the production of C3a, which mediates inflammation through its receptor C3aR1. In this article, we report that the administration of paclitaxel induced a significantly higher expression level of C3aR1 on dorsal root ganglion (DRG) macrophages and expansion of these macrophages in DRGs in wild-type (WT) compared with in C3aR1 knockout (KO) mice. We also found that paclitaxel induced less severe PIMA, along with a reduced DRG expression of transient receptor potential channels of the vanilloid subtype 4 (TRPV4), an essential mediator for PIMA, in C3aR1 KO than in WT mice. Treating WT mice or rats with a C3aR1 antagonist markedly attenuated PIMA in association with downregulated DRG TRPV4 expression, reduced DRG macrophages expansion, suppressed DRG neuron hyperexcitability, and alleviated peripheral intraepidermal nerve fiber loss. Administration of C3aR1 antagonist to TRPV4 KO mice further protected them from PIMA. These results suggest that complement regulates PIMA development through C3aR1 to upregulate TRPV4 on DRG neurons and promote DRG macrophage expansion. Targeting C3aR1 could be a novel therapeutic approach to alleviate this debilitating pain syndrome.

The Role of Neuroinflammation in Complex Regional Pain Syndrome: A Comprehensive Review.

Complex Regional Pain Syndrome (CRPS) is an excess and/or prolonged pain and inflammation condition that follows an injury to a limb. The pathogenesis of CRPS is multifaceted that remains incompletely understood. Neuroinflammation is an inflammatory response in the peripheral and central nervous systems. Dysregulated neuroinflammation plays a crucial role in the initiation and maintenance of pain and nociceptive neuronal sensitization, which may contribute to the transition from acute to chronic pain and the perpetuation of chronic pain in CRPS. The key features of neuroinflammation encompass infiltration and activation of inflammatory cells and the production of inflammatory mediators in both the central and peripheral nervous systems. This article reviews the role of neuroinflammation in the onset and progression of CRPS from six perspectives: neurogenic inflammation, neuropeptides, glial cells, immune cells, cytokines, and keratinocytes. The objective is to provide insights that can inform future research and development of therapeutic targets for CRPS.

Treatment of Refractory Low Back Pain Using Passive Recharge Burst in Patients Without Options for Corrective Surgery: Findings and Results From the DISTINCT Study, a Prospective Randomized Multicenter Controlled Trial.

OBJECTIVE: Spinal cord stimulation (SCS) is effective for relieving chronic intractable pain conditions. The Dorsal spInal cord STImulatioN vs mediCal management for the Treatment of low back pain study evaluates the effectiveness of SCS compared with conventional medical management (CMM) in the treatment of chronic low back pain in patients who had not undergone and were not candidates for lumbar spine surgery. METHODS AND MATERIALS: Patients were randomized to passive recharge burst therapy (n = 162) or CMM (n = 107). They reported severe pain and disability for more than a decade and had failed a multitude of therapies. Common diagnoses included degenerative disc disease, spondylosis, stenosis, and scoliosis-yet not to a degree amenable to surgery. The six-month primary end point compared responder rates, defined by a 50% reduction in pain. Hierarchical analyses of seven secondary end points were performed in the following order: composite responder rate (numerical rating scale [NRS] or Oswestry Disability Index [ODI]), NRS, ODI, Pain Catastrophizing Scale responder rate, Patient Global Impression of Change (PGIC) responder rate, and Patient-Reported Outcome Measure Information System-29 in pain interference and physical function. RESULTS: Intention-to-treat analysis showed a significant difference in pain responders on NRS between SCS (72.6%) and CMM (7.1%) arms (p < 0.0001). Of note, 85.2% of those who received six months of therapy responded on NRS compared with 6.2% of those with CMM (p < 0.0001). All secondary end points indicated the superiority of burst therapy over CMM. A composite measure on function or pain relief showed 91% of subjects with SCS improved, compared with 16% of subjects with CMM. A substantial improvement of 30 points was observed on ODI compared with a

Long-term efficacy of high-frequency (10 kHz) spinal cord stimulation for the treatment of painful diabetic neuropathy: 24-Month results of a randomized controlled trial.

AIMS: To evaluate the long-term efficacy of high-frequency (10 kHz) spinal cord stimulation (SCS) for treating refractory painful diabetic neuropathy (PDN). METHODS: The SENZA-PDN study was a prospective, multicenter, randomized controlled trial that compared conventional medical management (CMM) alone with 10 kHz SCS plus CMM (10 kHz SCS+CMM) in 216 patients with refractory PDN. After 6 months, participants with insufficient pain relief could cross over to the other treatment. In total, 142 patients with a 10 kHz SCS system were followed for 24 months, including 84 initial 10 kHz SCS+CMM recipients and 58 crossovers from CMM alone. Assessments included pain intensity, health-related quality of life (HRQoL), sleep, and neurological function. Investigators assessed neurological function via sensory, reflex, and motor tests. They identified a clinically meaningful improvement relative to the baseline assessment if there was a significant persistent improvement in neurological function that impacted the participant's well-being and was attributable to a neurological finding. RESULTS: At 24 months, 10 kHz SCS reduced pain by a mean of 79.9% compared to baseline, with 90.1% of participants experiencing ≥50% pain relief. Participants had significantly improved HRQoL and sleep, and 65.7% demonstrated clinically meaningful neurological improvement. Five (3.2%) SCS systems were explanted due to infection. CONCLUSIONS: Over 24 months, 10 kHz SCS provided durable pain relief and significant improvements in HRQoL and sleep. Furthermore, the majority of participants demonstrated neurological improvement. These long-term data support 10 kHz SCS as a safe and highly effective therapy for PDN. TRIAL REGISTRATION: ClincalTrials.gov Identifier, NCT03228420.

Pyridinium-Masked Enol as a Precursor for Constructing Alpha-Fluoromethyl Ketones.

We present herein a pyridinium-masked enol as a versatile platform to produce ketones bearing tri-, di-, and monofluoromethyl in the presence of [Ir(dF(Me)ppy)]2(dtbbpy)]PF6 under blue light (455 nm) irradiation. By simply changing the F-source, α-trifluoromethyl ketones, α-difluoromethyl ketones, and α-monofluoromethyl ketones could be easily prepared in moderate to excellent yields in one step, making it a practical tool for the synthesis of fluorine-containing ketones. In addition, the pyridinium-masked enol could also be extended to the synthesis of sulfonyl ketones. The findings of the present protocol contribute to the arsenal of fluorine chemistry and might have potential applications in the pharmaceutical and agrochemical industries.

Preparation and in vivo imaging of NIR-emissive carbonized polymer dots derived from biomass olive leaves with a quantum yield of 71.4.

The conversion of biomass materials into high value-added chemicals is receiving more and more attention. Herein, biomass olive leaves are converted into carbonized polymer dots (CPDs) through a simple hydrothermal reaction. The CPDs show near infrared light emission properties, and the absolute quantum yield reaches a record breaking value of 71.4% under the excitation wavelength of 413 nm. Detailed characterization determines that CPDs only contain three elements: carbon, hydrogen and oxygen, which is very different from most carbon dots which contain nitrogen atoms. Subsequently, NIR fluorescence imaging both in vitro and in vivo is performed to test their feasibility as fluorescence probes. The metabolic pathways of CPDs in the living body are inferred by studying the bio-distribution of CPDs in major organs. Their outstanding advantage is expected to further broaden the application field of this material.

Community-integrated multi-omics facilitates screening and isolation of the organohalide dehalogenation microorganism.

A variety of anthropogenic organohalide contaminants generated from industry are released into the environment and thus cause serious pollution that endangers human health. In the present study, we investigated the microbial community composition of industrial saponification wastewater using 16S rRNA sequencing, providing genomic insights of potential organohalide dehalogenation bacteria (OHDBs) by metagenomic sequencing. We also explored yet-to-culture OHDBs involved in the microbial community. Microbial diversity analysis reveals that Proteobacteria and Patescibacteria phyla dominate microbiome abundance of the wastewater. In addition, a total of six bacterial groups (Rhizobiales, Rhodobacteraceae, Rhodospirillales, Flavob a cteriales, Micrococcales, and Saccharimonadales) were found as biomarkers in the key organohalide removal module. Ninety-four metagenome-assembled genomes were reconstructed from the microbial community, and 105 hydrolytic dehalogenase genes within 42 metagenome-assembled genomes were identified, suggesting that the potential for organohalide hydrolytic dehalogenation is present in the microbial community. Subsequently, we characterized the organohalide dehalogenation of an isolated OHDB, Microbacterium sp. J1-1, which shows the dehalogenation activities of chloropropanol, dichloropropanol, and epichlorohydrin. This study provides a community-integrated multi-omics approach to gain functional OHDBs for industrial organohalide dehalogenation.

Blockade of Type 2A Protein Phosphatase Signaling Attenuates Complement C1q-Mediated Microglial Phagocytosis of Glutamatergic Synapses Induced by Amyloid Fibrils.

We previously reported the critical involvement of metabotropic GluR1 (mGluR1) signaling in complement C1q-dependent microglial phagocytosis of glutamatergic synapses in a rat model of Alzheimer's disease (AD) injected with amyloid fibrils. Here, we explored the role of type 2A protein phosphatase (type 2A PPase), a key enzyme downstream of mGluR1 signaling, in the pathogenesis of AD in rats. Significant local upregulation of PP2A expression was observed in the hippocampal CA1 after bilateral microinjection of amyloid-beta (Aß1-40) fibrils. Amyloid fibrils induced remarkable dephosphorylation of pFMRP (fragile X mental retardation protein) and C1q upregulation in hippocampal glutamatergic synapses, which was ameliorated by microinjection of type 2A PPase inhibitor okadaic acid (OA). Microinjection of OA further attenuated the microglial phagocytosis of glutamatergic synapses, recovered the hippocampal glutamatergic transmission, and improved the performance in Morris water maze test. These findings demonstrated that dysfunction of type 2A PPase signaling contributed to complement C1q-dependent microglial phagocytosis of glutamatergic synapses and the cognitive impairments in the rat model of AD.

Emerging roles of keratinocytes in nociceptive transduction and regulation.

Keratinocytes are the predominant block-building cells in the epidermis. Emerging evidence has elucidated the roles of keratinocytes in a wide range of pathophysiological processes including cutaneous nociception, pruritus, and inflammation. Intraepidermal free nerve endings are entirely enwrapped within the gutters of keratinocyte cytoplasm and form en passant synaptic-like contacts with keratinocytes. Keratinocytes can detect thermal, mechanical, and chemical stimuli through transient receptor potential ion channels and other sensory receptors. The activated keratinocytes elicit calcium influx and release ATP, which binds to P2 receptors on free nerve endings and excites sensory neurons. This process is modulated by the endogenous opioid system and endothelin. Keratinocytes also express neurotransmitter receptors of adrenaline, acetylcholine, glutamate, and γ-aminobutyric acid, which are involved in regulating the activation and migration, of keratinocytes. Furthermore, keratinocytes serve as both sources and targets of neurotrophic factors, pro-inflammatory cytokines, and neuropeptides. The autocrine and/or paracrine mechanisms of these mediators create a bidirectional feedback loop that amplifies neuroinflammation and contributes to peripheral sensitization.

Cooled and traditional thermal radiofrequency ablation of genicular nerves in patients with chronic knee pain: a comparative outcomes analysis.

INTRODUCTION: Genicular nerve radiofrequency ablation (GNRFA) is a minimally invasive intervention for patients with chronic knee pain (CKP) not responding to conservative treatments. Few investigations have compared treatment outcomes of cooled-RFA (c-RFA) and thermal-RFA (t-RFA), two common approaches of GNRFA. This study aims to investigate and compare outcomes, including probability of treatment success, between c-RFA and t-RFA in patients with CKP. METHODS: This retrospective cohort study analyzed a total of 208 propensity score matched patients, including 104 patients who received c-RFA and 104 patients who received t-RFA. The primary outcome was probability of pain relief after the procedure, defined as reduction in Numeric Rating Scale (NRS) pain score of 2 or greater. The secondary outcomes were degree of NRS pain score reductions, duration of relief, and the probability of patients receiving TKA within 1 year of treatment. RESULTS: T-RFA was associated with a higher probability of pain relief within 1, 3, and 6 months after procedure when compared with c-RFA. Probabilities of pain relief from t-RFA and c-RFA were 62% (95% CI 51% to 71%) and 43% (95% CI 34% to 53%; p=0.01) within 1 month, 78% (95% CI 68% to 85%) and 55% (95% CI 45% to 64%; p<0.001) within 3 months, and 79% (95% CI 70% to 86%) and 59% (95% CI 49% to 68%; p<0.01) within 6 months, respectively. t-RFA was also associated with greater mean NRS pain score reduction at 1 month after procedure: -4.71 (95% CI -5.3 to -4.1) when compared with -3.59 (95% CI -4.3 to -2.9; p=0.02) from c-RFA. T-RFA and c-RFA were comparable in pain score reduction at 3, 6, 9 and 12 months after procedure. Both groups demonstrated comparable duration of relief and probability of patients receiving TKA within 1 year. DISCUSSION: Both t-RFA and c-RFA effectively reduced NRS pain scores in most patients with CKP within the 1 year follow-up period. Genicular nerve t-RFA was associated with a higher probability of treatment success and a greater degree of pain relief at 1 month after the procedure when compared with c-RFA in propensity score matched patients with CKP.

A novel Diaphorobacter sp. strain isolated from saponification wastewater shows highly efficient phenanthrene degradation.

Polycyclic aromatic hydrocarbons (PAHs), such as phenanthrene, are a type of organic pollutants that exist widely in the environment. Of the currently known degradation methods, bioremediation is a desirable and feasible option. A novel Diaphorobacter sp. Strain MNS-0 was isolated from saponification wastewater and showed the ability to degrade phenanthrene, fluorene, acenaphthene, anthracene, benzo[a]anthracene, or chrysene using phenanthrene as the sole carbon source. Gas chromatography mass spectroscopy analysis of catabolic intermediates indicates that phenanthrene degradation occurs through the phthalic acid pathway in strain MNS-0. Genome sequencing shows that strain MNS-0 has two plasmids and one chromosome containing a presumptive phenanthrene degradation gene cluster. Strain MNS-0 was able to completely degrade 100 mg/L phenanthrene within 40 h and tolerate up to 10 g/L NaCl at pH 9.0, while maintaining phenanthrene degradation activity. We thus propose that strain MNS-0 is an effective degrader for bioremediation of PAHs pollution, even in relatively harsh alkali environments such as saponification wastewater.

High-Frequency 10-kHz Spinal Cord Stimulation Improves Health-Related Quality of Life in Patients With Refractory Painful Diabetic Neuropathy: 12-Month Results From a Randomized Controlled Trial.

Objective: To evaluate high-frequency (10-kHz) spinal cord stimulation (SCS) treatment in refractory painful diabetic neuropathy. Patients and Methods: A prospective, multicenter randomized controlled trial was conducted between Aug 28, 2017 and March 16, 2021, comparing conventional medical management (CMM) with 10-kHz SCS+CMM. The participants had hemoglobin A1c level of less than or equal to 10% and pain greater than or equal to 5 of 10 cm on visual analog scale, with painful diabetic neuropathy symptoms 12 months or more refractory to gabapentinoids and at least 1 other analgesic class. Assessments included measures of pain, neurologic function, and health-related quality of life (HRQoL) over 12 months with optional crossover at 6 months. Results: The participants were randomized 1:1 to CMM (n=103) or 10-kHz SCS+CMM (n=113). At 6 months, 77 of 95 (81%) CMM group participants opted for crossover, whereas none of the 10-kHz SCS group participants did so. At 12 months, the mean pain relief from baseline among participants implanted with 10-kHz SCS was 74.3% (95% CI, 70.1-78.5), and 121 of 142 (85%) participants were treatment responders (≥50% pain relief). Treatment with 10-kHz SCS improved HRQoL, including a mean improvement in the EuroQol 5-dimensional questionnaire index score of 0.136 (95% CI, 0.104-0.169). The participants also reported significantly less pain interference with sleep, mood, and daily activities. At 12 months, 131 of 142 (92%) participants were "satisfied" or "very satisfied" with the 10-kHz SCS treatment. Conclusion: The 10-kHz SCS treatment resulted in substantial pain relief and improvement in overall HRQoL 2.5- to 4.5-fold higher than the minimal clinically important difference. The outcomes were durable over 12 months and support 10-kHz SCS treatment in patients with refractory painful diabetic neuropathy. Trial registration: clincaltrials.gov Identifier: NCT03228420.

Transperineal Botulinum Toxin Injection for Chronic Pelvic Pain Syndrome after Transurethral Resection of the Prostate.

PURPOSE: To evaluate the efficacy of botulinum toxin type A (BTX-A) injection in patients with chronic pelvic pain syndrome (CPPS) after transurethral resection of the prostate (TURP). MATERIALS AND METHODS: Six patients after TURP received the injection of BTX-A around the prostate capsule or pelvic floor under ultrasound guidance. The clinical outcomes including overall pain intensity (assessed by visual analog scale, VAS), the Functional Pelvic Pain scale (FPPS), and mental state by anxiety and depression questionnaires, the generalized anxiety disorder (GAD-7) and Hamilton depression rating scale (HAM-D)) were assessed at pre-treatment, and 1, 4, 12 weeks after treatment. RESULTS: Six male patients, aged 65 to 76 years were enrolled. The improvement of VAS pain score, the Functional Pelvic Pain scale, and mental assessment were observed at 1, 4, and 12 weeks after treatment for all six patients. All 6 patients had no safety concerns through 12 weeks visit, except 3 patients complained transient pain at injection site. CONCLUSION: Injection of BTX-A around the prostate under ultrasound guidance may be effective and safe for patients with CPPS after TURP.

Attribution Assessment and Prediction of Runoff Change in the Han River Basin, China.

The ecological environment and water resources of the Han River Basin (HRB) are incredibly susceptible to global warming. Naturally, the analysis of future runoff in HRB is believed to offer a theoretical basis for water resources management and ecological protection in HRB. The purpose of this study is to investigate and forecast the effects of climate change and land use change on runoff in the HRB. This study uses CMIP6 data to simulate three future climate change scenarios (SSP126, SSP245 and SSP585) for changes in precipitation and temperature, a CA-Markov model to simulate future land use change scenarios, and the Budyko framework to predict future runoff changes. The results show that: (1) Between 1974 and 2014, annual runoff (R) and annual precipitation (P) in the HRB decline not so significantly with a rate of 1.3673 mm/a and 1.2709 mm/a, while maximum temperature (Tmax) and minimum temperature (Tmin) and potential evapotranspiration (E0) show a non-significantly increasing trend with 0.0296 °C/a, 0.0204 °C/a and 1.3313 mm/a, respectively. Precipitation is considered as main contributor to the decline in Han River runoff, accounting for 54.1%. (2) In the HRB, overall precipitation and temperature are estimated to rise in the coming years, with all other hydrological variables. The comparison of precipitation rise under each scenario is as follows: SSP126 scenario > SSP585 scenario > SSP245 scenario. The comparison of the temperature increase under each scenario is as follows: SSP585 scenario > SSP245 scenario > SSP126 scenario. (3) In the HRB, farmland and grassland land will continue to decline in the future. The amount of forest acreage is projected to decline but not so significantly. (4) The future runoff of the HRB shows an increasing trend, and the future runoff varies in different scenarios and periods. Under the land use scenarios of maintaining LUCC1992-2014 and LUCC2040 and LUCC2060, the R change rates in 2015-2040 are 8.27-25.47% and -8.04-19.35%, respectively, and the R in 2040-2060 are 2.09-13.66% and 19.35-31.52%. At the same time, it is very likely to overestimate the future runoff of the HRB without considering the changes in the land use data of the underlying surface in the future.