Perceived Value of a Women's Health Journal Club in Rural Hawai'i.

OBJECTIVES: Rural Hawai'i faces a shortage of physicians specializing in women's health. Improving clinician collaboration and access to the scientific literature are potential strategies for improving physician retention in this community. In 2021, a monthly women's health journal club was established for local clinicians and trainees on Hawai'i Island. Although journal clubs are common in large academic institutions, there are limited data regarding the value of journal clubs in rural and community practices. This study aimed to evaluate the value of a women's health journal club on Hawai'i Island. METHODS: We used an anonymous Web-based survey to evaluate the value of the journal club. RESULTS: Of the 18 eligible clinicians participating in the women's health journal club, 13 completed a Web-based survey (response rate 72%). The common reasons for attending journal club included wanting to learn about research methods/statistics (100%), seeking opportunities to discuss current best practices (86%), and desiring to practice critical review skills (71%). The majority of respondents (77%) believed that journal club was a valuable activity, and 92% of respondents would recommend this activity to a colleague. This journal club allowed participants to improve their understanding of research methods (85%) and stay up-to-date with medical advancements (85%). CONCLUSIONS: This community-based journal club is a valuable activity for clinicians practicing on Hawai'i Island. Other rural communities may similarly benefit from engaging in structured scholarly discussion.

Just World Beliefs among Medical Students and the General Public in Hawai'i.

Just World Beliefs (JWBs) are a psychological tendency to conclude the world is an inherently fair place in which people experience the outcomes they deserve. Strong JWBs positively correlate with a personal commitment to long-term ambitions and blaming people for their negative health outcomes. This study aimed to measure JWBs in medical students and the general population of Hawai'i. It was hypothesized that (1) medical students would have stronger JWBs than the general public, and (2) JWBs would be strongest for medical students in the latter part of their training. Current residents of Hawai'i and medical students at the University of Hawai'i at Manoa were recruited to complete a web-based survey measuring JWBs using the Global Belief in a Just World Scale. A t-test was used to compare JWB strength between the groups. A regression analysis identified factors predicting strength of JWBs. Contrary to both hypotheses, medical students in Hawai'i possessed weaker JWBs than Hawai'i residents (P<.01), and JWBs did not differ based on training duration (P=.97). Age (P<.01) was the only demographic variable to significantly predict JWBs. The difference in JWBs among medical and non-medical cohorts was no longer significant after controlling for age. Among medical students, younger age was associated with weaker JWBs. Future studies should explore the prevalence and effects of JWBs among diverse populations and the medical professionals that care for them.

Perceived Impact of a Core Rotation on Hawai'i Island on Future Career Intentions among Obstetrics and Gynecology Residents.

Hawai'i Island faces a growing shortage of obstetric and gynecology providers. Increased exposure of obstetrics and gynecology residents to rural rotations during their core training may increase their interest in rural practice after graduation. In an effort to address the health care needs of women on Hawai'i Island, the University of Hawai'i Obstetrics and Gynecology Residency Program established a 4-week required gynecology rotation in the town of Hilo. Between July 2019 and June 2020, third- and fourth-year obstetrics and gynecology residents provided outpatient gynecologic care and participated in gynecologic surgeries at Hilo-based medical facilities. A total of 9 residents participated in this Hilo-based rotation. This retrospective study extracted data from post-rotation evaluations. Eight out of 9 participating residents (89%) felt that the rotation slightly or far exceeded their expectations. After the rotation, 7 residents (78%) reported an interest in practicing in a rural community, while only 3 residents (33%) reported having this interest prior to the rotation. Underserved rural areas seeking to recruit and retain obstetrics and gynecology physicians may benefit from partnering with residency training programs.

Clinical outcomes of patients with giant cell arteritis treated with tocilizumab in real-world clinical practice: decreased incidence of new visual manifestations.

BACKGROUND: Placebo-controlled clinical trials have demonstrated the efficacy of tocilizumab (TCZ) for remission maintenance and glucocorticoid sparing in patients with giant cell arteritis (GCA). However, limited data exist on the effectiveness and safety of TCZ for GCA in real-world clinical practice. METHODS: This was a retrospective, single-center analysis of patients with GCA treated with intravenous or subcutaneous TCZ (2010-2018). Outcomes evaluated before and after TCZ initiation included occurrence of flare, time to flare, annualized flare rate, flare characteristics (i.e., polymyalgia rheumatica [PMR] symptoms, cranial manifestations), prednisone use, and safety. Flare was defined as the recurrence of unequivocal GCA manifestations requiring treatment intensification. Subgroup analyses of patients with PMR or visual manifestations at GCA diagnosis were performed. RESULTS: Sixty patients with GCA were included. The median (IQR) disease duration before and after the start of TCZ was 0.6 (0.2-1.6) and 0.5 (0.3-1.4) years, respectively. At least 1 flare was observed in 43 patients (71.7%) before and in 18 (30.0%) after TCZ initiation. Median (IQR) time to flare was 0.5 (0.3-0.7) years before TCZ treatment and 2.1 (0.6-2.6) years after TCZ initiation (HR 0.22; 95% CI 0.10-0.50; p = 0.0003). The annualized flare rate significantly decreased following TCZ use (before TCZ 1.4 [95% CI 1.0-2.1]; after TCZ 0.6 [95% CI 0.3-1.0] events/year; p < 0.001). Similar improvements were observed in patients with visual manifestations or PMR symptoms at GCA diagnosis. TCZ reduced the incidence of new visual manifestations, and no flares associated with permanent vision loss occurred while patients were receiving TCZ. Mean (SD) prednisone dose at TCZ onset and at the end of follow-up was 30 (18.3) and 5 (6.9) mg/day, respectively (p < 0.0001). After TCZ initiation, 46.6% of patients successfully discontinued prednisone. The incidence of adverse events, primarily attributed to glucocorticoids, was similar before and after TCZ initiation. CONCLUSIONS: In this real-world setting, TCZ improved GCA clinical outcomes significantly and demonstrated effectiveness in the subgroups of patients with PMR symptoms and GCA-related visual manifestations at GCA diagnosis. No new cases of blindness occurred after TCZ initiation. Adverse events, many attributable to glucocorticoids, were comparable before and after TCZ treatment.

Effect of disease duration and other characteristics on efficacy outcomes in clinical trials of tocilizumab for rheumatoid arthritis.

OBJECTIVE: To determine the extent to which disease duration, alone or in combination with other baseline clinical and non-clinical factors, explains variations in outcome of tocilizumab initiated in biologic-naïve patients with established RA. METHODS: In this pooled analysis of phase 3 and 4 clinical trials conducted by the sponsor, predictors of response, including demographics, disease characteristics at baseline (start of tocilizumab dosing) and study characteristics (e.g. patient inclusion criteria, tocilizumab dosing regimen) were evaluated. Response was measured as change from baseline to week 24 in Clinical Disease Activity Index (CDAI) and HAQ-Disability Index (HAQ-DI) scores and as the proportions of patients who experienced ≥50% improvement based on ACR criteria (ACR50) and CDAI remission (≤2.8) rates at week 24. RESULTS: Improvements in all outcomes investigated were observed in patients receiving tocilizumab. Although disease duration was statistically significant in the models, it accounted for <2% of variation in CDAI and HAQ-DI score changes from baseline to week 24; baseline CDAI and HAQ-DI values accounted for 32% and 15% of variations, respectively. Doubling of disease duration reduced the odds of achieving an ACR50 response by only 9%, and each additional 5-year period of disease duration decreased the odds of achieving CDAI remission by only 15%. CONCLUSION: RA duration, alone or in combination with other baseline characteristics, had a statistically significant but clinically small effect on the outcomes of tocilizumab initiated in biologic-naïve patients with established RA.

Documentation of Sexual and Menstrual Histories for Adolescent Patients in the Inpatient Setting.

STUDY OBJECTIVE: In this study, we aimed to determine the frequency of menstrual history and sexual history documentation in the inpatient setting. DESIGN, SETTING, AND PARTICIPANTS: A retrospective chart review was conducted for 307 female patients ages 11-18 years admitted from the emergency department at a single institution within a 7-month period. These charts were reviewed for documentation of menstrual and sexual history. INTERVENTIONS AND MAIN OUTCOME MEASURES: Rates of menstrual and sexual history documentation were compared according to patient age, chief complaint, admitting specialty, and medical complexity. RESULTS: Sexual history documentation was noted in 158 (45.9%) of the 344 reviewed charts. Sexual history documentation rates were higher for patients with mental health symptoms (62.9%; 61 of 98 charts; P = .02) and lower for patients admitted to surgical services (30.6%; 19 of 62 charts; P = .04). At least 1 aspect of menses was documented in 113 (32.8%) of the 344 reviewed charts. Last menstrual period was the most commonly documented aspect of menstrual history, appearing in 100 (29.1%) of the 344 reviewed charts. Menarche (4.4%; 15/344), menses frequency (7.0%; 24/344), menses duration (2.6%; 9/344), flow quantity (4.9%; 17/344), and dysmenorrhea (4.4%; 15/344) were rarely documented, regardless of chief complaint or admitting service. Menstrual history documentation rates were significantly higher for patients requiring a gynecology consultation (73.3%; 11 of 15 charts; P < .01). CONCLUSION: Menstrual and sexual history documentation rates for adolescent patients requiring inpatient admission were low, with fewer than half of patients having a documented menstrual or sexual history.

Long-term safety and effectiveness of tocilizumab in patients with rheumatoid arthritis and inadequate responses to csDMARDs and/or TNF inhibitors: an open-label study close to clinical practice.

OBJECTIVE: To assess the long-term safety, tolerability, and effectiveness of tocilizumab (TCZ) as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in clinical practice in patients with moderate to severe rheumatoid arthritis (RA). METHODS: Patients in the 24-week, open-label ACT-SURE study who had at least a moderate EULAR response by week 24 and were from a participating country were eligible for this long-term extension (LTE); the patients continued to receive TCZ 8 mg/kg intravenously every 4 weeks as monotherapy or in combination with ≥ 1 csDMARD for up to an additional 108 weeks. The primary endpoint was the incidence of adverse events (AEs) and serious AEs (SAEs). Effectiveness endpoints included Disease Activity Score in 28 joints (DAS28) responses, American College of Rheumatology (ACR) responses, and patient-reported outcomes (PROs). RESULTS: Of the 1102 patients who completed the core 24-week study, 934 participated in the LTE; the median exposure to TCZ was 64.3 weeks. From baseline to the end of the LTE, AEs and SAEs occurred in 90% and 9% of patients, respectively. The overall event rates (95% CI) of AEs and SAEs were 406.5 per 100 patient-years (PY) (395.5, 417.8) and 8.8 per 100 PY (7.3, 10.6), respectively. Mean (SD) improvement in DAS28 was 4.12 (1.18), P < 0.0001. The DAS28 remission rates, ACR response rates, and PRO scores were maintained during the LTE study. CONCLUSION: In clinical practice, TCZ as monotherapy or in combination with csDMARDs was safe, well tolerated, and efficacious in patients with moderate to severe RA.

Rhyzobius lophanthae Behavior is Influenced by Cycad Plant Age, Providing Odor Samples in a Y-tube Olfactometer.

The scale predator Rhyzobius lophanthae Blaisdell was introduced to Guam and Rota to control invasive Aulacaspis yasumatsui Takagi armored scale infestations on the native Cycas micronesica K.D. Hill populations. The predator demonstrated a clear preference for A. yasumatsui infesting adult plants, resulting in 100% seedling mortality due to the lack of a biocontrol of the scale on seedlings. A Y-tube olfactometer was employed to determine if scale-infested seedling leaves were less attractive to R. lophanthae than scale-infested mature tree leaves. Five paired combinations of seedling versus mature tree leaves were used. The R. lophanthae adults navigated toward scale-infested and un-infested leaves of adults and seedlings when paired with an empty chamber. However, a clear preference for adult leaves occurred when paired with seedling leaves. The results were unambiguous in charcoal-filtered air, intermediate in unfiltered air from an open laboratory, and most ambiguous when conducted with unfiltered in-situ air. The number of predators that did not make a choice was greatest for in-situ air and least for charcoal-filtered air. These results indicated that the substrate used in olfactometry influenced the results, and interpretations of charcoal-filtered air assays should be made with caution. Volatile chemical cues are involved in R. lophanthae preferring A. yasumatsui located on C. micronesica adults when infested adult and seedling leaves are present.

Diversity in Cycas (Cycadales: Cycadaceae) Species Offered as Larval Food Influences Fecundity of Chilades pandava (Lepidoptera: Lycaenidae) Adults.

Chilades pandava (Lepidoptera: Lycaenidae) larval food quality was studied to determine its influence on adult life history traits. A wild population from Cycas nongnoochiae (Cycadales: Cycadaceae) endemic habitat behaved similarly to the population collected from a garden setting. Cycas micronesica, Cycas revoluta, and Cycas seemannii leaves were used as high-quality food, whereas C nongnoochiae, Cycas taitungensis, and Cycas condaoensis leaves were used as low-quality food. The daily oviposition rate was not influenced by food quality, but longevity and lifetime fecundity of females were increased by high-quality larval food. These results indicate that in situ Cycas species impose a physiological constraint on the genetic capacity to produce offspring by C pandava. The removal of that constraint by high-quality novel Cycas species may be one reason this butterfly can increase in population rapidly after an invasion event and express greater herbivory of Cycas species within invaded regions.

Local signalling pathways regulate the Arabidopsis root developmental response to Mesorhizobium loti inoculation.

Numerous reports have shown that various rhizobia can interact with non-host plant species, improving mineral nutrition and promoting plant growth. To further investigate the effects of such non-host interactions on root development and functions, we inoculated Arabidopsis thaliana with the model nitrogen fixing rhizobacterium Mesorhizobium loti (strain MAFF303099). In vitro, we show that root colonization by M. loti remains epiphytic and that M. loti cells preferentially grow at sites where primary and secondary roots intersect. Besides resulting in an increase in shoot biomass production, colonization leads to transient inhibition of primary root growth, strong promotion of root hair elongation and increased apoplasmic acidification in periphery cells of a sizeable part of the root system. Using auxin mutants, axr1-3 and aux1-100, we show that a plant auxin pathway plays a major role in inhibiting root growth but not in promoting root hair elongation, indicating that root developmental responses involve several distinct pathways. Finally, using a split root device, we demonstrate that root colonization by M. loti, as well as by the bona fide plant growth promoting rhizobacteria Azospirillum brasilense and Pseudomonas, affect root development via local transduction pathways restricted to the colonised regions of the root system.

Stochastic Optimization for an Analytical Model of Saltwater Intrusion in Coastal Aquifers.

The present study implements a stochastic optimization technique to optimally manage freshwater pumping from coastal aquifers. Our simulations utilize the well-known sharp interface model for saltwater intrusion in coastal aquifers together with its known analytical solution. The objective is to maximize the total volume of freshwater pumped by the wells from the aquifer while, at the same time, protecting the aquifer from saltwater intrusion. In the direction of dealing with this problem in real time, the ALOPEX stochastic optimization method is used, to optimize the pumping rates of the wells, coupled with a penalty-based strategy that keeps the saltwater front at a safe distance from the wells. Several numerical optimization results, that simulate a known real aquifer case, are presented. The results explore the computational performance of the chosen stochastic optimization method as well as its abilities to manage freshwater pumping in real aquifer environments.

Chilades pandava mothers discriminate among Cycas species during oviposition choice tests, but only in an endemic naïve population.

Host and non-host plant species communicate with insect herbivores to influence oviposition decisions. We studied if Chilades pandava female adults expressed oviposition preferences among host Cycas species in 2 choice tests, counting 39,420 eggs among assays from 4 butterfly populations. A naïve butterfly population from Cycas nongnoochiae habitat oviposited 2.2-fold more eggs on leaves of Cycas species that are susceptible to butterfly herbivory than on leaves of its native host Cycas nongnoochiae. In contrast, Chilades pandava populations experienced with novel Cycas species in Thailand, Philippines, and Guam exhibited no preference in choice tests between leaves of susceptible versus leaves of minimally damaged Cycas species. The results indicated that oviposition deterrents and/or stimulants partly mediate the sustainable relationship between an endemic Cycas species and the naïve Chilades pandava population from its habitat. Alternatively, differences in infochemicals among Cycas species do not enable discrimination in oviposition choices for Chilades pandava populations that have experienced Cycas species exhibiting no evolutionary history with Chilades pandava.

HDAC1/2-Dependent P0 Expression Maintains Paranodal and Nodal Integrity Independently of Myelin Stability through Interactions with Neurofascins.

The pathogenesis of peripheral neuropathies in adults is linked to maintenance mechanisms that are not well understood. Here, we elucidate a novel critical maintenance mechanism for Schwann cell (SC)-axon interaction. Using mouse genetics, ablation of the transcriptional regulators histone deacetylases 1 and 2 (HDAC1/2) in adult SCs severely affected paranodal and nodal integrity and led to demyelination/remyelination. Expression levels of the HDAC1/2 target gene myelin protein zero (P0) were reduced by half, accompanied by altered localization and stability of neurofascin (NFasc)155, NFasc186, and loss of Caspr and septate-like junctions. We identify P0 as a novel binding partner of NFasc155 and NFasc186, both in vivo and by in vitro adhesion assay. Furthermore, we demonstrate that HDAC1/2-dependent P0 expression is crucial for the maintenance of paranodal/nodal integrity and axonal function through interaction of P0 with neurofascins. In addition, we show that the latter mechanism is impaired by some P0 mutations that lead to late onset Charcot-Marie-Tooth disease.

G-CSF receptor positive neuroblastoma subpopulations are enriched in chemotherapy-resistant or relapsed tumors and are highly tumorigenic.

Neuroblastoma is a neural crest-derived embryonal malignancy, which accounts for 13% of all pediatric cancer mortality, primarily due to tumor recurrence. Therapy-resistant cancer stem cells are implicated in tumor relapse, but definitive phenotypic evidence of the existence of these cells has been lacking. In this study, we define a highly tumorigenic subpopulation in neuroblastoma with stem cell characteristics, based on the expression of CSF3R, which encodes the receptor for granulocyte colony-stimulating factor (G-CSF). G-CSF receptor positive (aka G-CSFr(+) or CD114(+)) cells isolated from a primary tumor and the NGP cell line by flow cytometry were highly tumorigenic and capable of both self-renewal and differentiation to progeny cells. CD114(+) cells closely resembled embryonic and induced pluripotent stem cells with respect to their profiles of cell cycle, miRNA, and gene expression. In addition, they reflect a primitive undifferentiated neuroectodermal/neural crest phenotype revealing a developmental hierarchy within neuroblastoma tumors. We detected this dedifferentiated neural crest subpopulation in all established neuroblastoma cell lines, xenograft tumors, and primary tumor specimens analyzed. Ligand activation of CD114 by the addition of exogenous G-CSF to CD114(+) cells confirmed intact STAT3 upregulation, characteristic of G-CSF receptor signaling. Together, our data describe a novel distinct subpopulation within neuroblastoma with enhanced tumorigenicity and a stem cell-like phenotype, further elucidating the complex heterogeneity of solid tumors such as neuroblastoma. We propose that this subpopulation may represent an additional target for novel therapeutic approaches to this aggressive pediatric malignancy.

Expression of digestive enzymes and nutrient transporters in the intestine of Eimeria maxima-infected chickens.

Infection with the intestinal protozoa Eimeria causes destruction of intestinal epithelia, resulting in reduced feed efficiency and BW gain. The objective of this study was to investigate the effect of Eimeria maxima infection on the expression of 20 digestive enzymes as well as macro- and micronutrient transporters in the intestine. Expression of the brushborder membrane amino acid transporters EAAT3 (excitatory amino acid transporter 3) and b(o+)AT (Na(+)-independent neutral amino acid transporter) was decreased to 35 to 39% and 20% of control, respectively, in the intestine of E. maxima-infected chickens. Expression of the basolateral amino acid transporter LAT1 and the amino acid transporter ASCT1 was upregulated 17- to 19-fold and 12-fold, respectively, in E. maxima-infected chickens, whereas the zinc transporter was decreased to 20 to 44% of control. In addition, expression of the antimicrobial peptide LEAP-2 (liver-expressed antimicrobial peptide-2) was reduced to 5 to 24% of control. The other 13 digestive enzymes or nutrient transporters examined were unaffected. Together these results suggest a model whereby, upon infection, Eimeria causes a downregulation of LEAP-2. In response, there are changes in expression of the amino acid transporters that would result in a depletion of the energy source (glutamate) and some essential amino acids, which may lead to death of the cell and inhibition of pathogen replication.

Myelin is dependent on the Charcot-Marie-Tooth Type 4H disease culprit protein FRABIN/FGD4 in Schwann cells.

Studying the function and malfunction of genes and proteins associated with inherited forms of peripheral neuropathies has provided multiple clues to our understanding of myelinated nerves in health and disease. Here, we have generated a mouse model for the peripheral neuropathy Charcot-Marie-Tooth disease type 4H by constitutively disrupting the mouse orthologue of the suspected culprit gene FGD4 that encodes the small RhoGTPase Cdc42-guanine nucleotide exchange factor Frabin. Lack of Frabin/Fgd4 causes dysmyelination in mice in early peripheral nerve development, followed by profound myelin abnormalities and demyelination at later stages. At the age of 60 weeks, this was accompanied by electrophysiological deficits. By crossing mice carrying alleles of Frabin/Fgd4 flanked by loxP sequences with animals expressing Cre recombinase in a cell type-specific manner, we show that Schwann cell-autonomous Frabin/Fgd4 function is essential for proper myelination without detectable primary contributions from neurons. Deletion of Frabin/Fgd4 in Schwann cells of fully myelinated nerve fibres revealed that this protein is not only required for correct nerve development but also for accurate myelin maintenance. Moreover, we established that correct activation of Cdc42 is dependent on Frabin/Fgd4 function in healthy peripheral nerves. Genetic disruption of Cdc42 in Schwann cells of adult myelinated nerves resulted in myelin alterations similar to those observed in Frabin/Fgd4-deficient mice, indicating that Cdc42 and the Frabin/Fgd4-Cdc42 axis are critical for myelin homeostasis. In line with known regulatory roles of Cdc42, we found that Frabin/Fgd4 regulates Schwann cell endocytosis, a process that is increasingly recognized as a relevant mechanism in peripheral nerve pathophysiology. Taken together, our results indicate that regulation of Cdc42 by Frabin/Fgd4 in Schwann cells is critical for the structure and function of the peripheral nervous system. In particular, this regulatory link is continuously required in adult fully myelinated nerve fibres. Thus, mechanisms regulated by Frabin/Fgd4-Cdc42 are promising targets that can help to identify additional regulators of myelin development and homeostasis, which may crucially contribute also to malfunctions in different types of peripheral neuropathies.