Limitations of antifungal prophylaxis in preventing invasive Candida surgical site infections after liver transplant surgery.

Invasive primary Candida surgical site infections (IP-SSIs) are a common complication of liver transplantation, and targeted antifungal prophylaxis is an efficient strategy to limit their occurrence. We performed a retrospective single-center cohort study among adult single liver transplant recipients at Duke University Hospital in the period between 1 January 2015 and 31 December 2020. The study aimed to determine the rate of Candida IP-SSI according to the peri-transplant antifungal prophylaxis received. Of 470 adult single liver transplant recipients, 53 (11.3%) received micafungin prophylaxis, 100 (21.3%) received fluconazole prophylaxis, and 317 (67.4%) did not receive systemic antifungal prophylaxis in the peri-transplant period. Ten Candida IP-SSIs occurred among 5 of 53 (9.4%) micafungin recipients, 1 of 100 (1.0%) fluconazole recipients, and 4 of 317 (1.3%) recipients who did not receive antifungal prophylaxis. Our study highlights the limitations of antifungal prophylaxis in preventing invasive Candida IP-SSI after liver transplant surgery. We hypothesize that pathogen, host, and pharmacokinetic-related factors contributed to the occurrence of Candida IP-SSI despite antifungal prophylaxis. Our study reinforces the need for a risk-based, multi-pronged approach to fungal prevention, including targeted antifungal administration in patients with risks for invasive candidiasis and close monitoring, especially among patients with surgically complex procedures, with timely control of surgical leaks.

Rapamycin but not acarbose decreases age-related loss of outer hair cells in the mouse Cochlea.

Adding rapamycin or acarbose to diet at 9-10 months of age has been shown to significantly increase life span in both male and female UM-HET3 mice. The current study examined cochleae of male and female UM-HET3 mice at 22 months of age to determine if either treatment also influenced age-related loss of cochlear hair cells. A large loss of cochlear outer hair cells was observed at 22 months of age in untreated mice in both apical and basal halves of the cochlear spiral. Addition of acarbose to diet had no significant effect on the amount of outer hair cell loss at 22 months of age or in its pattern, with large loss in both apical and basal halves. The addition of rapamycin to diet, however, significantly reduced outer hair cell loss in the basal half of the cochlea at 22 months of age when compared to untreated mice. There was no significant difference between male and female mice in any of the conditions. Age-related outer hair cell loss in the apical cochlea precedes outer hair cell loss in the base in many mouse strains. The results of the present study suggest that rapamycin but not acarbose treatment can delay age-related loss of outer hair cells at doses at which each drug increases life span.

A Preliminary Study of Clinical Abbreviation Disambiguation in Real Time.

OBJECTIVE: To save time, healthcare providers frequently use abbreviations while authoring clinical documents. Nevertheless, abbreviations that authors deem unambiguous often confuse other readers, including clinicians, patients, and natural language processing (NLP) systems. Most current clinical NLP systems "post-process" notes long after clinicians enter them into electronic health record systems (EHRs). Such post-processing cannot guarantee 100% accuracy in abbreviation identification and disambiguation, since multiple alternative interpretations exist. METHODS: Authors describe a prototype system for real-time Clinical Abbreviation Recognition and Disambiguation (rCARD) - i.e., a system that interacts with authors during note generation to verify correct abbreviation senses. The rCARD system design anticipates future integration with web-based clinical documentation systems to improve quality of healthcare records. When clinicians enter documents, rCARD will automatically recognize each abbreviation. For abbreviations with multiple possible senses, rCARD will show a ranked list of possible meanings with the best predicted sense at the top. The prototype application embodies three word sense disambiguation (WSD) methods to predict the correct senses of abbreviations. We then conducted three experments to evaluate rCARD, including 1) a performance evaluation of different WSD methods; 2) a time evaluation of real-time WSD methods; and 3) a user study of typing clinical sentences with abbreviations using rCARD. RESULTS: Using 4,721 sentences containing 25 commonly observed, highly ambiguous clinical abbreviations, our evaluation showed that the best profile-based method implemented in rCARD achieved a reasonable WSD accuracy of 88.8% (comparable to SVM - 89.5%) and the cost of time for the different WSD methods are also acceptable (ranging from 0.630 to 1.649 milliseconds within the same network). The preliminary user study also showed that the extra time costs by rCARD were about 5% of total document entry time and users did not feel a significant delay when using rCARD for clinical document entry. CONCLUSION: The study indicates that it is feasible to integrate a real-time, NLP-enabled abbreviation recognition and disambiguation module with clinical documentation systems.

Different management practices are associated with mesophilic and thermophilic spore levels in bulk tank raw milk.

Bacterial endospores (also referred to as spores) present in raw milk are capable of surviving pasteurization and other adverse conditions encountered during dairy powder production. Therefore, requiring low spore levels in raw ingredients (e.g., raw milk) may be necessary for producing dairy powders with low spore counts. To identify potential associations between management practices and spore levels in raw milk, we sampled bulk tank raw milk from 33 farms throughout New York State every other month for 1yr. Following spore pasteurization (80°C for 12min), samples were incubated at 3 different temperatures to enumerate psychrotolerant (6°C for 10 d), mesophilic (32°C for 48h), and thermophilic (55°C for 48h) spores. An additional enrichment procedure was used to detect spores present at low levels (<10 spores/mL). Overall, psychrotolerant, mesophilic, and thermophilic spores were detected (at levels ≥10 spores/mL) in 1, 74, and 58% of bulk tank raw milk samples, respectively. Although thermophilic spore levels could not be quantified (due to bacterial swarming), mesophilic spore levels ranged from below detection (<10 spores/mL) to 680 spores/mL. Data collected through surveys were used to identify management practices associated with either mesophilic or thermophilic spore levels. We found that different management practices are associated with mesophilic and thermophilic spore levels. Low mesophilic spore levels in bulk tank raw milk samples were associated with (1) large herd size, (2) use of sawdust or sand bedding, and (3) not fore stripping during the premilking routine. Management practices that were associated with lower odds of having a thermophilic spore level ≥10 spores/mL are (1) large herd size, (2) spray-based application of the postmilking disinfectant, (3) dry massaging the udder during the premilking routine, and (4) the use of straw bedding. Collectively, these results suggest that different management practices may influence mesophilic and thermophilic spore levels in raw milk.

Age-related changes in auditory nerve-inner hair cell connections, hair cell numbers, auditory brain stem response and gap detection in UM-HET4 mice.

This study compared the timing of appearance of three components of age-related hearing loss that determine the pattern and severity of presbycusis: the functional and structural pathologies of sensory cells and neurons and changes in gap detection (GD), the latter as an indicator of auditory temporal processing. Using UM-HET4 mice, genetically heterogeneous mice derived from four inbred strains, we studied the integrity of inner and outer hair cells by position along the cochlear spiral, inner hair cell-auditory nerve connections, spiral ganglion neurons (SGN), and determined auditory thresholds, as well as pre-pulse and gap inhibition of the acoustic startle reflex (ASR). Comparisons were made between mice of 5-7, 22-24 and 27-29 months of age. There was individual variability among mice in the onset and extent of age-related auditory pathology. At 22-24 months of age a moderate to large loss of outer hair cells was restricted to the apical third of the cochlea and threshold shifts in the auditory brain stem response were minimal. There was also a large and significant loss of inner hair cell-auditory nerve connections and a significant reduction in GD. The expression of Ntf3 in the cochlea was significantly reduced. At 27-29 months of age there was no further change in the mean number of synaptic connections per inner hair cell or in GD, but a moderate to large loss of outer hair cells was found across all cochlear turns as well as significantly increased ABR threshold shifts at 4, 12, 24 and 48 kHz. A statistical analysis of correlations on an individual animal basis revealed that neither the hair cell loss nor the ABR threshold shifts correlated with loss of GD or with the loss of connections, consistent with independent pathological mechanisms.

Lessons learned from developing a drug evidence base to support pharmacovigilance.

OBJECTIVE: This work identified challenges associated with extraction and representation of medication-related information from publicly available electronic sources. METHODS: We gained direct observational experience through creating and evaluating the Drug Evidence Base (DEB), a repository of drug indications and adverse effects (ADEs), and supplemented this through literature review. We extracted DEB content from the National Drug File Reference Terminology, from aggregated MEDLINE co-occurrence data, and from the National Library of Medicine's DailyMed. To understand better the similarities, differences and problems with the content of DEB and the SIDER Side Effect Resource, and Vanderbilt's MEDI Indication Resource, we carried out statistical evaluations and human expert reviews. RESULTS: While DEB, SIDER, and MEDI often agreed on medication indications and side effects, cross-system shortcomings limit their current utility. The drug information resources we evaluated frequently employed multiple, disparate vaguely related UMLS concepts to represent a single specific clinical drug indication or adverse effect. Thus, evaluations comparing drug-indication and drug-ADE coverage for such resources will encounter substantial numbers of false negative and false positive matches. Furthermore, our review found that many indication and ADE relationships are too complex - logically and temporally - to represent within existing systems. CONCLUSION: To enhance applicability and utility, future drug information systems deriving indications and ADEs from public resources must represent clinical concepts uniformly and as precisely as possible. Future systems must also better represent the inherent complexity of indications and ADEs.

Communication gaps for solid organ transplant-transmitted infections among infectious disease physicians: an Emerging Infections Network survey.

Infectious disease (ID) physicians were surveyed concerning knowledge and management of potential transplant-transmitted infections (TTIs). On the basis of cumulative responses to 4 questions that assessed solid organ transplant-related clinical exposures and experience, respondents were divided into 3 groups: most, some, or little transplant experience. Rapid access to donor data was identified as the most important factor when evaluating a potential TTI. Despite varying experience in transplant infections, ID physicians are frequently asked for opinions regarding donor suitability and TTI management. Improved ID physician access to donor information and educational resources will allow more optimal management of potential TTIs.

50 years of informatics research on decision support: what's next.

OBJECTIVES: To reflect on the history, status, and future trends of decision support in health and biomedical informatics. To highlight the new challenges posed by the complexity and diversity of genomic and clinical domains. To examine the emerging paradigms for supporting cost-effective, personalized decision making. METHODS: A group of international experts in health and biomedical informatics presented their views and discussed the challenges and issues on decision support at the Methods of Information in Medicine 50th anniversary symposium. The experts were invited to write short articles summarizing their thoughts and positions after the symposium. RESULTS AND CONCLUSIONS: The challenges posed by the complexity and diversity of the domain knowledge, system infrastructure, and usage pattern are highlighted. New requirements and computational paradigms for representing, using, and acquiring biomedical knowledge and healthcare protocols are proposed. The underlying common themes identified for developing next-generation decision support include incorporating lessons from history, uniform vocabularies, integrative interfaces, contextualized decisions, personalized recommendations, and adaptive solutions.

A history of the INTERNIST-1 and Quick Medical Reference (QMR) computer-assisted diagnosis projects, with lessons learned.

The INTERNIST-1/Quick Medical Reference (QMR) diagnostic decision support project spans four decades, from 1971-onward. This paper describes the history of the project and details insights gained of relevance to the general clinical and informatics communities.

Characterization of uterine granular cell tumors in B6C3F1 mice: a histomorphologic, immunohistochemical, and ultrastructural study.

The granular cell tumor is most often a benign neoplasm of uncertain origin. Four uterine granular cell tumors in control and treated female B6C3F1 mice were identified in chronic studies at the National Toxicology Program. Two tumors occurred in untreated control animals and 2 in treated animals receiving different compounds. Tissue sections were evaluated histologically and stained with hematoxylin and eosin, periodic acid-Schiff with diastase resistance, Masson's trichrome, toluidine blue, phosphotungstic acid-hematoxylin, and stained immunohistochemically with a panel of antibodies to muscle (desmin, alpha smooth muscle actin), neural (S-100, neuron specific enolase), epithelial (wide-spectrum cytokeratin), and macrophage (F4/80) markers. The main histomorphologic feature of tumor cells was the presence of abundant cytoplasmic eosinophilic granules that stained positive for periodic acid-Schiff with diastase resistance. Tumors varied in appearance and were comprised of sheets and nests of round to polygonal cells with distinct borders. Nuclei were hyperchromatic, pleomorphic, and centrally to eccentrically located and often contained single nucleoli. Occasional multinucleated giant cells were observed. Tumors were pale pink and homogeneous with trichrome stain and negative with toluidine blue. Three tumors had positive to weakly positive immunoreactivity for desmin, and 1 was positive for alpha smooth muscle actin. Expression of S-100, wide-spectrum cytokeratin, and neuron-specific enolase was negative for all tumors. Ultrastructurally, prominent electron-dense cytoplasmic granules were abundant and contained secondary lysosomes with heterogeneous lysosomal contents. The characteristics of these uterine granular cell tumors were suggestive of a myogenic origin.

Design of aging intervention studies: the NIA interventions testing program.

The field of biogerontology has made great strides towards understanding the biological processes underlying aging, and the time is ripe to look towards applying this knowledge to the pursuit of aging interventions. Identification of safe, inexpensive, and non-invasive interventions that slow the aging process and promote healthy aging could have a significant impact on quality of life and health care expenditures for the aged. While there is a plethora of supplements and interventions on the market that purport to slow aging, the evidence to validate such claims is generally lacking. Here we describe the development of an aging interventions testing program funded by the National Institute on Aging (NIA) to test candidate interventions in a model system. The development of this program highlights the challenges of long-term intervention studies and provides approaches to cope with the stringent requirements of a multi-site testing program.

Care provider order entry (CPOE): a perspective on factors leading to success or to failure.

OBJECTIVE: Authors provide a perspective on factors leading to successful care provider order entry (CPOE) implementations. METHODS: Viewpoint of authors supported by background literature review. RESULTS: Authors review both benefits and challenges related to CPOE implementation using three guiding principles: (1) a clinical approach to clinical systems, which claims that CPOE implementation is analogous to a "good" clinician delivering care to a patient; (2) a commitment to quality, which advocates that no compromises should be made in implementing system functionality and clinical system content - the highest objective for CPOE implementation is to provide better quality of care and increased safety for patients; (3) a commitment to fairness, as evidenced by respect for individuals and support of local autonomy, which advocates for minimizing disruptions to clinician-users' workflows, and adequate local control over CPOE system design and evolution, including clinical content management. CONCLUSIONS: Past experiences with CPOE implementation can inform future installation attempts. Sociocultural factors dominate in determining the success of implementation, and should govern technical factors.

Predictors of success in surgical ligation of painful varicocele.

INTRODUCTION: Surgical ligation is used in the treatment of painful varicocele. We conducted this retrospective study to establish the effectiveness of varicocele ligation for the treatment of pain and to examine the factors that might predict outcomes. PATIENTS AND METHODS: Eighty-three patients underwent varicocele ligation for pain during the study period. Review of medical records and postal questionnaires were used to document patient age, grade and location of varicocele, duration and quality of pain, surgical approach, complications and the resolution of pain. RESULTS: Follow-up was available for 68 (82%) patients. In 76.5% patients there was marked or complete resolution of pain and 14 had partial resolution. Only 9% patients had persistent pain and 1.5% patient reported worsening pain. The quality of pain, dull ache or dragging, was the only factor that correlated with the resolution of pain following surgery. CONCLUSIONS: Surgical ligation is an effective treatment for the painful varicocele. The quality of pain at presentation may predict outcomes in selected patients.

Cellular proliferation in canine cutaneous mast cell tumors: associations with c-KIT and its role in prognostication.

Canine cutaneous mast cell tumor (MCT) is a common neoplastic disease in dogs. Due to the prevalence of canine MCTs and the variable biologic behavior of this disease, accurate prognostication and a thorough understanding of MCT biology are critical for the treatment of this disease. The goals of this study were to evaluate and compare the utility of the proliferation markers Ki67, proliferating cell nuclear antigen (PCNA), and argyrophilic nucleolar organizing region (AgNOR) as independent prognostic markers for canine MCTs and to evaluate the use of these markers in combination, as each marker assesses different aspects of cellular proliferation. An additional goal of this study was to evaluate the associations between cellular proliferation and c-KIT mutations and between cellular proliferation and aberrant KIT protein localization in canine MCTs. Fifty-six MCTs treated with surgical excision alone were included in this study. Each MCT was evaluated for Ki67 expression, PCNA expression, and KIT protein localization using immunohistochemistry; for AgNOR counts using histochemical staining; and for the presence of internal tandem duplication c-KIT mutations using polymerase chain reaction amplification. In this study, increased Ki67 and AgNOR counts were both associated with significantly decreased survival. On the basis of these results, we recommend that the evaluation of cellular proliferation, including evaluations of both Ki67 expression and AgNORs, should be routinely used in the prognostication of canine MCTs. Additionally, the results of this study show that MCTs with aberrant KIT protein localization or internal tandem duplication c-KIT mutations are associated with increased cellular proliferation, further suggesting a role for c-KIT in the progression of canine MCTs.

Time-of-flight ion mobility spectrometry and differential mobility spectrometry: A comparative study of their efficiency in the analysis of halogenated compounds.

The ion mobilities of halogenated aromatics which are of interest in environmental chemistry and process monitoring were characterized with field-deployable ion mobility spectrometers and differential mobility spectrometers. The dependence of mobility of gas-phase ions formed by atmospheric-pressure photoionization (APPI) on the electric field was determined for a number of structural isomers. The structure of the product ions formed was identified by investigations using the coupling of ion mobility spectrometry with mass spectrometry (APPI-IMS-MS) and APPI-MS. In contrast to conventional time-of-flight ion mobility spectrometry (IMS) with constant linear voltage gradients in drift tubes, differential mobility spectrometry (DMS) employs the field dependence of ion mobility. Depending on the position of substituents, differences in field dependence were established for the isomeric compounds in contrast to conventional IMS in which comparable reduced mobility values were detected for the isomers investigated. These findings permit the differentiation between most of the investigated isomeric aromatics with a different constitution using DMS.

The Gurnham equation in characterizing the compressibility of pharmaceutical materials.

Limitations of the Heckel equation in characterizing material compression behavior have been well reported. In this work, the Gurnham equation, which was first introduced in chemical engineering, is proposed as an alternate method of evaluating the compressibility of pharmaceutical powders. The Gurnham equation was adapted for tablet compression and the estimated slope parameter c was proposed to represent material compressibility. Data from the compression of four commonly used excipients (microcrystalline cellulose, corn starch, lactose monohydrate, and dibasic calcium phosphate dihydrate) and one drug (acetaminophen) were evaluated using the Gurnham equation. Using compression data at different peak pressures, linear relationships between porosity and lnPressure of the five materials were obtained. The determined parameter c expresses the compressibility of materials. The analysis of previous experimental data, including granulations, mixtures and co-processed materials also indicates that c might be a representative parameter for material compressibility.

On exemplary scientific conduct regarding submission of manuscripts to biomedical informatics journals.

As the Editors of leading international biomedical informatics journals, the authors report on a recent pattern of improper manuscript submissions to journals in our field. As a guide for future authors, we describe ethical and pragmatic issues related to submitting work for peer-reviewed journal publication. We propose a coordinated approach to the problem that our respective journals will follow. This Editorial is being jointly published in the following journals represented by the authors: Computer Methods and Programs in Biomedicine, International Journal of Medical Informatics, Journal of Biomedical Informatics, Journal of the American Medical Informatics Association, and Methods of Information in Medicine.

The expression of xenobiotic-metabolizing enzymes in human prostate and in prostate epithelial cells (PECs) derived from primary cultures.

BACKGROUND: Dietary heterocyclic amines (HCAs) are carcinogenic in rodent prostate requiring activation by enzymes such as cytochrome P450 (CYP) and N-acetyltransferase (NAT). METHODS: We investigated by Western blotting and immunohistochemistry the expression of CYP1A1, CYP1A2, and NAT1 in human prostate and in prostate epithelial cells (PECs) derived from primary cultures and tested their ability to activate the dietary carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and its N-hydroxy metabolite (N-OH-IQ) to DNA-damaging moieties. RESULTS: Western blotting identified CYP1A1, CYP1A2, and NAT1. Immunohistochemistry localized NAT1 to the cytoplasm of PECs. Inter-individual variation was observed in the expression levels of CYP1A1, 1A2, and NAT1 (11, 75, and 35-fold, respectively). PECs expressed CYP1A1 and NAT1 but not CYP1A2. When incubated with IQ or N-OH-IQ, PECs formed DNA adducts indicating their ability to metabolically activate these compounds. CONCLUSIONS: Prostate cells possess the capacity to activate dietary carcinogens. PECs may provide a useful model system to study their role in prostate carcinogenesis.

Atmospheric-pressure ionization studies and field dependence of ion mobilities of isomeric hydrocarbons using a miniature differential mobility spectrometer.

The ionization pathways and ion mobility were determined for sets of structural isomeric and stereoisomeric non-polar hydrocarbons (saturated and unsaturated cyclic hydrocarbons and aromatic hydrocarbons) using a novel miniature differential mobility spectrometer with atmospheric-pressure photoionization (APPI) to assess how structural and stereochemical differences influence ion formation and ion mobility. The analytical results obtained using the differential mobility spectrometry (DMS) were compared with the reduced mobility values measured using conventional time-of-flight ion mobility spectrometry (IMS) with the same ionization technique. The majority of differences in DMS ion mobility spectra observed among isomeric cyclic hydrocarbons can be explained by the formation of different product ions. Comparable differences in ion formation were also observed using conventional IMS and by investigations using the coupling of ion mobility spectrometry with mass spectrometry (APPI-IMS-MS) and APPI-MS. Using DMS, isomeric aromatic hydrocarbons can in the majority of cases be distinguished by the different behavior of product ions in the strong asymmetric radio frequency (rf) electric field of the drift channel. The different peak position of product ions depending on the electric field amplitude permits the differentiation between most of the investigated isomeric aromatics with a different constitution; this stands in contrast to conventional IMS in which comparable reduced mobility values were detected for the isomeric aromatic compounds.

Case report: angioleiomyoma of the spermatic cord: a rare scrotal mass.

We report a case of angioleiomyoma of the spermatic cord. Tumours arising from the spermatic cord are rare and most of them are benign. The commonest are lipomas with sarcomas being the predominant malignant variety. This is the first reported case of angioleiomyoma of the spermatic cord.