The frequency of selected polymorphisms, one in each gene coding for proteins with antioxidative properties (CAT, SOD2, GPX1, NQO1) was compared between patients suffering from pain-related temporomandibular disorders (TMDp;n=85) and control subjects (CTR;n=85). According to the Oral Behaviours Checklist score participants were divided into high-frequency parafunction (HFP;n=98) and low-frequency parafunction (LFP;n=72) groups. In addition, we have investigated the association of selected polymorphisms with participants' psychological (anxiety, depression) and psychosomatic (hypervigilance, somatosensory amplification) characteristics. Polymorphisms rs1001179, rs4880, rs1050450, rs689452 were genotyped using the genomic DNA extracted from buccal mucosa swabs and real-time TaqMan genotyping assays. No differences in genotype distribution between TMDp patients and control subjects were found. Still, TMDp patients who were homozygous for minor allele A, related to the GPX1 polymorphism rs1050450 reported significantly more waking-state oral behaviours compared to GA+GG genotype carriers (score: 30 vs. 23, p=0.019). Frequency of genotype AA for rs1050450 polymorphism was higher in HFP compared to LFP participants (14.3% vs. 4.2%, p =0.030). Most important predictors of waking-state oral behaviours were depression, anxiety, AA genotype (rs1050450) and female sex. Explored genetic factors were not found to be significant risk factors for either TMDp or sleep-related oral behaviours. The association of waking-state oral behaviours with selected gene polymorphisms additionally supports previous assumptions that the daytime bruxism is more closely linked to various stress manifestations, which might also be reflected through the variability related to cellular antioxidative activity.

(1) Background: The mediolateral patella displacement is of interest for diagnostics and clinically relevant research questions. Apart from manual testing, no standardized method is currently available. Proper quantification of patella mobility is necessary to understand pathologies at the patellofemoral joint better; (2) Methods: Patella mobility was assessed in 25 healthy individuals using a Patellostabilometer, a new prototype instrument for quantification of the mediolateral patella displacement. The participants underwent measurements of the mediolateral displacement three times using the Patellostabilometer. A maximal force of 10N was applied for patella movement. Additionally, leg length, circumference of the knee, upper- and lower leg was measured. (3) Results: Lateral patella displacement of 18.27±3.76 mm (range 15.85-20.64mm, interquartile range (IQR) of 4.79) was measured. The medial patella displacement showed 24.47±6.59mm (range 19.29-29.76mm, IQR of 10.47). The test-retest measurement error was 2.32±1.76mm (IQR of 2.38mm), with five outliers. There was greater test-retest variability between the measurements of the medial displacement comparing to the lateral one (4) Conclusions: The test-retest variability reached 7% of the patella displacement. Other parameters provided no significant correlations. Based on the natural patellofemoral mobility a precise and clinically relevant quantification of patella mobility is allowed.

Breast cancer is the most common malignant disease in women. Preclinical studies have confirmed that the local anesthetic levobupivacaine has a cytotoxic effect on breast cancer cells. We examined whether postoperative wound infiltration with levobupivacaine influences survival in 120 patients who were operated on for breast cancer and underwent quadrantectomy or mastectomy with axillary lymph node dissection. Groups with continuous levobupivacaine wound infiltration, bolus wound infiltration, and diclofenac analgesia were compared. Long-term outcomes examined were quality of life, shoulder disability, and hand grip strength (HGS) after one year, and survival after 5 and 10 years. Groups that had infiltration analgesia had better shoulder function compared to diclofenac after one year. Levobupivacaine PCA group had the best preserved HGS after 1 year (P=0.022). The most significant predictor of the 5-year outcome was HGS (P=0.03). Although the best survival after 5 and 10 years was registered in the bolus levobupivacaine group, statistical significance was not reached (P=0.36). The extent of the disease at the time of surgery is the most important predictor of long-term survival. A larger prospective clinical study could better confirm the effect of levobupivacaine wound infiltration on outcomes after breast cancer surgery observed in this pilot study. Trial number NCT05829707

Heel pain in the “funnel-shaped” space between the calcaneus, talus, and talocalcaneonavicular and subtalar joints may be representative of Sinus Tarsi syndrome. The pain is often characterized by a burning, numbness, or tingling sensation that can stem from strains and tears on the ligaments in that area. Injury treatment typically includes balance training, muscle exercises, bracing, foot orthosis, and non-steroidal anti-inflammatory drugs (NSAIDs). This study presents Wharton Jelly (WJ) tissue allografts as an alternative intervention for patients who fail standard-care treatments. WJ targets tissue defects, unlike other therapies, which aim to reduce swelling and symptomatic pain. This study includes five female patients who have previously failed standard-of-care treatment. Each received extracorporeal pulse-activated therapy (EPAT), WJ, laser therapy, and an orthotic. After an average of 80 days, the cohort had an overall 85.29% improvement in pain. The study's limitations include a small cohort size and a non-blinded design. Given the significant improvement in pain, WJ tissue allograft, combined with other techniques, presents an optimal patient care plan for tissue defects associated with Sinus Tarsi syndrome when standard-of-care treatments fail. These results provide evidence for a more extensive, randomized study to define dosage protocols further and confirm safety and efficacy.

Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN IV), is an exceedingly rare genetic disorder characterized by the inability to perceive pain, inability to sweat, and various neurological and orthopedic complications. This is a case report of a 3-year-old female patient diagnosed with CIPA syndrome who presented repeatedly to Children’s Clinical University Hospital (CCUH) in Riga, Latvia with severe orthopedic manifestations. The patient had repeated fractures, several surgeries, and extensive spread of the disease throughout the left leg, which caused significant functional impairment and decreased quality of life. Despite aggressive orthopedic interventions including surgical interventions and physical therapy, the patient's condition remained challenging to manage due to the inherent limitations posed by the insensitivity to pain. The council of doctors discussed the patient's condition and changes, deciding that reconstructive surgery is not feasible, and amputation is recommended. Through this case report, we aim to highlight the unique orthopedic challenges encountered in the management of CIPA patients, emphasizing the importance of a multidisciplinary approach involving orthopedic surgeons, pediatricians, geneticists, and physiotherapists. Additionally, we discuss the need for further research to elucidate optimal management strategies and improve outcomes in this rare and complex patient population.

The prolonged static sitting at the workplace is considered as one of the main risks for development of musculoskeletal disorders (MSDs) and adverse health effects. Factors such as poor posture and extended sitting are perceived to be a reason for conditions such as lumbar hyperlordosis and lower back pain (LBP), even though the scientific explanation of this relationship is still unclear and raises disputes in the scientific community. This publication proposes the low back pain assessment (LBPA) dataset collected through experiment with 100 participants and consisting of photogrammetric images with intentionally placed body markers, calculated postural angles and tags correct and incorrect posture assessed by habilitated rehabilitator, as well as questionnaire-based self-reports regarding the occurrence of LBP and similar symptoms among the participants. Machine learning models trained with this data are employed for recognizing incorrect body postures. Two scenarios have been elaborated for modeling purposes: scenario 1, based on natural body posture tagged as correct and incorrect, and scenario 2, based on incorrect body postures, corrected additionally by the rehabilitator. The achieved accuracies of respectively 75.3% and 85% for both scenarios reveal the potential for future research in enhancing awareness and actively managing posture-related issues that elevate the likelihood of developing lower back pain symptoms.

As a key mediator of chronic pain, neurotrophin nerve growth factor (NGF) binds to two neurotrophin receptors: p75 neurotrophin receptor (p75NTR) and tyrosine kinase receptor A (TrkA). The formation of the p75NTR-NGF-TrkA complex is implicated in the potentiation of chronic pain signals, making it an attractive target for therapeutic explorations. NGF analogues and monoclonal antibodies (mAbs) targeting NGF represent two distinct approaches in modulating the intricate signaling pathways involved in pain transduction mediated by the p75NTR-NGF-TrkA complex. While NGF analogues offer the advantage of tailored design to fine-tune neurotrophic responses, monoclonal antibodies provide a more systemic and comprehensive blockade of NGF, inhibiting its interactions with both p75NTR and TrkA receptors. However, the use of mAbs may pose challenges related to potential side effects and interference with the physiological functions of NGF. As a result, balancing the benefits and drawbacks of the two approaches is critical for advancing therapeutic strategies towards the alleviation of p75NTR-NGF-TrkA-mediated pain. In this study, therefore, a novel structural and biophysical approach was employed for the design of NGF analogues to suppress p75NTR-NGF-TrkA-related chronic pain signaling. Employing high-throughput structural modeling and biophysics-based intermolecular binding affinity calculations, this article for the first time puts forward a set of NGF analogues, including in particular NGF analogues with four site-specific mutations, for whose dimerizations the K d at 37 ^◦C were reduced by three orders of magnitude (from 10^-9 M to 10^-6 M) compared to the K d at 37 ^◦C for the dimerization of native NGFs. Overall, the integration of structural and biophysical perspectives enhances our understanding of the rational design of NGF analogues as promising candidates for the development of NGF-targeted analgesic therapies, which balances the benefits and drawbacks of anti-NGF antibodies and NGF analogues for advancing therapeutic strategies towards the alleviation of p75NTR-NGF-TrkA-mediated pain.

Low back pain (LBP) is a pandemic and costly musculoskeletal condition in the United States. Patients with LBP may endure surgery, injections, and expensive visits to emergency departments. Some suggest that using physical therapy or chiropractic in the earlier stage of LBP reduces the utilization of expensive health services and lowers the treatment costs. Nevertheless, there is no consistent evidence to declare which one of these methods is a cost-effective treatment within a short (less than a year) period of time. The purpose of this study was to investigate the cost-effectiveness of chiropractic versus physical therapy in the United States. A decision tree analytic model was used for estimating the economic outcomes. The findings showed that in the chiropractic group, the total average cost was $48.56 lower than the physical therapy group, and daily adjusted life years (DALY) was 0.0043 higher than the physical therapy group. Chiropractic care was shown to be a cost-effective alternative compared with physical therapy for adults with at least three weeks of low back pain over six months.

Regional anesthesia in postoperative pain management have developed in recent years, especially with the advent of fascial plane blocks. This study aims to compare the ultrasound-guided bilateral erector spinae plane block (ESPB) versus bilateral transversus abdominis plane block (TAPB) on postoperative analgesia after laparoscopic or robotic urologic surgery. This was a retrospective observational study; 97 patients (ESPB-group) received bilateral ultrasound-guided ESPB with 20 mL of ropivacaine 0.375% plus 0.5 mcg/kg of dexmedetomidine in each side at the level of T7-T9, and 93 patients (TAPB-group) received bilateral ultrasound-guided TAPB with ropivacaine 0.375% or 0.25%. The primary outcome was post-operative numeric rating scale (NRS) pain score, which was significantly lower in the ESPB-group on postoperative days 0, 2, and 3 (p=0.012, p=0.016 and p=0.004). Concerning the secondary outcomes, consumption of ropivacaine was significantly lower in ESPB-group (p<0.001) and the total amount of analgesic rescue doses was significantly lower in the ESPB-group than TAPB-group in postoperative days from 2 to 4 (1 vs 3, p>0.001). Incidence of postoperative nausea and vomiting was higher in the TAPB-group and no block related complications were observed. We conclude that ESPB provide better postoperative pain control with less consumption of local anesthetic and less total rescue analgesic therapies.

In cardiac surgery, post-sternotomy pain is a significant issue, peaking within 48 hours and requiring proper analgesia for both acute relief and to avoid chronicization. Opioids are commonly used for pain management post-surgery but pose risks like adverse effects and dependency. Post-cardiac surgery pain can stem from various sources - somatic, visceral, and neuropathic, making opioid reliance a concern. Multimodal analgesia, combining different medications and regional anesthesia techniques, is increasingly recommended to decrease opioid use and its related problems. Strategies include acetaminophen, gabapentinoids, NMDA antagonists, alpha-2 agonists, intravenous lidocaine, anti-inflammatory drugs, and regional anesthesia. Implementing these approaches can enhance pain control, lessen opioid reliance, and improve cardiac surgery outcomes. The ERAS® Cardiac Society strongly advocates for an opioid-sparing multimodal approach to benefit patient recovery by reducing complications and enhancing satisfaction. This review aims to consolidate current evidence to assist healthcare providers in customizing pain management for patients post-cardiac surgery, emphasizing reduced opioid use and optimizing the recovery process.

This review explores the application of the conservative management model for pain to sports-related concussions (SRCs), framing concussions as a distinct form of pain syndrome with a pathophysiological foundation in central sensitization. Drawing parallels with proven pain management models, we underscore the significance of a proactive approach to concussion management. Recognizing concussions as a pain syndrome allows for the tailoring of interventions in alignment with conservative principles. This review first covers the epidemiology and controversies surrounding prolonged concussion recovery and persistent post-concussion symptoms (PPCS). Next, the pathophysiology of concussions is presented within the central sensitization framework, emphasizing the need for early intervention to mitigate the neuroplastic changes that lead to heightened pain sensitivity. Five components of the central sensitization process specific to concussion injuries are highlighted as targets for conservative interventions in the acute period: peripheral sensitization, cerebral metabolic dysfunction, neuroinflammation, glymphatic system dysfunction, and pain catastrophizing. These proactive interventions are emphasized as pivotal in accelerating concussion recovery and reducing the risk of prolonged symptoms and PPCS, in line with the philosophy of conservative management.

Opioid analgesics are effective pain therapeutics but cause various adverse effects and addiction. For safer pain therapy, biased opioid agonists selectively target distinct m opioid receptor (MOR) conformations, while the potential of biased opioid antagonists has been neglected. Agonists convert a dormant receptor form (MOR-m) to a ligand-free active form (MOR-m*), which mediates MOR signaling. Moreover, MOR-m converts spontaneously to MOR-m* (basal signaling). Persistent upregulation of MOR-m* has been invoked as a hallmark of opioid dependence. Contrasting interactions with both MOR-m and MOR-m* can account for distinct pharmacological characteristics of inverse agonists (naltrexone), neutral antagonists (6b-naltrexol), and mixed opioid agonist-antagonists (buprenorphine). Upon binding to MOR-m*, naltrexone but not 6b-naltrexol suppresses MOR-m*signaling. Naltrexone blocks opioid analgesia non-competitively at MOR-m*with high potency, whereas 6BN must compete with agonists at MOR-m, accounting for ~100-fold lower in vivo potency. Buprenorphine’s bell-shaped dose-response curve may also result from opposing effects on MOR-m and MOR-m*. In contrast, we find that 6b-naltrexol potently prevents dependence, below doses affecting analgesia or causing withdrawal, possibly binding to MOR conformations relevant to opioid dependence. We propose that 6b-naltrexol is a biased opioid antagonist modulating opioid dependence at low doses, opening novel avenues for opioid pain therapy and use management.

Patients who have undergone surgery in early life may be at elevated risk for neuropathic pain in later life. The risk factors for this susceptibility are not fully understood. Here, we used a mouse chronic pain model to test the hypothesis that early exposure to general anesthetic (GA) causes cellular and molecular alterations in dorsal spinal cord (DSC) and dorsal root ganglion (DRG) that produces a predisposition to neuropathic pain via an upregulation of the mammalian target of the rapamycin (mTOR) signaling pathway. Mice were exposed to isoflurane at postnatal day 7 (P7) and underwent spared nerve injury at P28 which causes chronic pain. Selected groups were treated with rapamycin, an mTOR inhibitor, for eight weeks. Behavioral tests show early isoflurane exposure enhances susceptibility to chronic pain, and rapamycin treatment improves outcomes. Immunohistochemistry, Western blotting, and q-PCR indicates that isoflurane upregulates mTOR expression and neural activity in DSC and DRG. Accompanying upregulation of mTOR and rapamycin-reversible changes in chronic pain-associated markers, including N-cadherin, cAMP response element-binding protein (CREB), purinergic P2Y12 receptor, glial fibrillary acidic protein (GFAP) in DSC; and connexin 43, phospho-extracellular signal-regulated kinase (p-ERK), GFAP, Iba1 in DRG, were observed. We conclude that early GA exposure alters the development of pain circuits such that mice are subsequently more vulnerable to chronic neuropathic pain states.

The diversity and inclusion discussion permeates many sectors of society. Within this dialogue, science and scientists are acutely aware of the value of diversity and the need for inclusion. While demographic diversity in science has received considerable recent attention, very little research and understanding exists on inclusion. Our study presents empirical data on the meaning of inclusion using a crowdsourcing approach that sought responses to the question “What does inclusion mean to you?”. The most prominent concepts were those of empathy, warmth, support, love, acceptance and curiosity; diverse perspectives; and participation. We clustered conceptual elements of inclusion into four themes: access and participation, embracing diverse perspectives, a welcome environment, and team belonging. On the basis of these data, we theorize a conceptual framework model from which inclusion may be put into practice. Our model suggests a dynamic process of inclusion operating from principal structural elements of 1) a foundation that involves place, access and participation, and space; 2) reciprocal engagement as an engine for inclusion; and 3) expression of inclusion as culture. The framework model demonstrates a means by which the practice of diversity can be more than shifts in demographic statistics, and instead promote the full expression of benefits derived when the many dimensions of diversity are truly included.

Functional gastro-intestinal disorders (FGID) including irritable bowel syndrome (IBS) are frequently handled by self-management with over the counter (OTC) products such as hyoscine butylbromide (HBB), alone or in combination with paracetamol, and natural products such as peppermint oil. To obtain real-world information, we have performed an anonymous pharmacy-based patient survey among 1686 users of HBB, HBB + paracetamol and peppermint oil. Based on the distinct but overlapping indications for the three OTC products, multiple logistic regression was applied to compare them in users reporting gastrointestinal cramps and pain, bloating, flatulence, or IBS as cardinal symptom. All three treatments reduced symptoms and associated impairments of work/daily chores, leisure activities, and sleep by approximately 50%. Based on the four cardinal symptoms and the four dependent continuous variables of interest (change of intensity of symptoms and of the three impairment domains) a total of 16 logistic regression models were applied. HBB, HBB + paracetamol, and peppermint oil had similar reported overall effectiveness in those models. Gender, age, baseline symptom severity and impairment in one of three domains had small and inconsistent effects on perceived treatment success. We provide evidence that HBB, HBB + paracetamol, and peppermint oil have comparable effectiveness in their approved indications under real-world conditions in an OTC setting.

Background/Objectives: Intervertebral disc degeneration is the most common cause of low back pain (LBP) and lumbosciatica is a major challenge to healthcare systems worldwide. ''For years, ozone therapy has been used with excellent results in intervertebral disc disease and in patients with LBP, thanks to its anti-inflammatory and pain-relieving action.'' At the other side, the repair effect fulfilled by porcine collagen, is a novelty to approach this pathology. In vitro studies have demonstrated the positive action of porcine collagen in extracellular matrix remodeling and homeostasis These tissue changes, associated with LBP, may suggest an indication for combined ozone/collagen treatment in patients with LBP. However, no studies have been reported regarding this combination of treatments. Methods: The present work compared two treatment groups (each of 10 LBP patients): A) Oxygen-Ozone Therapy (OOT) vs. B) OOT plus porcine collagen type 1 injections (COL I). Pain intensity and physiological function were assessed by the numerical rating scale (NSR) method. The Roland-Morrison questionnaire was used to assess disability. Patient data were acquired before, during and at six months of follow-up. Significant differences were assessed by ANOVA and T-Student test. Results: The analyses revealed significant statistical differences comparing the two arms, where, the OOT COL I treatment demonstrated a booster efficacy in pain, while the questionnaire revealed a reduction in disability. Conclusions:. The combination of these two therapies could be effective for the management of LBP. However no studies have been reported in literature regarding this therapeutic combination.

Pain is a multifaceted multisystem disorder that adversely affects neuro-psychological processes. This study compares the effectiveness of central-stimulation (tDCS) and peripheral-stimulation (TENS) in pain-inhibition during a cognitive-task in healthy volunteers and to observe potential neuro-cognitive improvements. Healthy eighty volunteers went through a complete experimental protocol comprising pain-induction (CPT), administration of tDCS/TENS, EEG-data acquisition, and cognitive assessments. The protocol for this study is categorized into 04-groups: G1(Control), G2(TENS), G3(Anodal-tDCS), and G4(Cathodal-tDCS). Paired t-tests (p

The onset and progression of human inflammatory joint diseases are strongly controlled by the activation of resident synovium/infrapatellar fat pad (IFP) pro-inflammatory and pain-transmitting signaling. We recently reported that intra-articularly injected IFP-derived Mesenchymal Stem/Stromal Cells (IFP-MSC) acquire a potent immunomodulatory phenotype and actively degrade Substance P (SP) via neutral endopeptidase CD10 (neprilysin). Our hypothesis is that IFP-MSC robust immunomodulatory therapeutic ef-fects are largely exerted via their CD10-bound exosomal secretome (IFP-MSC EXOs) by attenuating synoviocyte pro-inflammatory activation and articular cartilage degradation. Herein, IFP-MSC EXOs were isolated from CD10High- and CD10Low-expressing IFP-MSC cultures and their exosomal miRNA cargo was assessed using multiplex methods. Functionally, we interrogated the effect of CD10High and CD10Low EXOs on stimulated by inflammatory/fibrotic cues synoviocytes monocultures and cocultures with IFP-MSC de-rived chondropellets. Finally, CD10High EXOs were tested in vivo for their therapeutic capacity in an animal model of acute synovitis/fat pad fibrosis. Our results showed that CD10High and CD10Low EXOs possess distinct miRNA profiles. Reactome analysis of miRNAs highly present in exosomes showed their involvement in the regulation of six gene groups, particularly the immune system. Stimulated synoviocytes exposed to IFP-MSC EXOs demonstrated significantly reduced proliferation and altered inflammation-related molecular profiles compared to control stimulated synoviocytes. Importantly, CD10High EXOs treatment of stimulated chondropellets/synoviocytes cocultures indicated a significant chondroprotective effects. Therapeutically, CD10High EXOs treatment resulted in robust chondroprotective effects by retaining articular cartilage structure/composition and PRG4 (lubricin)-expressing cartilage cells in the animal model of acute synovitis/IFP fibrosis. Our study suggests that CD10High EXOs possess immuno-modulatory miRNA attributes with strong chondroprotective/anabolic effects for articular cartilage in vivo. The results could serve as a foundation for EXOs-based therapeutics for the resolution of detrimental aspects of immune-mediated inflammatory joint changes associated with conditions such as osteoarthritis (OA).

Background: Symptomatic Pelvic Congestion Syndrome (PCS) is often underdiagnosed and undertreated. We investigate a symptoms-based screening algorithm and treatment algorithm focused on position and location of pain for each type of PCS. Methods: This study is a retrospective, single-institution, multi-site review of 343 female patients who presented with pelvic pain. Results: Following a symptoms-based algorithm, 302 patients fulfilled criteria for inclusion; 299 patients had positional symptoms with a positive predictive value (PPV) of 97.99%, sensitivity of 98.99% and Odds Ratio (OR) of 48.83 (p=0.0003) while duplex ultrasonography (DUS) had a PPV of 98.84%, sensitivity of 86.49%, and OR of 6.4 (p=0.0396) confirmed by contrast venography. Patients with Type I PCS were treated with embolization and 87.5% reported total relief of anterior symptoms. Patients with Type II PCS were treated with embolization and/or vascular stenting based on their associated lesion, May-Thurner syndrome or Nutcracker syndrome, and 88.54% reported ≥50% symptom relief and 59.03% reported ≥80% symptom relief. Full treatment resulted in a mean “overall satisfaction” score of 96.07%. Conclusions: Algorithmic approaches are essential for PCS evaluation, diagnosis, and treatment. Patients with positional pelvic symptoms consistent with PCS should undergo diagnostic venography. Distinguishing between the types of PCS and using symptoms as a guide may be beneficial over a “one-size-fits-all” approach.

Background: COVID-19 vaccines have been linked to myocarditis which in some circumstances can be fatal. This systematic review aims to investigate potential causal links between COVID-19 vaccines and death from myocarditis using post-mortem analysis. Methods: We performed a systematic review of all published autopsy reports involving COVID-19 vaccination-related myocarditis through July 3^rd, 2023. All autopsy studies that include COVID-19 vaccine-induced myocarditis as a possible cause of death were included, without imposing any additional restrictions. Causality in each case was determined by three independent reviewers with cardiac pathology experience and expertise. Results: We initially identified 1,691 studies and, after screening for our inclusion criteria, included 14 papers that contained 28 autopsy cases. The cardiovascular system was the only organ system affected in 26 cases. In 2 cases, myocarditis was characterized as a consequence from multisystem inflammatory syndrome (MIS). The mean and median number of days from last COVID-19 vaccination until death was 6.2 and 3 days, respectively. Most of the deaths occurred within a week from the last injection. We established that all 28 deaths were causally linked to COVID-19 vaccination by independent adjudication. Conclusions: The temporal relationship, internal and external consistency seen among cases in this review with known COVID-19 vaccine-induced myocarditis, its pathobiological mechanisms and related excess death, complemented with autopsy confirmation, independent adjudication, and application of the Bradford Hill criteria to the overall epidemiology of vaccine myocarditis, suggests there is a high likelihood of a causal link between COVID-19 vaccines and death from suspected myocarditis in cases where sudden, unexpected death has occurred in a vaccinated person. Urgent investigation is required for the purpose of risk stratification and mitigation in order to reduce the population occurrence of fatal COVID-19 vaccine-induced myocarditis.

Irritable bowel syndrome (IBS) is one of the most common gastrointestinal diseases in humans. It is characterized by visceral pain and/or discomfort, hypersensitivity and abnormal motor responses along with change in gut habits. Although the etio-pathogenesis of IBS is only partially understood, a main role has been attributed to psychosocial stress of different origin. Animals models such as neonatal maternal separation, water avoidance stress and wrap restraint stress have been developed as psychosocial stressors in the attempt to reproduce the IBS symptomatology and identify the cellular mechanisms responsible for the disease. The study of these models has led to the production of drugs potentially useful for IBS treatment. This review intends to give an overview on the results obtained with the animal models; to emphasize the role of the enteric nervous system in IBS appearance and evolution and as a possible target of drug therapies.