Rapid identification of inflammatory arthritis and associated adverse events following immune checkpoint therapy: a machine learning approach.

Introduction: Immune checkpoint inhibitor-induced inflammatory arthritis (ICI-IA) poses a major clinical challenge to ICI therapy for cancer, with 13% of cases halting ICI therapy and ICI-IA being difficult to identify for timely referral to a rheumatologist. The objective of this study was to rapidly identify ICI-IA patients in clinical data and assess associated immune-related adverse events (irAEs) and risk factors. Methods: We conducted a retrospective study of the electronic health records (EHRs) of 89 patients who developed ICI-IA out of 2451 cancer patients who received ICI therapy at Northwestern University between March 2011 to January 2021. Logistic regression and random forest machine learning models were trained on all EHR diagnoses, labs, medications, and procedures to identify ICI-IA patients and EHR codes indicating ICI-IA. Multivariate logistic regression was then used to test associations between ICI-IA and cancer type, ICI regimen, and comorbid irAEs. Results: Logistic regression and random forest models identified ICI-IA patients with accuracies of 0.79 and 0.80, respectively. Key EHR features from the random forest model included ICI-IA relevant features (joint pain, steroid prescription, rheumatoid factor tests) and features suggesting comorbid irAEs (thyroid function tests, pruritus, triamcinolone prescription). Compared to 871 adjudicated ICI patients who did not develop arthritis, ICI-IA patients had higher odds of developing cutaneous (odds ratio [OR]=2.66; 95% Confidence Interval [CI] 1.63-4.35), endocrine (OR=2.09; 95% CI 1.15-3.80), or gastrointestinal (OR=2.88; 95% CI 1.76-4.72) irAEs adjusting for demographics, cancer type, and ICI regimen. Melanoma (OR=1.99; 95% CI 1.08-3.65) and renal cell carcinoma (OR=2.03; 95% CI 1.06-3.84) patients were more likely to develop ICI-IA compared to lung cancer patients. Patients on nivolumab+ipilimumab were more likely to develop ICI-IA compared to patients on pembrolizumab (OR=1.86; 95% CI 1.01-3.43). Discussion: Our machine learning models rapidly identified patients with ICI-IA in EHR data and elucidated clinical features indicative of comorbid irAEs. Patients with ICI-IA were significantly more likely to also develop cutaneous, endocrine, and gastrointestinal irAEs during their clinical course compared to ICI therapy patients without ICI-IA.

Comparison of risk factors for Methicillin Resistant Staphylococcus aureus (MRSA) colonization in healthy newborns, born to mothers with and without MRSA colonization.

Objective: To compare the risk factors for MRSA colonization in healthy newborns, born of mothers with and without MRSA colonization. Methods: This case control study was conducted in post-natal unit of Lady Willingdon Hospital, affiliated with King Edward Medical University/Mayo Hospital, Lahore from January to June 2017. The vaginal and anterior nares swabs for MRSA culture were collected from mothers within six hours before planned delivery and the neonatal anterior nares swabs for MRSA culture were taken within one hour of birth. All the samples were cultured in Paediatric Microbiology laboratory in Mayo Hospital. Data were analyzed through SPSS 20.0 and logistic regression was applied for risk factors analysis. Results: Out of total 80 mothers and their newborns, 15 (18.75%) mothers and 16 neonates (20%) were MRSA colonized. The frequency of MRSA colonization in mothers' anterior nares and vaginal swab was 17.5% and 1.25% respectively. The significant risk factors were prolonged rupture of membranes for >18 hours (p-value 0.02, odds ratio 11.85, 95% CI 1.41-99.3), birth weight <2500 grams (p-value 0.01, odds ratio 5.39, 95% CI 1.35-21.4), history of presence of meconium (p-value 0.006, odds ratio 7.30, 95% CI 1.78-29.8). The non-significant factors were age of mother (p-value 0.682, odds ratio 0.765, 95% CI 1.0.212-2.76), parity (p-value 0.185, odds ratio 3.82, 95% CI 0.46-31.66) , gestation (p-value 0.615, odds ratio 0.797, 95% CI 0.714-0.89) , mode of delivery (p-value 0.576, odds ratio 0.543, 95% CI 0.062-4.76), sex of baby (p-value 0.546, odds ratio 0.683, 95% CI 0.196-2.37) and presentation of baby at birth (p-value 0.47, odds ratio 0.795, 95% CI 0.71-0.89). Conclusion: The presence of meconium, prolonged rupture of membranes and low birth weight were the significant risk factors for MRSA colonization in healthy new-borns, born to mothers with and without MRSA colonization.

STAT3 palmitoylation initiates a positive feedback loop that promotes the malignancy of hepatocellular carcinoma cells in mice.

Constitutive activation of the transcription factor STAT3 (signal transducer and activator of transcription 3) contributes to the malignancy of many cancers such as hepatocellular carcinoma (HCC) and is associated with poor prognosis. STAT3 activity is increased by the reversible palmitoylation of Cys108 by the palmitoyltransferase DHHC7 (encoded by ZDHHC7). Here, we investigated the consequences of S-palmitoylation of STAT3 in HCC. Increased ZDHHC7 abundance in HCC cases was associated with poor prognosis, as revealed by bioinformatics analysis of patient data. In HepG2 cells in vitro, DHHC7-mediated palmitoylation enhanced the expression of STAT3 target genes, including HIF1A, which encodes the hypoxia-inducible transcription factor HIF1α. Inhibiting DHHC7 decreased the S-palmitoylation of STAT3 and decreased HIF1α abundance. Furthermore, stabilization of HIF1α by cyclin-dependent kinase 5 (CDK5) enabled it to promote the expression of ZDHHC7, which generated a positive feedback loop between DHHC7, STAT3, and HIF1α. Perturbing this loop reduced the growth of HCC cells in vivo. Moreover, DHHC7, STAT3, and HIF1α were all abundant in human HCC tissues. Our study identifies a pathway connecting these proteins that is initiated by S-palmitoylation, which may be broadly applicable to understanding the role of this modification in cancer.

Obstructing Stage IV Adenocarcinoma of the Transverse Colon in a Young Patient With Vitiligo.

Advanced colorectal cancer, while uncommon, can occur in a young patient. We present a rare case of advanced transverse colon cancer in a young patient with vague symptoms and unique comorbid conditions, while reviewing the literature on colorectal cancer and its association with autoimmune conditions. With a recent increase in the incidence of colon cancer in young patients, further research is needed as to whether colorectal cancer screening is warranted in younger cohorts outside of current recommendations and guidelines. Investigations are needed into the factors that may explain this and the public health interventions that can be employed to improve colon cancer prevention. The objective of this report is to highlight the importance of recognizing alarming symptoms and raise awareness of the increasing incidence of early-onset colon cancer in young patients.

A cohort study investigating the role of Bisphenol A in the molecular pathogenesis of breast cancer.

BACKGROUND: Breast cancer is an abnormal division of breast cells. Bisphenol A (BPA), an environmental toxicant, is identified as an emerging risk factor for breast cancer development. However, to the best of our knowledge, no previous study has investigated the BPA levels in breast cancer patients in Pakistan. The present study sought to explore the role of BPA in tumor growth among the Pakistani population. METHODS: The levels of BPA were analyzed in the serum samples of breast cancer patients and controls by using HPLC. To elucidate the role of BPA to initiate tumorigenic events in breast tissue different biochemical assays along with expression analysis of tumor markers were performed. RESULTS: The level of BPA in the serum samples of breast cancer patients was significantly higher than control. Histological analysis of breast cancer tissue samples revealed distinct subtypes of tumor, such as ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC). There was a significant increase in ROS level while a significant decrease in the levels of superoxide dismutase (SOD) and catalase (CAT) enzymes in malignant breast tissue samples as compared to control tissue samples. We found upregulated expression of p53, ZEB1 and WNT1 genes at mRNA level in malignant breast tissue samples by 17 folds, 328 folds and 35 folds, respectively. p53 protein expression in malignant breast tissue samples was also enhanced at the translational level. CONCLUSION: Current findings suggest a relationship between BPA and the progression of breast cancer among the Pakistani population.

Botanical Briefs: Primula obconica Dermatitis.

Primula obconica, a household plant originally found in China that was introduced in Europe in the 1880s, has been reported to cause plant-induced contact dermatitis (CD). The condition more commonly is reported in Europe and less frequently in the United States, where the plant is not commonly included in patch testing protocols. Clinical features of P obconica CD can include facial and hand as well as fingertip dermatitis. The main allergens known to cause these findings are primin and miconidin. Treatment of P obconica CD mainly involves avoiding contact with the plant and applying a topical steroid.

Acetyltransferase from Akkermansia muciniphila blunts colorectal tumourigenesis by reprogramming tumour microenvironment.

OBJECTIVE: The protein post-translational modification (PTM) in host cells can be rewritten by bacterial enzymes and represents an unprecedented mechanism in the communication between intestinal flora and the host. Although Akkermansia muciniphila has been widely investigated as a probiotic and blunts colitis-associated tumourigenesis in mice, there is little understanding regarding whether A. muciniphila is involved in the PTM of colorectal cancer (CRC). This study investigates whether and how A. muciniphila engages in the PTM of host CRC. DESIGN: The secreting extracellular vesicles from A. muciniphila and purified Amuc_2172 were used for different tumourigenesis mice models. Amuc_2172-induced immune activity of CD8+ cytotoxic T lymphocytes (CTLs) were evaluated in vitro and in vivo. The acetyltransferase activity and downstream target genes of Amuc_2172 were investigated. RESULTS: Amuc_2172, a general control non-derepressible 5-related acetyltransferase of A. muciniphila, was accessible to colorectal cells by macropinocytosis and functioned as an acetyltransferase of Lys14 on histone H3 (H3K14ac). Elevated H3K14ac on Hspa1a loci promoted the transcription and secretion of heat-shock protein 70 (HSP70) in cancer cells. High level of HSP70 promoted the immune activity of CTLs in vitro and in vivo. Moreover, bioengineered nanoparticles provided a safe and reliable drug delivery strategy of Amuc_2172 for CRC treatment in an allograft mice model. CONCLUSION: Amuc_2172 reprogrammed tumour microenvironment by inducing HSP70 secretion and promoting CTL-related immune response in the process of tumourigenesis.

Ganglion Impar Block For Chronic Coccydynia.

BACKGROUND: Coccydynia is also known as coccygodynia or coccygeal neuralgia. Coccyx is a triangular bone located within the vertebral column. The cause of coccydynia is unknown in the literature; however, it is found to be common among obese individuals, particularly females. The probability of women having coccydynia is five times higher than among men, which may result from larger pressure during pregnancy and child delivery. It is treated well with ganglion impar block. The aim of our study was to assess pain relief after Ganglion Impair Block with subsequent improvement in quality of life. METHODS: A single-arm study was done in the department of Pain Medicine, Fauji Foundation Hospital, Rawalpindi from July 2021 to June 2022. A total of 50 patients with ≥3 months' coccygeal pain of either gender aged between 20-60 years unresponsive to analgesics & anti-inflammatory medications with no laboratory abnormalities were included. Fluoroscopic guided trans-sacro­coccygeal ganglion impair block was done with alcohol neurolysis. The patients were observed for 1 hour in the recovery room to record post-intervention complications that may occur like hypotension, bradycardia, signs, and symptoms of cardiotoxicity or neurotoxicity etc. and evaluated for pain scores on the basis of the numeric rating scale (NRS). Data collected was analyzed using the statistical package for social scientists (SPSS) version 21. The quantitative data, i.e., age and NRS score were analyzed using mean and standard deviation and compared between pre and post-intervention periods. RESULTS: The data from 50 patients who completed the follow-up period were used for analysis. The average age of the patients was 42.9±8.39 years, with a range of 38-60 years. Based on the data obtained, 30% of the patients experienced trauma (that is falling on the coccyx region). The mean score from NRS before intervention was 7.80±0.16 which decreased to 0.96±0.35, respectively, and this difference was statistically significant (p-value, <0.001). CONCLUSIONS: Ganglion Impar neurolysis is highly effective in the treatment of chronic coccydynia.

The involvement of TH17 cells in the pathogenesis of IBD.

The pathogenesis of inflammatory bowel disease (IBD) is still unclear. Immune dysfunction may play a key role in the pathogenesis of IBD, in which the role of CD4+ T helper (Th) cells is particularly important. Th17 cells are a major component of CD4+ T cells, and their differentiation is regulated by a variety of extracellular signals, transcription factors, RNA, and posttranslational modifications. Th17 cells specifically produce IL-17 and play an important role in the protection of mucous membranes and epithelial tissues against infection by extracellular microbes. However, when immune regulation is dysfunctional, Th17 cells abnormally proliferate and produce large amounts of proinflammatory cytokines that can recruit other inflammatory cells, which together induce abnormal immune responses and result in the development of many autoimmune diseases. In recent years, studies have confirmed that Th17 cells play an important role in the pathogenesis of IBD, which makes it a possible target for IBD therapy. This article reviews the recent progress of Th17 cells involved in the pathogenesis of IBD and its targeted therapy.

Rosuvastatin-Induced Dizziness and Pruritus: A Case Report and Summary of Statin-Associated Dizziness and Pruritus.

Drug-associated adverse events can present with varying symptoms, such as dizziness and pruritus. A 48-year-old woman initiated rosuvastatin to treat her elevated triglycerides. She developed rosuvastatin-associated adverse events, which included dizziness and pruritus within two weeks after starting treatment. After stopping the medication, the dizziness immediately cleared; the pruritus diminished during the next two weeks and eventually resolved completely. Side effects associated with rosuvastatin are discussed. The possibility of a medication-related etiology should be entertained when an individual suddenly develops either dizziness or pruritus or both.

Scaffolding Close Reading of Mathematical Text in Pre-service Primary Teacher Education at the Tertiary Level: Design and Evaluation.

Even in the digital age, learning mathematics at an academic level still requires much reading of mathematical text. Research has shown that reading mathematical text requires readers to engage with all the structures of the book and with its pedagogical voice, making connections, and plausible reasoning. Specific practices and strategies that support the close reading of mathematical text have been suggested; however, descriptions and empirical evaluations of materials designed to support these activities are rare. We present the design and first evaluation cycle of materials developed in a design research project that aims to scaffold close reading of mathematical text. The materials were designed and evaluated in a German university course on elementary geometry for first-year teacher education students who study mathematics to become primary teachers. The reading strategies were explained and modeled for students in reading-strategy videos. Additionally, close reading of mathematical text was scaffolded by close-reading tasks and homework tasks and problems that build on the reading strategies and were specifically designed to foster understanding of the mathematical text. Survey data were collected from 296 students to evaluate their use of and attitude toward the different materials. The quantitative results indicate that students used the materials and were generally able to learn the course content by themselves. From all provided materials, they found the close-reading tasks most helpful. A qualitative analysis of answers to open questions revealed issues with different materials, particularly with the script, and requests for additional materials. The issues with the script were categorized inductively. The categories are presented as a qualitative result of the study and discussed. Supplementary Information: The online version contains supplementary material available at 10.1007/s10763-022-10309-y.

Vitiligo-Associated Autoimmune Disorders: A Woman With Vitiligo and Incipient Hypothyroidism.

Vitiligo is a skin condition that causes loss of pigmentation, resulting in hypopigmented and depigmented patches on the skin. Vitiligo has been associated with many autoimmune conditions. A 27-year-old female with a history of vitiligo had a clinical presentation and laboratory studies that were consistent with incipient hypothyroidism. The relationship between vitiligo, hypothyroidism, and other autoimmune conditions is discussed.

Bupropion-Associated Delayed Onset Urticaria.

Bupropion is an oral antidepressant that is commonly used to treat various mood disorders. Its therapeutic mechanism of action results from inhibiting the reuptake of norepinephrine and dopamine. Bupropion is generally well-tolerated and patients usually experience no side effects or mild adverse events. Rarely, hypersensitivity reactions to bupropion, such as urticaria, have been observed. However, the prevalence of delayed onset bupropion-associated urticaria may not be properly reflected in the literature due to misdiagnosis of the condition caused by its atypical presentation. We report a 20-year-old man with delayed onset bupropion-associated urticaria; he had been on bupropion for three weeks and subsequently developed new severely pruritic, erythematous wheals on his abdomen, bilateral flanks, and upper extremities. The clinical features of this rare adverse reaction to bupropion are also summarized.

Recent Advances in Zinc Oxide Nanoparticles (ZnO NPs) for Cancer Diagnosis, Target Drug Delivery, and Treatment.

Cancer is regarded as one of the most deadly and mirthless diseases and it develops due to the uncontrolled proliferation of cells. To date, varieties of traditional medications and chemotherapies have been utilized to fight tumors. However, their immense drawbacks, such as reduced bioavailability, insufficient supply, and significant adverse effects, make their use limited. Nanotechnology has evolved rapidly in recent years and offers a wide spectrum of applications in the healthcare sectors. Nanoscale materials offer strong potential for curing cancer as they pose low risk and fewer complications. Several metal oxide NPs are being developed to diagnose or treat malignancies, but zinc oxide nanoparticles (ZnO NPs) have remarkably demonstrated their potential in the diagnosis and treatment of various types of cancers due to their biocompatibility, biodegradability, and unique physico-chemical attributes. ZnO NPs showed cancer cell specific toxicity via generation of reactive oxygen species and destruction of mitochondrial membrane potential, which leads to the activation of caspase cascades followed by apoptosis of cancerous cells. ZnO NPs have also been used as an effective carrier for targeted and sustained delivery of various plant bioactive and chemotherapeutic anticancerous drugs into tumor cells. In this review, at first we have discussed the role of ZnO NPs in diagnosis and bio-imaging of cancer cells. Secondly, we have extensively reviewed the capability of ZnO NPs as carriers of anticancerous drugs for targeted drug delivery into tumor cells, with a special focus on surface functionalization, drug-loading mechanism, and stimuli-responsive controlled release of drugs. Finally, we have critically discussed the anticancerous activity of ZnO NPs on different types of cancers along with their mode of actions. Furthermore, this review also highlights the limitations and future prospects of ZnO NPs in cancer theranostic.

Thalidomide-Then and Now: Case Report of a Woman With Thalidomide Embryopathy and Review of Current Thalidomide Uses.

Thalidomide was initially developed as a sedative; subsequently, its use was expanded to treat morning sickness in pregnant women. However, it was later discovered to be a teratogenic drug that was associated with embryopathy in women. A woman is described who was exposed to thalidomide in utero. She had several stigmata of thalidomide embryopathy. Although treatment of nausea and anxiety in pregnant women with thalidomide was discontinued in 1961, the drug has been found to be a useful agent for the management of several systemic conditions and dermatological disorders. Whether the treatment with thalidomide shall be incorporated in the therapeutic regime for patients with severe coronavirus disease 2019 (COVID-19) infection remains to be determined.

Acquired giant plantar fibrokeratoma: case report and review.

Acquired digital fibrokeratoma is a benign fibrous tumor usually located on the toes and fingers. A 63-year-old man with an acquired giant plantar fibrokeratoma is described. He presented with an asymptomatic exophytic nodule of ten years duration; there is no history of trauma to the site. It measured 15x10x5mm and was located on the plantar foot proximal to the third toe. Excisional biopsy established the diagnosis of fibrokeratoma. Giant acquired fibrokeratoma,has been described in 16 patients including ours: three women and 13 men. They are located on either the upper extremity (one man) or the lower extremity (15 individuals). Acquired plantar fibrokeratoma is rare. Including our patient, it has been reported in 11 patients: one woman and ten men. The woman was 13 years of age and the men ranged from 15 to 77-years-old. Plantar acquired fibrokeratomas are located on either the plantar aspect of the toes, the sole of the foot, or the heel. An excisional biopsy provided adequate treatment without subsequent recurrence of both giant and plantar fibrokeratomas.

General Anaesthesia Versus Regional Anaesthesia For Lumbar Laminectomy: A Review Of The Modern Literature.

BACKGROUND: Lumbar spine surgery can be performed using different anaesthetic techniques such as general endotracheal anaesthesia (GA) or spinal-based regional anaesthesia (RA). Few of the studies have been done to compare the outcomes of spinal anaesthesia versus general anaesthesia for lumbar laminectomies as both having some advantages as well as disadvantages but still it is controversial. The objective of current study is to make a comprehensive review of literature for comparing the outcomes of lumbar laminectomy performed under general anaesthesia versus spinal anaesthesia. METHODS: Literature search was performed by using PubMed, Google scholar and bibliography of related articles. To compare groups of general anaesthesia versus spinal anaesthesia, the variables focused were mean heart rate (HR), mean arterial pressure (MAP), blood loss during surgery, duration of surgery, post-operative anaesthesia care unit (PACU) time, postoperative narcotic use/pain scale, post-operative urinary retention, and post-operative nausea/vomiting. RESULTS: Data of eleven studies were presented in current article, of these five were randomized controlled trials, three case-controls and four were retrospective cohort studies. 5/8 studies reported that SA group having more hemodynamic stability with postoperative outcomes as compared to GA. Likewise, majority of reviewed studies (7/8) reported better pain control or decreased requirement of analgesics in SA group. Additionally, more than half of the reviewed studies (5/8) reported lower incidence of postoperative nausea and vomiting among patients of SA group.. CONCLUSIONS: The current study concluded that SA has better outcomes than GA in terms of hemodynamic stability and decrease postoperative adverse effects. So special attention should be paid for SA as an alternative to GA for lumbar laminectomy.