Biofilm exopolysaccharides alter sensory-neuron-mediated sickness during lung infection.

Infections of the lung cause observable sickness thought to be secondary to inflammation. Signs of sickness are crucial to alert others via behavioral-immune responses to limit contact with contagious individuals. Gram-negative bacteria produce exopolysaccharide (EPS) that provides microbial protection; however, the impact of EPS on sickness remains uncertain. Using genome-engineered Pseudomonas aeruginosa (P. aeruginosa) strains, we compared EPS-producers versus non-producers and a virulent Escherichia coli (E. coli) lung infection model in male and female mice. EPS-negative P. aeruginosa and virulent E. coli infection caused severe sickness, behavioral alterations, inflammation, and hypothermia mediated by TLR4 detection of the exposed lipopolysaccharide (LPS) in lung TRPV1+ sensory neurons. However, inflammation did not account for sickness. Stimulation of lung nociceptors induced acute stress responses in the paraventricular hypothalamic nuclei by activating corticotropin-releasing hormone neurons responsible for sickness behavior and hypothermia. Thus, EPS-producing biofilm pathogens evade initiating a lung-brain sensory neuronal response that results in sickness.

Efficacy of high thiamine dosage in treating patients with biotin thiamine responsive basal ganglia disease: a two case reports.

BACKGROUND: Biotin-thiamine-responsive basal ganglia disease (BTBGD) is a rare, autosomal recessive neurometabolic disorder caused by mutations in the SLC19A3 gene and characterized by recurrent sub-acute episodes of encephalopathy. Patients with BTBGD have classical neuroimaging findings and a dramatic response to high doses of thiamine. OBJECTIVE: To highlight the advantages of administering a higher dose of thiamine for patients with BTBGD who have not shown improvement with the standard recommended dosage. RESULTS: Herein, we report on two Saudi girls with classical clinical and radiological findings of BTBGD. Hallmark symptoms in these patients included an acute onset of ataxia, tremor, slurred speech, dystonia, and dysphagia. The initial routine laboratory workups were unremarkable. Brain magnetic resonance imaging revealed extensive hyperintense signals in the bilateral basal ganglia, which suggested the diagnosis of a BTBGD. Hence started empirically on biotin 10 mg/kg/day and thiamine 40 mg/kg/day, but there was no noticeable improvement. After increasing the thiamine to 75 mg/kg/day the patients started to improve significantly. Genetic testing was requested and came positive for the mutation of the SLC19A3 gene. After two months of initiating the management, thiamine was reduced to 30 mg/kg/day. Subsequent follow-ups showed complete improvement in their condition with no apparent long-term sequel or relapse. CONCLUSION: we conclude that administration of thiamine at a dosage of up to 40 mg/kg/day may not be sufficient in treating certain patients with BTBGD. Thus, considering a significantly higher dosage could potentially contribute to achieving remission.

Comparing the Outcomes of Scalpel and Diathermocoagulation Dissection in Abdominoplasty: A Systematic Review and Meta-Analysis.

BACKGROUND: Abdominoplasty, an emerging surgical procedure worldwide, associated with complications, as seroma, infection, and hematoma. This systematic review and meta-analysis compare the outcomes of abdominoplasty procedures performed using a scalpel versus a diathermocoagulation device (diathermy monopolar electrocautery), aiming to find a safer approach with fewer complications. METHODS: We conducted a systematic search in November 2023 using PubMed, Ovid Medline, and Ovid Chocrane databases. The methodological index for nonrandomized studies and the Revised Cochrane Risk of Bias assessment tools were used to assess risk of bias for observational studies and randomized controlled trials, respectively. The data were analyzed using RevMan software. RESULTS: Six articles (1135 patients) were included, 521 patients were operated using a scalpel and 614 using electrocautery. Our analysis suggests that both seroma and drain output were seen more among the electrocautery group, with an odds ratio (OR) of 0.62 (95% CI [0.39, 0.97], p = 0.04) and - 103.63 (95% CI [- 205.67, - 1.59], p = 0.05), respectively. It is important to note the high heterogeneity seen among the studies discussing the total drain output. Additionally, we did not find any statistical significance between both techniques in terms of the rate of hematoma, wound infection, operation time, and hospital stay length. CONCLUSION: When comparing the use of scalpel and electrocautery dissection in abdominoplasty, higher rates of seroma and total drain output are significantly associated with electrocautery dissection. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

TRPV1 Activation Promotes ß-arrestin2 Interaction with the Ribosomal Biogenesis Machinery in the Nucleolus:Implications for p53 Regulation and Neurite Outgrowth.

Transient receptor potential vanilloids (TRPV1) are non-selective cation channels that sense and transduce inflammatory pain signals. We previously reported that activation of TRPV1 induced the translocation of ß-arrestin2 (ARRB2) from the cytoplasm to the nucleus, raising questions about the functional role of ARRB2 in the nucleus. Here, we determined the ARRB2 nuclear signalosome by conducting a quantitative proteomic analysis of the nucleus-sequestered L395Q ARRB2 mutant, compared to the cytosolic wild-type ARRB2 (WT ARRB2), in a heterologous expression system. We identified clusters of proteins that localize to the nucleolus and are involved in ribosomal biogenesis. Accordingly, L395Q ARRB2 or WT ARRB2 after capsaicin treatment were found to co-localize and interact with the nucleolar marker nucleophosmin (NPM1), treacle protein (TCOF1) and RNA polymerase I (POL I). We further investigated the role of nuclear ARRB2 signaling in regulating neuroplasticity. Using neuroblastoma (neuro2a) cells and dorsal root ganglia (DRG) neurons, we found that L395Q ARRB2 mutant increased POL I activity, inhibited the tumor suppressorp53 (p53) level and caused a decrease in the outgrowth of neurites. Together, our results suggest that the activation of TRPV1 promotes the ARRB2-mediated regulation of ribosomal biogenesis in the nucleolus. The ARRB2-TCOF1-p53 checkpoint signaling pathway might be involved in regulating neurite outgrowth associated with pathological pain conditions.

Neural control of gut homeostasis.

The gut-brain axis is a coordinated communication system that not only maintains homeostasis, but significantly influences higher cognitive functions and emotions, as well as neurological and behavioral disorders. Among the large populations of sensory and motor neurons that innervate the gut, insights into the function of primary afferent nociceptors, whose cell bodies reside in the dorsal root ganglia and nodose ganglia, have revealed their multiple crosstalk with several cell types within the gut wall, including epithelial, vascular, and immune cells. These bidirectional communications have immunoregulatory functions, control host response to pathogens, and modulate sensations associated with gastrointestinal disorders, through activation of immune cells and glia in the peripheral and central nervous system, respectively. Here, we will review the cellular and neurochemical basis of these interactions at the periphery, in dorsal root ganglia, and in the spinal cord. We will discuss the research gaps that should be addressed to get a better understanding of the multifunctional role of sensory neurons in maintaining gut homeostasis and regulating visceral sensitivity.

The validity and reliability of the Arabic version of the Japanese Orthopedic Association Back Pain Evaluation Questionnaire: Can we implement it in Saudi Arabia?

BACKGROUND: The Japanese Orthopedic Association designed their back pain evaluation questionnaire (JOABPEQ) which was proven to be feasible, reliable and valid. The questionnaire's validity and reliability were confirmed when it was implemented in patients with different cultural background. Since the JOABPEQ still has not been utilized in any of the Arabic countries, we present the Arabic version with its validity and reliability. METHODS: After ensuring an optimal forward-backward translation of the JOABPEQ, the Arabic version was distributed among 151 patients visiting our clinics from December 2015 to February 2016. The reliability was tested using Cronbach's alpha. The convergent validity was assessed through aggregating and correlating the questionnaire's items with their previously designed and validated subscales described in the JOABPEQ validity study by Fukui et al. (four items for social function, seven for mental health, six for lumbar function, five for walking ability and four for low back pain); Spearman's correlation matrix was used. The correlation coefficient had to be greater than 0.40 for each item with its corresponding subscale to be satisfactory. Scores underwent descriptive analysis, and Mann-Whitney u test was performed to compare between categorical subgroups. RESULTS: 151 spine patients completed the questionnaire. The mean age (range) was 34.9 (10-72) years. The male respondents were 61 (40.4%) and the females were 90 (59.6%). The result of Cronbach's alpha for internal consistency (reliability) was 0.87 for the 25 items. The validity was confirmed since the correlation coefficient was greater than 0.4 for each item with only its relevant subscale. CONCLUSION: the Arabic version of the JOABPEQ is valid, reliable and feasible in assessing patients with spine disorders. We believe the JOABPEQ with its different versions are suitable questionnaires to be used across nations and can serve as a unified tool in conducting research and exchanging information in the future.

Knowledge around back pain and spinal disorders among Saudi patients: A cross-sectional study.

OBJECTIVE: To assess the knowledge of patients about low back pain and spinal disorders. METHODS: This cross-sectional study was conducted at King Saud University, Riyadh, Saudi Arabia, from December 2015 to February 2016, and comprised patients presenting with lower back pain. The low back pain knowledge questionnaire was translated to Arabic and distributed, after adding more questions, among patients. The scores were calculated as per the published guidelines. SPSS 21 was used for data analysis. RESULTS: There were 153 patients in the study. The reliability test revealed a Cronbach's alpha score of 0.834 for all items. The overall mean age was 40.2±19.3 years (range: 15-76 years). Besides, 61(39.9%) participants were males and 92(60.1%) were females. The overall median score was 9 (interquartile range: 0-19) out of 24 points. Both educational level and monthly income were found to be dependent variables (p<0.001; p=0.007). . CONCLUSIONS: The majority of patients with lower back pain had limited knowledge about their condition and the related complications.

Comprehensive evaluation of the child with global developmental delays or intellectual disability.

Global developmental delay (GDD) and intellectual disability (ID) are relatively common neurodevelopmental disorders that significantly impact affected children, their families, and society. The etiology of GDD/ID is notably diverse, encompassing both genetic and acquired factors. Although the precise cause of most GDD/ID cases remains unclear, an estimated half of all cases can be attributed to genetic factors. Thus, a detailed medical history and comprehensive physical examination remain pivotal for guiding diagnostic investigations into the underlying causes of GDD/ID. Advancements in genetic testing have supplanted traditional methods such as karyotyping and fluorescence in situ hybridization with chromosomal micro arrays, which are now the primary genetic tests for children with idiopathic GDD/ID. Moreover, the evaluation of Fragile X and Rett syndrome should be an integral component of initial diagnostic assessments. In recent years, whole-exome sequencing and whole-genome sequ-encing have emerged as important diagnostic tools for evaluating children with GDD/ID and have substantially enhanced the diagnostic yield rates. Gene therapy has emerged as a promising avenue and is poised to become a cornerstone in addressing various genetic developmental and epilepsy disorders. Early intervention facilitated by a proficient multidisciplinary team can markedly enhance the prognosis and outcomes of GDD/ID, particularly when parents or caregivers are actively engaged in the interventional process. This review discusses risk factors and common underlying causes, explores recent evidence and recommendations for genetic evaluation, and offers management strategies for children with GDD/ID.

Induction of antiviral interferon-stimulated genes by neuronal STING promotes the resolution of pain in mice.

Inflammation and pain are intertwined responses to injury, infection, or chronic diseases. While acute inflammation is essential in determining pain resolution and opioid analgesia, maladaptive processes occurring during resolution can lead to the transition to chronic pain. Here we found that inflammation activates the cytosolic DNA-sensing protein stimulator of IFN genes (STING) in dorsal root ganglion nociceptors. Neuronal activation of STING promotes signaling through TANK-binding kinase 1 (TBK1) and triggers an IFN-ß response that mediates pain resolution. Notably, we found that mice expressing a nociceptor-specific gain-of-function mutation in STING exhibited an IFN gene signature that reduced nociceptor excitability and inflammatory hyperalgesia through a KChIP1-Kv4.3 regulation. Our findings reveal a role of IFN-regulated genes and KChIP1 downstream of STING in the resolution of inflammatory pain.

Awareness and Underlying Factors for Total Knee Arthroplasty Reluctance in Saudi Arabia.

Background Total knee arthroplasty (TKA) is a successful surgical intervention for advanced knee arthritis. The efficacy of TKA in reducing pain and restoring joint function has been well documented. Despite the rewarding outcomes of TKA for knee osteoarthritis patients, their willingness to consider the procedure is limited. Aim This study aimed to assess patients' awareness and knowledge of total knee arthroplasty benefits and complications. Further, the reasons and factors contributing to reluctance among orthopedic patients in Saudi Arabia should be determined. Methods An online, structured, and self-administered questionnaire was used to collect data from adult orthopedic patients of both genders who were reluctant to undergo total knee arthroplasty despite surgeons' recommendations. The online questionnaire link was shared across multiple platforms, orthopedic forums, and healthcare social media channels. Qualitative data were presented as frequencies and percentages, while continuous data were reported as the mean (standard deviation [SD]). The statistical package for the social sciences software program was used for statistical analysis. Results A total of 629 participants were involved. The awareness of the expected benefits score, on a scale from 7 to 35, showed a mean (SD) of 20.9 (5.6). The score of the attitude towards expected complications, on a scale from 5 to 25, had a mean (SD) of 15.2 (3.6). The attitude towards the expected complications showed a significantly higher mean (SD) score in the older group aged >60 years than the younger one aged <40 years (15.7 (4.1) vs. 14.9 (3.5), respectively). Likewise, overweight and obese participants showed a significantly higher mean (SD) expected complications score compared to the healthy and underweight ones (15.4 (3.7) vs. 14.8 (3.5), respectively). The recorded reasons for refusal to undergo TKA were fear of anesthesia complications (317, 50.4%), followed by financial limitations (245, 39.0%), the unavailability of experienced surgeons (232, 36.9%), and fear of unfavorable outcomes (189, 30.0%). Conclusion There was a gap in knowledge and awareness of total knee arthroplasty among orthopedic patients in Saudi Arabia. Perceptions of benefits were inadequate, and there were misconceptions about the expected complications. The level of expected complications was higher among elderly and obese patients. Furthermore, fear of anesthesia complications and unfavorable outcomes, in addition to economic and financial problems, constituted major barriers to undergoing the procedure.

Pediatric Autoimmune Neuropsychiatric Disorder Linked to Streptococcal Infections.

Pediatric acute-onset neuropsychiatric syndrome (PANS) is a clinical condition with abrupt onset of obsessive-compulsive symptoms and/or severe eating restrictions and at least two concomitant cognitive, behavioral, or neurological symptoms. Pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) is a subtype of PANS with a controversial diagnosis. A case of a 12-year-old girl with severe eating restriction, obsessive-compulsive symptoms, anxiety, and neurological symptoms who initially was diagnosed with obsessive-compulsive disorder is presented. Published reports were reviewed for the evidence of diagnosis and treatment options of PANS/PANDAS. Studies show controversy regarding diagnosis. Moreover, study reports showed limited evidence for the treatment options. Selective serotonin reuptake inhibitors and psychotherapy are considered the main treatment with prompt infection treatment in the case of PANDAS.

Developing of Biotin-Thiamine Responsive Basal Ganglia Disease after Accidental Ingestion of Ethyl Alcohol: A Case Report.

Biotin-thiamine-responsive basal ganglia disease (BTBGD) is a rare, inherited neurometabolic disorder caused by mutations in the SLC19A3 gene and characterized by recurrent sub-acute episodes of encephalopathy that are often triggered by infections. Patients with BTBGD have classical neuroimaging findings and a dramatic response to high doses of thiamine. Herein, we report a 2 and a half-year-old Saudi girl presented with an acute onset of ataxia, slurred speech, and dysphagia, which was preceded by a history of accidental ingestion of around 20 mL of ethyl alcohol that is used in formulating perfumes 1 day earlier. Her older brother had a similar clinical presentation and was diagnosed with BTBGD. The patient was fully alert and spoke in full sentences with dysarthria. She was unable to walk unassisted. Investigation revealed a positive toxicity test for ethyl alcohol (10 mg/dL), and brain magnetic resonance imaging showed basal ganglia changes consistent with BTBGD. The dramatic response to high doses of thiamine suggested SLC19A3 as a strong candidate gene, and Sanger sequencing revealed a homozygous (NM_025243.4): c.1264A>G (p.Thr422Ala) mutation. Patients with BTBGD should be cautious and aware of ethyl alcohol products, which can lead to a BTBGD crisis. The administration of a high dose of thiamin may be required in patients who have not responded to the recommended dose. Further clinical research is required to determine the optimal doses.

Probing the interaction of cephalosporin antibiotic "cefoperazone" with lysozyme using spectroscopic and in silico methods: Effect of paracetamol on binding.

The interaction of lysozyme with cefoperazone was studied by means of spectroscopic and computational approaches. The change in the UV-visible spectrum of lysozyme in presence of cefoperazone was an indication of the complex formation between them. Fluorescence spectroscopy suggested that there was a fair interaction between the protein and drug which was taken place via dynamic quenching mechanism and the binding ratio was approximately 1:1. The binding was energetically feasible and principally supported by the hydrophobic forces. CD spectroscopic studies have shown that cefoperazone induced the secondary structure of lysozyme by increasing the α-helical contents of the latter. In silico studies revealed that the large nonpolar cavity was the preferred binding site of cefoperazone within lysozyme and the interaction was taken place mainly through hydrophobic forces with small involvement of hydrogen bonding and electrostatic interactions which is in good agreement with the experimental analyses. Effect of paracetamol was also seen on the binding and it was found that paracetamol had a negative influence on the binding between cefoperazone and lysozyme.

The Frequency and Precipitating Factors for Breakthrough Seizures in Children with Epilepsy.

Background and Purpose: To determine the common precipitating factors for breakthrough seizures in children with epilepsy. Methods: This retrospective study reviewed the charts of children with epilepsy who were followed up in the pediatric neurology clinic of King Fahad Hospital in Al-Baha region, Saudi Arabia, between January 2015 and August 2022. Children between 1 to 14 years of age who had epilepsy, as per the International League Against Epilepsy definition and received anti-seizure medication with a seizure-free period of at least 2 months before breakthrough seizure episode, were included in the study. Results: Of the 108 children included in the study, the mean age was 6.8±1.6 years, and among them (55.5%) were male. Most parents (69.5%) were unaware of the triggering factors of seizure. The majority of patients (88%) reported at least one precipitating factor for breakthrough seizures and the most common one was systemic infection associated with fever (52.8%), and then non-compliance to medications in (34.3%) of the patients. In terms of the electroencephalogram, around 84 patients (77.8%) had abnormal electroencephalogram. Finally, monotherapy was maintained in 63.9% of patients. Conclusions: We conclude that the most common trigger for breakthrough seizure is a systemic infection associated with fever and non-compliance to anti-seizure medications. Increasing the level of awareness by different methods may help limit or even prevent seizures from occurring. Randomized controlled trials could shed light on the adjustment of anti-seizure medications temporarily by increasing the dosage or giving extra doses during the infection to avoid breakthrough seizures.

Adverse Effects of Sinopharm COVID-19 Vaccine among Vaccinated Medical Students and Health Care Workers.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease caused a highly problematic situation worldwide. Various vaccines were launched to combat the COVID-19 pandemic. This study aims to investigate the adverse effects of first and second doses of the Sinopharm vaccine among vaccinated medical and dental students and healthcare workers. A well-established questionnaire was distributed online, and 414 medical and dental students and healthcare workers (HCW) comprising 355 females (85.7%) and 59 males (14.3%) participated; all were vaccinated with two doses of Sinopharm. The most common side effect was pain at the injection site after dose one in 253 respondents (61.3%) and after dose two in 161 respondents (38.9%). Other symptoms included general lethargy in 168 (40.6%), myalgia/body pain in 99 (23.9%), low-grade fever in 93 (22.4%), and headache in 87 (21%) respondents. Common side effects reported after the second dose of the vaccine following pain at the injection site included general lethargy in 21.3% (88), headache in 10.4% (43), myalgia/body pain in 9.9% (41), and low-grade fever in 6.1% (25) of the respondents. In conclusion, common adverse effects of the Sinopharm vaccine were pain at the injection site, general lethargy, myalgia, body pain, low-grade fever, and headache. These adverse effects were mild in intensity for both doses but slightly more frequent and severe for the first dose than the second dose.

Gut-innervating TRPV1+ Neurons Drive Chronic Visceral Pain via Microglial P2Y12 Receptor.

BACKGROUND & AIMS: Chronic abdominal pain is a common symptom of inflammatory bowel diseases (IBDs). Peripheral and central mechanisms contribute to the transition from acute to chronic pain during active disease and clinical remission. Lower mechanical threshold and hyperexcitability of visceral afferents induce gliosis in central pain circuits, leading to persistent visceral hypersensitivity (VHS). In the spinal cord, microglia, the immune sentinels of the central nervous system, undergo activation in multiple models of VHS. Here, we investigated the mechanisms of microglia activation to identify centrally acting analgesics for chronic IBD pain. METHODS: Using Designer Receptors Exclusively Activated by Designer Drugs (DREADD) expressed in transient receptor potential vanilloid member 1-expressing visceral neurons that sense colonic inflammation, we tested whether neuronal activity was indispensable to control microglia activation and VHS. We then investigated the neuron-microglia signaling system involved in visceral pain chronification. RESULTS: We found that chemogenetic inhibition of transient receptor potential vanilloid member 1+ visceral afferents prevents microglial activation in the spinal cord and subsequent VHS in colitis mice. In contrast, chemogenetic activation, in the absence of colitis, enhanced microglial activation associated with VHS. We identified a purinergic signaling mechanism mediated by neuronal adenosine triphosphate (ATP) and microglial P2Y12 receptor, triggering VHS in colitis. Inhibition of P2RY12 prevented microglial reactivity and chronic VHS post-colitis. CONCLUSIONS: Overall, these data provide novel insights into the central mechanisms of chronic visceral pain and suggest that targeting microglial P2RY12 signaling could be harnessed to relieve pain in patients with IBD who are in remission.

Glycemic Control for Type 2 Diabetes Mellitus Patients: A Systematic Review.

Diabetes mellitus is a chronic metabolic disorder resulting in hyperglycemia and microvascular and macrovascular complications in individuals globally. Type 2 diabetes mellitus (T2DM) is highly prevalent and accounts for 90% of patients. Maintaining blood glucose concentration is essential to avoid severe complications. Glycemic control is the optimal serum glucose concentration in diabetic patients. It is necessary to identify factors affecting the glycemic control of patients to prevent control and complications. We conducted this systematic review to assess the factors affecting glycemic control among type 2 diabetes mellitus patients. Published literature between the years 2020 to 2022 was retrieved from PubMed, Science Direct, and Google Scholar using different combinations of keywords: T2DM, Glycemic control, Poor, Good, Adequate, Inadequate, Factors, Association, and Determinants. All original articles written in the English language with full-text available and the value of glycemic control defined were included. A total of 1866 studies were retrieved. After the title, abstract, screening, and full-text screening, 12 studies were eligible. The prevalence of poor glycemic control was high, and it ranged between 45.2% and 93% among the studies. The factors associated with glycemic control were stratified into four categories: personal or body-related, clinical, medication-related, and behavioral factors. There was a high prevalence of poor glycemic control in all included studies. The glycemic control was associated with various factors; some were related to the patient or medical conditions while others were related to the behavior of the patients or the medication administrated.

Comparison of Biological, Pharmacological Characteristics, Indications, Contraindications and Adverse Effects of JYNNEOS and ACAM2000 Monkeypox Vaccines.

Human monkeypox is an emerging viral zoonotic disease, that has caused highly distinctive, challenging and threatening problems worldwide. The US Food and Drug Administration (FDA) has given interim authorization for the JYNNEOS and ACAM2000 vaccines for the outbreak of monkeypox 2022. The present study aims to highlight the globally derived evidence about the biological and pharmacological features, indications, contraindications and adverse effects of JYNNEOS and ACAM2000 vaccines. Initially, 82 documents were selected and, finally, 14 fact sheets, documents and international organizations were included. The data were recorded from the World Health Organization (WHO), Centers for Disease Control and Prevention (CDC), Food and Drug Administration (FDA) USA, ISI-Web of Science, PubMed, EMBASE and Scopus. The data revealed that the JYNNEOS vaccine has been recommended to children, adults, females during pregnancy and people of all age groups with a dose of 0.5 mL, and the complete vaccination cost per person is about USD 115. It provides immunogenicity, and the mean titer of neutralizing antibodies was 153.5. However, the ACAM2000 vaccine is contraindicated in infants and pregnant females, and recommended to people over 18 years of age and older, with a single dose of 0.0025 mL, and a cost of about USD 139. ACAM2000 provides immunogenicity, and the mean titer of neutralizing antibodies was 79.3. The JYNNEOS vaccine has mild adverse effects including pain, redness, swelling or itching at the site of the vaccine shot, fever, fatigue, headache, nausea and muscle pain. However, the ACAM2000 vaccine can cause pain, redness, edema, headache, fever, fatigue, muscle pain, body ache, nausea, vomiting, diarrhea, shortness of breath and increased risk of myopericarditis and cardiomyopathy. The evidence supports the view that both vaccines are beneficial, but the overall impact of JYNNEOS is better than that of ACAM2000.

The neuronal tyrosine kinase receptor ligand ALKAL2 mediates persistent pain.

The anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase known for its oncogenic potential that is involved in the development of the peripheral and central nervous system. ALK receptor ligands ALKAL1 and ALKAL2 were recently found to promote neuronal differentiation and survival. Here, we show that inflammation or injury enhanced ALKAL2 expression in a subset of TRPV1+ sensory neurons. Notably, ALKAL2 was particularly enriched in both mouse and human peptidergic nociceptors, yet weakly expressed in nonpeptidergic, large-diameter myelinated neurons or in the brain. Using a coculture expression system, we found that nociceptors exposed to ALKAL2 exhibited heightened excitability and neurite outgrowth. Intraplantar CFA or intrathecal infusion of recombinant ALKAL2 led to ALK phosphorylation in the lumbar dorsal horn of the spinal cord. Finally, depletion of ALKAL2 in dorsal root ganglia or blocking ALK with clinically available compounds crizotinib or lorlatinib reversed thermal hyperalgesia and mechanical allodynia induced by inflammation or nerve injury, respectively. Overall, our work uncovers the ALKAL2/ALK signaling axis as a central regulator of nociceptor-induced sensitization. We propose that clinically approved ALK inhibitors used for non-small cell lung cancer and neuroblastomas could be repurposed to treat persistent pain conditions.

Treatment response in elderly patients with advanced colorectal cancer at King Abdulaziz Medical City, Princess Norah Oncology Center, Jeddah.

INTRODUCTION: Colorectal carcinoma is the most evident carcinoma in the elderly. Despite its high incidence and mortality rate, there is insufficient research about the best treatment options for colorectal carcinoma. OBJECTIVE: This study was designed to assess the best treatment modality for colorectal carcinoma in elderly Saudi patients. METHODS: We conducted a retrospective analysis of medical records at the Princess Norah Oncology Center (PNOC), King Abdulaziz Medical City, Jeddah, Saudi Arabia. We included patients treated at PNOC between 2010 and 2015. Only patients aged above 70 years with advanced colon were included in the study. RESULTS: The cohort included 57 patients with an average age of 76.51 with 27 alive patients and 30 dead patients. Nonmucinous adenocarcinoma had significant higher mortality (n = 20). Most patients received surgical treatment which was associated with less risk for mortality; however, it was nonsignificant. Surgery was followed by first-line treatment which had a mortality rate of 50%. The least treatment associated with mortality was local liver treatment (n = 0). Survival analysis found that only treatment with significant higher survival was shift to next line of treatment (at least once) [HR = 0.06, 95% CI (0.00, 0.79), P value = 0.03]. Other treatments were not associated with significant mortality reduction. First-line treatment was associated with higher mortality risk; nevertheless, it was nonsignificant. CONCLUSION: Local radiotherapy and local liver ablation had the least mortality rate. However, in multivariate Cox regression analysis, we found that shift to next line of treatment was associated with the significant high survival rate.