Methodological Challenges and Confounders in Research on the Effects of Ketogenic Diets: A Literature Review of Meta-Analyses.

Several meta-analyses have found a positive association between a popular type of "fad diet", ketogenic diets, and their effect on anthropometric and blood parameters. However, the non-specific inclusion criteria for meta-analyses may lead to incorrect conclusions. The aim of this literature review is to highlight the main confounders and methodological pitfalls of meta-analyses on ketogenic diets by inspecting the presence of key inclusion criteria. The PubMed, Embase, and Web of Science databases and the Cochrane Database of Systematic Reviews were searched for meta-analyses. Most meta-analyses did not define the essential parameters of a ketogenic diet (i.e., calories, macronutrient ratio, types of fatty acids, ketone bodies, etc.) as inclusion criteria. Of the 28 included meta-analyses, few addressed collecting real, re-measured nutritional data from the ketogenic diet and control groups in parallel with the pre-designed nutritional data. Most meta-analyses reported positive results in favor of ketogenic diets, which can result in erroneous conclusions considering the numerous methodological pitfalls and confounders. Well-designed clinical trials with comparable results and their meta-analyses are needed. Until then, medical professionals should not recommend ketogenic diets as a form of weight loss when other well-known dietary options have been shown to be healthy and effective.

Melon and rostral muscle morphology of Gervais' beaked whale (Mesoplodon europaeus): Alternating patterns of bilateral asymmetry.

Toothed whales utilize specialized nasal structures such as the lipid-rich melon to produce sound and propagate it into the aquatic environment. Very little nasal morphology of mesoplodont beaked whales has been described in the literature, and the anatomy of the melon and associated musculature of Gervais' beaked whale (Mesoplodon europaeus) remains undescribed. Heads of three (n = 3) Gervais' beaked whales were examined in detail via dissection as well as computed tomography (CT) and magnetic resonance imaging (MRI). Two additional Gervais' beaked whale individuals (n = 2) were studied via archived CT and MRI scans. Representative transverse dissection sections of the melon were processed for polarized light imaging to verify the presence of tendons inserting into the melon tissue. Three-dimensional (3D) CT reconstructions of the melon, rostral muscles, and associated structures were performed to assess morphology and spatial relationships. In all individuals, the melon's main body demonstrated a bilaterally asymmetrical, curvilinear geometry. This curvilinear shape was defined by a pattern of alternating asymmetry in the medial rostral muscles that projected into the melon's tissue. In transverse polarized light imaging, a network of tendons originating from these asymmetrical rostral muscle projections was observed permeating the melon's lipid tissue. This curvilinear melon morphology and associated asymmetrical musculature suggest a means of lengthening the lipid pathway within a relatively short dimensional footprint. In addition, the species-specific arrangement of muscular projections suggests complex fine-tuning of the melon's geometry during echolocation. Further studies may lend additional insight into the function of this unusual melon morphology.

Angioinvasive gastrointestinal mucormycosis with duodenal necrosis and perforation in a patient with visceral myopathy.

A 55-year-old woman with a past medical history of visceral myopathy with multiple resultant abdominal surgeries, colectomy caused by severe pseudo-obstruction, and end-stage renal disease on hemodialysis presented with complaints of nausea, abdominal distention, vomiting, and diarrhea for five days. Small-bowel obstruction was identified on CT. She subsequently developed acute gastrointestinal bleeding, anemia, and hemodynamic instability. Extensive gastric ulceration with frank hemorrhage prompted urgent subtotal gastrectomy with multiple intraoperative findings, including a necrotic distal duodenum. Surgical pathology showed invasive fungal infection of the duodenum with perforation, morphologically compatible with invasive mucormycosis. The patient was started on intravenous liposomal amphotericin B, but despite best efforts, the patient ultimately succumbed to this invasive fungal infection in addition to sepsis and multi-organ failure.

Headaches in a Horseback Rider.

An immunocompetent woman presented with headaches. She previouslyworked at a farm in upstate New York. Brain MRI noted pituitary enlargement and neurosurgerypursued trans-sphenoidal pituitary biopsy. Histopathology revealed ill-defined granulomaswith clusters of yeast, consistent with Histoplasma.

Mixed-surface polyamidoamine polymer variants retain nucleic acid-scavenger ability with reduced toxicity.

Nucleic acid-binding polymers can have anti-inflammatory properties and beneficial effects in animal models of infection, trauma, cancer, and autoimmunity. PAMAM G3, a polyamidoamine dendrimer, is fully cationic bearing 32 protonable surface amines. However, while PAMAM G3 treatment leads to improved outcomes for mice infected with influenza, at risk of cancer metastasis, or genetically prone to lupus, its administration can lead to serosal inflammation and elevation of biomarkers of liver and kidney damage. Variants with reduced density of cationic charge through the interspersal of hydroxyl groups were evaluated as potentially better-tolerated alternatives. Notably, the variant PAMAM G3 50:50, similar in size as PAMAM G3 but with half the charge, was not toxic in cell culture, less associated with weight loss or serosal inflammation after parenteral administration, and remained effective in reducing glomerulonephritis in lupus-prone mice. Identification of such modified scavengers should facilitate their development as safe and effective anti-inflammatory agents.

Targeting DAMPs with nucleic acid scavengers to treat lupus.

Systemic lupus erythematosus (SLE) is a chronic and often progressive autoimmune disorder marked clinically by a variable constellation of symptoms including fatigue, rash, joint pains, and kidney damage. The lungs, heart, gastrointestinal system, and brain can also be impacted, and individuals with lupus are at higher risk for atherosclerosis, thrombosis, thyroid disease, and other disorders associated with chronic inflammation . Autoimmune diseases are marked by erroneous immune responses in which the target of the immune response is a "self"-antigen, or autoantigen, driven by the development of antigen-specific B or T cells that have overcome the normal systems of self-tolerance built into the development of B and T cells. SLE is specifically characterized by the production of autoantibodies against nucleic acids and their binding proteins, including anti-double stranded DNA, anti-Smith (an RNA binding protein), and many others . These antibodies bind their nuclear-derived antigens to form immune complexes that cause injury and scarring through direct deposition in tissues and activation of innate immune cells . In over 50% of SLE patients, immune complex aggregation in the kidneys drives intrarenal inflammation and injury and leads to lupus nephritis, a progressive destruction of the glomeruli that is one of the most common causes of lupus-related death . To counter this pathology increasing attention has turned to developing approaches to reduce the development and continued generation of such autoantibodies. In particular, the molecular and cellular events that lead to long term, continuous activation of such autoimmune responses have become the focus of new therapeutic strategies to limit renal and other pathologies in lupus patients. The focus of this review is to consider how the innate immune system is involved in the development and progression of lupus nephritis and how a novel approach to inhibit innate immune activation by neutralizing the activators of this response, called Damage Associated Molecular Patterns, may represent a promising approach to treat this and other autoimmune disorders.

A web-based personalized decision support tool for patients diagnosed with ductal carcinoma in situ: development, content evaluation, and usability testing.

PURPOSE: Patients diagnosed with ductal carcinoma in situ (DCIS) face trade-offs when deciding among different treatments, including surgery, radiation, and endocrine therapy. A less chosen option is active monitoring. While evidence from clinical trials is not yet available, observational studies show comparable results for active monitoring and immediate treatment on cancer outcomes in select subgroups of patients. We developed and tested a web-based decision support tool (DST) to help patients explore current knowledge about DCIS and make an informed choice. METHODS: The DST, an interactive web application, was informed by literature reviews and formative work with patients, breast surgeons, and health communication experts. We conducted iterative interviews to evaluate the DST content among women with and without a history of breast cancer, as well as breast cancer experts. For usability testing, we conducted an online survey among women with and without a history of breast cancer. RESULTS: For content evaluation, 5 women with and 10 women without a history of DCIS were interviewed. The sample included 11 White and 4 non-White women, with a mean age of 64 years. The expert sample consisted of 5 attendings and a physician assistant. The feedback was used to add, clarify, or reorganize information in the DST. For usability testing, 22 participants with a mean age of 61 years were recruited including 15 White and 7 Black women and 6 women with a history of DCIS. The mean usability score was 3.7 out of 5. Most participants (86%) found that the DST provided unbiased information about treatments. To improve usability, we reduced the per-page content and added navigation cues. CONCLUSION: Content and usability evaluation showed that the DST helps patients explore trade-offs of active monitoring and immediate treatment. By adopting a personalized approach, the tool will enable informed decisions aligned with patients' values and expectations.

Presence of gustatory and olfactory dysfunction in the time of the COVID-19 pandemic.

BACKGROUND: The unexpected outbreak of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused more than 49 million cases and an estimated 2,000,000 associated deaths worldwide. In Germany, there are currently more than 2,000,000 laboratory-confirmed coronavirus disease 2019 (COVID-19) cases including 51,800 deaths. However, regional differences also became apparent and with the second wave of infections, the detailed characterization of COVID-19 patients is crucial to early diagnosis and disruption of chains of infections. METHODS: Handing out detailed questionnaires to all individuals tested for COVID-19, we evaluated the clinical characteristics of negative and positive tested individuals. Expression of symptoms, symptom duration and association between predictor variables (i.e. age, gender) and a binary outcome (olfactory and gustatory dysfunction) were assessed. RESULTS: Overall, the most common symptoms among individuals who tested positive for SARS-CoV-2 were fatigue, headache, and cough. Olfactory and gustatory dysfunction were also reported by many SARS-CoV-2 negative individuals, more than 20% of SARS-CoV-2 negative tested individuals in our study reported olfactory and gustatory dysfunction. Independent of SARS-CoV-2 status, more females displayed symptoms of gustatory (29.8%, p = 0.0041) and olfactory dysfunction (22.9%, p = 0.0174) compared to men. CONCLUSIONS: Bringing early SARS-CoV-2 tests to the populations at risk must be a main focus for the upcoming months. The reliability of olfactory and gustatory dysfunction in COVID-19 negative tested individuals requires deeper investigation in the future.

Ultrasound evaluation of the radial artery in young adults - A pilot study.

The radial artery is a vessel frequently used in various medical procedures which carry a risk of complications. One such method used to minimize the number of complications is a profound knowledge of the artery's diameter, which allows for appropriate selection of an instrument to use for puncture. The purpose of this study is to determine the diameter of the radial artery and its depth from the skin surface in young adults. MATERIAL AND METHODS: 96 volunteers participated in the study. The average age of the volunteers was 20.43 years. All participants underwent a B-mode ultrasonography to measure the distal radial artery's diameter. Certified anthropometric instruments were used to determine the relation between the artery diameter and the selected basic anthropometric parameters. RESULTS: The mean right arterial diameter for the entire examined population at the level of the styloid process was mean 1.42 (SD 0.26) mm and its distance to the skin was mean 4.00 (SD1.20) mm. Statistical analysis revealed the presence of moderate positive relationship between the diameter of the radial artery and body weight and between the diameter of the radial artery and BMI. A weak correlation between the artery diameter and the width of the wrist was also present. CONCLUSION: In the present work, we aimed to determine the dimensions of the distal section of the radial artery in young people free from symptoms of cardiovascular diseases. The obtained initial study results advise selecting instruments for vascular puncture individually, with special attention paid to slender people with slim wrists.

Co-Medication and Nutrition in Hepatocellular Carcinoma: Potentially Preventative Strategies in Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, with about 841,000 new cases and 782,000 deaths annually. Given the clearly defined population at risk, mostly patients with liver cirrhosis, prevention of HCC could be highly effective. SUMMARY: Besides regular ultrasound surveillance, numerous publications have suggested protective effects of diverse drugs and nutrients. However, none of those preventive options has made it into clinical routine or practice guidelines. We therefore summarize the current status of preventive effects of drugs such as statins, acetylsalicylic acid (ASA), and metformin, but also dietary aspects and nutrients such as coffee, tea, and vitamin D supplementation. A successful implementation of some of these strategies may potentially lead to improved prevention of HCC development in patients with liver cirrhosis. Key Messages: Accumulating data suggest that particularly ASA, antidiabetic therapies, and statins may substantially decrease HCC incidence in patients at risk.

Concomitant use of capecitabine and proton pump inhibitors - Is it safe?

BACKGROUND: Capecitabine is a commonly used oral chemotherapy agent. Recent data suggest that concurrent use of proton pump inhibitors may reduce the efficacy of capecitabine by decreasing its absorption through increased gastric pH. Since proton pump inhibitors are widely used, we evaluated the supportive evidence for the probability of occurrence and potential seriousness of this drug interaction. METHODS: The probability of occurrence was evaluated based on the clinical, pharmacokinetic and in vitro evidence using the Drug Interaction Probability Scale. The possibility of seriousness was assessed based on the potential impact on the therapeutic intent of capecitabine therapy. RESULTS: The probability of occurrence of the interaction is doubtful. Clinical findings from two retrospective post hoc analyses showed inconsistent trends towards reduced survival. Pharmacokinetics studies found no significant decrease in systemic capecitabine level with concurrent gastric acid suppression with antacid or food intake. In vitro data do not support the proposed mechanism of reduced capecitabine absorption due to increased gastric pH. The possibility of seriousness varies depending on the treatment intent of capecitabine therapy. The most and least serious possible outcome would be reduced possibility of cure or survival and symptom control, respectively. CONCLUSION: Although the possible outcome may be serious, the probability of interaction between capecitabine and proton pump inhibitors is doubtful. Therefore, we suggest that intervention should be limited to minimal change to existing therapy plan. This may include routinely ascertaining the need for proton pump inhibitor use. Alternate acid suppressing agents may be considered based on the therapeutic intent of capecitabine therapy.

Reversal of lipophilic weak bases using pH gradient acidic centre liposomes: demonstration of effect in dabigatran-induced anticoagulation.

INTRODUCTION: Liposomes have recently emerged as rational vehicles for drug detoxification. Modification of the core pH may further enhance the ability of liposomes to sequester lipophilic toxins that are weak bases. Dabigatran, a reversible inhibitor of thrombin, has been widely promoted as a novel oral anticoagulant. As a lipophilic weak-base, it provides a rational target for reversal with acidic-centred liposomal preparations. The present study tests the hypothesis that acidic centre liposomes will reverse dabigatran induced anticoagulation. METHOD: Following enteric dabigatran dosing in vitro assessment of thrombin clotting times (TCT) was undertaken in rabbit plasma spiked with incremental liposome concentrations. Tail vein bleeding was assessed following intravenous liposome injection in rats after enteric dabigatran administration. RESULTS: Liposomes achieved reversal of TCT to baseline at low levels of thrombin inhibition, and partial reversal of TCT at higher levels. Liposomes completely reversed the effects of dabigatran on rat tail vein bleeding time (134.0 (6.7) s liposomes vs. 410 (37.8) s control; p < 0.01). CONCLUSION: Dabigatran-induced coagulopathy was reversed in vitro and in vivo by acidic-centred liposomes. pH-modified liposomes are a promising investigational entity in the antidotal treatment of pharmacologic weak bases that are lipid soluble at physiologic pH.

Individual and organizational predictors of pediatric psychiatric inpatient admission in connecticut hospitals: a 6 month secondary analysis.

The objective of this study is to test the hypotheses that bipolar disorders or depressive disorders, minority status, and the presence of pediatric inpatient psychiatric unit will be individual predictors of pediatric psychiatric inpatient admission, and to provide a model that will evaluate which individual and organizational characteristics predict pediatric psychiatric inpatient. For this purpose, a secondary analysis of the medical records of 1,520 pediatric patient visits between January 1, 2008 and June 30, 2008, was conducted using univariate and multivariate logistic regression. Independent predictors of pediatric psychiatric inpatient admission were presence of bipolar and depressive disorders, greater average daily census, and increasing operating margin. Minority status was a significant predictor of not being admitted, as was presence of an anxiety disorder, greater total margin and older age. The results indicate that both individual and organizational factors impact disposition outcomes in particular subsets of pediatric patients who present to emergency departments for psychiatric reasons.

The use of dynamic vapour sorption methods for the characterisation of water uptake in amorphous trehalose.

Water uptake by amorphous sugars is an issue of high importance for the food and pharmaceutical industries. However, while the processes associated with sorption-induced crystallisation have been widely studied, little is known regarding the uptake mechanisms associated with pre-crystallisation water levels. In the present investigation we use dynamic vapour sorption to study the water uptake mechanisms associated with amorphous trehalose. More specifically, we have prepared spray-dried amorphous trehalose with three initial water contents and studied water uptake as a function of time and relative humidity. We model the data obtained prior to crystallisation and suggest two mechanisms that are based on Type II diffusion (using the Peleg equation), which predominates under high humidity conditions (50% RH and above), while we use a Type I Fickian diffusion expression to model uptake under low relative humidity conditions (40% RH and below). The model allows prediction of equilibrium sorption values which correlate well with previously published data calculated from equilibrium vapour pressure data. We also note that the water content following recrystallisation is greater than that predicted by the stoichiometric ratio. A novel model is suggested whereby recrystallisation onset times may be estimated from the vapour sorption data. In conclusion the study has demonstrated that pre-crystallisation water sorption may be associated with two mechanisms depending on the humidity conditions and that such modelling allows insights into both the mechanisms of uptake and the storage behaviour of amorphous sugar samples.

Slow dynamics in glassy methyl alpha-l-rhamnopyranoside studied by 1D NMR exchange experiments.

It is widely known that the ability of sugar glasses to preserve anhydrobiotic systems in nature is important but the process is not yet fully understood. Molecular motions in the glassy state are likely to be important in the process but until now have remained largely uncharacterized. Here we describe the use of 1D 13C NMR exchange experiments using CODEX (centreband only detection of exchange) methods to study the dynamics of the well characterised model glassy monosaccharide, methyl alpha-l-rhamnopyranoside. The glass was prepared by fast cooling of a melt inside an NMR rotor. Molecular motions in the range of seconds to milliseconds were observed in the glass, whereas identical experiments using the crystalline material displayed no observable motions in the time-scales covered by the experiment. At 13 to 14 K above Tg the nature of the motion in the glass changed probably due to the onset of larger scale reorientation. A bimodal distribution of jump angles combined with a broad distribution of correlation times was found to best represent the observed motions.

Visuospatial working memory in school-aged children exposed in utero to cocaine.

OBJECTIVE: Among the neurocognitive impairments reported as associated with prenatal cocaine exposure, slower response time, and less efficient learning in school-aged children are common to findings from several laboratories. This study presents performance data on a spatial working memory task in 75 prenatally cocaine exposed (CE) and 55 nondrug-exposed (NDE) 8- to 10-year-old children. METHODS: Children were administered a novel neuropsychological measure of immediate- and short-term memory for visuospatial information, the Groton Maze Learning Test (GMLT), a computer-based hidden maze learning test that consists of a "timed chase test" (a simple measure of visuomotor speed), eight learning trials followed by a delayed recall trial after an 8-minute delay and a reverse learning trial. Performance is expressed as correct moves per second and number of errors per trial. RESULTS: Across all trials, the cocaine-exposed group showed significantly slower correct moves per second and made significantly more errors. There were no significant main effects for amounts of alcohol, tobacco, or marijuana exposure. After an 8-minute delay and compared to the eighth trial, cocaine-exposed children showed less consolidation in learning compared to nonexposed children. When asked to complete the maze in reverse, cocaine-exposed children showed a greater decrement in performance (decreased correct moves per second and increased errors) compared to the eighth learning trial. CONCLUSIONS: Children exposed in utero to cocaine exhibit a possible impairment in procedural learning and diminished efficiency in creating and accessing an internal spatial map to master the hidden maze.

Personal narratives of illness in schizophrenia: associations with neurocognition and symptoms.

Controversy exists regarding whether unawareness/denial of illness in schizophrenia results from neurocognitive deficits or a rejection of stigmatized social roles. One possibility is that some elements of a narrative of mental illness are primarily a matter of personal/social construction while others may be uniquely curtailed by neurocognitive deficits. Accordingly, we gathered narratives of illness among 52 persons with schizophrenia spectrum disorders using a semi-structured interview. Ratings of the plausibility, adequacy of detail, and temporal conceptual organization of each narrative were correlated with assessments of neurocognition, symptoms, and traditional insight measures. Degree of plausibility was significantly related to performance on the Wisconsin Card Sorting Test (WCST), a measure of executive function and levels of Positive symptoms on the Positive and Negative Syndrome Scale (PANSS). When entered into a regression to predict plausibility, positive symptoms and WCST performance made unique contributions (R2 = .51, p < .0001). Higher levels of Positive symptoms were associated with poorer temporal conceptual organization within narratives. Adequacy of detail within narratives of illness was related to traditional insight measures but not neurocognition or symptoms.