Dissociating antibacterial from ototoxic effects of gentamicin C-subtypes.

Gentamicin is a potent broad-spectrum aminoglycoside antibiotic whose use is hampered by ototoxic side-effects. Hospital gentamicin is a mixture of five gentamicin C-subtypes and several impurities of various ranges of nonexact concentrations. We developed a purification strategy enabling assaying of individual C-subtypes and impurities for ototoxicity and antimicrobial activity. We found that C-subtypes displayed broad and potent in vitro antimicrobial activities comparable to the hospital gentamicin mixture. In contrast, they showed different degrees of ototoxicity in cochlear explants, with gentamicin C2b being the least and gentamicin C2 the most ototoxic. Structure-activity relationships identified sites in the C4'-C6' region on ring I that reduced ototoxicity while preserving antimicrobial activity, thus identifying targets for future drug design and mechanisms for hair cell toxicity. Structure-activity relationship data suggested and electrophysiological data showed that the C-subtypes both bind and permeate the hair cell mechanotransducer channel, with the stronger the binding the less ototoxic the compound. Finally, both individual and reformulated mixtures of C-subtypes demonstrated decreased ototoxicity while maintaining antimicrobial activity, thereby serving as a proof-of-concept of drug reformulation to minimizing ototoxicity of gentamicin in patients.

Variation in global transcriptomic response to Perkinsus marinus infection among eastern oyster families highlights potential mechanisms of disease resistance.

Dermo disease, caused by the protozoan parasite Perkinsus marinus, negatively impacts wild and cultured Eastern oyster populations, yet our knowledge of the mechanistic bases for parasite pathogenicity and the Eastern oyster's response to it is limited. To better understand host responses to the parasite and identify molecular mechanisms underlying disease-resistance phenotypes, we experimentally challenged two families exhibiting divergent Dermo-resistance phenotypes with the parasite, generated global expression profiles using RNAseq and identified differentially expressed transcripts between control and challenged oysters from each family at multiple time points post-parasite injection. The susceptible and resistant families exhibited strikingly different transcriptomic responses to the parasite over a 28-day time period. The resistant family exhibited a strong, focused, early response to P. marinus infection, where many significantly upregulated transcripts were associated with the biological processes "regulation of proteolysis" and "oxidation-reduction process." P. marinus virulence factors are mainly comprised of proteases that facilitate parasite invasion and weaken host humoral defenses, thus host upregulation of transcripts associated with negative regulation of proteolysis is consistent with a Dermo-resistant phenotype. In contrast, the susceptible family mounted a very weak, disorganized, initial response to the parasite. Few transcripts were differentially expressed between control and injected oysters, and no functional enrichment was detected among them. At the final 28 d time point 2450 differentially expressed transcripts were identified and were associated with either "G-protein coupled receptor activity" (upregulated) or "microtubule-based process" (downregulated). A handful of protease inhibitors were differentially expressed between control and injected susceptible oysters, but this function was not enriched in the susceptible data set. The differential expression patterns observed in this study provide valuable insight into the functional basis of Dermo resistance and suggest that the timing of expression is just as important as the transcripts being expressed.

Aminoglycoside ribosome interactions reveal novel conformational states at ambient temperature.

The bacterial 30S ribosomal subunit is a primary antibiotic target. Despite decades of discovery, the mechanisms by which antibiotic binding induces ribosomal dysfunction are not fully understood. Ambient temperature crystallographic techniques allow more biologically relevant investigation of how local antibiotic binding site interactions trigger global subunit rearrangements that perturb protein synthesis. Here, the structural effects of 2-deoxystreptamine (paromomycin and sisomicin), a novel sisomicin derivative, N1-methyl sulfonyl sisomicin (N1MS) and the non-deoxystreptamine (streptomycin) aminoglycosides on the ribosome at ambient and cryogenic temperatures were examined. Comparative studies led to three main observations. First, individual aminoglycoside-ribosome interactions in the decoding center were similar for cryogenic versus ambient temperature structures. Second, analysis of a highly conserved GGAA tetraloop of h45 revealed aminoglycoside-specific conformational changes, which are affected by temperature only for N1MS. We report the h44-h45 interface in varying states, i.e. engaged, disengaged and in equilibrium. Third, we observe aminoglycoside-induced effects on 30S domain closure, including a novel intermediary closure state, which is also sensitive to temperature. Analysis of three ambient and five cryogenic crystallography datasets reveal a correlation between h44-h45 engagement and domain closure. These observations illustrate the role of ambient temperature crystallography in identifying dynamic mechanisms of ribosomal dysfunction induced by local drug-binding site interactions. Together, these data identify tertiary ribosomal structural changes induced by aminoglycoside binding that provides functional insight and targets for drug design.

Nephrogenic systemic fibrosis is associated with hypophosphataemia: a case-control study.

OBJECTIVE: Nephrogenic systemic fibrosis (NSF) is an iatrogenic fibrosing disorder that primarily affects individuals with chronic kidney disease (CKD) following exposure to gadolinium-based contrast agents (GBCAs). Derangements of calcium and phosphorus have been reported in patients with NSF. The aim of this study was to investigate potential factors in addition to GBCA exposure that may be involved in the pathogenesis of NSF. We hypothesized that patients with stage 5 CKD and NSF would manifest greater alterations in calcium, phosphorus and fibroblast growth factor 23 (FGF23) levels than those who do not have NSF. METHODS: Levels of phosphorus, calcium, FGF23 and 25-hydroxy-vitamin D were measured in 10 patients with stage 5 CKD and biopsy-proven NSF and in 19 patients with stage 5 CKD without NSF. Statistical analyses were performed using Fisher's exact test for categorical variables and the Kruskal-Wallis test for continuous variables. RESULTS: Patients with NSF had significantly lower phosphorus levels compared with controls (P = 0.01). There were no significant differences between NSF patients and controls in calcium, 25-hydroxy-vitamin D, intact parathyroid hormone or FGF23 levels. CONCLUSION: Differences in phosphorus metabolism may exist between patients with stage 5 CKD and NSF compared with patients with stage 5 CKD without NSF.

Electronic medical record: research tool for pancreatic cancer?

BACKGROUND: A novel data warehouse based on automated retrieval from an institutional health care information system (HIS) was made available to be compared with a traditional prospectively maintained surgical database. METHODS: A newly established institutional data warehouse at a single-institution academic medical center autopopulated by HIS was queried for International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) diagnosis codes for pancreatic neoplasm. Patients with ICD-9-CM diagnosis codes for pancreatic neoplasm were captured. A parallel query was performed using a prospective database populated by manual entry. Duplicated patients and those unique to either data set were identified. All patients were manually reviewed to determine the accuracy of diagnosis. RESULTS: A total of 1107 patients were identified from the HIS-linked data set with pancreatic neoplasm from 1999-2009. Of these, 254 (22.9%) patients were also captured by the surgical database, whereas 853 (77.1%) patients were only in the HIS-linked data set. Manual review of the HIS-only group demonstrated that 45.0% of patients were without identifiable pancreatic pathology, suggesting erroneous capture, whereas 36.3% of patients were consistent with pancreatic neoplasm and 18.7% with other pancreatic pathology. Of the 394 patients identified by the surgical database, 254 (64.5%) patients were captured by HIS, whereas 140 (35.5%) patients were not. Manual review of patients only captured by the surgical database demonstrated 85.9% with pancreatic neoplasm and 14.1% with other pancreatic pathology. Finally, review of the 254 patient overlap demonstrated that 80.3% of patients had pancreatic neoplasm and 19.7% had other pancreatic pathology. CONCLUSIONS: These results suggest that cautious interpretation of administrative data rely only on ICD-9-CM diagnosis codes and clinical correlation through previously validated mechanisms.

Understanding Crassostrea virginica tolerance of Perkinsus marinus through global gene expression analysis.

Disease tolerance, a host's ability to limit damage from a given parasite burden, is quantified by the relationship between pathogen load and host survival or reproduction. Dermo disease, caused by the protozoan parasite P. marinus, negatively impacts survival in both wild and cultured eastern oyster (C. virginica) populations. Resistance to P. marinus has been the focus of previous studies, but tolerance also has important consequences for disease management in cultured and wild populations. In this study we measured dermo tolerance and evaluated global expression patterns of two sensitive and two tolerant eastern oyster families experimentally challenged with distinct doses of P. marinus (0, 106, 107, and 108 parasite spores per gram wet weight, n = 3-5 individuals per family per dose). Weighted Gene Correlation Network Analysis (WGCNA) identified several modules correlated with increasing parasite dose/infection intensity, as well as phenotype. Modules positively correlated with dose included transcripts and enriched GO terms related to hemocyte activation and cell cycle activity. Additionally, these modules included G-protein coupled receptor, toll-like receptor, and tumor necrosis factor pathways, which are important for immune effector molecule and apoptosis activation. Increased metabolic activity was also positively correlated with treatment. The module negatively correlated with infection intensity was enriched with GO terms associated with normal cellular activity and growth, indicating a trade-off with increased immune response. The module positively correlated with the tolerant phenotype was enriched for transcripts associated with "programmed cell death" and contained a large number of tripartite motif-containing proteins. Differential expression analysis was also performed on the 108 dosed group using the most sensitive family as the comparison reference. Results were consistent with the network analysis, but signals for "programmed cell death" and serine protease inhibitors were stronger in one tolerant family than the other, suggesting that there are multiple avenues for disease tolerance. These results provide new insight for defining dermo response traits and have important implications for applying selective breeding for disease management.

Reiki as a pain management adjunct in screening colonoscopy.

The purpose of this study was to determine whether the use of Reiki decreases the amount of meperidine administered to patients undergoing screening colonoscopy. The literature review reveals limited studies to show whether Reiki has been able to decrease the amount of opioid the patient receives during screening colonoscopy. A chart review of 300 patients was conducted to obtain baseline average doses of meperidine patients received as the control. Following the chart review, 30 patients were recruited to the Reiki study. Twenty-five of the study arm patients received Reiki in conjunction with meperidine. Five randomly chosen study arm patients received placebo Reiki in conjunction with meperidine in an attempt to blind the clinicians to the treatment received by the patients. Results showed that there were no significant differences in meperidine administration between the patients in the chart review group (control) and the Reiki group. The study revealed that 16% who received Reiki, together with intravenous administration of conscious sedation, received less than 50 mg of meperidine. All the patients in the chart review group received more than 50 mg of meperidine. Results from this pilot study suggest that there may be a decrease in meperidine needed during screening colonoscopy when patients receive Reiki treatments before the procedure. A larger study powered to detect smaller medication differences is the next step in more accurately determining the effect of Reiki on pain management.

Rethinking primary prevention of child trafficking: Recommendations from the Human Trafficking Task Force of the Global Alliance for Behavioral Health and Social Justice.

Child trafficking is one of the most egregious violations of children's rights and well-being. In 2014, the Global Alliance for Behavioral Health and Social Justice formed a task force to focus on the issue. After completing two comprehensive reviews and consultations with experts in the field, the task force identified the need for a coherent framework, which conceptualized the primary prevention of child trafficking, which includes children vulnerable to being trafficked and becoming traffickers. This article describes the process undertaken to develop the primary prevention framework, an innovative, aspirational plan for communities to be absent of trafficking. It describes the framework in detail, including the theories that underlie it and the principles that guide it. The framework's flexibility is evident in its application to such worldwide challenges as racism, inequities, and a pandemic. Although the full consequences of the impact of the COVID-19 pandemic on children are not yet known, this article describes certain trends, which have been identified and discusses critical lessons for applying a dynamic framework, as global disruptors will continue. The article ends with examples of how the framework could be implemented by all stakeholders in the community, to address the primary prevention of child trafficking in both the physical and the virtual world. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

A neoadjuvant strategy for pancreatic adenocarcinoma increases the likelihood of receiving all components of care: lessons from a single-institution database.

BACKGROUND: Recent studies have shown adjuvant therapy improves outcomes from pancreatic cancer (PC). This study investigates receipt and timing of PC treatments, and association with outcomes. METHODS: The analysis cohort consisted of patients with newly-diagnosed PC at a single institution over 5 years. Primary Endpoints were (i) receipt of recommended therapy, and (ii) overall survival (OS). RESULTS: Among 102 patients, 52 underwent resection. Out of 36 localized resected and 16 locally advanced resected (LAR) patients, 26 and 13, respectively, received adjuvant therapy. Six of the latter group received neoadjuvant therapy. Median OS for resected patients was 15.7 months (range 0.6-51.4), compared with 7.7 for unresected patients (range 0.4-32.0) (P < 0.001), and 14.0 months for patients with resection alone (range 0.6-24.4) vs. 16.1 for patients who also received adjuvant therapy (range 3.2-51.4) (P= 0.027). Out of 46 patients undergoing up-front resection, 33 had R0 surgical margins. For the six LAR patients undergoing neoadjuvant therapy, all margins were R0. CONCLUSION: After resection, a substantial proportion of patients do not receive adjuvant therapy, and have worse survival. In this study, neoadjuvant treatment increased both the proportion of patients receiving all components of recommended therapy and the R0 resection rate.

Mind Your Ears: A New Antidote to Aminoglycoside Toxicity?

Aminoglycoside antibiotics are known toxins to cochlear hair cells, causing permanent hearing loss. Using the zebrafish lateral line system as a platform for drug screen and subsequent validation in the rat cochlea in vivo, Chowdhury et al. characterized a novel otoprotectant working against aminoglycoside-induced hearing loss.

National outcomes after gastric resection for neoplasm.

HYPOTHESIS: That factors affecting outcomes of surgical resection in the treatment of gastric cancer can be identified using a large US database. DESIGN: Retrospective observational study. SETTING: The Nationwide Inpatient Sample from January 1, 1998, through December 31, 2003. PATIENTS: We included 13 354 patient discharges (approximately 66 096 nationally by weighted analysis) who underwent gastric resection for neoplasm. MAIN OUTCOME MEASURE: In-hospital mortality. Univariate analyses were performed by means of chi(2) tests. A multivariate logistic regression was performed to determine which variables were independently predictive of in-hospital mortality. RESULTS: During the study period, 50 738 patients (approximately 250 420 nationally) were discharged with the diagnosis of gastric neoplasm. Of those, 13 354 (26.3%) underwent gastric resection during their hospitalization. In-hospital mortality for patients undergoing surgery was 6.0%, without significant change from 1998 through 2003. Factors predictive of significantly increased in-hospital mortality included low annual hospital surgical volume (lowest [or= 11 gastrectomies per year], 6.8% vs 4.9%; adjusted odds ratio [OR], 1.5; 95% confidence interval [CI], 1.2-1.8]), older patient age (50-69 vs <50 years, 4.0% vs 2.1%; adjusted OR, 1.5; 95% CI, 1.1-2.2) (>or =70 vs <50 years, 8.6% vs 2.1%; adjusted OR, 2.9; 95% CI, 2.0-4.3), male sex (male vs female, 6.7% vs 5.0%; adjusted OR, 1.3; 95% CI, 1.1-1.5), and procedure type (total gastrectomy vs all other resections, 8.0% vs 5.3%; adjusted OR, 1.4; 95% CI, 1.2-1.7). CONCLUSIONS: Higher annual surgical volume is predictive of lower in-hospital mortality for patients undergoing gastric resection for neoplasm. Other factors significantly associated with superior outcomes after gastric resection included diagnosis type, procedure type, younger age, female sex, and fewer comorbid conditions.

Towards the Prevention of Aminoglycoside-Related Hearing Loss.

Aminoglycosides are potent antibiotics deployed worldwide despite their known side-effect of sensorineural hearing loss. The main etiology of this sensory deficit is death of inner ear sensory hair cells selectively triggered by aminoglycosides. For decades, research has sought to unravel the molecular events mediating sensory cell demise, emphasizing the roles of reactive oxygen species and their potentials as therapeutic targets. Studies in recent years have revealed candidate transport pathways including the mechanotransducer channel for drug entry into sensory cells. Once inside sensory cells, intracellular targets of aminoglycosides, such as the mitochondrial ribosomes, are beginning to be elucidated. Based on these results, less ototoxic aminoglycoside analogs are being generated and may serve as alternate antimicrobial agents. In this article, we review the latest findings on mechanisms of aminoglycoside entry into hair cells, their intracellular actions and potential therapeutic targets for preventing aminoglycoside ototoxicity.

Treatment of Cognition in the Schizophrenia Spectrum: The Context of Psychiatric Rehabilitation.

Evidence-based approaches and modalities for targeting and treating the cognitive impairments of schizophrenia have proliferated over the past 15 years. The impairments targeted are distributed across the cognitive spectrum, from elemental perception, attention, and memory, to complex executive and social-cognitive functioning. Cognitive treatment is most beneficial when embedded in comprehensive programs of psychiatric rehabilitation. To personalize comprehensive treatment and rehabilitation of schizophrenia spectrum disorders, practitioners and participants must select from a rapidly expanding array of particular modalities and apply them in the broad context of the participant's overall recovery. At present, no particular treatment, cognitive or otherwise, can be considered more important or primary than the context in which it is applied. Persistent difficulty in dissemination of new technology for severe and disabling mental illness compounds the significance of the context created by a full treatment array. In this article, a case-study of a mental health service system is described, showing the broad-ranging effects of degrading the rehabilitative context of treatments, obviating the benefits of cognitive treatment and other modalities. To realize the promise of cognitive treatment, the problems that prevent dissemination and maintenance of complete psychiatric rehabilitation programs have to be addressed.

An Analysis of Overstory Tree Canopy Cover in Sites Occupied by Native and Introduced Cottontails in the Northeastern United States with Recommendations for Habitat Management for New England Cottontail.

The New England cottontail (Sylvilagus transitionalis) is a high conservation priority in the Northeastern United States and has been listed as a candidate species under the Endangered Species Act. Loss of early successional habitat is the most common explanation for the decline of the species, which is considered to require habitat with dense low vegetation and limited overstory tree canopy. Federal and state wildlife agencies actively encourage landowners to create this habitat type by clearcutting blocks of forest. However, there are recent indications that the species also occupies sites with moderate overstory tree canopy cover. This is important because many landowners have negative views about clearcutting and are more willing to adopt silvicultural approaches that retain some overstory trees. Furthermore, it is possible that clearcuts with no overstory canopy cover may attract the eastern cottontail (S. floridanus), an introduced species with an expanding range. The objective of our study was to provide guidance for future efforts to create habitat that would be more favorable for New England cottontail than eastern cottontail in areas where the two species are sympatric. We analyzed canopy cover at 336 cottontail locations in five states using maximum entropy modelling and other statistical methods. We found that New England cottontail occupied sites with a mean overstory tree canopy cover of 58% (SE±1.36), and was less likely than eastern cottontail to occupy sites with lower overstory canopy cover and more likely to occupy sites with higher overstory canopy cover. Our findings suggest that silvicultural approaches that retain some overstory canopy cover may be appropriate for creating habitat for New England cottontail. We believe that our results will help inform critical management decisions for the conservation of New England cottontail, and that our methodology can be applied to analyses of habitat use of other critical wildlife species.

In-hospital mortality after pancreatic resection for chronic pancreatitis: population-based estimates from the nationwide inpatient sample.

BACKGROUND: Pancreatic resection can be performed to ameliorate the sequelae of chronic pancreatitis in selected patients. The perceived risk of pancreatectomy may limit its use. Using a national database, this study compared mortality after pancreatic resections for chronic pancreatitis with those performed for neoplasm. STUDY DESIGN: Patient discharges with chronic pancreatitis or pancreatic neoplasm were queried from the Nationwide Inpatient Sample, 1998 to 2006. To account for the Nationwide Inpatient Sample weighting schema, design-adjusted analyses were used. RESULTS: There were 11,048 pancreatic resections. Malignant neoplasms represented 64.2% of the sample; benign neoplasms and pancreatitis comprised 17.1% and 18.7%, respectively. In-hospital mortality rates were 2.2% and 1.7% for the pancreatitis and benign tumor cohorts, respectively, compared with 5.9% for the malignancy cohort (overall p < 0.01). A multivariable logistic regression examined differences in mortality among diagnoses while adjusting for patient and hospital characteristics; covariates included patient gender, race, age, comorbidities, type of pancreatectomy, payor, hospital teaching status, hospital size, and hospital volume. After adjustment, patients undergoing resection for pancreatitis were at a significantly lower risk of in-hospital mortality when compared with those with malignant neoplasm (odds ratio, 0.43; 95% CI, 0.28 to 0.67). CONCLUSIONS: Pancreatectomies for chronic pancreatitis have lower in-hospital mortality than those performed for malignancy and similar rates as resection for benign tumors. Pancreatic resection, which can improve quality of life in chronic pancreatitis patients, can be performed with moderate mortality rates and should be considered in appropriate patients.

Pancreatic neuroendocrine tumors: the impact of surgical resection on survival.

BACKGROUND: Although surgical resection is generally recommended for patients with localized pancreatic neuroendocrine tumors (PNETs), the impact of resection on overall survival is unknown. The authors investigated the survival advantage of pancreatic resection using a national database. METHODS: This is a retrospective survival analysis of patients with PNETs from the Surveillance, Epidemiology, and End Results database (1988-2002). RESULTS: A total of 728 patients with PNETs were identified with a median survival of 43 months using Kaplan-Meier survival methods. Resection of tumor was associated with significantly improved survival compared with those patients who were recommended for but did not undergo resection (114 months vs 35 months; P < .0001). This survival benefit was demonstrated for patients with localized, regional, and metastatic disease. A multivariable Cox proportional hazards model was constructed to assess the overall effect of surgical resection on survival, and demonstrated an adjusted odds ratio of 0.48 (95% confidence interval, 0.35-0.66) compared with those who were recommended for surgery but did not proceed to surgery. CONCLUSIONS: The authors have demonstrated in a large national study that resection of primary tumor in patients with PNETs is associated with improved survival across all disease stages. Patients with localized, regional, and metastatic PNETs who are reasonable operative candidates should be considered for resection of their primary tumors.

Perioperative mortality for pancreatectomy: a national perspective.

OBJECTIVE: To analyze in-hospital mortality after pancreatectomy using a large national database. SUMMARY AND BACKGROUND DATA: Pancreatic resections, including pancreaticoduodenectomy, distal pancreatectomy, and total pancreatectomy, remain the only potentially curative interventions for pancreatic cancer. The goal of this study was to define factors affecting outcomes after pancreatectomy for neoplasm. METHODS: A retrospective analysis was performed using all patients undergoing pancreatic resections for neoplastic disease identified from the Nationwide Inpatient Sample from 1998 to 2003. Crude in-hospital mortality was analyzed by chi. A multivariable model was constructed to adjust for age, sex, hospital teaching status, hospital surgical volume, year of resection, payer status, and selected comorbid conditions. RESULTS: In all, 279,445 patient discharges were identified with a primary diagnosis of pancreatic neoplasm. A total of 39,463 (14%) patients underwent resection during that hospitalization. In-hospital mortality was 5.9% with a significant decrease from 7.8% to 4.6% from 1998 to 2003 by trend analysis (P < 0.0001). Resections done at low (<5 procedures/year)- and medium (5-18/year)-volume centers had higher mortality compared with those at high (>18/year)-volume centers (low-volume odds ratio = 3.3; 95% confidence interval, 2.3-4.; medium-volume, odds ratio = 2.1; 95% confidence interval, 1.5-3.0). The proportion of procedures performed at high volume centers increased from 30% to 39% over the 6-year time period (P < 0.0001) by trend test. CONCLUSIONS: This large observational study demonstrates an improvement in operative mortality for patients undergoing pancreatectomy for neoplastic disease from 1998 to 2003. In addition, a greater proportion of pancreatectomies were performed at high-volume centers in 2003. The regionalization of pancreatic surgery may have partially contributed to the observed decrease in mortality rates.