Development of a Multiplexed Sphingolipids Method for Diagnosis of Inborn Errors of Ceramide Metabolism.

BACKGROUND: Sphingolipids play a crucial role in cellular functions and are essential components of cell membranes, signaling molecules, and lipid metabolism. In particular, ceramide is a key intermediate in sphingolipid metabolism and defects in ceramide metabolism can lead to various inborn errors of metabolism, making ceramides important targets for clinical screening and diagnosis. Detecting altered concentration patterns of sphingolipids is desirable for distinguishing related inborn errors of metabolism for diagnosis and treatment monitoring. METHODS: We developed a liquid chromatography-tandem mass spectrometry method with a pathway-oriented approach to focus on sphingolipids involved in ceramide metabolism. A total of 47 sphingolipids bearing different head groups and side chains were targeted. Precision/reproducibility, linearity, and spike recovery extraction efficiency tests were performed on plasma and serum samples from confirmed cases of sphingolipidosis. RESULTS: Linearity of the method showed the coefficient of determination (r2) for all standards to be >0.99 with a slope of 1.00 ± 0.01. Intra- and interday reproducibility of standards spiked into plasma and serum revealed a coefficient of variation <20%. Spike and recovery assessment showed recovery values of 80%-120% for all standards. Altered levels of sphingolipids from patients with hereditary sensory and autonomic neuropathy caused by pathogenic variants in SPTLC2 and hypomyelinating leukodystrophy related to variants in DEGS1 were detected, in agreement with trends reported in earlier studies confirming the utility of this pathway-centric method. CONCLUSIONS: This method can serve as a useful tool to simultaneously monitor sphingolipids, enabling screening and diagnosis of inborn errors of ceramide metabolism.

Take a break: should breaks be enforced during digital breast tomosynthesis reading sessions?

OBJECTIVES: Digital breast tomosynthesis (DBT) can improve diagnostic accuracy compared to 2D mammography, but DBT reporting is time-consuming and potentially more fatiguing. Changes in diagnostic accuracy and subjective and objective fatigue were evaluated over a DBT reporting session, and the impact of taking a reporting break was assessed. MATERIALS AND METHODS: Forty-five National Health Service (NHS) mammography readers from 6 hospitals read a cancer-enriched set of 40 DBT cases whilst eye tracked in this prospective cohort study, from December 2020 to April 2022. Eye-blink metrics were assessed as objective fatigue measures. Twenty-one readers had a reporting break, 24 did not. Subjective fatigue questionnaires were completed before and after the session. Diagnostic accuracy and subjective and objective fatigue measures were compared between the cohorts using parametric and non-parametric significance testing. RESULTS: Readers had on average 10 years post-training breast screening experience and took just under 2 h (105.8 min) to report all cases. Readers without a break reported greater levels of subjective fatigue (44% vs. 33%, p = 0.04), which related to greater objective fatigue: an increased average blink duration (296 ms vs. 286 ms, p < 0.001) and a reduced eye-opening velocity (76 mm/s vs. 82 mm/s, p < 0.001). Objective fatigue increased as the trial progressed for the no break cohort only (ps < 0.001). No difference was identified in diagnostic accuracy between the groups (accuracy: 87% vs. 87%, p = 0.92). CONCLUSIONS: Implementing a break during a 2-h DBT reporting session resulted in lower levels of subjective and objective fatigue. Breaks did not impact diagnostic accuracy, which may be related to the extensive experience of the readers. CLINICAL RELEVANCE STATEMENT: DBT is being incorporated into many mammography screening programmes. Recognising that reporting breaks are required when reading large volumes of DBT studies ensures this can be factored in when setting up reading sessions. TRIAL REGISTRATION: Clinical trials registration number: NCT03733106 KEY POINTS: • Use of digital breast tomosynthesis (DBT) in breast screening programmes can cause significant reader fatigue. • The effectiveness of incorporating reading breaks into DBT reporting sessions, to reduce mammography reader fatigue, was investigated using eye tracking. • Integrating breaks into DBT reporting sessions reduced reader fatigue; however, diagnostic accuracy was unaffected.

Bile Culture May Guide Antibiotic Stewardship in Acute Bacterial Cholangitis.

BACKGROUND: Bile cultures are often sent with blood cultures in patients with acute bacterial cholangitis. AIMS: To assess the yield of blood and bile cultures in patients with cholangitis and the clinical utility of bile cultures in guiding therapy. METHODS: All patients diagnosed with cholangitis, based on the Tokyo 2013/2018 guidelines were recruited retrospectively over ten years. The clinical and investigation details were recorded. The results of bile and blood cultures including antibiotic sensitivity patterns were noted. The concordance of microorganisms grown in blood and bile cultures and their sensitivity pattern were assessed. RESULTS: A total of 1063 patients with cholangitis were included. Their mean age was 52.7 ± 14 years and 65.4% were males. Blood cultures were positive in 372 (35%) patients. Bile culture was performed in 384 patients with 84.4% being positive, which was significantly higher than the yield of blood culture (p < 0.001). Polymicrobial growth was more in bile (59.3%) than in blood cultures (13.5%, p < 0.001). E.coli, Klebsiella, Enterococcus and Pseudomonas were the four most common organisms isolated from both blood and bile. Extended spectrum betalactamase producing organisms were isolated in 57.7% and 58.8% of positive blood and bile cultures, respectively. Among 127 patients with both blood and bile cultures positive, complete or partial concordance of organisms was noted in about 90%. CONCLUSION: Bile and blood cultures have a similar microbial profile in most patients with cholangitis. As bile cultures have a significantly higher yield than blood cultures, they could effectively guide antimicrobial therapy, especially in those with negative blood cultures.

Central nervous system manifestations of dengue infection: data from a tertiary care Centre in South India.

BACKGROUND: Dengue fever is the second most common mosquito-borne disease affecting human beings and neurological manifestations (NMs) of this arboviral infection are increasingly being reported. METHODS: In this retrospective study, conducted in a tertiary care centre in south India, we sought to describe the spectrum of NMs of dengue fever. The records of all patients admitted in the Department of Internal Medicine over 8 years, with a diagnosis of dengue-based on clinical symptoms and the detection of dengue IgM antibodies or detection of NS1 antigen or nucleic acid by reverse transcriptase-polymerase chain reaction (RT-PCR); with Glasgow coma score (GCS) ≤14, neck stiffness, focal neurological signs, seizures, or visual disturbances-were explored. RESULTS: Of 1121 patients admitted with dengue fever, 341 (30%) had severe dengue and 23 (2%) had NMs. Encephalopathy was seen in 9 patients (39%), encephalitis in 6 (27%), cerebellitis in 4 (17%), acute disseminated encephalomyelitis (ADEM) in 2 (9%), ischaemic stroke in 1 (4%) patient, and neuro-ophthalmological manifestations in 1 (4%) patient. The median duration of hospital stay was 7 days. Nine (39% of) patients required intensive care unit (ICU) admission and 5 (22%) had fatal outcomes. There was no association between thrombocytopenia, metabolic acidosis, transaminitis, hyponatremia, the type of dengue infection, and the various NMs described. CONCLUSIONS: The NMs of dengue infection are varied, and a high index of suspicion is needed to identify them in patients who present with lethargy or altered sensorium on the background of an acute febrile illness suggestive of dengue.

Influence of temperature on regulation of key virulence and stress response genes in Listeria monocytogenes biofilms.

Temperature is a major determinant of Listeria (L.) monocytogenes adherence and biofilm formation on abiotic surfaces. However, its role on gene regulation of L. monocytogenes mature biofilms has not been investigated. In the present study, we aimed to evaluate the impact of temperature up- and down-shift on L. monocytogenes biofilms gene transcription. L. monocytogenes strain EGD-e biofilms were first developed on stainless steel surfaces in Brain Heart Infusion broth at 20 °C for 48 h. Then, nutrient broth was renewed, and mature biofilms were exposed to 10 °C, 20 °C or 37 °C for 24 h. Biofilm cells were harvested and RNA levels of plcA, prfA, hly, mpl, plcB, sigB, bapL, fbpA, fbpB, lmo2178, lmo0880, lmo0160, lmo1115, lmo 2089, lmo2576, lmo0159 and lmo0627 were evaluated by quantitative RT-PCR. The results revealed an over-expression of all genes tested in biofilm cells compared to planktonic cells. When biofilms were further allowed to proliferate at 20 °C for 24 h, the transcription levels of key virulence, stress response and putative binding proteins genes plcA, sigB, fbpA, fbpB, lmo1115, lmo0880 and lmo2089 decreased. A temperature-dependent transcription for sigB, plcA, hly, and lmo2089 genes was observed after biofilm proliferation at 10 °C or 37 °C. Our findings suggest that temperature differentially affects gene regulation of L. monocytogenes mature biofilms, thus modulating attributes such as virulence, stress response and pathogenesis.

Microbiological Quality Estimation of Meat Using Deep CNNs on Embedded Hardware Systems.

Spectroscopic sensor imaging of food samples meta-processed by deep machine learning models can be used to assess the quality of the sample. This article presents an architecture for estimating microbial populations in meat samples using multispectral imaging and deep convolutional neural networks. The deep learning models operate on embedded platforms and not offline on a separate computer or a cloud server. Different storage conditions of the meat samples were used, and various deep learning models and embedded platforms were evaluated. In addition, the hardware boards were evaluated in terms of latency, throughput, efficiency and value on different data pre-processing and imaging-type setups. The experimental results showed the advantage of the XavierNX platform in terms of latency and throughput and the advantage of Nano and RP4 in terms of efficiency and value, respectively.

Vitamin-D Status and Clinical Outcomes in Critically Ill Children.

Aims and background: To study if 25-hydroxy cholecalciferol levels correlate with clinical outcomes in a cohort of critically ill children requiring pediatric intensive care unit (PICU) admission. Materials and methods: All children between the ages of 1 month and 14 years admitted to a PICU were included in this study. The vitamin-D level was measured within 24 hours of admission to the PICU for each patient. The patient's clinical details, vitamin-D levels, and biochemical parameters were collected. Results: There were 119 critically ill children (47 females and 72 males) admitted to our PICU. A total of 56 children were in the vitamin-D-deficient group, giving a prevalence of 47.05%. Sixty-three children had either insufficient or normal levels of 25(OH)D. Mean serum 25-OH cholecalciferol was 22.82 ± 16.48 nmol/L. There were no significant differences in O2 utilization, ventilation requirement, length of PICU stay, or the frequencies of use of antibiotics and steroids between the groups. The overall mortality rate in this study was 5.8% (three children died in the deficient group as compared with four in the insufficient/normal group). Conclusion: Even though vitamin-D deficiency was highly prevalent in the PICU, there were no statistically significant differences in O2 utilization, length of PICU stay, duration of mechanical ventilation, the use of antibiotics/steroids, and mortality outcome for both deficient and insufficient/normal groups. How to cite this article: Loni R, Zameer S, Hasan FA, Abbas I, Mesrati H, George J, et al. Vitamin-D Status and Clinical Outcomes in Critically Ill Children. Indian J Crit Care Med 2023;27(7):503-509.

The Use of Pectoralis Blocks in Breast Surgery: A Practice Advisory and Narrative Review from the Society for Ambulatory Anesthesia (SAMBA).

Although pectoralis (PECS) blocks are commonly used for breast surgery, recommendations regarding the efficacy of these blocks have thus far not been developed by any professional anesthesia society. Given the potential impact of PECS blocks on analgesia after outpatient breast surgery, The Society for Ambulatory Anesthesia (SAMBA) convened a task force to develop a practice advisory on the use of this analgesic technique. In this practice advisory, we compare the efficacy of PECS blocks with systemic analgesia, local infiltration anesthesia, and paravertebral blockade. Our objectives were to advise on two clinical questions. (1) Does PECS-1 and/or -2 blockade provide more effective analgesia for breast-conserving surgery than either systemic analgesics or surgeon-provided local infiltration anesthesia? (2) Does PECS-1 and/or -2 blockade provide equivalent analgesia for mastectomy compared with a paravertebral block (PVB)? Among patients undergoing breast-conserving surgery, PECS blocks moderately reduce postoperative opioid use, prolong time to analgesic rescue, and decrease postoperative pain scores when compared with systemic analgesics. SAMBA recommends the use of a PECS-1 or -2 blockade in the absence of systemic analgesia (Strength of Recommendation A). No evidence currently exists that strongly favors the use of PECS blocks over surgeon-performed local infiltration in this surgical population. SAMBA cannot recommend PECS blocks over surgical infiltration (Strength of Recommendation C). For patients undergoing a mastectomy, a PECS block may provide an opioid-sparing effect similar to that achieved with PVB; SAMBA recommends the use of a PECS block if a patient is unable to receive a PVB (Strength of Recommendation A).

Pirfenidone ameliorates chronic pancreatitis in mouse models through immune and cytokine modulation.

Chronic pancreatitis (CP) is an irreversible fibro-inflammatory disease of the pancreas with no current targeted therapy. Pirfenidone, an anti-fibrotic and anti-inflammatory drug, is FDA approved for treatment of Idiopathic Pulmonary Fibrosis (IPF). Its efficacy in ameliorating CP has never been evaluated before. We recently reported that pirfenidone improves acute pancreatitis in mouse models. The aim of the current study was to evaluate the therapeutic efficacy of pirfenidone in mouse models of CP. We used caerulein and L-arginine models of CP and administered pirfenidone with ongoing injury, or in well-established disease. We evaluated for fibrosis by Sirius-red staining for collagen, immunohistochemistry, western blotting, and qPCR for fibrosis markers to show the salutary effects of pirfenidone in CP. Our results suggest that treatment with pirfenidone ameliorated CP related changes in the pancreas (i.e., atrophy, acinar cell loss, fibrosis, and inflammation) not only when administered with ongoing injury, but also in well-established models of caerulein as well as L-arginine induced CP. It reduces the pro-fibrotic phenotype of macrophages (in-vivo and in-vitro), reduces macrophage infiltration into the pancreas and alters the intra-pancreatic cytokine milieu preceding changes in histology. The therapeutic effect of pirfenidone is abrogated in absence of macrophages. Furthermore, it reduces collagen secretion, cytokine levels and fibrosis markers in pancreatic stellate cells in-vitro. As it is FDA approved, our findings in mouse models simulating clinical presentation of patients to the clinic, can be used as the basis of a clinical trial evaluating the efficacy of this drug as a therapeutic agent for CP.

Rapid Assessment of Microbial Quality in Edible Seaweeds Using Sensor Techniques Based on Spectroscopy, Imaging Analysis and Sensors Mimicking Human Senses.

The expansion of the seaweed aquaculture sector along with the rapid deterioration of these products escalates the importance of implementing rapid, real-time techniques for their quality assessment. Seaweed samples originating from Scotland and Ireland were stored under various temperature conditions for specific time intervals. Microbiological analysis was performed throughout storage to assess the total viable counts (TVC), while in parallel FT-IR spectroscopy, multispectral imaging (MSI) and electronic nose (e-nose) analyses were conducted. Machine learning models (partial least square regression (PLS-R)) were developed to assess any correlations between sensor and microbiological data. Microbial counts ranged from 1.8 to 9.5 log CFU/g, while the microbial growth rate was affected by origin, harvest year and storage temperature. The models developed using FT-IR data indicated a good prediction performance on the external test dataset. The model developed by combining data from both origins resulted in satisfactory prediction performance, exhibiting enhanced robustness from being origin unaware towards microbiological population prediction. The results of the model developed with the MSI data indicated a relatively good prediction performance on the external test dataset in spite of the high RMSE values, whereas while using e-nose data from both MI and SAMS, a poor prediction performance of the model was reported.

Recent Advances and Applications of Rapid Microbial Assessment from a Food Safety Perspective.

Unsafe food is estimated to cause 600 million cases of foodborne disease, annually. Thus, the development of methods that could assist in the prevention of foodborne diseases is of high interest. This review summarizes the recent progress toward rapid microbial assessment through (i) spectroscopic techniques, (ii) spectral imaging techniques, (iii) biosensors and (iv) sensors designed to mimic human senses. These methods often produce complex and high-dimensional data that cannot be analyzed with conventional statistical methods. Multivariate statistics and machine learning approaches seemed to be valuable for these methods so as to "translate" measurements to microbial estimations. However, a great proportion of the models reported in the literature misuse these approaches, which may lead to models with low predictive power under generic conditions. Overall, all the methods showed great potential for rapid microbial assessment. Biosensors are closer to wide-scale implementation followed by spectroscopic techniques and then by spectral imaging techniques and sensors designed to mimic human senses.

Subcutaneous, abdominal, and thoracic encapsulated fat necrosis in bowhead whales Balaena mysticetus from Alaska, USA.

We describe a case series of encapsulated fat necrosis with subcutaneous, abdominal, and thoracic locations in 7 subsistence-harvested bowhead whales Balaena mysticetus. Masses had a variably-dense fibrous capsule surrounding necrotic adipocytes and calcium salts (saponification). One animal also had prior concussive injury, pleural fibrosis, and hepatic lipoma; the other animals had no significant findings. The described condition is uncommon in bowhead whales, with 7/575 (1.2%) observed from 1996 to 2015. The exact mechanisms of development of encapsulated fat necrosis in bowhead whales remain to be determined. Encapsulated fat necrosis has been reported in other baleen whales, humans, and cows. It is usually an incidental finding during post-mortem examination that needs to be differentiated from neoplastic and inflammatory lesions, as the latter may have public health implications. Assessment of further cases in bowhead whales and other baleen whales is warranted to better understand their pathogenesis.

Evolution of fungal community associated with ready-to-eat pineapple during storage under different temperature conditions.

The international market of fresh-cut products has witnessed dramatic growth in recent years, stimulated by consumer's demand for healthy, nutritious and convenient foods. One of the main challenging issues for the quality and safety of these products is the potential microbial spoilage that can significantly reduce their shelf-life. The complete identification of fresh-cut product microbiota together with the evaluation of environmental factors impact on microbial composition is of primary importance. We therefore assessed the fungal communities associated with the spoilage of ready-to-eat (RTE) pineapple using a metagenetic amplicon sequencing approach, based on the ITS2 region. Our results revealed a significant variability on fungal species composition between the different batches of RTE pineapple. The initial microbiota composition was the main influencing factor and determined the progress of spoilage. Temperature and storage time were the secondary factors influencing spoilage and their impact was depending on the initial prevalent fungal species, which showed different responses to the various modifications. Our results strongly suggest that further large-scale sampling of RTE pineapple production should be conducted in order to assess the full biodiversity range of fungal community involved in the spoilage process and for unravelling the impact of important environmental factors shaping the initial microbiota.

Spoilage potential of Bacillus subtilis in a neutral-pH dairy dessert.

The objective of this study was the characterization of the microbiota associated with spoilage of vanilla cream pudding during storage at different temperatures. Commercial cream samples were stored aerobically at 4, 8, 12 and 15 °C for a maximum time period of 40 days. At appropriate time intervals, cream samples were subjected to: (i) microbiological analyses, and (ii) high-performance liquid chromatography (HPLC). Furthermore, the spoilage microbiota was identified through repetitive extragenic palindrome-PCR, while selected isolates were further characterized based on sequencing of the V1-V3 region of the 16S rRNA gene. Microbial growth was observed only during storage of cream samples at 12 and 15 °C, with the applied genotypic analysis demonstrating that Bacillus subtilis subsp. subtilis was the dominant spoilage microorganism of this product. Based on the HPLC analysis results, citric acid and sucrose were the most abundant organic acid and sugar, respectively throughout storage of cream pudding, whereas notable changes mainly included: (i) increase in the concentration of lactic acid and to a lesser extent of formic and acetic acids, and (ii) increase in the concentration of glucose and fructose at the expense of sucrose and lactose. The results of this study should be useful for the dairy industry in detecting and controlling microbiological spoilage in cream pudding and other chilled, neutral-pH dairy desserts.

Linking gene expression and phenotypic changes in the developmental and evolutionary origins of osteosclerosis in the ribs of bowhead whales (Balaena mysticetus).

Bowhead whales are among the longest-lived mammals with an extreme lifespan of about 211 years. During the first 25 years of their lives, rib bones increase in mineral density and the medulla transitions from compact to trabecular bone. Molecular drivers associated with these phenotypic changes in bone remain unknown. This study assessed expression levels of osteogenic genes from samples of rib bones of bowheads. Samples were harvested from prenatal to 86-year-old whales, representing the first third of the bowhead lifespan. Fetal to 2-year-old bowheads showed expression levels consistent with the rapid deposition of the bone extracellular matrix. Sexually mature animals showed expression levels associated with low rates of osteogenesis and increased osteoclastogenesis. After the first 25 years of life, declines in osteogenesis corresponded with increased expression of EZH2, an epigenetic regulator of osteogenesis. These findings suggest EZH2 may be at least one epigenetic modifier that contributes to the age-related changes in the rib bone phenotype along with the transition from compact to trabecular bone. Ancient cetaceans and their fossil relatives also display these phenotypes, suggesting EZH2 may have shaped the skeleton of whales in evolutionary history.

Design, fabrication and characterization of a distributed Bragg reflector for reducing the étendue of a wavelength converting system.

In this work, the design, fabrication and characterization are reported for a distributed Bragg reflector (DBR) filter with a specific wavelength and angular dependency, which aims to improve the light collection from a wavelength-converter-based light source into a smaller angle than the full angle Lambertian emission. The desired design is obtained by optimizing the transmission characteristics of a multi-layer structure. Titania (TiO2) and silica (SiO2) are used as high and low refractive index materials, respectively. The deposition is made by electron beam evaporation without substrate heating, followed by a post-annealing procedure. The optical properties of the evaporated layers are analyzed by ellipsometer and spectrometer measurements. The angular and wavelength dependency of the fabricated DBR is in good agreement with simulations for the designed structure.

Improvement of liquid crystal tunable lenses with weakly conductive layers using multifrequency driving.

A common technique to realize the gradient electric field profile that is required in liquid crystal tunable lenses is the use of a weakly conductive layer. Thanks to this layer, an applied voltage with a certain frequency allows us to obtain a refractive index profile that is required for the lens operation. Due to the limited degrees of freedom, however, it is not possible to avoid aberrations in a weakly conductive layer-based tunable lens for a continuously tunable focal length. In this work, we discuss the use of additional higher frequency components in the voltage signal to reduce the lens aberrations drastically.

Extracellular release of ATP promotes systemic inflammation during acute pancreatitis.

In the current study, we explored the role of extracellular ATP (eATP) in promoting systemic inflammation during development of acute pancreatitis (AP). Release of extracellular (e)ATP was evaluated in plasma and bronchoalveolar lavage fluid (BALF) of mice with experimental acute pancreatitis (AP). Prophylactic intervention using apyrase or suramin was used to understand the role and contribution of eATP in pancreatitis-associated systemic injury. AP of varying severity was induced in C57BL/6 mice using 1-day or 2-day caerulein, caerulein + LPS and l-arginine models. eATP was measured in plasma and BALF. Mice were treated with suramin or apyrase in the caerulein and l-arginine models of AP. Plasma cytokines, lung, and pancreatic myeloperoxidase, and morphometric analysis of pancreatic and lung histology, were used to assess the severity of pancreatitis. Plasma eATP and purinergic 2 (P2) receptors in the pancreas and lungs were significantly elevated in the experimental models of AP. Blocking the effect of eATP by suramin led to reduced levels of plasma IL-6 and TNFα as well as reduced lung, and pancreatic injury. Neutralizing eATP with apyrase reduced systemic injury but did not ameliorate local injury. The results of this study support the role of eATP and P2 receptors in promoting systemic inflammation during AP. Modulating purinergic signaling during AP can be an important therapeutic strategy in controlling systemic inflammation and, thus, systemic inflammatory response syndrome during AP.NEW & NOTEWORTHY Released ATP from injured cells promotes systemic inflammation in acute pancreatitis.

Structure of the external auditory meatus of the Bowhead whale (Balaena mysticetus) and its relation to their seasonal migration.

The external auditory meatus (EAM) in many species of mysticete whales is filled with a waxy ear plug. Though this lamellated structure is often used to age a whale, its formation and development remain undescribed. It is thought that growth layer groups (GLGs) are laid down annually, thereby increasing the size of this structure. Since some mysticete whales are migratory and many undergo molting, we hypothesized that the cyclical production of these GLGs may be related to these processes. The epithelia of both EAM and glove finger (a part of the tympanic membrane protruding into the EAM) of one juvenile and multiple adult bowhead whales from both fall (October: non-molting) and spring (May: molting) seasons were dissected and examined anatomically and histologically. These tissue samples were compared with the adult oral epithelia at the same time periods. These epithelia shared a similar basic broad structure, though there were differences in thickness and presence of intraepithelial structures. All epithelia in the October specimens were rich in both glycogen and lipid. The parakeratinized epithelium of the oral cavity in the juvenile and some May specimens shed via the production of several superficial epithelial fissures. Other adult May specimens exhibited deep epithelial fissures, reminiscent of pressure ulcers, which would cause the detachment of the entire epithelium from the dermis. We propose that sloughed epithelial lining is the source of the GLGs in the ear plug. Correlating a potential molting sequence with these observations explained the presence of epidermal glycogen, deep epidermal fissures and dermal glycolipid, and to some extent calls into question the origin and structure of the ear plug itself. Further morphological characterization of ear plugs in bowheads is needed to better understand cell origin and ear plug formation.

Incidence of pancreatitis with the use of immune checkpoint inhibitors (ICI) in advanced cancers: A systematic review and meta-analysis.

BACKGROUND: Systemic immune side effects including pancreatitis have been reported with the use of Immune Checkpoint Inhibitors (ICI) (CTLA-4, PD-1 and PDL-1). However, the true incidence, risk, causes (tumor or drug specific) of pancreatitis and relation to other immune side effects, especially diabetes mellitus (DM) are unknown. METHODS: We performed a systematic review and meta-analysis of all clinical trials using ICI for the incidence of any grade lipase elevation, pancreatitis or DM. RESULTS: The incidence of asymptomatic lipase elevation after ICI use is 2.7% (211/7702) and grade 2 pancreatitis is 1.9% (150/7702). No pancreatitis related mortality has been reported in these clinical trials. Patients treated with CTLA-4 inhibitors have increased incidence of pancreatitis when compared to patients treated with PD1 inhibitors 3.98% (95% CI: 2.92 to 5.05) vs 0.94% (95% CI: 0.48 to 1.40); P value < 0.05. Patients treated with ICI for melanoma have increased incidence of pancreatitis when compared to non-melanoma cancers. We also noted an additive increase in incidence of pancreatitis with combination of CTLA4 and PD-1 inhibitors (10.60; 95% CI: 7.89 to 13.32) compared with either CTLA-4 or PD-1 inhibitors alone. CONCLUSIONS: Our study provides precise data for the incidence of pancreatitis among patients using ICI based on tumor types and ICI regimens. ICI use for solid tumors is associated with increased incidence of all grades of lipase elevation and pancreatitis, especially for CTLA-4 agents and ICI combination. Although it does not appear to be associated with mortality, ICI related pancreatitis should be recognized early for appropriate treatment and to potentially reduce long term complications.