bluuebunny/crossref_metadata_2025 huggingface dataset:
Dopamine D1 Agonists, Working Memory, and the Prefrontal Cortex: Effect of Receptor Functional Selectivity/Signaling Bias
Authors: Yang Yang , Mailman Richard B.
Published: April 2020

Dopamine D1 agonists produce an ‘inverted‐U’ dose‐response on working memory‐related behavioral tasks (i.e., low doses improve but high doses have no effect or tend to impair performance). This dose‐dependency has been observed at the single neuron level in the prefrontal cortex, where the cellular basis of working memory is represented. Few studies, however, have examined this process at the neuron population level and its signaling mechanism(s) is still unclear. In the current study, two D1 agonists, 2‐methyldihydrexidine (2MDHX) and CY208,243 (CY208), were examined and compared in rats performing a spatial working memory‐related T‐maze task. 2MDHX is a full agonist at adenylate cyclase and a super‐agonist at β‐arrestin recruitment, whereas CY208 has relatively high intrinsic activity at adenylate cyclase, but much lower at β‐arrestin recruitment. Both compounds had inverted U‐dose response curves at both the behavioral and prefrontal neuron population level, albeit with distinct differences. At behavioral level, they both caused similar improvement with high potency (10 nmol/kg). Conversely, the right‐hand (descending) part of the inverted U dose‐response curve had a great slope for 2MDHX than for CY208, suggesting an extended effective range for a compound with lower β‐arrestin activity. At the neuron population level, both drugs affected the percentage, uniformity, and ensemble strength of sensitivity in a dose‐dependent manner, but 2MDHX influenced neuron activity more before the choice in the T‐maze task whereas CY208 influenced it more after the choice. As the off‐target effects were not likely engaged at the very low doses (i.e., nmol/kg range) utilized in the current study, the differences between 2MDHX and CY208 most likely are related to their specific D1 functional selectivity profiles. The ‘inverted‐U’ dose‐response of D1 agonists on cognitive performance has been observed in many of animal models and confirmed in humans. Although the cognitive improvement at the optimal dose is impressive, the biphasic effect complicates potential clinical use of D1 drugs. Our data indicate that differential signaling may play a role in D1‐related dose‐dependent regulation of cognition, and suggest that D1‐related dose‐dependent regulation of working memory could be modified by functionally selective/biased ligands. This may help guide the discovery of novel D1 compounds that may yield a more monotonic response and therefore translate to the clinic more readily.

Support or Funding Information

Brain & Behavior Research Foundation Young Investigator Grant # 19469 to YY, the 2017 Children’s Miracle Network Research Grant #10 to YY and RBM, the Penn State Translational Brain Research Center, and R01 NS105471 to RBM. Conflict of interest: Dr. Mailman is an inventor on patents related to D1 ligand discovery, and this conflict is disclosed and managed by the Penn State College of Medicine.
3‐hydroxy fatty acids Induce Placental Trophoblast Necroptosis during Acute Fatty Liver of Pregnancy
Authors: Sahoo Prakash Kumar , Natarajan Sathish Kumar
Published: April 2020

Acute fatty liver of pregnancy (AFLP) is a rare catastrophic metabolic dysfunction developing in the third trimester of pregancy with significant maternal and perinatal mortality. AFLP develops as a result of a fetal homozygous mutation (1528G>C) in the gene encoding mitochondrial long‐chain 3‐hydroxy acyl Co‐A dehydrogenase (LCHAD) replacing glutamic acid with glutamine (E474Q) at position 474 in the catalytic domain of LCHAD. As a result of loss of activity in LCHAD, there is drastic decrease in fatty acid beta‐oxidation in mitochondria promoting accumulation of toxic metabolites including long‐chain free fatty acids, 3‐hydroxy fatty acids and acyl carnitines. Later the toxic metabolites get shunted to the maternal circulation leading to liver injury observed in patients with AFLP. While many studies has focused solely on liver, we wanted to understand AFLP pathology in placenta. In order to understand the underlying pathologies in placenta, we took advantage of established placental trophoblast cells (immortalized and choriocarcinoma derived). Upon treatment with 3‐hydroxy fatty acids (3‐HFAs) at different concentration we observed cell death and our results showed that the cell death is non‐apoptotic. Using necroptosis inhibitor we confimed that the cells are undergoing necroptotic cell death, while immunoblot analysis revealed increased phosphorylation of RIPK1. We also obsered mitochondrial damage upon treatment with 3‐hydroxy fatty acids. Together, these results suggest 3‐HFAs are highly toxic to cells and induce non‐apoptotic cell death in the form of necroptosis, while damagaing mitochondria.

Support or Funding Information

This study is supported by funding from NIH P20GM104320 grant.
Transcriptional Activation of Tumor Suppressor p73 is Modulated by MCL1 Through a Novel Protein Interaction
Authors: Widden Hayley , Kacmarczyk Aneta , Whitaker Robert H. , Placzek William J.
Published: April 2020

Precise regulation of apoptosis and cellular response to DNA damage are central to the development of multi‐cellular organisms. In eukaryotes, the BCL2 family of pro‐ and anti‐apoptotic proteins mediate multiple pro‐survival and stress signals to regulate mitochondrial membrane integrity and ultimately apoptosis. Likewise, the p53 family of transcription factors activate multiple pro‐death and cellular senescence pathways in response to DNA damage. Recent studies to develop anti‐cancer agents targeting the BCL2 family have demonstrated that one of the anti‐apoptotic proteins, MCL1, is a critical therapeutic target as it has been shown to inhibit apoptosis in response to a variety of chemotherapeutic agents. MCL1 activity centers around the availability of its BH3 binding cleft to form heterodimers with other pro‐apoptotic BCL2 family proteins. In our search for novel agents that could inhibit these interactions, we identified a novel peptide motif, that we call the reverse BH3 (rBH3) motif, that can interact with the BH3 cleft of MCL1. Here, we show that the p53 homolog, p73, contains a rBH3 motif in its tetramerization domain and that this motif mediates a direct protein‐protein interaction between MCL1 and p73. Furthermore, we show that this interaction allows MCL1 to regulate p73 target gene activation. With MCL1 inhibitors now in clinical trials, we are interrogating the impact that pharmacological inhibition of MCL1 has on DNA damage response signaling in cancer cells who rely on p73 for induction of cell cycle arrest and apoptosis.

Support or Funding Information

NIH grant R01GM117391 to WJP
Anatomy‐based Community Education Using Plastinated Organs
Authors: Hillmer Ryan , Patitucci Teresa
Published: April 2020

Community outreach is an institutional mission at the Medical College of Wisconsin (MCW); which has three campuses spread throughout Wisconsin. There are numerous outreach programs established at each location run by medical students. These outreach programs are largely targeted at middle and high school‐aged students, focusing on promoting physical wellness and fostering an interest in healthcare‐related careers. Extension of these programs to underserved students who may not be able to travel to an MCW site is of particular interest. Although each MCW campus has plastic anatomical models and fixed anatomical specimens set aside for these programs, both have hindrances for use in community education. Plastic anatomical models are a step removed from actual specimens, and do not fully represent the potential for anatomical variations. Although most engaging, wet formalin‐fixed specimens can be irritating to the eyes and respiratory system and must be handled in a well‐ventilated environment. Using funding from the Medical College of Wisconsin and the American Association for Anatomy (AAA), we created a small library of plastinated organs to use during community outreach programs. The plastination process consists of initial organ fixation followed by dehydration of the organ in acetone. Following dehydration, polymer is infused into the organ via vacuum‐pressure and the organ is ultimately cured using gas or UV‐light. These organs are odorless, non‐toxic hardened tissue specimens that do not decay and can be easily transported and handled freely at both on and off‐campus environments. For this project, 3 hearts, 3 kidneys, and 3 brains were harvested from body donors enrolled in MCW’s Anatomical Gift Registry program. These organs were plastinated and sectioned to highlight internal and external anatomical features. Plastination kits consisting of a heart, kidney, and brain (along with educational pamphlets describing relevant anatomy of each organ) were distributed to each campus. Following interaction with plastinated organs, program participants are asked to complete a survey about their learning and interactions with these specimens. All research involving human subjects undergoes strict review by MCW’s IRB. Since their recent implementation, these programs have reached 201 community students and are ongoing throughout the year at all campus locations. We are currently collecting and analyzing user perception surveys, evaluating what students learned during their interactions with the plastinated organs and their preferences for using plastinated vs. wet‐fixed specimens. Preliminary feedback has been positive, where MCW medical students have expressed these plastinates provide a beneficial resource for community outreach programs.

Support or Funding Information

Funding for this project was obtained through the following sources: AAA ‐ Education Outreach Grant and MCW Dean’s Programmatic Dollars.
Chronic hindbrain administration of oxytocin elicits weight loss in high fat diet‐induced obese mice
Authors: Blevins James Ernest , Edwards Mélise Marie , Nguyen Ha Khanh , Herbertson Adam Jay , Dodson Andrew Dale , Wietecha Tomasz Adam , Wolden-Hanson Tami , Graham James Lawrence , Havel Peter Joseph
Published: April 2020

Previous studies indicate that oxytocin (OXT) reduces body weight (BW) in high fat diet (HFD)‐induced obese (DIO) rodents through mechanisms that may involve an enhanced ability of OXT to reduce food intake as well as increase energy expenditure. We have previously demonstrated that chronic fourth ventricular (4V) infusions of OXT (as a strategy to target hindbrain OXT receptors) evokes weight loss in DIO rats. Based on these findings, we hypothesized that increased hindbrain OXT signaling would elicit BW loss in DIO mice maintained on a HFD (60% kcal from fat). To test this hypothesis, age‐matched mice were fed HFD or chow for 4 months prior to implantation of 4V cannulas and 28‐day minipumps that infused OXT (16 nmol/day) or vehicle (VEH; saline). Food intake and BW were tracked for 28 days. Body composition was assessed immediately prior to VEH or OXT treatment and near treatment completion using Quantitative Magnetic Resonance (QMR; EchoMRI 4‐in‐1). OXT preferentially reduced BW by approximately 4.5±1.4% in DIO mice relative to chow‐fed mice (P<0.05; N=9–11/group). OXT‐elicited BW loss was associated with reductions in body adiposity, adipocyte size [inguinal white adipose tissue (IWAT)] and serum leptin (P<0.05). These effects were attributed, in part, to an enhanced effect of OXT to reduce energy intake in DIO mice (P<0.05) at a dose that was not associated with increased kaolin intake (pica behavior; P=NS). While reductions in energy intake contribute to OXT’s effects on BW, chronic 4V OXT appeared to increase uncoupling protein‐1 (UCP‐1) expression in IWAT (0.05<P<0.1; N=9–10/group) suggesting that OXT may also stimulate beiging of WAT. To assess OXT‐elicited changes in brown adipose tissue (BAT) thermogenesis, we examined the effects of acute 4V injections of OXT on interscapular BAT temperature (TIBAT) in mice. Consistent with our previous findings in rats, preliminary data in mice indicate that acute 4V injections of a lower dose (1 μg) appeared to elevate TIBAT at 0.5‐ (P=0.1) and 1.25‐h post‐injection (P=0.15) while a higher dose (5 μg) appeared to elevate TIBAT at 1.5‐ (P<0.05) and 4‐h (0.05<P<0.1) post‐injection (N=4/group). Together, these findings support the hypothesis that chronic hindbrain OXT treatment evokes sustained weight loss in DIO mice by reducing energy intake and increasing BAT thermogenesis and beiging of WAT at a dose that is not associated with visceral illness.

Support or Funding Information

National Institutes of Health R01 DK115976 and VA Merit Review Award BX004102
Serum deprivation primes cancer cells to adapt and survive oxidative stress
Authors: White Elshaddai , Pennant Nakea , Carter Jada , Nash Erica , Hawsawi Ohuod , Oderah-Marah Valerie , Hinton Cimona
Published: April 2020

Inadequate nutrient intake, a survival benchmark in cancer cells, leads to oxidative stress (OS) disrupting homeostasis, activating signaling, and altering metabolism. As reactive oxygen species (ROS) increase, oxidative stressors activate mechanisms allowing cancer cells to adapt and survive. Our data suggests that nutrient‐deprived cancer cells tolerate OS. Moreover, a quiescent phenotype along with nuclear factor‐kappaB (NF‐κB) signaling may synergistically protect tumor cells from OS induced by nutrient deprivation. In DU145 prostate cancer cell line, we observed that serum‐deprived cells maintained viability after exposure to H2O2 and transitioned to a quiescent phenotype via up‐regulated quiescent markers. Additionally, we transiently silenced NF‐κB (RelA/p65) via siRNA, and demonstrated the percentage of total apoptosis in DU145 cells significantly increased in serum‐deprived cells exposed to H2O2. Furthermore, we observed that inhibition of quiescence significantly reduced NF‐κB‐mediated cell survival in response to OS using two quiescence inhibitors targeting Mirk/Dyrk1b kinase (quiescence inducer), AZ191 and NCGC00185981‐05/ML195; concomitantly, a distinct NF‐κB nuclear localization was not observed. It is unclear how prostate cancer cells adapt and survive oxidative stress; however, we hypothesize nutrient deprivation primes cancer cells for OS cell survival, concurrent with a transition to a quiescent phenotype and NF‐κB signaling.

Support or Funding Information

These studies were supported by the NIH/NIGMS/RISE #5R25GM060414‐15 and NIH/NIHMD/RCMI #5G12MD007590.
Anti‐proliferative effect of Ca2+‐activated K+ channel KCa2.2 blocker in prostate cancer LNCaP cells
Authors: Niwa Satomi , Kobayashi Yuki , Tanaka Satoshi , Ohya Susumu
Published: April 2020

Androgen receptors (AR) are essential for the growth of prostate cancer (PC) cells. Androgen deprivation (castration) therapy as antiandrogens is the powerful treatments for PC. However, the most hormone‐sensitive PC patients after the powerful treatment suffer from progression to hormone‐refractory, castration‐resistant PC (CRPC). Therefore, the novel therapeutic targets are required for PC treatment. Ca2+‐activated K+ (KCa) channels are highly expressed in various types of cancers including prostate cancer, and high level KCa channel expression is associated with high metastatic risk, poor prognosis, and lower overall survival. K+ channel activity was measured by plasma membrane potential imaging with voltage‐sensitive fluorescent dye, DiBAC4(3) and whole‐cell patch clamp recordings, and intracellular Ca2+ concentration was measured by Ca2+ imaging with fluorescent Ca2+ indicator, Fura 2‐AM. Of 5 KCa channels, KCa2.2 was predominantly expressed in human androgen‐sensitive prostate cancer LNCaP cells. The potent and selective KCa2.x blocker, UCL1684‐induced depolarization reduced store‐operated Ca2+ entry (SOCE), and LNCaP cell proliferation was suppressed by the treatment with UCL1684. Both pharmacological and siRNA‐mediated blockades of AR using antiandrogens and AR siRNA decreased the expression levels of KCa2.2 in LNCaP cells, whereas the treatment with UCL1684 did not alter the expression levels of AR, suggesting that KCa2.2 may work as a downstream effector of AR signaling. Of interest, the long‐term androgen deprivation for 96 hr increased the expression levels of AR and KCa2.2 in LNCaP cells. These results provide KCa2.2 may be a potential therapeutic candidate in advanced, recurrent hormone‐sensitive PC and CRPC.
Environmental noise is a cardiovascular risk factor – mechanistic insights on oxidative stress, inflammatory pathways and endothelial dysfunction and preliminary data from diabetic mice.
Authors: Jimenez Maria Teresa Bayo , Frenis Katie , Kalinovic Sanela , Kvandová Miroslava , Helmstädter Johanna , Mirski Ksenija Vujacic , Oelze Matthias , Steven Sebastian , Daiber Andreas , Münzel Thomas , Kröller-Schön Swenja
Published: April 2020

Most traditional cardiovascular risk factors (diabetes, smoking or hyperlipidemia) are associated with vascular complications such as endothelial dysfunction, oxidative stress and inflammation. During the last two decades, large epidemiological studies have shown that the physical environment such as noise from road, aircraft or railway may facilitate the development of cardiovascular and metabolic diseases. These studies have demonstrated a link between the incidence of ischemic heart diseases or metabolic disease such as diabetes and exposure to noise, supporting its role as an independent cardiovascular risk factor (reviewed in the WHO Noise Guidelines for the European Region).

We investigated the influence of aircraft noise exposure on molecular mechanisms identifying oxidative stress and inflammation as central players in mediating vascular dysfunction (Münzel et al. Eur. Heart J. 2017; Kröller‐Schön et al. Eur Heart J. 2018). Peak sound levels of 85 and mean sound level of 72 dB(A) applied for 1, 2 and 4 days caused an increase in systolic blood pressure, stress hormones and induced endothelial dysfunction, oxidative stress and inflammation. Control exposures to white noise for 4 days did not induce these changes.

The potential additive effects of noise exposure and preexisting diabetes as well as the underlying molecular mechanisms are currently being investigated in a mouse model since the characteristics of noise induced vascular dysfunction considerably resemble the mechanisms of vascular dysfunction observed in diabetes.

Support or Funding Information

Our experimental studies on noise effects in mice were supported by vascular biology research grants from the Foundation Heart of Mainz and the Boehringer Ingelheim Foundation for the collaborative research group „Novel and neglected cardiovascular risk factors: molecular mechanisms and therapeutic implications”.
The Physiological Function of Sigmar1 in the Skeletal Muscle in Mice
Authors: Aishwarya Richa , Abdullah Chowdhury S. , Alam Shafiul , Morshed Mahboob , Remex Naznin Sultana , Orr A. Wayne , Hartman Brandon , King Judy A. , Bhuiyan Md. Shenuarin
Published: April 2020

Rationale

Sigmar1 is an abundantly expressed molecular chaperone protein encoded by the SIGMAR1 gene. Mutations in SIGMAR1 have been associated with distal hereditary motor neuropathy, amyotrophic lateral sclerosis, silver‐like syndrome, and frontotemporal lobar degeneration. All these human mutation associated pathologies show skeletal muscle phenotypes like muscle wasting and atrophy. However, the physiological function of Sigmar1 in skeletal muscle has not been explored yet.

Objectives

We aim to determine the expression and physiological function of Sigmar1 in skeletal muscle structure and function in mice.

Methods and Results

We first confirmed the Sigmar1 mRNA and protein expression in different types of skeletal muscles (gastrocnemius, quadriceps, soleus, extensor digitorum longus (EDL), and tibialis anterior (TA)) isolated from mice. Immunostaining with the Sigmar1 antibody demonstrated Sigmar1’s localization predominantly in type 1 muscle. We used Sigmar1 global knockout (Sigmar1−/−) mice to determine the physiological function of Sigmar1 in skeletal muscle. Morphometric analysis showed normal muscle weight‐to‐tibia length ratio in all these muscles across the group. The cross‐sectional area of the muscles determined by WGA staining showed that quadriceps and gastrocnemius muscles isolated from Sigmar1−/− mice have bigger muscle fibers compared to wildtype (Wt) mice. Interestingly, absence of Sigmar1 in gastrocnemius and quadriceps muscle of Sigmar1−/− mice results in slow‐to‐fast fiber‐type switch. Interestingly, absence of Sigmar1 in different types of skeletal muscle isolated from Sigmar1−/− mice showed an increased number of central nuclei (H&E staining), increased collagen deposition (Picro‐Sirius red staining) and fibrosis (Masson’s trichrome staining) compared to Wt mice.

Conclusions

Our findings suggested an abundant expression of Sigmar1 in different types of skeletal muscle and possess an essential physiological function in these muscles. Sigmar1 absence results in alterations in muscle fiber size, increased number of central nuclei, fiber‐type switch, and fibrotic remodeling suggesting Sigmar1’s function in maintaining healthy skeletal muscle.

Support or Funding Information

This work was supported by NIH/NHLBI grants R00 HL122354, R01HL145753, R01HL145753‐01S1 and PGM121307A to Dr. Bhuiyan. American Heart Association postdoctoral fellowship to Dr. Alam; Malcolm Fiest post‐ and pre‐doctoral fellowships to Dr. Abdullah and Aishwarya by CCDS, LSUHSC‐S.
Inflammatory marker changes following vertical sleeve gastrectomy in Black Americans and White Americans
Authors: Phillips Charles L. , Welch Bradley A. , Vick Kenneth D. , Dungey Adam L. , Grayson Bernadette E.
Published: April 2020

Obesity is a disease of excess adiposity accompanied by chronic low‐grade inflammation that has diverse negative impacts on various organ systems, including immuno‐hematologic parameters. Surgical weight loss procedures like vertical sleeve gastrectomy (VSG) are sufficient in resolving obesity comorbidities and are touted to reduce the burden of pro‐inflammatory cytokines and augment release of anti‐inflammatory cytokines. Recent published work suggests that resolution of obesity‐related parameters does not occur in Black Americans to the same extent as seen in White Americans following bariatric surgery. This study aims to determine if early changes to immunoglobulins and general markers of inflammation occur similarly after bariatric surgery in a sampling of Black and White American participants. To test this aim, we collected samples from 12 Black American and 12 White American patients before and 6 weeks after VSG. Collectively, Immunoglobulin G (IgG), TGFβ, and C‐reactive protein were all significantly reduced in the cohort following VSG. However, initial and post‐surgery IgG levels were higher in the Black Americans in comparison to White Americans (p < 0.01). No differences were observed with surgery by either race or time for IgA though IgM levels trended to be elevated in White Americans in comparison to Black Americans. Taken in context to previous work, our data suggest there is a disparity between African American and White American immunoglobulin and cytokine production following bariatric surgery. Further research is necessary to investigate the extent of this divergence and additional chronological changes with bariatric surgery.
Preimplantation Genetic Testing for Aneuploidy Versus Morphology as Selection Criteria for Single Frozen-Thawed Embryo Transfer in Good-Prognosis Patients: A Multicenter Randomized Clinical Trial
Authors: Munné Santiago , Kaplan Brian , Frattarelli John L. , Child Tim , Nakhuda Gary , Shamma F. Nicholas , Silverberg Kaylen , Kalista Tasha , Handyside Alan H. , Katz-Jaffe Mandy , Wells Dagan , Gordon Tony , Stock-Myer Sharyn , Willman Susan
Published: April 2020

(Abstracted from Fertil Steril 2019;112:1071–1079.e7)

The rate of embryonic aneuploidy increases exponentially in women over the age of 35 years, coinciding with a dramatic decrease in the success of in vitro fertilization (IVF) in women of advanced maternal age. Despite advancements in preimplantation genetic testing for aneuploidy (PGT-A) including the introduction of next generation sequencing (NGS), morphologic assessment remains the primary method of embryo selection in IVF.
Valgus slipped capital femoral epiphysis: presentation, treatment, and clinical outcomes using patient-reported measurements
Authors: Gelink Andrés , Cúneo Alejandro , Silveri Claudio , Tiderius Carl J. , Loder Randall , von Heideken Johan
Published: April 2020

Valgus slipped capital femoral epiphysis (SCFE), is rare. This study describes the diagnosis, treatment and outcome of valgus SCFE in Uruguay. The medical records and radiographs were reviewed in eight consecutive children [mean age 11.9 years (range 9–13; six female)] with valgus SCFE between 1997–2017. In 2018–2019, all patients were reexamined clinically, new radiographs obtained, and patient-reported outcomes completed using the international tool of hip results (iHOT-12). The prevalence of clinical femoroacetabular impingement (FAI), avascular necrosis, and surgical complications were also studied. There were 11 valgus SCFEs in eight patients; two had primary bilateral SCFEs, and one child later developed a valgus SCFE in the contralateral hip. Seven out of eight patients were overweight. All were stable idiopathic SCFEs. The mean femoral head shaft angle on the anteroposterior radiographs for the 11 SCFEs was 145° (range 140–168) and 141° (range 139–145) for the six healthy contralateral hips. Slip severity measured on the Lauenstein projection was mild (<30°) in eight hips and moderate (30°–60°) in three hips. At a mean follow-up of 87 months (range 24–252), there were no cases of avascular necrosis. The mean iHOT12 was 74 (range 13–97). Significant remodeling was detected in both head shaft angle (8°) and alpha angle (10°) in the affected hips. Nine hips (81%) demonstrated clinical signs of FAI. Our study is the first to describe long-term results using both clinical and patient outcome measures (iHOT-12). A majority of patients have residual symptoms, likely associated with FAI.
Concomitant Aspirin and Anticoagulation Is Associated With Increased Risk for Major Bleeding in Surgical Patients Requiring Postoperative Intensive Care*
Authors: Rayes Hamza A. , Subat Yosuf W. , Weister Timothy , Johnson Madeline Q. , Hanson Andrew , Schulte Phillip J. , Trivedi Vrinda , Gajic Ognjen , Warner Matthew A.
Published: April 2020

Objectives:

Critically ill surgical patients may receive concomitant aspirin and therapeutic anticoagulation postoperatively, yet the safety of this practice remains unknown. We evaluated the risk of major bleeding with concomitant therapy compared with anticoagulation alone.

Design:

Observational cohort study. Inverse probability of treatment weighting was used to assess the association between concomitant therapy and a primary outcome of major bleeding.

Setting:

Postoperative ICUs at an academic medical center.

Patients:

Adults (≥ 18 yr old) receiving anticoagulation during postoperative ICU admission between 2007 and 2016.

Interventions:

None.

Measurements and Main Results:

Nine thousand five hundred eighteen anticoagulated patients were included, including 3,237 (34%) receiving aspirin. A total of 1,874 unique patients (19.7%) experienced a major bleeding event. In inverse probability of treatment weighting analyses, concomitant therapy was associated with increased odds for major bleeding (odds ratio, 1.20; 95% CI, 1.05–1.36; p = 0.006) compared with anticoagulation alone. An interaction test suggested a differential relationship between aspirin use and major bleeding based on aspirin use in the 7 days prior to anticoagulation, such that a strong association between aspirin and major bleeding was observed for recent initiators of aspirin (1.40; 1.13–1.72;p = 0.002) but not for those continuing prior aspirin use. Aspirin use prior to anticoagulation did not modify the relationship between concomitant therapy and new myocardial infarction or stroke (i.e., rates were not increased with aspirin discontinuation prior to anticoagulation).

Conclusions:

Concomitant aspirin and anticoagulation in critically ill surgical patients was associated with an increased rate of major bleeding. Future investigations are warranted to further define optimal management of antiplatelet therapy during anticoagulation in surgical patients.
Respiratory Dialysis—A Novel Low Bicarbonate Dialysate to Provide Extracorporeal Co 2 Removal
Authors: Cove Matthew E. , Vu Lien Hong , Ring Troels , Federspiel William J. , Kellum John A.
Published: April 2020

Objectives:

We designed a novel respiratory dialysis system to remove Co
2 from blood in the form of bicarbonate. We aimed to determine if our respiratory dialysis system removes Co
2 at rates comparable to low-flow extracorporeal Co
2 removal devices (blood flow < 500 mL/min) in a large animal model.

Design:

Experimental study.

Setting:

Animal research laboratory.

Subjects:

Female Yorkshire pigs.

Interventions:

Five bicarbonate dialysis experiments were performed. Hypercapnia (Pco
2 90–100 mm Hg) was established in mechanically ventilated swine by adjusting the tidal volume. Dialysis was then performed with a novel low bicarbonate dialysate.

Measurements and Main Results:

We measured electrolytes, blood gases, and plasma-free hemoglobin in arterial blood, as well as blood entering and exiting the dialyzer. We used a physical-chemical acid-base model to understand the factors influencing blood pH after bicarbonate removal. During dialysis, we removed 101 (±13) mL/min of Co
2 (59 mL/min when normalized to venous Pco
2 of 45 mm Hg), corresponding to a 29% reduction in Paco
2 (104.0 ± 8.1 vs 74.2 ± 8.4 mm Hg; p < 0.001). Minute ventilation and body temperature were unchanged during dialysis (1.2 ± 0.4 vs 1.1 ± 0.4 L/min; p = 1.0 and 35.3°C ± 0.9 vs 35.2°C ± 0.6; p = 1.0). Arterial pH increased after bicarbonate removal (7.13 ± 0.04 vs 7.21 ± 0.05; p < 0.001) despite no attempt to realkalinize the blood. Our modeling showed that dialysate electrolyte composition, plasma albumin, and plasma total Co
2 accurately predict the measured pH of blood exiting the dialyser. However, the final effluent dose exceeded conventional doses, depleting plasma glucose and electrolytes, such as potassium and phosphate.

Conclusions:

Bicarbonate dialysis results in Co
2 removal at rates comparable with existing low-flow extracorporeal Co
2 removal in a large animal model, but the final dialysis dose delivered needs to be reduced before the technique can be used for prolonged periods.
Repeated nicotine vapor inhalation induces behavioral sensitization in male and female C57BL/6 mice
Authors: Honeycutt Sarah C. , Garrett Patrick I. , Barraza Allyson G. , Maloy Andrew N. , Hillhouse Todd M.
Published: April 2020

Electronic cigarette use has significantly increased over the past decade. However, there is limited preclinical research on the behavioral and abuse-related effects of nicotine vapor inhalation in rodents. The present study evaluates the effects of repeated nicotine vapor inhalation in male and female mice using a nicotine behavioral sensitization model. Male and female C57BL/6 mice were administered vaporized nicotine (0–10.0 mg/ml) or the positive control of intraperitoneally administered nicotine (0.5 mg/kg) once daily for 5 days, and locomotor activity was assessed. Body temperatures were measured before and after nicotine vapor inhalation to assess hypothermia. Nicotine vapor inhalation (1.0–3.0 mg/ml) produced a dose-dependent behavioral sensitization effect and produced hypothermia in male and female mice. Nicotine (0.5 mg/kg) also produced significant behavioral sensitization. No sex differences were found for nicotine behavioral sensitization with either route of administration. Pretreatment with the nonselective nicotinic antagonist mecamylamine blocked the behavioral sensitization produced by 1.0 mg/ml of nicotine vapor inhalation. These results established that nicotine vapor inhalation produces behavioral sensitization in an inverted U-shaped curve that is similar to the effects of injected nicotine across several behavioral models. Additionally, pretreatment with mecamylamine demonstrated that nicotinic receptor activation was responsible for the behavioral sensitization produced by nicotine vapor inhalation and was not a conditioned response to the vapor. The methods used in the present study provide an additional behavioral approach for evaluating the behavioral effects of repeated nicotine vapor inhalation that allows the manipulation of several variables, including e-liquid oil blend, e-liquid flavors, puff duration, etc.
Do trends of adiposity and metabolic parameters vary in women with different ovarian reserve status? A population-based cohort study
Authors: Amiri Mina , Ramezani Tehrani Fahimeh , Rahmati Maryam , Firouzi Faezeh , Azizi Feriedoun
Published: April 2020

Objective:

To investigate whether trends of adiposity and glucose metabolism parameters in women with low ovarian reserve status based on their anti-Mullerian hormone (AMH) levels differ from those with high ovarian reserve.

Methods:

In this population-based prospective study, eligible women, aged 20 to 50 years, were selected from among participants of the Tehran Lipid and Glucose Study (TLGS). Generalized estimating equation (GEE) models were applied to compare changes in various adiposity and metabolic parameters across time between women in the first and fourth quartiles of age-specific AMH, after adjustment for confounders. Pooled logistic regression was used to compare progression of prediabetes mellitus (pre-DM) and diabetes mellitus (DM) between the women of these two age-specific AMH quartiles.

Results:

In this study of a total of 1,015 participants and with a median follow-up of 16 years, we observed that over time, both groups of women in the first and fourth quartiles of age-specific AMH experienced significant positive trends in their adiposity indices including central obesity, waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), a body shape index (ABSI), and a negative trend in visceral adiposity index (VAI), whereas there was no significant difference in these parameters between the two groups. This study revealed that odds ratios of diabetes and prediabetes in women in the first quartile of age-specific AMH were not significantly different, compared with those in the fourth quartile.

Conclusion:

Women with lower ovarian reserve do not experience different over time trends of adiposity and glucose metabolism parameters during their reproductive life span.
Telemedicine Home-Based Cardiac Rehabilitation
Authors: Berry Robert , Brawner Clinton A. , Kipa S. George , Stevens Courtney , Bloom Charles , Keteyian Steven J.
Published: April 2020

Details of the Clinical Case:

In this case series report, we review 2 patients who were among the first to participate in the Henry Ford telemedicine home-based cardiac rehabilitation (TM-HBCR) program. These patients had barriers to full participation in a facility-based cardiac rehabilitation (CR) program due to return to work and access to transportation. However, they were willing and able to participate in the TM-HBCR program.

Discussion:

The two cases discussed herein are examples of individuals who likely would not have fully participated in CR if the only option available was a facility-based program. While HBCR is not an option for all patients, it does address several barriers that are known to limit participation in facility-based CR for some individuals.

Technology has made it possible to provide the key components of a facility-based CR program through a TM-HBCR model using a secure connection to the patients via their personal mobile device.
FIVE-YEAR INCIDENCE AND VISUAL ACUITY OUTCOMES FOR INTRAVITREAL THERAPY IN BILATERAL NEOVASCULAR AGE-RELATED MACULAR DEGENERATION
Authors: Cornish Elisa E. , Teo Kelvin Y. , Nguyen Vuong , Squirrel David , Young Stephanie , Gillies Mark C. , Barthelmes Daniel
Published: April 2020

Purpose:

To compare treatment intensity and mean visual acuity gains for first- and second-affected eyes with age-related macular degeneration nAMD over 5 years of treatment. The cumulative incidence of second-eye involvement was assessed.

Method:

We analyzed data from the Fight Retinal Blindness! project database, a prospectively designed registry of “real-world” outcomes from Australia, New Zealand, Switzerland, and Singapore. Patients with bilateral age-related macular degeneration with ≥5 years of follow-up on treatment were included.

Results:

Six thousand five hundred and forty-two eyes being treated for age-related macular degeneration were tracked from 2005 to 2017. Thousand two hundred and sixty-one patients had bilateral age-related macular degeneration; of whom, 302 had 5 years of follow-up. Of these, 170 patients started treatment for each eye at least 2 months apart. The mean baseline visual acuity of second-affected eyes was significantly higher than that of first-eyes (20/50 + 2 vs. 20/80; P < 0.01). Second-affected eyes lost a mean of 5.8 (−9.1 to −2.6) logarithm of the minimum angle of resolution letters after 5 years of treatment, whereas the vision of the first-affected eyes remained stable (P = 0.01). Second-affected eyes received fewer injections than the first-affected eyes after the first year of treatment (6.2/year vs. 7.8/year; P < 0.01) and reactivated earlier (376 vs. 507 days; P = 0.04). The cumulative incidence of second eye involvement was 54% over 5 years.

Conclusion:

Second-affected eyes received fewer treatments and reactivated earlier. Care should be taken to avoid undertreating second-affected eyes.
COMPARISON OF THE INTERNAL LIMITING MEMBRANE INSERTION TECHNIQUE AND THE INVERTED INTERNAL LIMITING MEMBRANE FLAP TECHNIQUE WITH VITRECTOMY TO TREAT MACULAR HOLE–ASSOCIATED RETINAL DETACHMENT
Authors: Zhu Ke , Lei Boya , Wong Wenghang , Zhang Juan , Guo Yue , Chen Han , Song Fang , Chang Qing , Xu Gezhi , Zhang Yanqiong
Published: April 2020

Purpose:

To compare the anatomical and functional outcomes of macular hole (MH)-associated retinal detachment after vitrectomy with the internal limiting membrane (ILM) insertion technique or the inverted ILM flap technique.

Methods:

In this retrospective observational study, we reviewed the medical records of 49 eyes with MH-associated retinal detachment that underwent vitrectomy with the ILM insertion (26 eyes) or ILM flap (23 eyes) technique.

Results:

The MH closure rate at 12 months was greater in the ILM flap group versus the ILM insertion group (95% vs. 73%, respectively, P = 0.059). The postoperative best-corrected visual acuity (BCVA) at 12 months was significantly better in the ILM flap group (P = 0.014). All eyes (100%) showed an improvement in the BCVA of ≥0.3 logarithm of the minimum angle of resolution (15 Early Treatment Diabetic Retinopathy Study letters) in the ILM flap group versus 20 eyes (77%) in the ILM insertion group (P = 0.026). The preoperative BCVA and the ILM flap technique were significantly correlated with the postoperative BCVA (P = 0.028 and 0.027, respectively) and BCVA improvement (≥0.3 logarithm of the minimum angle of resolution [15 Early Treatment Diabetic Retinopathy Study letters]; P = 0.003 and 0.026, respectively).

Conclusion:

The inverted ILM flap technique was more effective in improving the postoperative BCVA in patients with MH-associated retinal detachment when compared with the ILM insertion technique. The preoperative BCVA and the ILM flap technique were independent prognostic factors for visual outcomes in patients with MH-associated retinal detachment.
Performance of New Hypothermic Corneal Storage Media With an Antimycotic Tablet in Comparison to Traditional Hypothermic Media During Simulated Eye Bank Processing
Authors: Perry Isaac , Peterson Kristen , Tóthová Jana D'Amato , Tramber Mike , Botsay Sara , Tremblay David
Published: April 2020

Purpose:

To compare the performance of Kerasave (AL.CHI.MI.A. S.R.L., Ponte San Nicolò, Italy) containing 2.5 μg/mL of amphotericin B and Optisol-GS (Bausch & Lomb, Bridgewater, NJ) cold corneal storage media on donor corneas during routine eye bank procedures.

Methods:

Forty-four paired donor corneas were preserved after swab sample collection and povidone-iodine decontamination. Right and left corneas were immersed in Kerasave and Optisol-GS, respectively, and stored at 4°C before the initial evaluation. Paired corneas were assigned to processing subgroups for penetrating keratoplasty (n = 20), Descemet stripping automated endothelial keratoplasty (n = 14), or Descemet membrane endothelial keratoplasty (n = 10). Endothelial cell density, central corneal thickness, slit-lamp examination, and endothelial cell damage were assessed at different intervals. Sterility testing was performed on media samples.

Results:

At the initial evaluation, after 25.6 ± 3.2 hours of storage, the mean central corneal thickness of all corneas in Kerasave (n = 22) was greater than those in Optisol-GS (n = 22) (571 ± 12 μm vs. 526 ± 10 μm, respectively; P = 0.006). All other metrics were comparable between Kerasave and Optisol-GS in processing subgroups at all time intervals. Corneal swabs were positive in 90% of corneas before decontamination with povidone-iodine. At the initial evaluation, fungal contamination was detected in 24% and 19% of Kerasave and Optisol-GS, respectively. At the final evaluation, no fungi was detected in Kerasave and 1 Optisol-GS sample was positive (P = 0.999).

Conclusions:

Metrics of corneas stored in Kerasave and Optisol-GS were comparable. Kerasave might be considered an antifungal-possessing alternative to Optisol-GS.
High Fluence Increases the Antibacterial Efficacy of PACK Cross-Linking
Authors: Kling Sabine , Hufschmid Fong Siang , Torres-Netto Emilio A. , Randleman J. Bradley , Willcox Mark , Zbinden Reinhard , Hafezi Farhad
Published: April 2020

Purpose:

Photoactivated chromophore for keratitis cross-linking (PACK-CXL) is used as an adjunct therapy to antibiotic medication in infectious keratitis. This experimental study aimed at quantifying the PACK-CXL efficacy as a function of UV fluence using several bacterial strains and irradiated volumes.

Methods:

Six distinct bacterial strains, including standardized strains and clinically isolated strains from patients with keratitis, were analyzed. Bacterial concentrations between 102and 108cells/mL were used (simulating small corneal ulcers). Volumes of either 11 μL (≈285 μm stromal thickness) or 40 μL (≈1000 μm stromal thickness) were irradiated within a microtiter plate at different fluences (5.4–27 J/cm2) and irradiances (3, 9 and 18 mW/cm2). The ratio of bacterial killing (B†) was determined to evaluate the antimicrobial efficacy of PACK-CXL.

Results:

B† was similar (51 ± 11%) in bacterial concentrations between 103and 105per ml. In 11 μL volume,Staphylococcus aureus(SA) 8325-4 ATCC 29213,Bacillus subtilis(BS) 212901, andPseudomonas aeruginosa(PA) 2016-866624 were most sensitive to PACK-CXL at 5.4 J/cm2(on average B† = 49 ± 8%), whereasKlebsiella oxytoca(KO) 2016-86624 (B† = 25%) was least sensitive. When irradiating a larger volume, B† was on average lower in 40 μL (19 ± 18%), compared with 11 μL (45 ± 17%,P< 0.001). By contrast, applying a higher UV fluence increased B† of SA ATCC 29213, from 50% at 5.4 J/cm2to 92% at 10.8 J/cm2, to 100% at 16.2 J/cm2and above.

Conclusions:

Applying higher UV fluences substantially increases the bacterial killing rates. Safety limits for clinical application require further investigation.
Comparative Evaluation of Central Corneal Thickness in Cross-Linked Keratoconic Eyes
Authors: Kosekahya Pinar , Koc Mustafa , Yalcinsoy Kubra Ozdemir , Kocabas Dilara Ozkoyuncu , Toker Mustafa Ilker
Published: April 2020

Purpose:

To compare the central corneal thickness (CCT) measurements measured by using the Pentacam Scheimpflug system with the CCT measured using ultrasound pachymetry (UP) and to compare the compatibility between the methods in normal, keratoconic, and cross-linked keratoconic corneas.

Methods:

The study included 50 eyes of 50 patients with keratoconus (keratoconus group), 50 eyes of 50 patients with progressive keratoconus who underwent corneal cross-linking treatment (CCL group), and 50 eyes of 50 healthy subjects (control group). Patients in the keratoconus and CCL groups were further classified into mild (mean keratometry [Km] ≤ 47 D) and moderate keratoconus subgroups (47.0 < Km < 52.0 D). CCT values were noted from the Pentacam Scheimpflug and UP.

Results:

The difference between the Pentacam and UP values was largest in the CCL group (−20.9 0.21.5 μm), followed by the keratoconus and control groups (−10.6 0.20.3 and 0.4 0.6.8 μm). The Pentacam and UP measurements were not comparable in the keratoconus and CCL groups (P = 0.001 and P < 0.001), whereas they were comparable in the control group (P = 0.62). In subgroup analysis, the 2 methods were comparable in the mild keratoconus subgroup (P = 0.12) and not comparable in the moderate keratoconus subgroup and in both mild and moderate subgroups of the CCL group (P = 0.001, P < 0.001 and P < 0.001).

Conclusions:

Pentacam Scheimpflug tomography and UP can be used interchangeably in normal and mild keratoconic eyes, but not in moderate keratoconic and cross-linked keratoconic eyes. Pachymetry measurements from Scheimpflug must be interpreted with extreme caution with different methods before planning an invasive procedure in these eyes.
Sequelae Following Acute Encephalitis Syndrome Caused by Orientia Tsutsugamushi
Authors: Prakash Gangwar Surya , Thangaraj Jeromie Wesley Vivian , Zaman Kamran , Vairamani Vignesh , Mittal Mahima , Murhekar Manoj
Published: April 2020

We evaluated 146 patients with acute encephalitis syndrome caused by Orientia tsutsugamushi, after median interval of 5 months of hospitalization, to estimate the proportion and spectrum of disability. Fifty-six (38.4%) had mild, whereas 19 (13%) had moderate to severe degree of disability. Most patients had impairment in the domain of cognition and behavior.
Implementation of Point-of-Care Ultrasound in a Physician Assistant Curriculum
Authors: Perdue Mark , Bosse Bobby , Pasha Jabraan , Davison Meredith
Published: April 2020

Purpose

This study evaluated the benefits and challenges of implementing point-of-care ultrasound (POCUS) training in a physician assistant program curriculum.

Methods

Physician assistant students were introduced to POCUS during 2 semesters of Physical Diagnosis. The students were assessed for understanding of applications, effectiveness in obtaining images of target anatomy, and the time required to obtain those images. Student attitudes and the cost of implementation were also recorded.

Results

After 13 hours of training, the 24 students were able to obtain all the target anatomy images and describe the associated structures with an average accuracy rating of 97%. Understanding of POCUS in clinical applications, including recognition of abnormal scan images, was assessed at an average of 85%. Student attitudes toward POCUS were assessed with 88.69% affirming “strongly agree.” Although the costs associated with implementation might vary depending on the setting, they were feasible in our program.

Conclusion

Our study confirmed that POCUS training can be effectively implemented with faculty time burdens and costs that are not prohibitive.