Long-Term Proton Pump Inhibitor-Acid Suppressive Treatment Can Cause Vitamin B12 Deficiency in Zollinger-Ellison Syndrome (ZES) Patients.

Whether the long-term treatment of patients with proton pump inhibitors (PPIs) with different diseases [GERD, Zollinger-Ellison syndrome (ZES), etc.] can result in vitamin B12 (VB12) deficiency is controversial. In this study, in 175 patients undergoing long-term ZES treatment with anti-acid therapies, drug-induced control acid secretory rates were correlated with the presence/absence of VB12 deficiency, determined by assessing serum VB12 levels, measurements of VB12 body stores (blood methylmalonic acid (MMA) and total homocysteine[tHYC]), and other features of ZES. After a mean of 10.2 yrs. of any acid treatment (5.6 yrs. with PPIs), 21% had VB12 deficiency with significantly lower serum and body VB12 levels (p < 0.0001). The presence of VB12 deficiency did not correlate with any feature of ZES but was associated with a 12-fold lower acid control rate, a 2-fold higher acid control pH (6.4 vs. 3.7), and acid control secretory rates below those required for the activation of pepsin (pH > 3.5). Over a 5-yr period, the patients with VB12 deficiency had a higher rate of achlorhydria (73% vs. 24%) and a lower rate of normal acid secretion (0% vs. 49%). In conclusion, in ZES patients, chronic long-term PPI treatment results in marked acid hyposecretion, resulting in decreased serum VB12 levels and decreased VB12-body stores, which can result in VB12 deficiency.

Occult residual ovarian tissue at the time of minimally invasive risk reducing surgery in women with BRCA mutations.

OBJECTIVE: To describe extension of ovarian tissue beyond visible and National Comprehensive Cancer Network recommended margins among patients with BRCA mutations undergoing minimally invasive risk-reducing salpingo-oophorectomy. METHODS: A prospective study of patients with BRCA mutations who underwent minimally invasive risk-reducing bilateral salpingo-oophorectomy was conducted. Patient enrollment occurred between October 2021 and 2023. Tissue specimens were analyzed according to the Sectioning and Extensively Examining the Fimbriated End protocol. RESULTS: Twenty women with BRCA mutations were prospectively enrolled. All patients underwent minimally invasive surgery with 70% undergoing concurrent hysterectomy (n = 14). Approximately half of these procedures were performed with robotic assistance (n = 9, 45%). One patient was admitted overnight (5%); the other nineteen were discharged on the day of surgery (95%). One patient experienced a major complication and required readmission (5%). Extension of ovarian tissue beyond the visible ovary was noted on pathologic examination of six specimens (30%). In one patient this was observed on the left (17%), in three on the right (50%), and in two bilateral extension (33%) was noted. The distance ovarian stroma extended microscopically beyond the visible ovary was between 2 and 14 mm, with a median of 5 mm. Among patients with microscopic extension of ovarian tissue, the majority (n = 5, 83%) had a BRCA2 mutation. CONCLUSION: In women with BRCA mutations undergoing risk-reducing minimally invasive surgery, approximately one third had microscopic extension of ovarian stroma beyond the visible ovary. Current guidelines which recommend resection of at least 20 mm of tissue beyond the visible ovary are likely adequate in this population.

Consensus panel recommendations for the optimization of EPIDIOLEX® treatment for seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex.

Following the approval of Epidiolex® (cannabidiol; CBD) for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and tuberous sclerosis complex (TSC), healthcare professionals (HCPs) have had substantial experience in treating patients with Epidiolex. However, confusion still remains among HCPs, caregivers, and patients regarding dosing, drug interactions, safety monitoring, and differentiation between Epidiolex and nonapproved CBD products. To establish consensus recommendations for Epidiolex treatment optimization in LGS, DS, and TSC, a panel of seven HCPs with expertise in epilepsy was convened. Panelists participated in a premeeting survey based on a literature review of Epidiolex for the treatment of LGS, DS, and TSC, and survey responses were compiled for discussion. A modified Delphi method was used to assess agreement among panelists regarding recommendation statements following two rounds of discussion. Panelists identified two broad themes - overcoming barriers to initiation and optimization of treatment for seizures associated with LGS, DS, and TSC - for consensus guidelines. Accurate identification of patients with these rare epilepsies is critical for optimization of Epidiolex treatment. Providers should differentiate Epidiolex from nonapproved CBD products and set expectations for the therapeutic effect and safety/tolerability of Epidiolex. Initial target dose and titration rate should be individualized by baseline variables, prior response to antiseizure medications, and therapeutic goals. Awareness of strategies to manage adverse events and concomitant medications, including drug-drug interactions, is critical. Tracking response to the maximum tolerated dose is an important measure of effectiveness. These consensus recommendations provide real-world experience from neurology HCPs with experience in prescribing Epidiolex and can inform optimal use of Epidiolex for the treatment of seizures associated with LGS, DS, and TSC. PLAIN LANGUAGE SUMMARY: Epidiolex® (cannabidiol) is approved for treating seizures in Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex. Although healthcare professionals have experience in treating patients with Epidiolex, there is a need for better understanding of dosing, drug interactions, and safety of this drug. Therefore, a group of epilepsy experts developed guidelines for best practices in Epidiolex treatment. Two main areas were identified: overcoming barriers to starting Epidiolex and considerations related to Epidiolex dosing. Within these areas, topics, including correct disease identification, managing adverse events, and determining individualized dose, were discussed. These guidelines provide real-world experience to inform optimal Epidiolex use.

Clinical Reasoning: A 17-Year-Old Adolescent Boy With New Altered Mental Status in the Pediatric Intensive Care Unit.

We present the case of a 17-year-old adolescent boy admitted to the Pediatric Intensive Care Unit with an extensive necrotizing soft tissue infection who subsequently developed altered mental status and autonomic instability. Altered mental status is a common occurrence in critically ill children with a broad differential of etiologies. After ruling out organic causes of encephalopathy, management is typically focused on avoiding deliriogenic agents, including benzodiazepines. Dopamine antagonist medications may also be administered adjunctively to manage agitation or delirium that is refractory to other measures. We review the workup and differential diagnosis for altered mentation in critically ill children and discuss the current understanding of a rare etiology of altered mental status in the pediatric population.

hTERT Epigenetics Provides New Perspectives for Diagnosis and Evidence-Based Guidance of Chemotherapy in Cancer.

Strong epigenetic pan-cancer biomarkers are required to meet several current, urgent clinical needs and to further improve the present chemotherapeutic standard. We have concentrated on the investigation of epigenetic alteration of the hTERT gene, which is frequently epigenetically dysregulated in a number of cancers in specific developmental stages. Distinct DNA methylation profiles were identified in our data on early urothelial cancer. An efficient EpihTERT assay could be developed utilizing suitable combinations with sequence-dependent thermodynamic parameters to distinguish between differentially methylated states. We infer from this data set, the epigenetic context, and the related literature that a CpG-rich, 2800 bp region, a prominent CpG island, surrounding the transcription start of the hTERT gene is the crucial epigenetic zone for the development of a potent biomarker. In order to accurately describe this region, we have named it "Acheron" (Ἀχέρων). In Greek mythology, this is the river of woe and misery and the path to the underworld. Exploitation of the DNA methylation profiles focused on this region, e.g., idiolocal normalized Methylation Specific PCR (IDLN-MSP), opens up a wide range of new possibilities for diagnosis, determination of prognosis, follow-up, and detection of residual disease. It may also have broad implications for the choice of chemotherapy.

Unexpected Low Rate of Amyloid-ß Pathology in Multiple Sclerosis Patients.

The life expectancy of people with multiple sclerosis (MS) has increased, yet we have noted that development of a typical Alzheimer disease dementia syndrome is uncommon. We hypothesized that Alzheimer disease pathology is uncommon in MS patients. In 100 MS patients, the rate of amyloid-ß plasma biomarker positivity was approximately half the rate in 300 non-MS controls matched on age, sex, apolipoprotein E proteotype, and cognitive status. Interestingly, most MS patients who did have amyloid-ß pathology had features atypical for MS at diagnosis. These results support that MS is associated with reduced Alzheimer disease risk, and suggest new avenues of research. ANN NEUROL 2024.

The Concealment of Health Information at the Intersection of Sexual Orientation and Race.

Purpose: Sexually and racially minoritized people often have mistrust toward the healthcare system due to both perceived and actual experiences of discrimination. This may result in increased privacy concerns and a reluctance to share health-related information with health care providers. Drawing upon minority stress and an intersectionality framework, this study examines how rates of concealing health information differ between non-Hispanic White heterosexual people, non-Hispanic White lesbian, gay, and bisexual (LGB) people, racially minoritized heterosexual people, and those who are both sexually and racially minoritized. Methods: Using nationally representative cross-sectional data from the Health Information National Trends Survey from 2017 and 2018 (n = 4575), we fit logistic regression models to examine (1) whether sexually and racially minoritized people conceal health information from their providers more than their counterparts and (2) whether this tendency increases for those with multiple marginalized identities. Furthermore, we fit linear regression models to examine whether and how concealing health information from providers are linked to health outcomes. Results: Sexually and racially minoritized people had higher odds of concealing health information from providers than their counterparts. Those with multiple marginalized identities had even higher odds of withholding health information than other groups. Finally, we found a significant negative association between concealing health information and mental health. Conclusion: Our findings underscore the need to consider how the intersection of multiple marginalized identities shape health experiences and concerns over privacy in health care matters. We call for further research to better understand the complex dynamics of patient-provider relationships for marginalized populations.

Ideal strategy for nonvariceal upper gastrointestinal bleeding.

PURPOSE OF REVIEW: Over 300 000 hospital admissions in the United States each year are due to patients with upper gastrointestinal (GI) bleeding (UGIB). Common etiologies of nonvariceal UGIB include peptic ulcers, mucosal erosions of the esophagus, stomach or duodenum, Mallory-Weiss tears, Dieulafoy lesions, upper GI tract malignancy, or other etiology. RECENT FINDINGS: Peptic ulcers classified as Forrest Ia, Ib, or IIa require endoscopic hemostasis, while IIb ulcers may be considered for endoscopic clot removal with endoscopic treatment of any underlying major stigmata. Endoscopic hemostasis for ulcers classified as Forrest IIc or III is not advised due to the low risk of recurrent bleeding. Endoscopic hemostasis in ulcer bleeding can be achieved using injection, thermal, and/or mechanical modalities. SUMMARY: This review focuses on the currently recommended endoscopic therapies of patients presenting with acute nonvariceal upper gastrointestinal hemorrhage.

Bayesian Estimation Improves Prediction of Outcomes after Epilepsy Surgery.

Low power is a problem in many fields, as underpowered studies that find a statistically significant result will exaggerate the magnitude of the observed effect size. We quantified the statistical power and magnitude error of studies of epilepsy surgery outcomes. The median power across all studies was 14%. Studies with a median sample size or less (n<=56) and a statistically significant result exaggerated the true effect size by a factor of 5.4 (median odds ratio 9.3 vs. median true odds ratio 1.7), while the Bayesian estimate of the odds ratio only exaggerated the true effect size by a factor of 1.6 (2.7 vs. 1.7). We conclude that Bayesian estimation of odds ratio attenuates the exaggeration of significant effect sizes in underpowered studies. This approach could help improve patient counseling about the chance of seizure freedom after epilepsy surgery.

Ventrointermediate thalamic stimulation improves motor learning in humans.

Ventrointermediate thalamic stimulation (VIM-DBS) modulates oscillatory activity in a cortical network including primary motor cortex, premotor cortex, and parietal cortex. Here we show that, beyond the beneficial effects of VIM-DBS on motor execution, this form of invasive stimulation facilitates production of sequential finger movements that follow a repeated sequence. These results highlight the role of thalamo-cortical activity in motor learning.

Flexing with lignin: lignin-based elastomers synthesised from untreated kraft black liquor.

The synthesis and characterisation of a lignin-based elastomer system using lignin-epoxy-resins is presented. Untreated kraft black liquor was used to synthesise glycidyl lignin or black liquor-based epoxy resin (BLER), following a published procedure. A flexible, elastomeric thermoset was produced by cross-linking BLER with succinic anhydride (SA). The produced material was characterised in respect to its chemical, thermal, mechanical and swelling characteristics. In addition, vertical burning tests were performed. The obtained lignin-based elastomeric thermoset had a tensile strength of 1.0 ± 0.20 MPa and elastic moduli of 1.6 ± 1.4 and 0.44 ± 0.35 MPa at 5% and 50% elongation, respectively. A maximum elongation of 151 ± 49% was found.

Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity.

Isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated metabolic gene across human cancers. Mutant IDH1 (mIDH1) generates the oncometabolite (R)-2-hydroxyglutarate, disrupting enzymes involved in epigenetics and other processes. A hallmark of IDH1-mutant solid tumors is T cell exclusion, whereas mIDH1 inhibition in preclinical models restores antitumor immunity. Here, we define a cell-autonomous mechanism of mIDH1-driven immune evasion. IDH1-mutant solid tumors show selective hypermethylation and silencing of the cytoplasmic double-stranded DNA (dsDNA) sensor CGAS, compromising innate immune signaling. mIDH1 inhibition restores DNA demethylation, derepressing CGAS and transposable element (TE) subclasses. dsDNA produced by TE-reverse transcriptase (TE-RT) activates cGAS, triggering viral mimicry and stimulating antitumor immunity. In summary, we demonstrate that mIDH1 epigenetically suppresses innate immunity and link endogenous RT activity to the mechanism of action of a US Food and Drug Administration-approved oncology drug.

Acquisitions of behavioral health treatment facilities from 2010 to 2021.

Private equity (PE) and other for-profit ownership of behavioral health (mental health and substance use) treatment facilities have become increasingly prevalent, but data on these acquisitions are not readily available. In this study, we describe a novel database that contains information on the universe of behavioral health acquisitions that occurred between 2010 and 2021. We found that the frequency of behavioral health facilities involved in acquisitions increased substantially, from 32 facilities in 2010 to 1330 in 2021. The total number of facilities involved in acquisitions was 2806. Most of these facilities provided outpatient services only (N = 2073) and offered only mental health services (N = 1428). Private equity-backed acquisitions accounted for around 60% of all acquisition activity (N = 1678 facilities PE, N = 1128 facilities other for-profit). 25% of acquired facilities were located within 20 miles of one another (N = 561), 50% occurred within 80 miles (N = 1403), and 75% occurred within 319 miles (N = 2104). Future research should evaluate the effects of this consolidation on behavioral healthcare access, quality, spending, and patient outcomes.

Skin color reporting in basal cell carcinoma-related randomized controlled trials in top dermatology journals: a systematic review.

OBJECTIVES: To determine the rate skin color is reported in randomized controlled trials (RCTs) involving basal cell carcinoma (BCC) identification and treatment in the top ten dermatology journals. METHODS: A systematic review was conducted of RCTs involving BCC among the top ten dermatology journals, determined by impact factor, from inception to July 11th, 2023. Studies were included if they reviewed the prevention, detection, and treatment of BCC, directly involved patients, and were classified as RCTs. Studies were classified as positive for reporting skin of color (SOC) if the demographic data in the methods or results included any of the following terms: Fitzpatrick scale, race, ethnicity, skin of color, or sunburn tendency. RESULTS: Of the 51 studies identified, only 23 articles reported data pertaining to skin color within the results section (45.1%); whereas 28 articles mentioned skin color somewhere within the text (54.9%). Subgroup analysis was performed, and no statistical significance was found for study location or year of publication. CONCLUSION: Dark skin color can make it more difficult to diagnose skin tumors and it is unknown if race affects response to treatment. Less than 50% of RCTs related to basal cell carcinoma in top international dermatology journals included skin color within the demographic portion of their results section pertaining to study participants. Subgroup analysis demonstrated that studies performed within the United States reported skin color less than half the time (40%). Additionally, there has been no statistically significant difference in reporting over the past 4 decades. Further research is necessary to determine whether low reporting rates of race/skin color in BCC-related RCTS could impact diagnostic or treatment recommendations for patient care in this group.

Continuous Assessment of Active-Duty Army Special Operations and Reconnaissance Marines Using Digital Devices and Custom Software: The Digital Comprehensive Operator Readiness Assessment (DcORA) Study.

BACKGROUND: Continuous exposure to extreme and chronic stress from uncontrollable events has been linked to increased psychological and physiological reactivity. Prolonged, frequent deployments may test coping skills over time, ultimately rendering Servicemembers vulnerable to mental health problems and suicide. This study develops a methodology for accurately collecting holistic health measures from Servicemembers using digital tools, including custom-built phone software and body-worn sensors. METHODS: The secure research platform and mobile app continuously collect multiple health measures and, after data analysis, deliver continuously updated summary data back to the Servicemember. This system provides novel insights into the relationships between the measures while helping individuals track their progress toward self-established goals. Participants were given an iPhone (including the study app) and an Apple Watch. Participants tracked their data for more than 6 months and responded to baseline, daily, and weekly questions and assessments. Physiologic, psychologic, and cognitive assessment data across the Preservation of the Force and Family program (POTFF) domains were collected, displayed to the individual, and analyzed in aggregate. RESULTS: When coupled with custom-built software, this hardware can be elevated from a fitness tracker to a user-facing health monitoring, educational, and delivery system. CONCLUSION: This wearable system measured vital factors associated with the health and human performance of Servicemembers. In real-time, it engaged Servicemembers in health and human performance optimization practices to achieve a goal of prevention of physical or mental injury.

Persistence and Sexual Dimorphism of Gut Dysbiosis and Pathobiome after Sepsis and Trauma.

OBJECTIVE: To evaluate the persistence of intestinal microbiome dysbiosis and gut-plasma metabolomic perturbations following severe trauma or sepsis weeks after admission in patients experiencing chronic critical illness (CCI). SUMMARY: Trauma and sepsis can lead to gut dysbiosis and alterations in the plasma and fecal metabolome. However, the impact of these perturbations and correlations between gut dysbiosis and the plasma metabolome in chronic critical illness have not been studied. METHODS: A prospective observational cohort study was performed with healthy subjects, severe trauma patients, patients with sepsis residing in an intensive care unit (ICU) for 2-3 weeks. A high-throughput multi-omics approach was utilized to evaluate the gut microbial and gut-plasma metabolite responses in critically ill trauma and sepsis patients 14-21 days after ICU admission. RESULTS: Patients in the sepsis and trauma cohorts demonstrated strikingly depleted gut microbiome diversity, with significant alterations and specific pathobiome patterns in the microbiota composition compared to healthy subjects. Further subgroup analyses based on sex revealed resistance to changes in microbiome diversity among female trauma patients compared to healthy counterparts. Sex-specific changes in fecal metabolites were also observed after trauma and sepsis, while plasma metabolite changes were similar in both males and females. CONCLUSIONS: Dysbiosis induced by trauma and sepsis persists up to 14-21 days after onset and is sex-specific, underscoring the implication of pathobiome and entero-septic microbial-metabolite perturbations in post-sepsis and post-trauma CCI. This indicates resilience to infection or injury in females' microbiome and should inform and facilitate future precision/personalized medicine strategies in the intensive care unit.

Disturbance theory for ecosystem ecologists: A primer.

Understanding what regulates ecosystem functional responses to disturbance is essential in this era of global change. However, many pioneering and still influential disturbance-related theorie proposed by ecosystem ecologists were developed prior to rapid global change, and before tools and metrics were available to test them. In light of new knowledge and conceptual advances across biological disciplines, we present four disturbance ecology concepts that are particularly relevant to ecosystem ecologists new to the field: (a) the directionality of ecosystem functional response to disturbance; (b) functional thresholds; (c) disturbance-succession interactions; and (d) diversity-functional stability relationships. We discuss how knowledge, theory, and terminology developed by several biological disciplines, when integrated, can enhance how ecosystem ecologists analyze and interpret functional responses to disturbance. For example, when interpreting thresholds and disturbance-succession interactions, ecosystem ecologists should consider concurrent biotic regime change, non-linearity, and multiple response pathways, typically the theoretical and analytical domain of population and community ecologists. Similarly, the interpretation of ecosystem functional responses to disturbance requires analytical approaches that recognize disturbance can promote, inhibit, or fundamentally change ecosystem functions. We suggest that truly integrative approaches and knowledge are essential to advancing ecosystem functional responses to disturbance.