The Future of Atopic Dermatitis Treatment.

This chapter thoroughly examines recent breakthroughs in atopic dermatitis (AD) treatment, with a primary focus on the medications in the development pipeline. Biologics agents targeting new interleukin receptors like interleukin-31, interleukin-22, and interleukin-2 are discussed along with the novel pathway looking at the OX40-OX40L interaction. Oral agents and small molecule therapies like Janus kinase inhibitors, sphingosine-1-phosphate modulators, and Bruton's tyrosine kinase inhibitors are also discussed along with the various new topical medications. Newly approved topicals like phosphodiesterase-4 and JAK inhibitors are highlighted while also discussing the potential of tapinarof and emerging microbiome-targeted therapies. Beyond conventional approaches, the chapter touches upon unconventional therapies currently being studied. The goal of this chapter is to discuss new advances in AD treatment from medications in the initial stages of development to those nearing FDA approval.

Adherence in Atopic Dermatitis.

Atopic dermatitis is a chronic dermatologic condition requiring extended treatment times with topical application of medications. While atopic dermatitis treatments can be highly effective when used as directed, oftentimes patients do not respond as expected, raising concern for nonadherence versus nonresponse. This chapter aims to describe what is currently known about adherence in atopic dermatitis and to discuss strategies to improve adherence in order to improve treatment outcomes. Whether intentional or unintentional, nonadherence to treatment can limit patient outcomes of this disease for a variety of reasons. These include frustration with medication efficacy, inconvenience, and fear of side effects. Other factors include forgetfulness, financial burden of treatment, lack of trust in the physician, dislike of prescribed medication, or lack of understanding of disease or treatment. Several interventions have been studied with the aim of improving adherence in atopic dermatitis-such as educational workshops for patients and caregivers, earlier follow-up visits, and text messages reminders-however, these are often limited by sample size and power. Further research is needed to study both specific patterns of nonadherence in atopic dermatitis, as well as methods to improve them.

Conditioned inhibition of fear and reward in male and female rats.

Stimuli in our environment are not always associated with an outcome. Some of these stimuli, depending on how they are presented, may gain inhibitory value or simply be ignored. If experienced in the presence of other cues predictive of appetitive or aversive outcomes, they typically gain inhibitory value and become predictive cues indicating the absence of appetitive or aversive outcomes. In this case, these cues are referred to as conditioned inhibitors. Here, male and female Long Evans rats underwent cue discrimination training where a reward cue was paired with sucrose, a fear cue with footshock, and an inhibitor cue resulted in neither sucrose or footshock. During a subsequent summation test for conditioned inhibition of fear and reward, the inhibitor cue was presented concurrently with the reward and fear cues without any outcome, intermixed with trials of reinforced reward and fear trials. Males showed significant conditioned inhibition of freezing, while females did not, which was not dependent on estrous. Both males and females showed significant conditioned inhibition of reward. During a retardation of fear acquisition test, the inhibitor was paired with footshock and both males and females showed delayed acquisition of fear. During a retardation of reward acquisition test, the inhibitor was paired with sucrose, and females showed delayed acquisition of reward, while males did not. In summary, males and females showed significant reward-fear-inhibitor cue discrimination, conditioned inhibition of reward, and retardation of fear acquisition. The main sex difference, which was not estrous-dependent, was the lack of conditioned inhibition of freezing in females. These data imply that while the inhibitor cue gained some inhibitory value in the females, the strength of this inhibitory value may not have been great enough to effectively downregulate freezing elicited by the fear cue.

Evaluating diaphragmatic dysfunction and predicting non-invasive ventilation failure in acute exacerbation of chronic obstructive pulmonary disease in India.

BACKGROUND: Baseline diaphragmatic dysfunction (DD) at the initiation of non-invasive ventilation (NIV) correlates positively with subsequent intubation. We investigated the utility of DD detected 2 hours after NIV initiation in estimating NIV failure in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) patients. METHODS: In a prospective-cohort design, we enrolled 60 consecutive patients with AECOPD initiated on NIV at intensive care unit admission, and NIV failure events were noted. The DD was assessed at baseline (T1 timepoint) and 2 hours after initiating NIV (T2 timepoint). We defined DD as ultrasound-assessed change in diaphragmatic thickness (ΔTDI) <20% (predefined criteria [PC]) or its cut-off that predicts NIV failure (calculated criteria [CC]) at both timepoints. A predictive-regression analysis was reported. RESULTS: In total, 32 patients developed NIV failure, nine within 2 hours of NIV and remaining in next 6 days. The ∆TDI cut-off that predicted NIV failure (DD-CC) at T1 was ≤19.04% (area under the curve [AUC], 0.73; sensitivity, 50%; specificity, 85.71%; accuracy; 66.67%), while that at T2 was ≤35.3% (AUC, 0.75; sensitivity, 95.65%; specificity, 57.14%; accuracy, 74.51%; hazard ratio, 19.55). The NIV failure rate was 35.1% in those with normal diaphragmatic function by PC (T2) versus 5.9% by CC (T2). The odds ratio for NIV failure with DD criteria ≤35.3 and <20 at T2 was 29.33 and 4.61, while that for ≤19.04 and <20 at T1 was 6, respectively. CONCLUSIONS: The DD criterion of ≤35.3 (T2) had a better diagnostic profile compared to baseline and PC in prediction of NIV failure.

Assessing the Efficacy of Imiquimod Use in Patients With Persistent Locally Advanced Melanoma In Situ

BACKGROUND: The standard of care when treating melanoma in situ (MMIS) is an excision with at least 5 mm surgical margins.1 Some studies have suggested up to 9 mm margins to maximize local recurrence-free survival.2 This retrospective review aims to assess the efficacy of imiquimod as a topical treatment for persistently positive MMIS at the margins of prior excisions or where surgery is not an option. METHODS: Retrospective study conducted at Moffitt Cancer Center between 2019 and 2021 with patients aged > 18 years with MMIS at the margins of excision of an invasive melanoma or MMIS. Included patients were not ideal candidates for primary or additional surgical resection due to non-feasibility of surgery because of comorbidity or cosmetically sensitive location and/or the need for repeated skin grafting, or due to patient's refusal. Patients received imiquimod on protocol for 16 weeks and were monitored for treatment response and side effects. Following completion of the treatment, scouting biopsies were performed to assess histological response, and dermoscopy was used to determine the clinical disease status. RESULTS: Ten patients completed 16 weeks of imiquimod. Seven (75%) had a median of 2 surgical resections, and 3 refused surgery despite discussion that surgery was standard of care. Seven were deemed free of disease on post-imiquimod treatment scouting biopsies, while 2 were found to be clinically free of disease following confocal microscopy, indicating a tumor clearance rate of 90% with imiquimod treatment. One patient was found to have persistent residual disease following 2 rounds of imiquimod and was taken for an additional surgical excision after which they were deemed free of disease. Median follow-up duration from the onset of imiquimod therapy to the last clinic visit was 18 months, without any recurrences to date. CONCLUSION: Imiquimod appears to demonstrate an encouraging tumor clearance among patients with persistent MMIS after surgery where further surgical resection may not be feasible. Although long-term durability has not been demonstrated in this study, a 90% tumor clearance rate is promising. J Drugs Dermatol. 2023;22(5): doi:10.36849/JDD.6987.

Clinical significance of Notch receptors in triple negative breast cancer.

BACKGROUND: The Notch signaling pathway is an evolutionary conserved cell signaling pathway that plays an indispensable role in essential developmental processes. Aberrant activation of Notch pathway is known to initiate wide array of diseases and cancers. OBJECTIVE: To evaluate the clinical significance of Notch receptors in Triple Negative Breast Cancer. METHODS: We evaluated the association between Notch receptors and clinicopathological parameters including disease-free survival and overall survival of one hundred TNBC patients by immunohistochemistry. RESULTS: Positive expression of nuclear Notch1 receptor (18%) was found be significantly correlated with positive lymph node (p = 0.009), high BR score (p = 0.02) and necrosis (p = 0.004) while cytoplasmic expression of Notch2 receptor (26%) was significantly correlated with metastasis (p = 0.05), worse DFS (p = 0.05) and poor OS (p = 0.02) in TNBC patients. Membrane (18%) and cytonuclear (3%) Notch3 expression were significantly associated with poorly differentiated tumors (p = 0.007), high BR score (p = 0.002) and necrosis (p = 0.03) respectively. However, cytoplasmic Notch3 and Notch4 expression were negatively correlated with poor prognostic factors. CONCLUSIONS: Our data indicated that Notch receptors play a key role in promoting TNBC and mainly, Notch2 may contribute to poor prognosis of the disease. Hence, it is implicated that Notch2 may serve as a potential biomarker and therapeutic target for TNBC.

Investigating the resistance mechanism of 5-fluorouracil in colorectal cancer based on surface markers of cancer stemness and cytokine level: A pre-clinical study.

BACKGROUND: Colorectal cancer (CRC) is the deadliest malignancy in the world. The first-line chemotherapy used for CRC is 5-fluorouracil (5-FU). 5-FU completely eradicates rapidly proliferating and terminally differentiated tumor cells but fails to target cancer stem cells (CSCs). As a result, the tumor may shrink temporarily, but remnant CSC multiplies and forms a tumor again more aggressively. The recurrence and resistance lead to metastasis. METHODOLOGY: CRC was induced in 12 Sprague-Dawley (RPCP/IAEC/2019-20/R2) rats by 1,2 dimethyl hydrazine. Later, animals were treated with 5-FU for 7 weeks at a 10 mg/kg dose by the subcutaneous route. At the end of treatment, half population was sacrificed (6), whereas the remaining half (6) was left without treatment of 5-FU for 5 weeks and then sacrificed. Parameters such as body weight, complete blood count (CBC), immune cell subset (CD4, CD8, and NK cells), colon length to weight index, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) level, occult blood in stool, tumor multiplicity, and liver metastasis were estimated. In addition, the dissected colon was fixed in formalin and sent to the histology lab for hematoxylin-eosin staining and immunohistochemistry at both intervals. RESULTS: All blood and tissue-based markers have shown significant differences (p < 0.05) between the animals sacrificed at the end of the 27th week and the end of the 32nd week for 5-FU treatment. CONCLUSION: It can be concluded that 5-FU up-regulates inflammatory cytokines and cell surface markers of CSC that promote CRC stemness via the Wnt/ß-catenin pathway. Also, involvement of Nf-κB, fibronectin, MMP-9, and RANKL leads to tumorigenesis, disease aggressiveness, metastasis, and resistance.

Complete heart block in COVID-19 without prior cardiac disease.

Cardiac involvement in COVID-19 is not rare but underdiagnosed. We report a 78-year-old man with COVID-19 and complete heart block, timely managed by teamwork involving internist, cardiologist, and intensivist. This case highlights the importance of involvement of the conducting system of the heart in COVID-19 that needs immediate life-saving intervention, especially in community.

Mucormycosis, Diabetes and COVID-19 Pneumonia: Unleashing the Facts.

Background Mucormycosis (MM) is an angioinvasive locally destructive fungal infection. Before the coronavirus disease 2019 (COVID-19) pandemic, it was associated with diabetes (particularly diabetic ketoacidosis), immunosuppressive drugs and trauma. Among its various forms, cerebral invasion is considered to be highly fatal even if with long-term treatment. Treatment with injection amphotericin B (Amph-B) with early surgical interventions is highly efficacious. Liposomal preparation is considered to be superior in the context of fewer side effects. Methods We present a single-centre prospective study of 124 patients with MM in a tertiary care hospital. After the approval from the ethics committee, basic information was taken from all patients including all available past history about the COVID-19 infection and treatment. The studied outcomes were discharge, death and number of days of hospitalisation. Secondary objectives were to estimate the association of MM with known risk factors, to find the association of an outcome with various inflammatory markers, to determine adverse events with the use of injection Amph-B and posaconazole and to find the case fatality rate of MM. Results In our study, we observed that the number of patients with MM was double in the less than 60 years age group. However, mortality was 33.3% in the elderly as compared to 15.29% in patients less than 60 years of age. The majority of the patients (69.35%) were males, but no significant difference in mortality was seen between males and females. The case fatality rate was 20.97%. Ocular symptoms such as orbital swelling and pain were the common presenting symptoms. Almost all patients (93.54%) were diabetics. The non-diabetic group consisted of only 8 (6.4%) patients, and therefore, the comparison was not possible. A total of 20 (16%) out of 124 patients who had received high-dose steroids showed higher mortality (55%). Maximum patients (65.32%) had presented with MM following a past COVID-19 infection. However, a significant number of MM patients (20.96%) had a recent COVID infection and had higher mortality (57.69%) compared to their counterparts. The most common site of involvement in our study was the paranasal sinus (50%) and the outcome was the best in those patients whose disease was localised only to the sinuses, although among 14 (11.29%) patients with cerebral involvement, mortality was maximum (42.85%). Renal impairment and dyselectrolytemia were the most common adverse effects of Amph-B, and 46.42% of patients required surgical removal of the local part. Conclusion We saw that diabetes was a major contributory factor in the etiopathogenesis of MM. COVID-19 could also be a major causative factor by impairing the immune system; however, further studies at the molecular level are required to establish an association. The use of steroid cannot be the only independent risk factor, and other associated factors must be present. Treatment with antifungal and early surgical intervention had good outcomes. Treatment with conventional lyophilized Amph-B was equally efficacious as lipid-based solutions, but with more side effects. Hypokalemia and hypocalcemia were the most common electrolyte abnormalities associated with the use of injection Amph-B. Uncontrolled diabetes, the severity of the COVID-19 infection at presentation, acidosis, a high C-reactive protein level (above 100) and local brain involvement were associated with a poor outcome.

Spectrum of pneumothorax/pneumomediastinum in patients with coronavirus disease 2019.

BACKGROUND: Spontaneous pneumothorax/pneumomediastinum is an uncommon complication of coronavirus disease 2019 (COVID-19). Herein, we describe the clinical spectrum and outcomes of COVID-19-associated pneumothorax/pneumomediastinum in critical care settings. MATERIALS AND METHODS: We hereby present a case series of 12 patients who tested positive for COVID-19 and developed air leak injuries in critical care settings in a tertiary care center in Northern India. Infection with severe acute respiratory syndrome coronavirus-2 was confirmed by nasal/oropharyngeal swab testing using real-time reverse-transcription polymerase chain reaction test. The clinical spectrum and outcomes of these patients were assessed. Each case has been presented as a brief synopsis. RESULTS: The onset of pneumothorax/pneumomediastinum varied from 11 to 28 days after the occurrence of initial symptoms and caused worsening of respiratory parameters in most patients. Of the 12 patients, eight were males who developed air leak injuries. One patient was a current smoker, and three patients had underlying lung disorders. Two patients with spontaneous breathing were managed conservatively. All intubated patients who developed air leak injuries died (100% mortality rate). CONCLUSION: Pneumothorax/pneumomediastinum is a rare and life-threatening complication in mechanically ventilated patients with COVID-19. Further research is needed to understand the pathophysiology behind the development of air leak injuries in patients with COVID-19.

Ventilator-associated pneumonia due to carbapenem-resistant Providencia rettgeri.

Ventilator-associated pneumonia (VAP) is one of the leading cause of mortality and morbidity in critically ill patients on mechanical ventilation. We report a case of VAP caused by Providencia rettgeri in a postoperative 58-year-old man with prepyloric perforation. The patient's ICU stay was complicated by VAP. As the organism was carbapenem resistant, high-dose extended infusion of meropenem along with cefepime was started. Early identification and treatment helped in successful weaning of the patient from the ventilator. Providencia is an emerging nosocomial pathogen with an increase in resistance pattern. This case highlights the rarity and importance of Providencia as a cause of VAP.