The Effects of Dry Needling on Hamstring Range of Motion: A Critically Appraised Topic.

CLINICAL SCENARIO: Hamstring range of motion (ROM) and the influence it has on injury risk is among great discussion in the literature. Hamstring injury may result from hamstring tightness, poor flexibility, or decreased ROM, and many argue that this can be prevented through various intervention strategies. In active populations, risk of further injury, pain, and complications throughout the kinetic chain can occur if minimal hamstring ROM is left untreated. One therapeutic intervention that has been applied to varying parts of the body to help improve function while relieving pain is dry needling (DN). This intervention includes the application of needles to structures to induce responses that might benefit healing and overall stimulation of a neurological response. In this review, the intent is to identify evidence and the effects of DN on hamstring ROM. CLINICAL QUESTION: What are the effects of DN on hamstring ROM? SUMMARY OF KEY FINDINGS: Among total 11 articles, 1 single-blinded randomized controlled trial and 2 double-blinded randomized controlled trials were included in this critically appraised topic. All 3 articles had inconclusive evidence to isolate the application of the DN intervention. There was insufficient evidence to identify if DN independently improved hamstring ROM; however, in combination with interventions such as exercise and stretch plans, there were improvements on ROM. CLINICAL BOTTOM LINE: DN does not significantly increase or decrease the ROM of the hamstrings. When combined with exercise and stretch plans, DN could increase ROM. STRENGTH OF RECOMMENDATION: The grade of B is recommended by the Strength of Recommendation Taxonomy for inconsistent or limited-quality patient-oriented evidence.

Reproducibility of graph measures derived from resting-state MEG functional connectivity metrics in sensor and source spaces.

Prior studies have used graph analysis of resting-state magnetoencephalography (MEG) to characterize abnormal brain networks in neurological disorders. However, a present challenge for researchers is the lack of guidance on which network construction strategies to employ. The reproducibility of graph measures is important for their use as clinical biomarkers. Furthermore, global graph measures should ideally not depend on whether the analysis was performed in the sensor or source space. Therefore, MEG data of the 89 healthy subjects of the Human Connectome Project were used to investigate test-retest reliability and sensor versus source association of global graph measures. Atlas-based beamforming was used for source reconstruction, and functional connectivity (FC) was estimated for both sensor and source signals in six frequency bands using the debiased weighted phase lag index (dwPLI), amplitude envelope correlation (AEC), and leakage-corrected AEC. Reliability was examined over multiple network density levels achieved with proportional weight and orthogonal minimum spanning tree thresholding. At a 100% density, graph measures for most FC metrics and frequency bands had fair to excellent reliability and significant sensor versus source association. The greatest reliability and sensor versus source association was obtained when using amplitude metrics. Reliability was similar between sensor and source spaces when using amplitude metrics but greater for the source than the sensor space in higher frequency bands when using the dwPLI. These results suggest that graph measures are useful biomarkers, particularly for investigating functional networks based on amplitude synchrony.

Pelvic Inflammatory Disease: Diagnosis, Management, and Prevention.

Pelvic inflammatory disease (PID) is an infection of the upper genital tract occurring predominantly in sexually active young women. Chlamydia trachomatis and Neisseria gonorrhoeae are common causes; however, other cervical, enteric, bacterial vaginosis-associated, and respiratory pathogens, including Mycobacterium tuberculosis, may be involved. PID can be acute, chronic, or subclinical and is often underdiagnosed. Untreated PID can lead to chronic pelvic pain, infertility, ectopic pregnancy, and intra-abdominal infections. The diagnosis is made primarily on clinical suspicion, and empiric treatment is recommended in sexually active young women or women at risk for sexually transmitted infections who have unexplained lower abdominal or pelvic pain and cervical motion, uterine, or adnexal tenderness on examination. Mild to moderate disease can be treated in an outpatient setting with a single intramuscular injection of a recommended cephalosporin followed by oral doxycycline for 14 days. Additionally, metronidazole is recommended for 14 days in the setting of bacterial vaginosis, trichomoniasis, or recent uterine instrumentation. Hospitalization for parenteral antibiotics is recommended in patients who are pregnant or severely ill, in whom outpatient treatment has failed, those with tubo-ovarian abscess, or if surgical emergencies cannot be excluded. Treatment does not change in patients with intrauterine devices or those with HIV. Sex partner treatment is recommended; expedited partner treatment is recommended where legal. Prevention of PID includes screening for C. trachomatis and N. gonorrhoeae in all women younger than 25 years and those who are at risk or pregnant, plus intensive behavioral counseling for all adolescents and adults at increased risk of sexually transmitted infections.

Selective head cooling during neonatal seizures prevents postictal cerebral vascular dysfunction without reducing epileptiform activity.

Epileptic seizures in neonates cause cerebrovascular injury and impairment of cerebral blood flow (CBF) regulation. In the bicuculline model of seizures in newborn pigs, we tested the hypothesis that selective head cooling prevents deleterious effects of seizures on cerebral vascular functions. Preventive or therapeutic ictal head cooling was achieved by placing two head ice packs during the preictal and/or ictal states, respectively, for the ∼2-h period of seizures. Head cooling lowered the brain and core temperatures to 25.6 ± 0.3 and 33.5 ± 0.1°C, respectively. Head cooling had no anticonvulsant effects, as it did not affect the bicuculline-evoked electroencephalogram parameters, including amplitude, duration, spectral power, and spike frequency distribution. Acute and long-term cerebral vascular effects of seizures in the normothermic and head-cooled groups were tested during the immediate (2-4 h) and delayed (48 h) postictal periods. Seizure-induced cerebral vascular injury during the immediate postictal period was detected as terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive staining of cerebral arterioles and a surge of brain-derived circulating endothelial cells in peripheral blood in the normothermic group, but not in the head-cooled groups. During the delayed postictal period, endothelium-dependent cerebral vasodilator responses were greatly reduced in the normothermic group, indicating impaired CBF regulation. Preventive or therapeutic ictal head cooling mitigated the endothelial injury and greatly reduced loss of postictal cerebral vasodilator functions. Overall, head cooling during seizures is a clinically relevant approach to protecting the neonatal brain by preventing cerebrovascular injury and the loss of the endothelium-dependent control of CBF without reducing epileptiform activity.

Sources of Rapid and Delayed New Lower Jaw Input in the Forepaw Barrel Subfield (FBS) in Rat Primary Somatosensory Cortex (SI) Following Forelimb Deafferentation.

Previously, we reported an immediate emergence of new lower jaw input to the anterior forepaw barrel subfield (FBS) in primary somatosensory cortex (SI) following forelimb deafferentation. However, a delay of 7 weeks or more post-amputation results in the presence of this new input to both anterior and posterior FBS. The immediate change suggests pre-existing latent lower jaw input in the FBS, whereas the delayed alteration implies the involvement of alternative sources. One possible source for immediate lower jaw responses is the neighboring lower jaw barrel subfield (LJBSF). We used anatomical tracers to investigate the possible projection of LJBSF to the FBS in normal and forelimb-amputated rats. Our findings are as follows: (1) anterograde tracer injection into LJBSF in normal and amputated rats labeled fibers and terminals exclusively in the anterior FBS; (2) retrograde tracer injection in the anterior FBS in normal and forelimb-amputated rats, heavily labeled cell bodies predominantly in the posterior LJBSF, with fewer in the anterior LJBSF; (3) retrograde tracer injection in the posterior FBS in normal and forelimb-amputated rats, sparsely labeled cell bodies in the posterior LJBSF; (4) retrograde tracer injection in anterior and posterior FBS in normal and forelimb-amputated rats, labeled cells exclusively in ventral posterior lateral (VPL) nucleus and posterior thalamus (PO); (5) retrograde tracer injection in LJBSF-labeled cell bodies exclusively in ventral posterior medial thalamic nucleus and PO. These findings suggest that LJBSF facilitates rapid lower jaw reorganization in the anterior FBS, whereas VPL and/or other subcortical sites provide a likely substrate for delayed reorganization observed in the posterior FBS.

Myocardial scaffold-based cardiac tissue engineering: application of coordinated mechanical and electrical stimulations.

Recently, we developed an optimal decellularization protocol to generate 3D porcine myocardial scaffolds, which preserve the natural extracellular matrix structure, mechanical anisotropy, and vasculature templates and also show good cell recellularization and differentiation potential. In this study, a multistimulation bioreactor was built to provide coordinated mechanical and electrical stimulation for facilitating stem cell differentiation and cardiac construct development. The acellular myocardial scaffolds were seeded with mesenchymal stem cells (10(6) cells/mL) by needle injection and subjected to 5-azacytidine treatment (3 µmol/L, 24 h) and various bioreactor conditioning protocols. We found that after 2 days of culturing with mechanical (20% strain) and electrical stimulation (5 V, 1 Hz), high cell density and good cell viability were observed in the reseeded scaffold. Immunofluorescence staining demonstrated that the differentiated cells showed a cardiomyocyte-like phenotype by expressing sarcomeric α-actinin, myosin heavy chain, cardiac troponin T, connexin-43, and N-cadherin. Biaxial mechanical testing demonstrated that positive tissue remodeling took place after 2 days of bioreactor conditioning (20% strain + 5 V, 1 Hz); passive mechanical properties of the 2 day and 4 day tissue constructs were comparable to those of the tissue constructs produced by stirring reseeding followed by 2 weeks of static culturing, implying the effectiveness and efficiency of the coordinated simulations in promoting tissue remodeling. In short, the synergistic stimulations might be beneficial not only for the quality of cardiac construct development but also for patients by reducing the waiting time in future clinical scenarios.

Improving First-Year Family Medicine Residents' Confidence in Safe Opioid Prescribing Through a Multiactivity Educational Program.

BACKGROUND AND OBJECTIVE: It is documented that some of the opioids prescribed to manage chronic pain are diverted and used for nonmedical purposes. We investigated whether a skill-based, chronic pain management (CPM) educational program could improve first-year family medicine residents' comfort, knowledge, and concerns in assessing and managing patients who use opioids for chronic noncancer pain. METHODS: A total of 72 first-year residents (four cohorts of 18) participated in a 3-month CPM training intervention that consisted of didactic lectures, objective structured clinical examination (OSCE) activities, and post-OSCE debriefing with faculty, one being a behavioral health specialist, between 2017 and 2020. We used a single-sample, pre/post design. At three points in time (baseline, 3-months, and 6-months postintervention), participants completed a set of measures assessing comfort, knowledge, and concern. We used repeated measures analyses to assess changes in outcome measures. RESULTS: Participants reported improvements compared with baseline at both follow-up time points. At 6 months postintervention, the participants had significantly better scores on measures of comfort (F[1, 71]=65.22; P<.001), knowledge (F[1, 71]=22.38, P<.001), and concern (F[1, 71]=37.89, P<.001) in prescribing opioids for chronic noncancer pain. CONCLUSION: A multiactivity CPM educational program for first-year residents was associated with improvement in perceived sense of comfort, knowledge, and concerns in assessing and managing patients who use opioids for chronic noncancer pain. CPM training interventions may be an effective tool to educate first-year residents to implement best practices for pain management with the goal of reducing the chances of inappropriately prescribing controlled substances or denying analgesia.

Improving Chronic Pain Management in a Family Medicine Residency.

BACKGROUND AND OBJECTIVE: Although the opioid epidemic continues to affect millions of Americans, many family physicians feel underprepared to perform chronic pain management (CPM) and treat opioid use disorder (OUD). To address this gap, we created organizational policy changes and implemented a didactic curriculum to help improve patient care, including medication-assisted treatment (MAT) into our residency. We investigated whether the educational program improved the comfort and ability of family physicians to prescribe opioids and utilize MAT. METHOD: Clinic policies and protocols were updated to align with the 2016 Centers for Disease Control and Prevention Guidelines for Prescribing Opioids. A didactic curriculum was created to improve resident and faculty comfort with CPM and introduce MAT. An online survey was completed pre- and postintervention between December 2019 and February 2020, utilizing paired sample t test and percentage effective (z test) to assess for change in provider comfort with opioid prescribing. Assessments were made using clinical metrics to monitor compliance with the new policy. RESULTS: Following the interventions, providers reported improved comfort with CPM (P=.001) and perception of MAT (P<.0001). Within the clinical setting there was significant improvement in the number of CPM patients who had a pain management agreement on file (P<.001) and completed a urine drug screen within the past year (P<.001). CONCLUSION: Provider comfort with CPM and OUD increased over the course of the intervention. We were also able to introduce MAT, adding a tool to the toolbox to help our residents and graduates treat OUD.

Lower jaw-to-forepaw rapid and delayed reorganization in the rat forepaw barrel subfield in primary somatosensory cortex.

We used the forepaw barrel subfield (FBS), that normally receives input from the forepaw skin surface, in rat primary somatosensory cortex as a model system to study rapid and delayed lower jaw-to-forepaw cortical reorganization. Single and multi-unit recording from FBS neurons was used to examine the FBS for the presence of "new" lower jaw input following deafferentations that include forelimb amputation, brachial plexus nerve cut, and brachial plexus anesthesia. The major findings are as follows: (1) immediately following forelimb deafferentations, new input from the lower jaw becomes expressed in the anterior FBS; (2) 7-27 weeks after forelimb amputation, new input from the lower jaw is expressed in both anterior and posterior FBS; (3) evoked response latencies recorded in the deafferented FBS following electrical stimulation of the lower jaw skin surface are significantly longer in both rapid and delayed deafferents compared to control latencies for input from the forepaw to reach the FBS or for input from lower jaw to reach the LJBSF; (4) the longer latencies suggest that an additional relay site is imposed along the somatosensory pathway for lower jaw input to access the deafferented FBS. We conclude that different sources of input and different mechanisms underlie rapid and delayed reorganization in the FBS and suggest that these findings are relevant, as an initial step, for developing a rodent animal model to investigate phantom limb phenomena.

Esophageal electric fields are predictive of atrial defibrillation thresholds.

BACKGROUND: Atrial fibrillation (AF) is a common cardiac arrhythmia characterized by disorganized cardiac electrical activity. Defibrillation electrode placement has been shown to affect the amount of energy and number of shocks required to defibrillate. The objective of this study was to investigate the relationship between esophageal electric fields (EEFs) and atrial defibrillation thresholds (ADFTs) to determine the feasibility of using EEFs during a low-strength shock to predict patient-specific defibrillation electrode placements. METHODS: AF was induced and defibrillated according to a Bayesian four-shock protocol for 12-electrode placements in six pigs. EEFs were measured during each of the four shocks of the protocol and during a 1-J shock for each electrode placement. Squared EEFs (EEF(2) s) during all shocks were compared to the ADFTs using a linear regression. RESULTS: There was a negative relationship between EEF(2) s during the 1-J shocks and ADFTs, with median R(2) values of 0.863 and 0.840 for anterior-anterior (AA) and anterior-posterior (AP) electrode placements, respectively. There was a strong, positive relationship between applied energy and EEF(2) s, with median R(2) values of at least 0.866 for all animals. The placement with the highest EEF(2) resulted in the lowest ADFT for both AA and AP placements in four of six pigs. In the other two animals, this held for one electrode set but not both. CONCLUSIONS: There was a strong negative relationship between EEF(2) s during 1-J shocks and ADFTs for both AA and AP electrode placements. These preliminary results suggest that using EEF(2) s to predict patient-specific electrode placements is feasible.

Structural and biomechanical characterizations of porcine myocardial extracellular matrix.

Extracellular matrix (ECM) of myocardium plays an important role to maintain a multilayered helical architecture of cardiomyocytes. In this study, we have characterized the structural and biomechanical properties of porcine myocardial ECM. Fresh myocardium were decellularized in a rotating bioreactor using 0.1 % sodium dodecyl sulfate solution. Masson's trichrome staining and SEM demonstrated the removal of cells and preservation of the interconnected 3D cardiomyocyte lacunae. Movat's pentachrome staining showed the preservation of cardiac elastin ultrastructure and vascular elastin distribution/alignment. DNA assay result confirmed a 98.59 % reduction in DNA content; the acellular myocardial scaffolds were found completely lack of staining for the porcine α-Gal antigen; and the accelerating enzymatic degradation assessment showed a constant degradation rate. Tensile and shear properties of the acellular myocardial scaffolds were also evaluated. Our observations showed that the acellular myocardial ECM possessed important traits of biodegradable scaffolds, indicating the potentials in cardiac regeneration and whole heart tissue engineering.

Acellular Myocardial Scaffolds and Slices Fabrication, and Method for Applying Mechanical and Electrical Simulation to Tissue Construct.

Cardiac tissue engineering/regeneration using decellularized myocardium has attracted great research attention due to its potential benefit to myocardial infarction (MI) treatment. Here, we described an optimal decellularization protocol to generate 3D porcine myocardial scaffolds with well-preserved cardiomyocyte lacunae, myocardial slices as a biomimetic cell culture and delivery platform, and a multi-stimulation bioreactor that is able to provide coordinated mechanical and electrical stimulations for facilitating cardiac construct development.

Spironolactone prevents the inducibility of ventricular tachyarrhythmia in rats with aldosteronism.

Myocardial fibrosis is considered a substrate for fatal ventricular arrhythmias (VAs). In rats receiving aldosterone/salt treatment (ALDOST) for ≥4 weeks, foci of myocardial scarring that replace necrotic cardiomyocytes appear scattered throughout the right and left sides of the heart. We hypothesized that this adverse structural remodeling would promote the inducibility of VA, which could be prevented by cotreatment with spironolactone (A+Spiro), an aldosterone receptor antagonist and cardioprotective agent. In controls and each treatment group, we monitored: (1) electrocardiogram, ventricular electrogram, and arterial pressure before, during, and after bipolar electrical stimulation of the right ventricular outflow tract and apex at a strength 3× the pacing threshold, using both programmed stimulation with premature extra stimuli and 50-Hz burst pacing for 3 different durations; and (2) myocardial collagen volume fraction (CVF) as a marker of cardiac fibrosis. We found that VA (duration >200 ms accompanied by declining arterial pressure) was more inducible (P < 0.05) at 4 weeks (4 of 6) and with even greater frequency at 6 weeks (9 of 10) of ALDOST versus controls (0 of 6) and A+Spiro for 6 weeks (2 of 11). CVF (%) was proportionally increased (P < 0.05) at 4 and 6 weeks (8.4 ± 0.74 and 13.9 ± 1.9, respectively) of ALDOST compared with control group (2.6 ± 0.4) and A+Spiro group (5.3 ± 0.7). However, the effective refractory period was indistinguishable between groups, whereas the probability of VA was nonlinearly related to CVF. Thus, in rats with aldosteronism, in which a reduction in effective refractory period was not evident, the mechanism for VA susceptibility is presumably linked to a decrease in conduction velocity and/or increased dispersion of refractoriness, probably caused by consequential myocardial fibrosis.

Structural and functional organization of the lower jaw barrel subfield in rat primary somatosensory cortex.

Barrel subfields in rodent primary somatosensory cortex (SI) are important model systems for studying cortical organization and reorganization. During cortical reorganization that follows limb deafferentation, neurons in deafferented forelimb SI become responsive to previously unexpressed inputs from the lower jaw. Although the lower jaw barrel subfield (LJBSF) is a likely source of the input, this subfield has received little attention. Our aim was to describe the structural and functional organization of the normal LJBSF. To investigate LJBSF organization, a nomenclature for lower jaw skin surface was developed, cytochrome oxidase (CO) was used to label flattened-cut LJBSF sections, microelectrodes were used to map the lower jaw skin surface representation in SI, and electrolytic lesions, recovered from electrode penetrations, were used to align the physiological map to the underlying barrel map. LJBSF is a tear-shaped subfield containing approximately 24 barrels, arranged in eight mediolateral rows and a barrel-free zone capping the anterior border. The representation of the lower jaw skin consisting of chin vibrissae and microvibrissae embedded in common fur is somatotopically organized in a single map in the contralateral SI. This physiological map shows that the activity from the vibrissae aligns with the CO-staining of the underlying LJBSF. LJBSF barrels receive topographically ordered barrel-specific input from individual vibrissa and microvibrissae in the lower jaw but not from trident whiskers. The barrel-free zone receives topographically ordered input from the lower lip. These data demonstrating that the LJBSF is a highly organized subfield are essential for understanding its possible role in cortical reorganization.

Focality of the Induced E-Field Is a Contributing Factor in the Choice of TMS Parameters: Evidence from a 3D Computational Model of the Human Brain.

Transcranial magnetic stimulation (TMS) is a promising, non-invasive approach in the diagnosis and treatment of several neurological conditions. However, the specific results in the cortex of the magnitude and spatial distribution of the secondary electrical field (E-field) resulting from TMS at different stimulation sites/orientations and varied TMS parameters are not clearly understood. The objective of this study is to identify the impact of TMS stimulation site and coil orientation on the induced E-field, including spatial distribution and the volume of activation in the cortex across brain areas, and hence demonstrate the need for customized optimization, using a three-dimensional finite element model (FEM). A considerable difference was noted in E-field values and distribution at different brain areas. We observed that the volume of activated cortex varied from 3000 to 7000 mm3 between the selected nine clinically relevant coil locations. Coil orientation also changed the induced E-field by a maximum of 10%, and we noted the least optimal values at the standard coil orientation pointing to the nose. The volume of gray matter activated varied by 10% on average between stimulation sites in homologous brain areas in the two hemispheres of the brain. This FEM simulation model clearly demonstrates the importance of TMS parameters for optimal results in clinically relevant brain areas. The results show that TMS parameters cannot be interchangeably used between individuals, hemispheres, and brain areas. The focality of the TMS induced E-field along with its optimal magnitude should be considered as critical TMS parameters that should be individually optimized.

Repetitive microstimulation in rat primary somatosensory cortex (SI) strengthens the connection between homotopic sites in the opposite SI and leads to expression of previously ineffective input from the ipsilateral forelimb.

The primary somatosensory cortex (SI) receives input from the contralateral forelimb and projects to homotopic sites in the opposite SI. Since homotopic sites in SI are linked by a callosal pathway, we proposed that repetitive intracortical microstimulation (ICMSr) of neurons in layer V of SI forelimb cortex would increase spike firing in the opposite SI cortex thereby strengthening the callosal pathway sufficiently to allow normally ineffective stimuli from the ipsilateral forelimb to excite cells in the ipsilateral SI. The forelimb representation in SI in one hemisphere was mapped using mechanical and electrical stimulation of the contralateral forelimb, a homotopic site was similarly identified in the opposite SI, the presence of ipsilateral peripheral input was tested in both homotopic sites, and ICMS was used to establish an interhemispheric connection between the two homotopic recording sites. The major findings are: (1) each homotopic forelimb site in SI initially received short latency input only from the contralateral forelimb; (2) homotopic sites in layer V in each SI were interconnected by a callosal pathway; (3) ICMSr delivered to layer V of the homotopic SI in one hemisphere generally increased evoked response spike firing in layer V in the opposite homotopic site; (4) increased spike firing was often followed by the expression of a longer latency normally ineffective input from the ipsilateral forelimb; (5) these longer latency ipsilateral responses are consistent with a delay time sufficient to account for travel across the callosal pathway; (6) increased spike firing and the resulting ipsilateral peripheral input were also corroborated using in-vivo intracellular recording; and (7) inactivation of the stimulating site in SI by lidocaine injection or local surface cooling abolished the ipsilateral response, suggesting that the ipsilateral response was very likely relayed across the callosal pathway. These results suggest that repetitive microstimulation can do more than expand receptive fields in the territory adjacent to the stimulating electrode but in addition can also alter receptive fields in homotopic sites in the opposite SI to bring about the expression of previously ineffective input from the ipsilateral forelimb.

Telemetry-controlled simultaneous stimulation-and-recording device (SRD) to study interhemispheric cortical circuits in rat primary somatosensory (SI) cortex.

BACKGROUND: A growing need exists for neuroscience platforms that can perform simultaneous chronic recording and stimulation of neural tissue in animal models in a telemetry-controlled fashion with signal processing for analysis of the chronic recording data and external triggering capability. We describe the system design, testing, evaluation, and implementation of a wireless simultaneous stimulation-and-recording device (SRD) for modulating cortical circuits in physiologically identified sites in primary somatosensory (SI) cortex in awake-behaving and freely-moving rats. The SRD was developed using low-cost electronic components and open-source software. The function of the SRD was assessed by bench and in-vivo testing. RESULTS: The SRD recorded spontaneous spiking and bursting neuronal activity, evoked responses to programmed intracortical microstimulation (ICMS) delivered internally by the SRD, and evoked responses to external peripheral forelimb stimulation. CONCLUSIONS: The SRD is capable of wireless stimulation and recording on a predetermined schedule or can be wirelessly synchronized with external input as would be required in behavioral testing prior to, during, and following ICMS.

A newly identified nociresponsive region in the transitional zone (TZ) in rat sensorimotor cortex.

The primary somatosensory cortex (S1) comprises a number of functionally distinct regions, reflecting the diversity of somatosensory receptor submodalities innervating the body. In particular, two spatially and functionally distinct nociceptive regions have been described in primate S1 (Vierck et al., 2013; Whitsel et al., 2019). One region is located mostly in Brodmann cytoarchitectonic area 1, where a subset of neurons exhibit functional characteristics associated with myelinated Aδ nociceptors and perception of 1st/sharp, discriminative pain. The second region is located at the transition between S1 and primary motor cortex (M1) in area 3a, where neurons exhibit functional characteristics associated with unmyelinated C nociceptors and perception of 2nd/slow, burning pain. To test the hypothesis that in rats the transitional zone (TZ) - which is a dysgranular region at the transition between M1 and S1 - is the functional equivalent of the nociresponsive region of area 3a in primates, extracellular spike discharge activity was recorded from TZ neurons in rats under general isoflurane anesthesia. Thermonoxious stimuli were applied by lowering the contralateral forepaw or hindpaw into a 48-51 °C heated water bath for 5-10 s. Neurons in TZ were found to be minimally affected by non-noxious somatosensory stimuli, but highly responsive to thermonoxious skin stimuli in a slow temporal summation manner closely resembling that of nociresponsive neurons in primate area 3a. Selective inactivation of TZ by topical lidocaine application suppressed or delayed the nociceptive withdrawal reflex, suggesting that TZ exerts a tonic facilitatory influence over spinal cord neurons producing this reflex. In conclusion, TZ appears to be a rat homolog of the nociresponsive part of monkey area 3a. A possibility is considered that this region might be primarily engaged in autonomic aspects of nociception.

Causality Assessment of Olfactory and Gustatory Dysfunction Associated with Intranasal Fluticasone Propionate: Application of the Bradford Hill Criteria.

Causality assessment is crucial to post-marketing pharmacovigilance and helps optimize safe and appropriate use of medicines by patients in the real world. Self-reported olfactory and gustatory dysfunction are common in the general population as well as in patients with allergic rhinitis and nasal polyposis. Intranasal corticosteroids, including intranasal fluticasone propionate (INFP), are amongst the most effective drugs indicated in the treatment of allergic rhinitis and nasal polyposis. While intranasal corticosteroids are associated with olfactory and gustatory dysfunction and are currently labeled for these adverse events, causality assessment has not been performed to date. Although there is no single widely accepted method to assess causality in pharmacovigilance, the Bradford Hill criteria offer a robust and comprehensive approach because nine distinct aspects of an observed potential drug-event association are assessed. In this literature-based narrative review, Hill's criteria were applied to determine causal inference between INFP and olfactory and gustatory dysfunction.