Detección y caracterización de defectos del campo visual mediante perimetría Octopus en glaucoma congénito primario / Detection and characterisation of visual field defects using Octopus perimetry in congenital glaucoma

Detectar y caracterizar los defectos del campo visual (CV) mediante perimetría Octopus en pacientes con glaucoma congénito primario (GCP) y determinar la calidad y duración del CV. Material y métodos: Se incluyeron 88 ojos de 70 pacientes diagnosticados de GCP. Las evaluaciones se realizaron con un Octopus 900 y cada ojo se evaluó con el algoritmo de perimetría orientada por tendencias (G-TOP). Se recogieron datos cuantitativos de CV: datos de calidad (respuestas falsa positiva y negativa, y duración del tiempo) y resultados de desviación media (DM) y raíz cuadrada de la varianza de pérdida (sLV). También se recogieron datos cualitativos: presencia de defectos difusos y localizados, hemicampo afectado y grado de defectos utilizando la clasificación de Aulhorn y Karmeyer. Se analizaron las correlaciones entre los resultados perimétricos y las variables clínicas. Resultados: La mediana de edad fue de 11 (8-17) años. El 65,9% (58/88) de los ojos con GCP presentaban defectos de CV. Se observaron defectos difusos en 10/58 ojos (16,94%) (DM media=23,92 [DE: 2,52]) dB) y defectos localizados en 48/58 ojos (82,75%). El defecto más frecuente fue el escotoma incipiente paracentral (n=15), el escalón nasal (n=8), el defecto arciforme añadido (n=2), el semianular (n=13) y el defecto concéntrico con isla central (n=9). El hemicampo visual afectado con mayor frecuencia fue el inferior. La duración media de la prueba fue de 2min 12s (DE: 21,6s). Los valores MD y sLV se correlacionaron con la agudeza visual mejor corregida, la relación excavación/disco y el número de cirugías de glaucoma (todas p<0,001). Conclusión: Se identificó un alto número de defectos difusos y localizados utilizando la perimetría Octopus en pacientes con GCP. El defecto más frecuente fue el escotoma paracentral, y el hemicampo inferior fue el más afectado.(AU)

Purpose: To detect and characterise visual field (VF) defects using static Octopus perimetry in patients with primary congenital glaucoma (PCG) and to determine VF quality and time duration. Material and methods: Eighty-eight eyes of 70 patients diagnosed with PCG were included. Assessments were performed using an Octopus 900 and each eye was assessed with the tendency-oriented perimetry (G-TOP) algorithm. Quantitative VF data were collected: quality data (false positive and negative response, and time duration) and results of mean deviation (MD) and square root of loss variance (sLV). Qualitative data were collected: the presence of diffuse and localized defects, the affected hemifield and grade of defects using the Aulhorn and Karmeyer classification. Correlations between perimetric results and clinical variables were analysed. ResultsMedian age was 11 (8-17) years. 65.9% (58/88) of PCG eyes showed VF defects. Diffuse defects were observed in 10/58 eyes (16.94%) (mean MD=23.92 [SD: 2.52]) dB) and localized defects in 48/58 eyes (82.75%). The most frequent defect was spot-like/stroke-like/incipient paracentral scotoma (n=15), nasal step (n=8), adding arcuate defect (n=2), half ring-shaped (n=13) and concentric defect with a central island (n=9). And the most frequent affected visual hemifield was inferior hemifield. Mean test duration was 2min 12s (SD: 21.6s). MD and sLV values were correlated with best corrected visual acuity (BCVA), cup to disc ratio and number of antiglaucoma surgeries (all P<.001). Conclusion: A high number of diffuse and localized defects were identified using Octopus perimetry in PCG patients. The most frequent defect was paracentral scotoma and inferior hemifield was the most affected.(AU)

The bidirectional relationship between metabolism and cell cycle control.

The relationship between metabolism and cell cycle progression is complex and bidirectional. Cells must rewire metabolism to meet changing biosynthetic demands across cell cycle phases. In turn, metabolism can influence cell cycle progression through direct regulation of cell cycle proteins, through nutrient-sensing signaling pathways, and through its impact on cell growth, which is linked to cell division. Furthermore, metabolism is a key player in mediating quiescence-proliferation transitions in physiologically important cell types, such as stem cells. How metabolism impacts cell cycle progression, exit, and re-entry, as well as how these processes impact metabolism, is not fully understood. Recent advances uncovering mechanistic links between cell cycle regulators and metabolic processes demonstrate a complex relationship between metabolism and cell cycle control, with many questions remaining.

Detection and characterisation of visual field defects using Octopus perimetry in congenital glaucoma.

PURPOSE: To detect and characterise visual field (VF) defects using static Octopus perimetry in patients with primary congenital glaucoma (PCG) and to determine VF quality and time duration. MATERIAL AND METHODS: Eighty-eight eyes of 70 patients diagnosed with PCG were included. Assessments were performed using an Octopus 900 and each eye was assessed with the tendency-oriented perimetry (G-TOP) algorithm. Quantitative VF data were collected: quality data (false positive and negative response, and time duration) and results of mean deviation (MD) and square root of loss variance (sLV). Qualitative data were collected: the presence of diffuse and localized defects, the affected hemifield and grade of defects using the Aulhorn and Karmeyer classification. Correlations between perimetric results and clinical variables were analysed. RESULTS: Median age was 11 (8-17) years. 65.9% (58/88) of PCG eyes showed VF defects. Diffuse defects were observed in 10/58 eyes (16.94%) (mean MD = 23.92 [SD: 2.52]) dB) and localized defects in 48/58 eyes (82.75%). The most frequent defect was spot-like/stroke-like/incipient paracentral scotoma (n = 15), nasal step (n = 8), adding arcuate defect (n = 2), half ring-shaped (n = 13) and concentric defect with a central island (n = 9). And the most frequent affected visual hemifield was inferior hemifield. Mean test duration was 2 min 12 s (SD: 21.6 s). MD and sLV values were correlated with best corrected visual acuity (BCVA), cup to disc ratio and number of antiglaucoma surgeries (all P < .001). CONCLUSION: A high number of diffuse and localized defects were identified using Octopus perimetry in PCG patients. The most frequent defect was paracentral scotoma and inferior hemifield was the most affected.

The Complex Patchwork of Transportation for In-Center Hemodialysis.

Reliable transportation is an important determinant of access to health care and health outcomes that carries particular significance for people with ESKD. In the United States, there are almost half a million patients receiving treatment with in-center dialysis, translating into more than 70 million roundtrips to dialysis centers annually. Difficulty with transportation can interfere with patients' quality of life and contribute to missed or shortened dialysis treatments, increasing their risk for hospitalization. Medicare, the principal payer for dialysis in this country, has not traditionally provided coverage for nonemergency medical transportation, placing the burden of traveling to and from the dialysis center on patients and families and a range of other private and public entities that were not designed and are poorly equipped for this purpose. Here, we review the relationship between access to reliable transportation and health outcomes such as missed and shortened dialysis treatments, hospitalizations, and quality of life. We also describe current approaches to the delivery of transportation for patients receiving in-center hemodialysis, highlighting potential opportunities for improvement.

Increased Incidence of Legionellosis after Improved Diagnostic Methods, New Zealand, 2000-2020.

Legionellosis, notably Legionnaires' disease, is recognized globally and in New Zealand (Aotearoa) as a major cause of community-acquired pneumonia. We analyzed the temporal, geographic, and demographic epidemiology and microbiology of Legionnaires' disease in New Zealand by using notification and laboratory-based surveillance data for 2000‒2020. We used Poisson regression models to estimate incidence rate ratios and 95% CIs to compare demographic and organism trends over 2 time periods (2000-2009 and 2010-2020). The mean annual incidence rate increased from 1.6 cases/100,000 population for 2000-2009 to 3.9 cases/100,000 population for 2010-2020. This increase corresponded with a change in diagnostic testing from predominantly serology with some culture to almost entirely molecular methods using PCR. There was also a marked shift in the identified dominant causative organism, from Legionella pneumophila to L. longbeachae. Surveillance for legionellosis could be further enhanced by greater use of molecular typing of isolates.

Dependence of corneal hysteresis on non-central corneal thickness in healthy subjects.

OBJECTIVE: To evaluate the dependence of corneal hysteresis (CH) on non-central corneal thickness. METHODS: Cross-sectional study of 1561 eyes of 1561 healthy volunteers with IOP less than 21mmHg, open angles on gonioscopy and no prior eye surgeries or local or systemic diseases. Pentacam-Scheimpflug technology was employed to segment the cornea into 6 circular zones centered on the apex (zones 1-6) and to determine the mean corneal thickness of these areas. CH was measured with ORA. Univariate and multivariate linear regression models adjusted for age and sex were created to model the dependence of CH on corneal thickness in zones 1 to 6. RESULTS: In the univariate linear regression models, we found that CH was dependent on mean corneal thickness of zone 1 (B=0,004; R2=0.95%; P<0.001), zone 2 (B=0,004; R2=0.57%; P=0.002), zone 4 (B=0,005; R2=1.50%; P<0.001) and zone 6 (B=0,003; R2=0.92%; P<0.001). Similar results were obtained in the multivariate model (R2=3.46%; P<0.001). CONCLUSION: This study suggests a significant dependence of CH on non-central corneal thickness. The model of corneal thickness segmentation into circular zones centered on the corneal apex is able to explain 3.47% of the variation in CH measurements.

Environmental Investigation and Surveillance for Legionella in Aotearoa New Zealand, 2000-2020.

The reported rate of legionellosis is increasing in Aotearoa New Zealand (NZ) with most cases community-acquired, sporadic (non-outbreak) and without an identifiable source. This analysis used two datasets to describe the environmental sources that contribute to Legionella in NZ, based on linkages with outbreaks and sporadic clinical cases, and analysis of environmental testing data. These findings highlight the need for enhanced environmental investigation of clinical cases and outbreaks. There is also a need for systematic surveillance testing of high-risk source environments to support more rigorous controls to prevent legionellosis.

Analysis of the influence of corneal properties and densitometry on applanation and rebound tonometry in primary open angle glaucoma.

PURPOSE: To evaluate the influence of corneal densitometry on portable applanation (Perkins) and rebound (iCare ic100 and PRO) tonometry. A secondary goal was to assess if there was a relationship between various corneal properties and the severity of primary open angle glaucoma (POAG). MATERIAL AND METHODS: Seventy-five eyes of 75 patients with primary open angle glaucoma were studied, divided by severity into 3 groups: 25 mild, 25 moderate and 25 advanced. Intraocular pressure (IOP) was measured 3 times in each participant with a Perkins applanation tonometer (PAT), a handheld version of the Goldman applanation tonometer (GAT), an iCare PRO and an iCare ic100. Mean values were then calculated. Corneal topography with the Pentacam HR (Oculus, Wetzlar, Germany) was also performed in all individuals. RESULTS: Mean age and sex were comparable in all groups, as were densitometry values (P>0.05). The mean visual field defect (MD) was 2.85 (±1.23) dB in the mild glaucoma group, 8.26 (±1.90) dB in the moderate group and 15.66 (±3.46) dB in the advanced group. Three multivariate regression analyses were performed. The first and second calculations assessed the effect of IOP obtained with iCare ic100 and PAT as dependent variables with age, sex, CCT and mean keratometry (Km) within the glaucoma subgroups and the global sample. The third analysis was carried out to assess the relationship between corneal densitometry as the dependant variable and the aforementioned corneal parameters among the glaucoma groups. In the first multivariate regression analysis, a statistically significant correlation was found between ic100 rebound tonometry and CCT in the POAG global sample (coef. 0.117; IC [-0.21-(-0.01)]; P=0.025). No statistically significant correlation was found in the subgroup analyses. In the second multivariate analysis, no significant correlation was found between PAT and CCT, Km, age or sex (P>0.05). In the third analysis, densitometry was correlated with age in all glaucoma subgroups (P<0.001) and with CCT in the moderate glaucoma subgroup (coef. -0.037; IC [-0.67-(-0.01)]; P=0.021). Tonometry appeared to be minimally influenced by corneal densitometry, with a mild positive linear correlation seen (R=0.03). IOP values were similar with 3 of the tonometers: PAT 16.07 (±3.18) mmHg, PRO 16.27 (±3.42) mmHg and ic100 15.17 (±4.28) mmHg. There was, however, a significant underestimation of IOP with ic100 (-0.89mmHg) compared to PAT (P=0.007). CONCLUSION: Corneal densitometry did not show significant differences between glaucoma severity groups. A positive correlation was seen with CCT and both corneal densitometry and age. No correlation was found with keratometry or severity of glaucoma. The influence of corneal densitometry on IOP measurements appears weak, with little clinical relevance identified.

Epidemiology and direct health care costs of hospitalised legionellosis in New Zealand, 2000-2020.

BACKGROUND: Legionellosis is a collective term used for disease caused by Legionella species which result in community and hospital acquired pneumonia worldwide. The aim of this analysis was to describe the epidemiology of legionellosis hospitalisations in Aotearoa New Zealand (NZ) over a 21-year period and quantify the health care costs. METHOD: This study combined national legionellosis notification and hospital discharge data that were linked via the National Health Index (NHI) to provide a more complete dataset of hospitalised cases. The direct cost of hospital care was estimated by multiplying the diagnosis-related group cost-weight by the national price and inflating to 2020/2021 values. RESULTS: There were 1479 records matched across notifications and discharge databases, including 990 with principal and 489 with additional diagnosis of legionellosis. Incidence rose to an average of 143 cases per annum for 2016-2020, a rate of 3·2/100,000. The median LOS was 6 days (IQR 4-13·5) with direct costs of $2·1 million per annum over that period. Rates were highest in those aged 65 years and above, male, and of European/Other ethnicity. Hospitalisations showed a peak in spring and summer. CONCLUSION: The rate of hospitalised legionellosis in New Zealand rose from 2000 to 2015, largely reflecting improved diagnosis. This preventable disease results in substantial health care costs. Greater efforts are needed to identify and control sources of exposure. Surveillance could be improved by routine integration of notification and hospital discharge data.

Translation, adaptation, and validation of the Filipino version of the Telehealth Usability (TUQ-F)

Introduction@#Telemedicine services have steadily been relied upon since the onset of the COVID-19 pandemic. Understanding its usability and contextual performance is of paramount importance if it were to pervade the local health delivery system. Hence, a tool to assess usability is warranted. @*Objective@#The study aims to adapt a reliable and validated instrument in English to Filipino, the Telehealth Usability Questionnaire (TUQ), on evaluating the usability of telemedicine services in the Philippines. @*Methodology@#The research is a translation and validation study. The methodology includes forward translation in collaboration with our UST Sentro sa Salin at Araling Salin and expert panel review with five experts using the telehealth system. It was followed by pretesting (pilot testing and cognitive debriefing) of the pre-final tool to 30 family medicine telehealth patients and field testing of the final instrument to 85 telehealth patients from USTH. Appropriate statistical methods for assessment included internal consistency, content validity and linguistic with conceptual equivalence. @*Results@#All translated items were retained, but through the focus group discussion, several statements were modified to fit the cultural context. Each item and the overall tool showed excellent validity and internal consistency. The mean difference scores for each item and domain were less than ±0.25. Tests of equivalence showed that majority of items and each domain were not statistically different (p>0.05), suggesting that both questionnaires are similar and homogenous. Furthermore, the Bland-Altman plots for each dimension/domain are within the upper and lower boundaries indicating agreement between the two versions. @*Conclusion@#TUQ-Filipino is a valid and appropriate instrument to assess telehealth usability in the local setting.

Is the Window of Learning Only Cracked Open? Parents' Perspectives on Virtual Learning for Deaf and Hard of Hearing Students.

During the COVID-19 pandemic, parents quickly assumed the role of teachers to support their children's learning at home. Deaf and hard of hearing (DHH) students often rely on additional accommodations to access their education. The authors investigated the perspectives of 40 parents of K-12 DHH students on the use of virtual learning during the pandemic. An electronic survey was distributed through Qualtrics to gain an understanding of the new learning environment of remote instruction. The participants' responses revealed that they felt that challenges occurred in the areas of time management, language access, technology, motivation, and children's ability to function independently. The respondents were almost evenly split between satisfaction and dissatisfaction with their child's overall educational experience during the pandemic. The results indicated that degree of access significantly influenced the children's experiences of education in virtual learning settings.

Nucleotide imbalance decouples cell growth from cell proliferation.

Nucleotide metabolism supports RNA synthesis and DNA replication to enable cell growth and division. Nucleotide depletion can inhibit cell growth and proliferation, but how cells sense and respond to changes in the relative levels of individual nucleotides is unclear. Moreover, the nucleotide requirement for biomass production changes over the course of the cell cycle, and how cells coordinate differential nucleotide demands with cell cycle progression is not well understood. Here we find that excess levels of individual nucleotides can inhibit proliferation by disrupting the relative levels of nucleotide bases needed for DNA replication and impeding DNA replication. The resulting purine and pyrimidine imbalances are not sensed by canonical growth regulatory pathways like mTORC1, Akt and AMPK signalling cascades, causing excessive cell growth despite inhibited proliferation. Instead, cells rely on replication stress signalling to survive during, and recover from, nucleotide imbalance during S phase. We find that ATR-dependent replication stress signalling is activated during unperturbed S phases and promotes nucleotide availability to support DNA replication. Together, these data reveal that imbalanced nucleotide levels are not detected until S phase, rendering cells reliant on replication stress signalling to cope with this metabolic problem and disrupting the coordination of cell growth and division.

Treatment of open-angle glaucoma and ocular hypertension with preservative-free tafluprost/timolol fixed-dose combination therapy: 6 case reports and clinical outcomes.

BACKGROUND: Treatment of open angle glaucoma (OAG) and/or ocular hypertension (OHT) focuses on achievement of target intraocular pressure (IOP), with the objective of slowing disease progression. However, ocular surface health is an important consideration in the optimization of treatment. We report 6 patient cases in which enhanced IOP control was achieved following appropriate management of ocular surface inflammation and a therapeutic switch to the preservative-free (PF) tafluprost (0.0015%)/timolol (0.5%) fixed-dose combination (FC). CASE PRESENTATION: Six patient cases, aged 48-74 years, presented with OAG or OHT. Each patient had signs and symptoms of ocular surface disease (OSD). Cases 1-3 were each receiving maximal medical therapy for OAG; regimens comprising prostaglandin analogue (PGA), ß-blocker, carbonic anhydrase inhibitor (CAI) and α-2 agonist agents (including treatments containing preservative agent). Cases 1 and 2 reported IOP values ≥23 mmHg in each eye, and wide IOP fluctuations were identified when reviewing patient data concerning case 3 (11-20 mmHg). Maximal therapy was ceased and PF tafluprost/timolol FC was initiated, after which the signs and symptoms of OSD were improved and IOP was reduced (≤18 mmHg for cases 1-3) and stabilized. Cases 4 and 5 were diagnosed with OAG and case 6 had OHT. Each had symptoms and signs of OSD and were treated with a preserved PGA monotherapy (latanoprost 0.005% or bimatoprost 0.03%). At presentation, IOP was 24 mmHg in both eyes (case 4), ≥18 mmHg (case 5) and ≥ 22 mmHg (case 6). Following a switch to the PF tafluprost/timolol FC, OSD symptoms were improved and IOP was 14 mmHg (both eyes; case 4), ≤14 mmHg (case 5) and 16 mmHg (both eyes; case 6). CONCLUSIONS: In addition to IOP-lowering efficacy, approaches to the management of OAG and OHT should consider the impact of treatment tolerability and the susceptibility of these patients to OSD. The presence of ocular surface inflammation appears to be detrimental to adherence and therefore to the effectiveness of topical medications. Addressing OSD through the use of PF FC formations, such as the PF tafluprost/timolol FC, reduces exposure to potentially toxic agents and facilitates improvements in IOP control.

Chronic health conditions, acute health events, and healthcare utilization among adults over age 50 in Hawai'i who use cannabis: A matched cohort study.

BACKGROUND: Research on cannabis-related health outcomes in diverse older adults is limited. The current study utilized a matched cohort study design to compare older adults in Hawai'i with identified cannabis diagnoses and matched controls on chronic health conditions, acute health events, and healthcare utilization from 2016 to 2020. METHOD: Patients age 50 + were identified using ICD-10 diagnostic codes for cannabis use, abuse, and dependence using electronic health record data from an integrated health system (Kaiser Permanente Hawai'i). Those with cannabis diagnoses (n = 275) were compared to matched non-using controls (n = 275; based on age, sex) on chronic health conditions (coronary heart disease, hypertension, COPD, chronic non-cancer pain), acute health events (myocardial infarction, respiratory symptoms, stroke, persistent or cyclic vomiting, injuries), and healthcare utilization (outpatient, inpatient, and emergency department visits) following case identification for two years. RESULTS: Participants were 19.3% Native Hawaiian/Pacific Islander, 24.4% Asian, 47.8% White, and 8.5% Other/Unknown, with an average age of 62.8 years (SD=7.3). Adjusting for covariates as possible, participants with a cannabis diagnosis had significantly greater risk of coronary heart disease, chronic non-cancer pain, stroke, myocardial infarction, cyclic vomiting, and injuries, over time, compared to controls. Cannabis use was associated with any and greater frequency of outpatient, inpatient, and emergency department visits. CONCLUSIONS: In a diverse sample, older adults who used cannabis had worse health conditions and events and used more health services over a two-year period. Future studies should evaluate cannabis-related health outcomes, effects of cannabis problem severity, as well as implications for healthcare in aging populations.

Posterior chamber implantation of a Preserflo Microshunt in a patient with a compromised endothelium.

The objective of the present case is to describe a variation in the Preserflo Microshunt surgical technique, placing it in the posterior chamber to minimise the risk of endothelial cell loss in cases with a compromised endothelium. The patient was a 72-year-old pseudophakic woman, with granular dystrophy and a primary diagnosis of open-angle glaucoma presenting with a progressive visual field defect and an IOP of 26 mmHg with maximal medical therapy. The cornea had incipient stromal folds with an endothelial count of 700 cells/mm2. A Preserflo Microshunt was implanted in the posterior chamber to minimise the possibility of further damage to the corneal endothelium. Six months after surgery, the implant remains functional. The IOP is 9 mmHg without medications. As far as we know, this is the first Preserflo implanted in the posterior chamber described in the literature.

Implante de Preserflo Microshunt en cámara posterior en un paciente con endotelio comprometido / Posterior chamber implantation of a Preserflo Microshunt in a patient with a compromised endothelium

The objective of the present case is to describe a variation in the Preserflo Microshunt surgical technique, placing it in the posterior chamber to minimise the risk of endothelial cell loss in cases with a compromised endothelium.The patient was a 72-year-old pseudophakic woman, with granular dystrophy and a primary diagnosis of open-angle glaucoma presenting with a progressive visual field defect and an IOP of 26mmHg with maximal medical therapy. The cornea had incipient stromal folds with an endothelial count of 700 cells/mm2. A Preserflo Microshunt was implanted in the posterior chamber to minimise the possibility of further damage to the corneal endothelium. Six months after surgery, the implant remains functional. The IOP is 9mmHg without medications. As far as we know, this is the first Preserflo implanted in the posterior chamber described in the literature (AU)

El objetivo del presente caso es describir una variación en la técnica quirúrgica del Preserflo Microshunt colocándolo en la cámara posterior para minimizar el riesgo de pérdida de células endoteliales en casos con endotelio comprometido.Se trata de una mujer de 72 años pseudofáquica con una distrofia granular y diagnóstico primario de glaucoma de ángulo abierto que presentaba un defecto campimétrico que había progresado y una PIO de 26mmHg con tratamiento médico máximo. La córnea presentaba pliegues estromales incipientes con un recuento endotelial de 700 células/mm2. Se implantó un Preserflo Microshunt en la cámara posterior para minimizar la posibilidad de daño adicional al endotelio corneal. Seis meses después de la cirugía el implante permanece funcionante, con una PIO de 9mmHg sin medicamentos. Hasta donde sabemos, este es el primer Preserflo implantado en la cámara posterior descrito en la literatura (AU)

Global Perspective of Legionella Infection in Community-Acquired Pneumonia: A Systematic Review and Meta-Analysis of Observational Studies.

Legionnaires' disease (LD) (Legionella) is a common cause of community-acquired pneumonia (CAP) in those requiring hospitalization. Geographical variation in the importance of Legionella species as an aetiologic agent of CAP is poorly understood. We performed a systematic review and meta-analysis of population-based observational studies that reported the proportion of Legionella infection in patients with CAP (1 January 1990 to 31 May 2020). Using five electronic databases, articles were identified, appraised and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The quality of the included studies was assessed using the Newcastle-Ottawa Scale. Univariate and multivariate meta-regression analyses were conducted using study design, WHO region, study quality and healthcare setting as the explanatory variables. We reviewed 2778 studies, of which 219 were included in the meta-analysis. The mean incidence of CAP was 46.7/100,000 population (95% CI: 46.6-46.8). The mean proportion of Legionella as the causative agent for CAP was 4.6% (95% CI: 4.4 to 4.7). Consequently, the mean Legionella incidence rate was 2.8/100,000 population (95% CI: 2.7-2.9). There was significant heterogeneity across all studies I2 = 99.27% (p < 0.0001). After outliers were removed, there was a decrease in the heterogeneity (I2 = 43.53%). Legionella contribution to CAP has a global distribution. Although the rates appear highest in high income countries in temperate regions, there are insufficient studies from low- and middle-income countries to draw conclusions about the rates in these regions. Nevertheless, this study provides an estimate of the mean incidence of Legionella infection in CAP, which could be used to estimate the regional and global burden of LD to support efforts to reduce the impact of this infection as well as to fill important knowledge gaps.

Maternal oxytocin administration modulates gene expression in the brains of perinatal mice.

OBJECTIVES: Oxytocin (OXT) is widely used to facilitate labor. However, little is known about the effects of perinatal OXT exposure on the developing brain. We investigated the effects of maternal OXT administration on gene expression in perinatal mouse brains. METHODS: Pregnant C57BL/6 mice were treated with saline or OXT at term (n=6-7/group). Dams and pups were euthanized on gestational day (GD) 18.5 after delivery by C-section. Another set of dams was treated with saline or OXT (n=6-7/group) and allowed to deliver naturally; pups were euthanized on postnatal day 9 (PND9). Perinatal/neonatal brain gene expression was determined using Illumina BeadChip Arrays and real time quantitative PCR. Differential gene expression analyses were performed. In addition, the effect of OXT on neurite outgrowth was assessed using PC12 cells. RESULTS: Distinct and sex-specific gene expression patterns were identified in offspring brains following maternal OXT administration at term. The microarray data showed that female GD18.5 brains exhibited more differential changes in gene expression compared to male GD18.5 brains. Specifically, Cnot4 and Frmd4a were significantly reduced by OXT exposure in male and female GD18.5 brains, whereas Mtap1b, Srsf11, and Syn2 were significantly reduced only in female GD18.5 brains. No significant microarray differences were observed in PND9 brains. By quantitative PCR, OXT exposure reduced Oxtr expression in female and male brains on GD18.5 and PND9, respectively. PC12 cell differentiation assays revealed that OXT induced neurite outgrowth. CONCLUSIONS: Prenatal OXT exposure induces sex-specific differential regulation of several nervous system-related genes and pathways with important neural functions in perinatal brains.

Targeting serine hydroxymethyltransferases 1 and 2 for T-cell acute lymphoblastic leukemia therapy.

Despite progress in the treatment of acute lymphoblastic leukemia (ALL), T-cell ALL (T-ALL) has limited treatment options, particularly in the setting of relapsed/refractory disease. Using an unbiased genome-scale CRISPR-Cas9 screen we sought to identify pathway dependencies for T-ALL which could be harnessed for therapy development. Disruption of the one-carbon folate, purine and pyrimidine pathways scored as the top metabolic pathways required for T-ALL proliferation. We used a recently developed inhibitor of SHMT1 and SHMT2, RZ-2994, to characterize the effect of inhibiting these enzymes of the one-carbon folate pathway in T-ALL and found that T-ALL cell lines were differentially sensitive to RZ-2994, with the drug inducing a S/G2 cell cycle arrest. The effects of SHMT1/2 inhibition were rescued by formate supplementation. Loss of both SHMT1 and SHMT2 was necessary for impaired growth and cell cycle arrest, with suppression of both SHMT1 and SHMT2 inhibiting leukemia progression in vivo. RZ-2994 also decreased leukemia burden in vivo and remained effective in the setting of methotrexate resistance in vitro. This study highlights the significance of the one-carbon folate pathway in T-ALL and supports further development of SHMT inhibitors for treatment of T-ALL and other cancers.