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.

Reimplantation of DES for the treatment of DES ISR (same or different) is safe but associated with a high rate of recurrences at 1 year regardless of the initial DES type. Other treatment modalities for ISR of DES should be considered to further improve the overall TVR-MACE.

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Herpes simplex virus type 1 (HSV-1) is a prevalent human pathogen that infects over 3.72 billion individuals worldwide and can cause potentially blinding recurrent corneal herpetic disease. HSV-1 establishes latency within sensory neurons of trigeminal ganglia (TG) and TG-resident CD8+ T cells play a critical role in preventing its reactivation. The repertoire, phenotype and function of protective CD8+ T cells are unknown. Bolstering the apparent feeble numbers of CD8+ T cells in TG remains a challenge for immunotherapeutic strategies. In this study, a comprehensive panel of 467 HLA-A*0201-restricted CD8+ T cell epitopes were predicted from the entire HSV-1 genome. CD8+ T cell responses to these genome-wide epitopes were compared in HSV-1 seropositive symptomatic (SYMP) individuals (with a history of numerous episodes of recurrent herpetic disease) vs. asymptomatic (ASYMP) individuals (who are infected but never experienced any recurrent herpetic disease). Frequent polyfunctional HSV-specific effector memory IFN-γ+CD107a/b+CD44highCD62LlowCD8+ TEM cells were detected in ASYMP individuals and were mainly directed against three “ASYMP” epitopes. In contrast, SYMP individuals have more mono-functional central memory CD44highCD62LhighCD8+ TCM cells. Furthermore, therapeutic immunization with an innovative prime/pull vaccine, based on priming with multiple “ASYMP” epitopes (prime) and neurotropic TG delivery of the T-cell attracting chemokine CXCL-10 (pull), boosted the number and function of CD44highCD62LlowCD8+ TEM and tissue-resident CD103highCD8+ TRM cells in TG of latently infected HLA-A*0201 Tg mice and reduced recurrent ocular herpes following UV-B induced reactivation. These findings have profound implications in the development of T-cell-based immunotherapeutic strategies to treat blinding recurrent herpes infection and disease.

Herpes simplex virus 1 (HSV-1) glycoprotein B (gB)-specific CD8؉ T cells protect mice from herpes infection and disease. However, whether and which HSV-1 gB-specific CD8؉ T cells play a key role in the "natural" protection seen in HSV-1-seropositive healthy asymptomatic (ASYMP) individuals (who have never had clinical herpes disease) remain to be determined. In this study, we have dissected the phenotypes and the functions of HSV-1 gB-specific CD8 O ver a billion individuals worldwide carry herpes simplex virus 1 (HSV-1), which causes a wide range of mild to life-threatening diseases (1-3). Although the virus reactivates from latency and is shed multiple times each year in body fluids (i.e., tears, saliva, and nasal and vaginal secretions), most reactivations are subclinical due to an efficient immune-mediated containment of the infection and disease (4-7). Thus, most infected individuals are asymptomatic (ASYMP) and do not present any apparent recurrent herpetic disease (e.g., cold sores, genital, or ocular herpetic disease). However, a small proportion of individuals experience endless recurrences of herpetic disease, usually multiple times a year, often necessitating continuous antiviral therapy (i.e., with acyclovir and derivatives) (8,9). In those symptomatic (SYMP) individuals, HSV-1 frequently reactivates from latency, reinfects the eyes, and may trigger recurrent and severe corneal herpetic disease, a leading cause of infectious corneal blindness in

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Herpes simplex virus 1 (HSV-1) infection is widespread among humans. The HSV-1 virion protein 13/14 (VP13/14), also known as UL47, is a tegument antigen targeted by CD8 ϩ T cells from HSV-seropositive individuals. However, whether VP13/14-specific CD8 ϩ T cells play a role in the natural protection seen in asymptomatic (ASYMP) individuals (individuals who have never had a clinical herpetic disease) has not been elucidated. Using predictive computer-assisted algorithms, we identified 10 potential HLA-A*02:01-restricted CD8 ϩ T-cell epitopes from the 693-amino-acid sequence of the VP13/14 protein. Three out of 10 epitopes exhibited a high to moderate affinity of binding to soluble HLA-A*02:01 molecules. The phenotype and function of CD8 ϩ T cells specific for each epitope were compared in HLA-A*02:01-positive ASYMP individuals and symptomatic (SYMP) individuals (individuals who have frequent clinical herpetic diseases) using determination of a combination of tetramer frequency and the levels of granzyme B, granzyme K, perforin, gamma interferon, tumor necrosis factor alpha, and interleukin-2 production and CD107 a/b cytotoxic degranulation. High frequencies of multifunctional CD8 ϩ T cells directed against three epitopes, VP13/14 from amino acids 286 to 294 (VP13/14 286 -294 ), VP13/14 from amino acids 504 to 512 (VP13/14 504 -512 ), and VP13/14 from amino acids 544 to 552 (VP13/14 544 -552 ), were detected in ASYMP individuals, while only low frequencies were detected in SYMP individuals. The three epitopes also predominantly recalled more CD45RA low CD44 high CCR7 low CD62L low CD8 ϩ effector memory T cells (T EM cells) in ASYMP individuals than SYMP individuals. Moreover, immunization of HLA-A*02:01 transgenic mice with the three CD8 ϩ T EM -cell epitopes from ASYMP individuals induced robust and polyfunctional HSV-specific CD8 ϩ T EM cells associated with strong protective immunity against ocular herpesvirus infection and disease. Our findings outline the phenotypic and functional features of protective HSV-specific CD8 ϩ T cells that should guide the development of a safe and effective T-cell-based herpes simplex vaccine.IMPORTANCE Although most herpes simplex virus 1 (HSV-1)-infected individuals shed the virus in their body fluids following reactivation from latently infected sen-

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