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Objectives Calcium-binding motifs are shared by multiple bacteriophage lysins; however, the influence of calcium on the enzymatic activity and host range of these enzymes is still not understood. To address this, ClyF, a chimeric lysin with a putative calcium-binding motif, was used as a model for in vitro and in vivo investigations. Methods The concentration of calcium bound to ClyF was determined by atomic absorption spectrometry. The influence of calcium on the structure, activity and host range of ClyF was assessed by circular dichroism and time–kill assays. The bactericidal activity of ClyF was evaluated in various sera and a mouse model of Streptococcus agalactiae bacteraemia. Results ClyF has a highly negatively charged surface around the calcium-binding motif that can bind extra calcium, thereby increasing the avidity of ClyF for the negatively charged bacterial cell wall. In line with this, ClyF exhibited significantly enhanced staphylolytic and streptolytic activity in various sera containing physiological calcium, including human serum, heat-inactivated human serum, mouse serum and rabbit serum. In a mouse model of S. agalactiae bacteraemia, intraperitoneal administration of a single dose of 25 μg/mouse ClyF fully protected the mice from lethal infection. Conclusions The present data collectively showed that physiological calcium improves the bactericidal activity and host range of ClyF, making it a promising candidate for the treatment of infections caused by multiple staphylococci and streptococci.

So far COVID-19 has resulted in mass deaths and huge economic losses across the world. Various measures such as quarantine and social distancing have been taken to prevent the spread of this disease. These prevention measures have changed the transmission dynamics of COVID-19 and introduced new challenges for epidemic modelling and prediction. In this paper, we study a novel disease spreading model with two important aspects. First, the proposed model takes the quarantine effect of confirmed cases on transmission dynamics into account, which can better resemble the real-world scenario. Second, our model incorporates two types of human mobility, where the intra-region human mobility is related to the internal transmission speed of the disease in the focal area and the inter-region human mobility reflects the scale of external infectious sources to a focal area. With the proposed model, we use the human mobility data from 24 cities in China and 8 states in the USA to analyse the disease spreading patterns. The results show that our model could well fit/predict the reported cases in both countries. The predictions and findings shed light on how to effectively control COVID-19 by managing human mobility behaviours.

Background The past two decades have witnessed a surge in the use of cervical spine joint procedures including joint injections, nerve blocks and radiofrequency ablation to treat chronic neck pain, yet many aspects of the procedures remain controversial. Methods In August 2020, the American Society of Regional Anesthesia and Pain Medicine and the American Academy of Pain Medicine approved and charged the Cervical Joint Working Group to develop neck pain guidelines. Eighteen stakeholder societies were identified, and formal request-for-participation and member nomination letters were sent to those organizations. Participating entities selected panel members and an ad hoc steering committee selected preliminary questions, which were then revised by the full committee. Each question was assigned to a module composed of 4–5 members, who worked with the Subcommittee Lead and the Committee Chairs on preliminary versions, which were sent to the full committee after revisions. We used a modified Delphi method whereby the questions were sent to the committee en bloc and comments were returned in a non-blinded fashion to the Chairs, who incorporated the comments and sent out revised versions until consensus was reached. Before commencing, it was agreed that a recommendation would be noted with >50% agreement among committee members, but a consensus recommendation would require ≥75% agreement. Results Twenty questions were selected, with 100% consensus achieved in committee on 17 topics. Among participating organizations, 14 of 15 that voted approved or supported the guidelines en bloc, with 14 questions being approved with no dissensions or abstentions. Specific questions addressed included the value of clinical presentation and imaging in selecting patients for procedures, whether conservative treatment should be used before injections, whether imaging is necessary for blocks, diagnostic and prognostic value of medial branch blocks and intra-articular joint injections, the effects of sedation and injectate volume on validity, whether facet blocks have therapeutic value, what the ideal cut-off value is for designating a block as positive, how many blocks should be performed before radiofrequency ablation, the orientation of electrodes, whether larger lesions translate into higher success rates, whether stimulation should be used before radiofrequency ablation, how best to mitigate complication risks, if different standards should be applied to clinical practice and trials, and the indications for repeating radiofrequency ablation. Conclusions Cervical medial branch radiofrequency ablation may provide benefit to well-selected individuals, with medial branch blocks being more predictive than intra-articular injections. More stringent selection criteria are likely to improve denervation outcomes, but at the expense of false-negatives (ie, lower overall success rate). Clinical trials should be tailored based on objectives, and selection criteria for some may be more stringent than what is ideal in clinical practice.

BackgroundThe past two decades have witnessed a surge in the use of lumbar facet blocks and radiofrequency ablation (RFA) to treat low back pain (LBP), yet nearly all aspects of the procedures remain controversial.MethodsAfter approval by the Board of Directors of the American Society of Regional Anesthesia and Pain Medicine, letters were sent to a dozen pain societies, as well as representatives from the US Departments of Veterans Affairs and Defense. A steering committee was convened to select preliminary questions, which were revised by the full committee. Questions were assigned to 4–5 person modules, who worked with the Subcommittee Lead and Committee Chair on preliminary versions, which were sent to the full committee. We used a modified Delphi method, whereby the questions were sent to the committee en bloc and comments were returned in a non-blinded fashion to the Chair, who incorporated the comments and sent out revised versions until consensus was reached.Results17 questions were selected for guideline development, with 100% consensus achieved by committee members on all topics. All societies except for one approved every recommendation, with one society dissenting on two questions (number of blocks and cut-off for a positive block before RFA), but approving the document. Specific questions that were addressed included the value of history and physical examination in selecting patients for blocks, the value of imaging in patient selection, whether conservative treatment should be used before injections, whether imaging is necessary for block performance, the diagnostic and prognostic value of medial branch blocks (MBB) and intra-articular (IA) injections, the effects of sedation and injectate volume on validity, whether facet blocks have therapeutic value, what the ideal cut-off value is for a prognostic block, how many blocks should be performed before RFA, how electrodes should be oriented, the evidence for larger lesions, whether stimulation should be used before RFA, ways to mitigate complications, if different standards should be applied to clinical practice and clinical trials and the evidence for repeating RFA (see table 12 for summary).ConclusionsLumbar medial branch RFA may provide benefit to well-selected individuals, with MBB being more predictive than IA injections. More stringent selection criteria are likely to improve denervation outcomes, but at the expense of more false-negatives. Clinical trials should be tailored based on objectives, and selection criteria for some may be more stringent than what is ideal in clinical practice.

What We Already Know about This Topic What This Article Tells Us That Is New Background With facet interventions under scrutiny, the authors’ objectives were to determine the effectiveness of different lumbar facet blocks and their ability to predict radiofrequency ablation outcomes. Methods A total of 229 participants were randomized in a 2:2:1 ratio to receive intraarticular facet injections with bupivacaine and steroid, medial branch blocks, or saline. Those with a positive 1-month outcome (a 2-point or more reduction in average pain score) and score higher than 3 (positive satisfaction) on a 5-point satisfaction scale were followed up to 6 months. Participants in the intraarticular and medial branch block groups with a positive diagnostic block (50% or more relief) who experienced a negative outcome proceeded to the second phase and underwent radiofrequency ablation, while all saline group individuals underwent ablation. Coprimary outcome measures were average reduction in numerical rating scale pain score 1 month after the facet or saline blocks, and average numerical rating scale pain score 3 months after ablation. Results Mean reduction in average numerical rating scale pain score at 1 month was 0.7 ± 1.6 in the intraarticular group, 0.7 ± 1.8 in the medial branch block group, and 0.7 ± 1.5 in the placebo group; P = 0.993. The proportions of positive blocks were higher in the intraarticular (54%) and medial branch (55%) groups than in the placebo group (30%; P = 0.01). Radiofrequency ablation was performed on 135 patients (45, 48, and 42 patients from the intraarticular, medial branch, and saline groups, respectively). The average numerical rating scale pain score at 3 months was 3.0 ± 2.0 in the intraarticular, 3.2 ± 2.5 in the medial branch, and 3.5 ± 1.9 in the control group (P = 0.493). At 3 months, the proportions of positive responders in the intraarticular, medial branch block, and placebo groups were 51%, 56%, and 24% for the intraarticular, medial branch, and placebo groups, respectively (P = 0.005). Conclusions This study establishes that facet blocks are not therapeutic. The higher responder rates in the treatment groups suggest a hypothesis that facet blocks might provide prognostic value before radiofrequency ablation.

The visual characteristics of landslide susceptibility have not yet been fully explored. Professional or trained technicians have to take much time and effort to interpret remote sensing images and locate landslides accordingly. Although conventional machine learning methods based on hand-crafted features for landslide susceptibility prediction (LSP) have acquired remarkable performance, they have certain requirements for prior knowledge. Aiming to learn complex and inherent visual patterns of landslides through minimal manual intervention and achieve fine-grained prediction, in this paper, we define LSP as a semantic segmentation problem on optical remote sensing images. Six widely used semantic segmentation models including Fully Convolutional Network, U-Net, Pyramid Scene Parsing Network, Global Convolutional Network (GCN), DeepLab v3 and DeepLab v3+ are introduced and evaluated for LSP. As the lack of landslide datasets, an open labeled landslide dataset of remote sensing imagery is created for research. The results show that GCN and DeepLab v3 are more applicable for this problem scenario, and the best Mean Intersection-over-Union and Pixel Accuracy of models are 54.2% and 74.0% respectively, which could be further improved by more targeted network architectures. In conclusion, semantic segmentation methods are demonstrated to be effctive for predicting new potential landslides based on remote sensing images.

Occipital neuralgia (ON) is characterized by lancinating pain and tenderness overlying the occipital nerves. Both steroid injections and pulsed radiofrequency (PRF) are used to treat ON, but few clinical trials have evaluated efficacy, and no study has compared treatments. We performed a multicenter, randomized, double-blind, comparative-effectiveness study in 81 participants with ON or migraine with occipital nerve tenderness whose aim was to determine which treatment is superior. Forty-two participants were randomized to receive local anesthetic and saline, and three 120 second cycles of PRF per targeted nerve, and 39 were randomized to receive local anesthetic mixed with deposteroid and 3 rounds of sham PRF. Patients, treating physicians, and evaluators were blinded to interventions. The PRF group experienced a greater reduction in the primary outcome measure, average occipital pain at 6 weeks (mean change from baseline -2.743 ± 2.487 vs -1.377 ± 1.970; P < 0.001), than the steroid group, which persisted through the 6-month follow-up. Comparable benefits favoring PRF were obtained for worst occipital pain through 3 months (mean change from baseline -1.925 ± 3.204 vs -0.541 ± 2.644; P = 0.043), and average overall headache pain through 6 weeks (mean change from baseline -2.738 ± 2.753 vs -1.120 ± 2.1; P = 0.037). Adverse events were similar between groups, and few significant differences were noted for nonpain outcomes. We conclude that although PRF can provide greater pain relief for ON and migraine with occipital nerve tenderness than steroid injections, the superior analgesia may not be accompanied by comparable improvement on other outcome measures.

WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: With facet interventions under scrutiny, the authors' objectives were to determine the effectiveness of different lumbar facet blocks and their ability to predict radiofrequency ablation outcomes.A total of 229 participants were randomized in a 2:2:1 ratio to receive intraarticular facet injections with bupivacaine and steroid, medial branch blocks, or saline. Those with a positive 1-month outcome (a 2-point or more reduction in average pain score) and score higher than 3 (positive satisfaction) on a 5-point satisfaction scale were followed up to 6 months. Participants in the intraarticular and medial branch block groups with a positive diagnostic block (50% or more relief) who experienced a negative outcome proceeded to the second phase and underwent radiofrequency ablation, while all saline group individuals underwent ablation. Coprimary outcome measures were average reduction in numerical rating scale pain score 1 month after the facet or saline blocks, and average numerical rating scale pain score 3 months after ablation.Mean reduction in average numerical rating scale pain score at 1 month was 0.7 ± 1.6 in the intraarticular group, 0.7 ± 1.8 in the medial branch block group, and 0.7 ± 1.5 in the placebo group; P = 0.993. The proportions of positive blocks were higher in the intraarticular (54%) and medial branch (55%) groups than in the placebo group (30%; P = 0.01). Radiofrequency ablation was performed on 135 patients (45, 48, and 42 patients from the intraarticular, medial branch, and saline groups, respectively). The average numerical rating scale pain score at 3 months was 3.0 ± 2.0 in the intraarticular, 3.2 ± 2.5 in the medial branch, and 3.5 ± 1.9 in the control group (P = 0.493). At 3 months, the proportions of positive responders in the intraarticular, medial branch block, and placebo groups were 51%, 56%, and 24% for the intraarticular, medial branch, and placebo groups, respectively (P = 0.005).This study establishes that facet blocks are not therapeutic. The higher responder rates in the treatment groups suggest a hypothesis that facet blocks might provide prognostic value before radiofrequency ablation.

Background: Cervical radicular pain is a major cause of disability. No studies have been published comparing different types of nonsurgical therapy. Methods: A comparative-effectiveness study was performed in 169 patients with cervical radicular pain less than 4 yr in duration. Participants received nortriptyline and/or gabapentin plus physical therapies, up to three cervical epidural steroid injections (ESI) or combination treatment over 6 months. The primary outcome measure was average arm pain on a 0 to 10 scale at 1 month. Results: One-month arm pain scores were 3.5 (95% CI, 2.8 to 4.2) in the combination group, 4.2 (CI, 2.8 to 4.2) in ESI patients, and 4.3 (CI, 2.8 to 4.2) in individuals treated conservatively (P = 0.26). Combination group patients experienced a mean reduction of −3.1 (95% CI, −3.8 to −2.3) in average arm pain at 1 month versus −1.8 (CI, −2.5 to −1.2) in the conservative group and −2.0 (CI, −2.7 to −1.3) in ESI patients (P = 0.035). For neck pain, a mean reduction of −2.2 (95% CI, −3.0 to −1.5) was noted in combination patients versus −1.2 (CI, −1.9 to −0.5) in conservative group patients and −1.1 (CI, −1.8 to −0.4) in those who received ESI; P = 0.064). Three-month posttreatment, 56.9% of patients treated with combination therapy experienced a positive outcome versus 26.8% in the conservative group and 36.7% in ESI patients (P = 0.006). Conclusions: For the primary outcome measure, no significant differences were found between treatments, although combination therapy provided better improvement than stand-alone treatment on some measures. Whereas these results suggest an interdisciplinary approach to neck pain may improve outcomes, confirmatory studies are needed.

Cancer pain is a distressing result of disease, both primary and metastatic, as well as complications caused by cancer treatment. Medication management often is insufficient to adequately treat the ensuing pain or the complications of medical management limit acceptable dosage for pain control. In these instances, interventional modalities are an additional tool in the pain physician's armamentarium. Most commonly employed are intrathecal opioids, local anesthetic and clonidine infusions, neurolytic-nerve and sympathetic-ganglion blockade, and radiofrequency techniques. These are discussed in this article concomitantly with current outcome data as reported in the medical literature.

Objective To evaluate whether an epidural steroid injection or gabapentin is a better treatment for lumbosacral radiculopathy. Design A multicenter randomized study conducted between 2011 and 2014. Computer generated randomization was stratified by site. Patients and evaluating physicians were blinded to treatment outcomes. Settings Eight military, Veterans Administration, and civilian hospitals. Participants 145 people with lumbosacral radicular pain secondary to herniated disc or spinal stenosis for less than four years in duration and in whom leg pain is as severe or more severe than back pain. Interventions Participants received either epidural steroid injection plus placebo pills or sham injection plus gabapentin. Main outcome measures Average leg pain one and three months after the injection on a 0-10 numerical rating scale. A positive outcome was defined as a ≥2 point decrease in leg pain coupled with a positive global perceived effect. All patients had one month follow-up visits; patients whose condition improved remained blinded for their three month visit. Results There were no significant differences for the primary outcome measure at one month (mean pain score 3.3 (SD 2.6) and mean change from baseline −2.2 (SD 2.4) in epidural steroid injection group versus 3.7 (SD 2.6) and −1.7 (SD 2.6) in gabapentin group; adjusted difference 0.4, 95% confidence interval −0.3 to 1.2; P=0.25) and three months (mean pain score 3.4 (SD 2.7) and mean change from baseline −2.0 (SD 2.6) versus 3.7 (SD 2.8) and −1.6 (SD 2.7), respectively; adjusted difference 0.3, −0.5 to 1.2; P=0.43). Among secondary outcomes, one month after treatment those who received epidural steroid injection had greater reductions in worst leg pain (−3.0, SD 2.8) than those treated with gabapentin (−2.0, SD 2.9; P=0.04) and were more likely to experience a positive successful outcome (66% v 46%; number needed to treat=5.0, 95% confidence interval 2.8 to 27.0; P=0.02). At three months, there were no significant differences between treatments. Conclusions Although epidural steroid injection might provide greater benefit than gabapentin for some outcome measures, the differences are modest and are transient for most people. Trial registration ClinicalTrials.gov Identifier: NCT01495923.

Background:Cervical radicular pain is a major cause of disability. No studies have been published comparing different types of nonsurgical therapy.Methods:A comparative-effectiveness study was performed in 169 patients with cervical radicular pain less than 4 yr in duration. Participants received no

A number of studies have demonstrated the ability of retinoic acid (RA) to inhibit the growth of estrogen receptor-positive (ER+) human breast cancer cell lines. The precise mechanism of growth inhibition is not known. However, the biological effects of RA in other model systems have been shown to be mediated via the nuclear retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). While several laboratories have examined the expression of RARs in various breast cancer cell lines, no information is available concerning the role of the RXRs and 9-cis-RA, the natural ligand of RXRs, in the response of breast cancer cells to RA. Using a representative panel of breast cancer cell lines, we determined the effect of 9-cis-RA on growth and cell cycle stage distribution, analyzed steady-state mRNA levels of RXR-alpha, -beta, and -gamma, and determined the effect of all-trans-RA and 9-cis-RA on RXR expression. Our results show that: (1) the growth of ER+/RA-sensitive breast cancer cells is inhibited by treatment with 9-cis-RA by blocking entry into S phase; (2) both ER+/RA-sensitive and ER-/RA-resistant breast cancer cell lines express RXR-alpha and RXR-beta mRNAs but not RXR-gamma; however, levels of these transcripts did not correlate with the RA response; and (3) levels of RXR-alpha and RXR-beta mRNA were not significantly altered following treatment with either all-trans-RA or 9-cis-RA. These results suggest that the mechanism responsible for the retinoid sensitivity of breast cancer cells does not involve transcriptional modulation of the RXRs by RA.

Pain, an experience that is both sensory and emotional, profoundly affects an individual’s physiological and psychological being. It should be managed in the context of the whole person. Interventional pain management is best practiced as an aspect of a multidisciplinary approach for pain relief. This chapter will provide an overview of the common peripheral nerve, neuraxial and sympathetic blocks, trigger point injection, and intrathecal therapy for chronic pain from diseases across the life course. Discussions will also provide sufficient details on how the procedures are performed, their efficacy and complications.

N-(4-Hydroxyphenyl)-retinamide (4-HPR ; Fenretinide) is a synthetic retinoid which is undergoing investigation as a cancer chemopreventive agent. However, 4-HPR alters vitamin A kinetics and reduces the concentration of plasma retinol. We have conducted studies to examine the effects of 4-HPR on the activity of the enzyme lecithin :retinol acyltransferase (LRAT). This enzyme is implicated in the absorption and storage of vitamin A and is regulated, in liver, by vitamin A nutritional status. To determine whether 4-HPR, like retinoic acid, is able to induce liver LRAT activity, vitamin A-deficient rats having negligible liver LRAT activity were treated with single doses of 4-HPR (0.02-2.5 mg) and liver homogenates were assayed for LRAT activity using 3 H-retinol bound to the cellular-retinol binding protein, CRBP, as substrate. Treatment with 4-HPR resulted in a dose- and time-dependent increase in liver LRAT activity which reached a maximum at 24 h. The activity of LRAT assayed in vitro and of hepatic 3 H-retinyl ester content determined after an in vivo pulse of 3 H-retinol were highly correlated (r = 0.802, P < 0.0002). When vitamin A-sufficient rats were fed a 4-HPR-supplemented diet for 30 d, LRAT activity differed significantly from control values in the liver (P < 0.0001) but not the small intestines. Changes in hepatic retinol metabolism which favor the esterification of vitamin A may be related to the mechanism by which 4-HPR alters vitamin A kinetics in vivo.

Previously we reported that vitamin A-deficient rats have a low number of natural killer (NK) cells in their blood and spleen. The current studies were designed to address whether other cells of the immune system are also affected and whether dietary retinoic acid is able to reverse the changes caused by a deficiency of retinol and its metabolites. Total white blood cells, differential counts and spleen cell numbers were compared in vitamin A-sufficient rats (controls) and rats deficient in vitamin A, and lymphocyte and NK cell populations were identified and enumerated by flow cytometry. In comparison with control rats, the blood of deficient rats had three times the number of granulocytes, and fewer B lymphocytes (73% of control) and NK cells (38% of control). The numbers of splenic B cells (OX12+), CD5+ (OX19+) and CD4+ (W3/25+) T lymphocytes and NK cells (NKR-P1+) were also significantly reduced. When vitamin A-deficient rats were fed a retinoic acid supplement (4.2 mg all-trans retinoic acid/kg diet) for 28 d, the numbers of blood granulocytes and NK cells equaled those of control rats and NK cell cytotoxicity was significantly elevated. Blood lymphocyte number was increased 40% due to increases of B cells and T cells of the CD5+, CD4+ and CD8+ subsets. These data indicate that vitamin A deficiency affects a number of cells of the immune system and that repletion with retinoic acid effectively reestablishes the number of circulating lymphocytes. In addition, retinoic acid may stimulate NK cell function.