A phase 2 multicenter trial of ruxolitinib to treat bronchiolitis obliterans syndrome after allogeneic HCT.

Bronchiolitis obliterans syndrome (BOS) occurring after allogeneic hematopoietic cell transplantation (HCT) is a high-risk manifestation of chronic graft-versus-host disease. In this prospective, multicenter phase 2 trial (ClinicalTrials.gov, NCT03674047), adult participants with BOS were treated with ruxolitinib 10mg twice daily, continuously in 28-day cycles for up to 12 cycles. Participants enrolled into newly diagnosed (<6 months since BOS diagnosis, cohort A) or established (≥6 months since BOS diagnosis, cohort B) disease cohorts, respectively. The primary objective was to evaluate the early treatment effect of ruxolitinib, assessed by the change in forced expiratory volume in 1 second (FEV1) at 3 months compared to enrollment. The primary endpoint differed according to cohort (Cohort A: improvement, defined as ³10% increase in FEV1; Cohort B: stabilization, defined as absence of ³10% decrease in FEV1). Between 2019 and 2022, 49 participants meeting criteria for BOS were enrolled and treated (cohort A, n=36; cohort B, n=13). The primary endpoint was achieved by 27.8% of participants with new BOS and 92.3% of participants with established BOS. According to the 2014 NIH Consensus Criteria, the best lung-specific overall response rate on ruxoltinib for the 49 participants was 34.7% (16.3% complete response, 18.4% partial response), with most responses occurring in mild or moderate disease. Non-infectious severe (grade ≥3) treatment-emergent adverse events were infrequent. Nine severe infectious events occurred and were largely respiratory in nature. These results support the use of ruxolitinib in the management of BOS after allogeneic HCT.

Movement-evoked Pain versus Pain at Rest in Postsurgical Clinical Trials and in Meta-analyses: An Updated Systematic Review.

BACKGROUND: Given the widespread recognition that postsurgical movement-evoked pain is generally more intense, and more functionally relevant, than pain at rest, the authors conducted an update to a previous 2011 review to re-evaluate the assessment of pain at rest and movement-evoked pain in more recent postsurgical analgesic clinical trials. METHODS: The authors searched MEDLINE and Embase for postsurgical pain randomized controlled trials and meta-analyses published between 2014 and 2023 in the setting of thoracotomy, knee arthroplasty, and hysterectomy using methods consistent with the original 2011 review. Included trials and meta-analyses were characterized according to whether they acknowledged the distinction between pain at rest and movement-evoked pain and whether they included pain at rest and/or movement-evoked pain as a pain outcome. For trials measuring movement-evoked pain, pain-evoking maneuvers used to assess movement-evoked pain were tabulated. RESULTS: Among the 944 included trials, 504 (53%) did not measure movement-evoked pain (vs. 61% in 2011), and 428 (45%) did not distinguish between pain at rest and movement-evoked pain when defining the pain outcome (vs. 52% in 2011). Among the 439 trials that measured movement-evoked pain, selection of pain-evoking maneuver was highly variable and, notably, was not even described in 139 (32%) trials (vs. 38% in 2011). Among the 186 included meta-analyses, 94 (51%) did not distinguish between pain at rest and movement-evoked pain (vs. 71% in 2011). CONCLUSIONS: This updated review demonstrates a persistent limited proportion of trials including movement-evoked pain as a pain outcome, a substantial proportion of trials failing to distinguish between pain at rest and movement-evoked pain, and a lack of consistency in the use of pain-evoking maneuvers for movement-evoked pain assessment. Future postsurgical trials need to (1) use common terminology surrounding pain at rest and movement-evoked pain, (2) assess movement-evoked pain in virtually every trial if not contraindicated, and (3) standardize movement-evoked pain assessment with common, procedure-specific pain-evoking maneuvers. More widespread knowledge translation and mobilization are required in order to disseminate this message to current and future investigators.

A Perfect Storm.

Our authors, who direct the Addiction Institute for the Mount Sinai Health System in New York City, address the substance-abuse avalanche brought on by the Covid-19 pandemic.

Cost of human papillomavirus vaccine delivery at district and health facility levels in Zimbabwe: A school-based vaccination program targeting multiple cohorts.

BACKGROUND: After a pilot project in 2014-15 Zimbabwe introduced the human papillomavirus (HPV) vaccine nationally in 2018 for girls aged 10-14 years through a primarily school-based vaccination campaign with two doses administered at 12-month intervals. In 2019, a first dose was delivered to a new cohort of girls in grade 5 of girls age 10 years if out-of-school (OOS), along with a second dose to the 2018 multiple cohorts. Additional effort was made to identify and mobilize OOS girls by Village Health Workers (VHWs) in the community. Zimbabwe reported 1,569,905 doses of HPV vaccine administered during the 2018 and 2019 campaigns. This analysis evaluated the cost of Zimbabwe's national HPV vaccine introduction. METHODS: A retrospective, incremental, ingredients-based cost analysis from the provider perspective was conducted in 2018 and 2019. Financial and economic cost data were collected at district and health facility levels using a two-stage cluster sampling approach and four cost dimensions: program activity, resource input, payer, and administrative level. Costs are presented in 2020 US$ in total and per dose. RESULTS: The total weighted costs for combined district and health facility administrative levels were US$ 828,731 (financial) and US$ 2,060,943 (economic). For service delivery, the total weighted cost per dose was US$ 0.16 (financial) and US$ 0.59 (economic). The program activities with the largest share of total weighted financial cost were training (37% of total) and service delivery (30%), while the largest shares of total weighted economic costs were service delivery (45%) and training (19%). Efforts by VHWs to reach OOS girls resulted in an additional US$ 2.99 in financial cost per dose and US$ 7.79 in economic cost per dose. CONCLUSION: The service delivery cost per dose was lower than that documented in the pilot program cost analysis in Zimbabwe and studies elsewhere, reflecting a campaign delivery approach that spread fixed costs over a large vaccination cohort. The additional cost of reaching OOS girls with the HPV vaccine was documented for the first time in low- and middle-income countries, which may provide information on potential costs for other countries.

National introduction of HPV vaccination in Senegal-Successes, challenges, and lessons learned.

Following successful school-based demonstration programs in 2014-2016, the human papillomavirus (HPV) vaccine was introduced nationwide in Senegal for 9-year-old girls in 2018, using a routine service delivery strategy at health facilities, schools, and other outreach sites. We reviewed the HPV vaccine introduction in Senegal to understand the successes, challenges, and lessons learned. Focusing on three key domains (program decision-making, planning, and implementation), we conducted ten semi-structured interviews during 2019-2020 with purposively selected national-level stakeholders (government, expert advisory committee, key technical and implementation partners) and comprehensive desk reviews of country documents on HPV vaccine introduction. Due to the global HPV vaccine shortage, the introduction was limited to a single-age cohort; therefore, 9-year-old girls were chosen. This strategy enabled Senegal to potentially reach more girls in primary education because school enrolment rates decline thereafter. Vaccination through routine delivery platforms (i.e., health facility, school-based, and community outreach) was perceived to be more cost-effective than a campaign approach. High-level political commitment and collaborations between immunization and education partners were frequently cited by key informants as reasons for a successful vaccine introduction. All key informants reported that the health care worker (HCW) strike, rumors, and vaccine hesitancy negatively impacted the introduction. Other challenges noted included insufficient information on attitudes towards HPV vaccination among HCWs, teachers, and community members. Senegal successfully introduced HPV vaccine into the national immunization schedule, using a routine delivery strategy. Strong leadership and a multi-sectoral approach likely contributed to this success. To build sustainability of the HPV vaccination program in the future, it is important to improve the understanding and engagement among all stakeholders, including HCWs and community members, and to strengthen and innovate communication and crisis management strategies. To better understand the efficiency and effectiveness of Senegal's vaccination strategy, additional assessments of the operational costs and coverage achieved are needed.

Feasibility and acceptability of nationwide HPV vaccine introduction in Senegal: Findings from community-level cross-sectional surveys, 2020.

In Senegal, cervical cancer is the most common cancer among women and the leading cause of morbidity and mortality from all cancers. In 2018, Senegal launched a national human papillomavirus (HPV) vaccination program with Gavi, the Vaccine Alliance (Gavi), support. HPV vaccination was incorporated into the national immunization program as a two-dose schedule, with a 6-12-month interval, to nine-year-old girls via routine immunization (RI) services at health facilities, schools and community outreach services throughout the year. During February to March 2020, we conducted interviews to assess the awareness, feasibility, and acceptability of the HPV vaccination program with a cross-sectional convenience sample of healthcare workers (HCWs), school personnel, community healthcare workers (cHCWs), parents, and community leaders from 77 rural and urban health facility catchment areas. Participants were asked questions on HPV vaccine knowledge, delivery, training, and community acceptability of the program. We conducted a descriptive analysis stratified by respondent type. Data were collected from 465 individuals: 77 HCW, 78 school personnel, 78 cHCWs, 152 parents, and community leaders. The majority of HCWs (83.1%) and cHCWs (74.4%) and school personnel (57.7%) attended a training on HPV vaccine before program launch. Of all respondents, most (52.5-87.2%) were able to correctly identify the target population. The majority of respondents (60.2-77.5%) felt that the vaccine was very accepted or accepted in the community. Senegal's HPV vaccine introduction program, among the first national programs in the African region, was accepted by community stakeholders. Training rates were high, and most respondents identified the target population correctly. However, continued technical support is needed for the integration of HPV vaccination as a RI activity for this non-traditional age group. The Senegal experience can be a useful resource for countries planning to introduce the HPV vaccine.

Cost of human papillomavirus vaccine delivery in a single-age cohort, routine-based vaccination program in Senegal.

INTRODUCTION: In 2018, Senegal introduced human papillomavirus (HPV) vaccine into its routine immunization program for all nine-year-old girls nationwide. We evaluated the costs of Senegal's introduction of HPV vaccine via this delivery approach. METHODS: We conducted a retrospective, incremental, ingredients-based cost evaluation from the provider perspective. The study timeframe included Senegal's first planning meeting in 2018 through data collection in early 2020. We collected costs from all involved units at the national and regional levels. A multi-stage cluster sampling approach was used to obtain a nationally representative sample of districts and health facilities. Weights were applied to costs from sampled units to estimate costs across all units. The cost evaluation was based on four dimensions: program activity, resource input, payer, and administrative level. Total costs were divided by the number of HPV doses administered to determine cost per dose and per dimension. RESULTS: Excluding vaccine program activity costs, the total financial and economic delivery costs of Senegal's HPV vaccination program were US$ 1,152,351 and US$ 2,838,466, respectively (US$ 3.07 and US$ 7.56 per dose, respectively). A total of 375,608 HPV vaccine doses were administered during the cost evaluation. Training and per diem represented the largest shares of financial costs. Service delivery and personnel time accounted for the largest shares of economic costs. By administrative level, district and health facility levels had the largest shares of financial and economic costs, respectively. Senegal's Ministry of Health accounted for the largest share of financial and economic costs. Including vaccine program activity costs (US$ 4.68/per dose), the total financial cost was US$ 2,911,343 (US$ 7.75 per dose). CONCLUSION: This cost evaluation can support Senegal's future vaccine introductions and inform other countries planning to introduce HPV vaccine nationwide. These findings support previous costing studies which anticipated potential economies of scale during the transition from HPV vaccine pilot demonstration projects to national introduction.

Multiple cohort HPV vaccination in Zimbabwe: 2018-2019 program feasibility, awareness, and acceptability among health, education, and community stakeholders.

INTRODUCTION: Zimbabwe introduced human papillomavirus (HPV) vaccine nationally in May 2018, targeting multiple cohorts (girls aged 10-14 years) through a school-based vaccination campaign. One year later, the second dose was administered to the multiple cohorts concurrently with the first dose given to a new single cohort of girls in grade 5. We conducted cross-sectional surveys among health workers, school personnel, and community members to assess feasibility of implementation, training, social mobilization, and community acceptability. METHODS: Thirty districts were selected proportional to the volume of the HPV vaccine doses delivered in 2018; two health facilities were randomly selected within each district. One health worker, school health coordinator, village health worker, and community leader were surveyed at each selected health facility and surrounding area during January-February 2020, using standard questionnaires. Descriptive analysis was completed across groups. RESULTS: There were 221 interviews completed. Over 60% of health workers reported having enough staff to carry out vaccination sessions in schools while maintaining routine vaccination services in health facilities. All school health coordinators felt the HPV vaccine should be delivered in schools in the future. Knowledge of the correct target cohort eligibility decreased from 91% in 2018 to 50% in 2020 among health workers. Understanding of HPV infection and use of HPV vaccine for cervical cancer prevention was above 90% for all respondents. Forty-two percent of respondents reported hearing rumors about the HPV vaccine, primarily regarding infertility and safety. CONCLUSIONS: Findings demonstrate the presence of highly knowledgeable staff at health facilities and schools, strong community acceptance, and a school-based HPV program considered feasible to implement in Zimbabwe. However, misunderstandings regarding target eligibility and rumors persist, which can impact vaccine uptake and coverage. Continued social mobilization efforts to maintain community demand and training on eligibility were recommended. Integration, partnerships, and resource mobilization are also needed to ensure program sustainability.

Single-Session Thrombolysis-Free Treatment of Deep Vein Thrombosis With a Novel Mechanical Thrombectomy Device.

Catheter-directed thrombolysis of iliofemoral deep vein thrombosis (DVT) carries an increased risk of major bleeding and may fail to rapidly remove thrombus or prevent post-thrombotic syndrome. We describe an alternative, thrombolysis-free, advanced DVT treatment strategy with rapid single-session percutaneous mechanical thrombectomy using the ClotTriever system. (Level of Difficulty: Intermediate.).

AAAPT Diagnostic Criteria for Acute Thoracic Surgery Pain.

Patients undergoing thoracic surgery experience particular challenges for acute pain management. Availability of standardized diagnostic criteria for identification of acute pain after thoracotomy and video assisted thoracic surgery (VATS) would provide a foundation for evidence-based management and facilitate future research. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the United States Food and Drug Administration, the American Pain Society (APS), and the American Academy of Pain Medicine (AAPM) formed the ACTTION-APS-AAPM Pain Taxonomy (AAAPT) initiative to address absence of acute pain diagnostic criteria. A multidisciplinary working group of pain experts was invited to develop diagnostic criteria for acute thoracotomy and VATS pain. The working group used available studies and expert opinion to characterize acute pain after thoracotomy and VATS using the 5-dimension taxonomical structure proposed by AAAPT (i.e., core diagnostic criteria, common features, modulating factors, impact/functional consequences, and putative mechanisms). The resulting diagnostic criteria will serve as the starting point for subsequent empirically validated criteria. PERSPECTIVE ITEM: This article characterizes acute pain after thoracotomy and VATS using the 5-dimension taxonomical structure proposed by AAAPT (ie, core diagnostic criteria, common features, modulating factors, impact and/or functional consequences, and putative mechanisms).

Addiction Medicine Training Fellowships in North America: A Recent Assessment of Progress and Needs.

OBJECTIVES: Although unhealthy substance use and addiction contribute to 1 in 4 deaths and are estimated to cost the US more than $740 billion annually, fewer than 12 hours of physician education over the 7 years of medical school and primary residency training specifically address alcohol and other drug-related issues. Addiction Medicine was formally recognized as a medical subspecialty in 2016 to address the need for physicians trained in prevention, treatment, and management of substance use. This study examines the characteristics of the Addiction Medicine fellowships in operation during this critical period in the subspecialty's development to identify needs and potential. METHODS: This study is a cross-sectional survey of Addiction Medicine Fellowship Directors from 46 fellowships accredited as of 2017 (43 in the United States and 3 in Canada). The response rate was 100%. RESULTS: Directors estimated significant growth in available fellowship slots between 2016 to 2017 and 2017 to 2018 (F = 49.584, P < .001). The majority of Directors reported that demand for their graduates was high (79.5%). Fellow training in screening, brief intervention, and referral to treatment spanned many substances and age groups, although fewer programs focused on nicotine and on adolescent populations. Notably, most directors reported that graduates completed waiver training to prescribe buprenorphine-naloxone (77.5%) and gained clinical experience in an opioid treatment setting (89.1%). Funding was the #1 need among 56.8% of Directors. CONCLUSIONS: Despite significant growth in Addiction Medicine fellowships over the past 6 years, meeting future workforce demands for Addiction Medicine specialists depends on access to funding to support fellowships.

Movement-Evoked Pain Versus Pain at Rest in Postsurgical Clinical Trials and Meta-Analyses: Protocol for a Follow-Up Systematic Review.

BACKGROUND: Postoperative pain is one of the most prevalent and disabling complications of surgery that is associated with personal suffering, delayed functional recovery, prolonged hospital stay, perioperative complications, and chronic postsurgical pain. Accumulating evidence has pointed to the important distinction between pain at rest (PAR) and movement-evoked pain (MEP) after surgery. In most studies including both measures, MEP has been shown to be substantially more severe than PAR. Furthermore, as MEP is commonly experienced during normal activities (eg, breathing, coughing, and walking), it has a greater adverse functional impact than PAR. In a previous systematic review conducted in 2011, only 39% of reviewed trials included MEP as a trial outcome and 52% failed to identify the pain outcome as either PAR or MEP. Given the recent observations of postsurgical pain trials that continue to neglect the distinction between PAR and MEP, this updated review seeks to evaluate the degree of progress in this area. OBJECTIVE: This updated review will include postsurgical clinical trials and meta-analyses in which the primary outcome was early postoperative pain intensity. The primary outcome for this review is the reporting of MEP (vs PAR) as an outcome measure for each trial and meta-analysis. Secondary outcomes include whether trials and meta-analyses distinguished between PAR and MEP. METHODS: To be consistent with the 2011 review that we are updating, this review will again focus on randomized controlled trials and meta-analyses, from Medical Literature Analysis and Retrieval System Online and EMBASE databases, focusing on pain treatment after thoracotomy, knee arthroplasty, and hysterectomy in humans. Trials and meta-analyses will be characterized as to whether or not they assessed PAR and MEP; whether their pain outcome acknowledged the distinction between PAR and MEP; and, for trials assessing MEP, which pain-evoking maneuver(s) were used. RESULTS: Scoping review and pilot data extraction are under way, and the results are expected by March 2020. CONCLUSIONS: It is our belief that every postsurgical analgesic trial should include MEP as an outcome measure. The previous 2011 review was expected to have an impact on more widespread assessment of MEP in subsequent postoperative pain treatment trials. Thus, the purpose of this follow-up review is to reevaluate the frequency of use of MEP as a trial outcome, compared with PAR, in more recently published postoperative pain trials. TRIAL REGISTRATION: PROSPERO CRD42019125855; https://tinyurl.com/qw9dty8. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/15309.

Preoperative Patient Expectations of Postoperative Pain Are Associated with Moderate to Severe Acute Pain After VATS.

OBJECTIVE: The goal of this post hoc analysis of subjects from a prospective observational study was to identify the predictors of patients developing moderate to severe acute pain (mean numerical rating scale [NRS] ≥4, 0-10) during the first three days after video-assisted thoracoscopic surgery (VATS) from a comprehensive evaluation of demographic, psychosocial, and surgical factors. METHODS: Results from 82 patients who were enrolled one week before VATS and evaluated during the first three postoperative days are presented. The primary outcome variable of the current study was the presence of moderate to severe acute pain after VATS. RESULTS: Fifty-nine percent (95% confidence interval, 47-69%) of study subjects developed moderate to severe acute pain after VATS. Factors univariately associated with the presence of moderate to severe acute pain were greater average expected postoperative pain, greater pain to a suprathreshold cold stimulus, and longer durations of surgery and hospital stay (P < 0.05). When considered in the multiple logistic regression models, the patients' preoperative average intensity of expected postoperative pain (NRS, 0-10) was the only measure associated with the moderate to severe acute pain. Average intensity of postoperative pain expected by patients when questioned preoperatively mediated the effect of reported intensity of pain to the suprathreshold cold stimulus for moderate to severe acute pain levels. Preoperative patient expectations had greater predictive value than other assessed variables including psychosocial factors such as catastrophizing or anxiety assessed one week before surgery. CONCLUSIONS: None of the preoperative psychosocial measures were associated with the moderate to severe acute pain after VATS. Average expected postoperative pain was the only measure associated with the development of moderate to severe acute pain after VATS.

Deep Tissue Incision Enhances Spinal Dorsal Horn Neuron Activity During Static Isometric Muscle Contraction in Rats.

Translational correlates to pain with activities after deep tissue injury have been rarely studied. We hypothesized that deep tissue incision causes greater activation of nociception-transmitting neurons evoked by muscle contraction. In vivo neuronal activity was recorded in 203 dorsal horn neurons (DHNs) from 97 rats after sham, skin-only, or skin + deep muscle incision. We evaluated DHN responses to static, isometric muscle contractions induced by direct electrical stimulation of the muscle. The effect of pancuronium on DHN response to contractions was also examined. Approximately 50% of DHNs with receptive fields in the hindpaw were excited during muscle contraction. One-second .5- and 1.0-g muscle contractions produced greater DHN activity after skin + deep muscle incision (median [interquartile range], 32 [5-39] impulses, P = .021; and 36 [26-46] impulses, P = .006, respectively) than after sham (6 [0-21] and 15 [8-32] impulses, respectively). Neuromuscular blockade with pancuronium inhibited the muscle contractions and DHN activation during electrical stimulation, demonstrating contraction-induced activation. The greater response of spinal DHNs to static muscle contraction after skin + deep muscle incision may model and inform mechanisms of dynamic pain after surgery. PERSPECTIVE: Completion of various activities is an important milestone for recovery and hospital discharge after surgery. Skin + deep muscle incision caused greater activation of nociception-transmitting DHNs evoked by muscle contraction compared with skin-only incision. This result suggests an important contribution of deep muscle injury to activity-evoked hyperalgesia after surgery.

Analytical Validation of a Hybrid Capture-Based Next-Generation Sequencing Clinical Assay for Genomic Profiling of Cell-Free Circulating Tumor DNA.

Genomic profiling of circulating tumor DNA derived from cell-free DNA (cfDNA) in blood can provide a noninvasive method for detecting genomic biomarkers to guide clinical decision making for cancer patients. We developed a hybrid capture-based next-generation sequencing assay for genomic profiling of circulating tumor DNA from blood (FoundationACT). High-sequencing coverage and molecular barcode-based error detection enabled accurate detection of genomic alterations, including short variants (base substitutions, short insertions/deletions) and genomic re-arrangements at low allele frequencies (AFs), and copy number amplifications. Analytical validation was performed on 2666 reference alterations. The assay achieved >99% overall sensitivity (95% CI, 99.1%-99.4%) for short variants at AF >0.5%, >95% sensitivity (95% CI, 94.2%-95.7%) for AF 0.25% to 0.5%, and 70% sensitivity (95% CI, 68.2%-71.5%) for AF 0.125% to 0.25%. No false positives were detected in 62 samples from healthy volunteers. Genomic alterations detected by FoundationACT demonstrated high concordance with orthogonal assays run on the same clinical cfDNA samples. In 860 routine clinical FoundationACT cases, genomic alterations were detected in cfDNA at comparable frequencies to tissue; for the subset of cases with temporally matched tissue and blood samples, 75% of genomic alterations and 83% of short variant mutations detected in tissue were also detected in cfDNA. On the basis of analytical validation results, FoundationACT has been approved for use in our Clinical Laboratory Improvement Amendments-certified/College of American Pathologists-accredited/New York State-approved laboratory.

Effect of Thoracic Epidural Anesthesia in a Rat Model of Phrenic Motor Inhibition after Upper Abdominal Surgery.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: One important example of impaired motor function after surgery is diaphragmatic dysfunction after upper abdominal surgery. In this study, the authors directly recorded efferent phrenic nerve activity and determined the effect of the upper abdominal incision. The authors hypothesized that phrenic motor output would be decreased after the upper abdominal incision; it was also hypothesized that blocking sensory input from the incision using thoracic epidural anesthesia would diminish this incision-induced change in phrenic motor activity. METHODS: Efferent phrenic activity was recorded 1 h to 10 days after upper abdominal incision in urethane-anesthetized rats. Ventilatory parameters were measured in unanesthetized rats using whole-body plethysmography at multiple time points after incision. The authors then determined the effect of thoracic epidural anesthesia on phrenic nerve activity and ventilatory parameters after incision. RESULTS: Phrenic motor output remained reduced by approximately 40% 1 h and 1 day after incision, but was not different from the sham group by postoperative day 10. One day after incision (n = 9), compared to sham-operated animals (n = 7), there was a significant decrease in spike frequency area-under-the-curve (median [interquartile range]: 54.0 [48.7 to 84.4] vs. 97.8 [88.7 to 130.3]; P = 0.0184), central respiratory rate (0.71 [0.63 to 0.79] vs. 0.86 [0.82 to 0.93]/s; P = 0.0460), and inspiratory-to-expiratory duration ratio (0.46 [0.44 to 0.55] vs. 0.78 [0.72 to 0.93]; P = 0.0023). Unlike humans, a decrease, not an increase, in breathing frequency has been observed after the abdominal incision in whole-body plethysmography. Thoracic epidural anesthesia attenuated the incision-induced changes in phrenic motor output and ventilatory parameters. CONCLUSIONS: Upper abdominal incision decreased phrenic motor output and ventilatory parameters, and this incision-induced impairment was attenuated by thoracic epidural anesthesia. The authors' results provide direct evidence that afferent inputs from the upper abdominal incision induce reflex inhibition of phrenic motor activity.

Ovine model of neuropathic pain for assessing mechanisms of spinal cord stimulation therapy via dorsal horn recordings, von Frey filaments, and gait analysis.

BACKGROUND: It is becoming increasingly important to understand the mechanisms of spinal cord stimulation (SCS) in alleviating neuropathic pain as novel stimulation paradigms arise. PURPOSE: Additionally, the small anatomic scale of current SCS animal models is a barrier to more translational research. METHODS: Using chronic constriction injury (CCI) of the common peroneal nerve (CPN) in sheep (ovine), we have created a chronic model of neuropathic pain that avoids motor deficits present in prior large animal models. This large animal model has allowed us to implant clinical grade SCS hardware, which enables both acute and chronic testing using von Frey filament thresholds and gait analysis. Furthermore, the larger anatomic scale of the sheep allows for simultaneous single-unit recordings from the dorsal horn and SCS with minimal electrical artifact. RESULTS: Detectable tactile hypersensitivity occurred 21 days after nerve injury, with preliminary indications that chronic SCS may reverse it in the painful limb. Gait analysis revealed no hoof drop in the CCI model. Single neurons were identified and discriminated in the dorsal horn, and their activity was modulated via SCS. Unlike previous large animal models that employed a complete transection of the nerve, no motor deficit was observed in the sheep with CCI. CONCLUSION: To our knowledge, this is the first reported large animal model of chronic neuropathic pain which facilitates the study of both acute and chronic SCS using complementary behavioral and electrophysiologic measures. As demonstrated by our successful establishment of these techniques, an ovine model of neuropathic pain is suitable for testing the mechanisms of SCS.

Expanded cellular clones carrying replication-competent HIV-1 persist, wax, and wane.

The latent reservoir for HIV-1 in resting CD4+ T cells is a major barrier to cure. Several lines of evidence suggest that the latent reservoir is maintained through cellular proliferation. Analysis of this proliferative process is complicated by the fact that most infected cells carry defective proviruses. Additional complications are that stimuli that drive T cell proliferation can also induce virus production from latently infected cells and productively infected cells have a short in vivo half-life. In this ex vivo study, we show that latently infected cells containing replication-competent HIV-1 can proliferate in response to T cell receptor agonists or cytokines that are known to induce homeostatic proliferation and that this can occur without virus production. Some cells that have proliferated in response to these stimuli can survive for 7 d while retaining the ability to produce virus. This finding supports the hypothesis that both antigen-driven and cytokine-induced proliferation may contribute to the stability of the latent reservoir. Sequencing of replication-competent proviruses isolated from patients at different time points confirmed the presence of expanded clones and demonstrated that while some clones harboring replication-competent virus persist longitudinally on a scale of years, others wax and wane. A similar pattern is observed in longitudinal sampling of residual viremia in patients. The observed patterns are not consistent with a continuous, cell-autonomous, proliferative process related to the HIV-1 integration site. The fact that the latent reservoir can be maintained, in part, by cellular proliferation without viral reactivation poses challenges to cure.