A case series evaluating patient perceptions after switching from nusinersen to risdiplam for spinal muscular atrophy.

INTRODUCTION/AIMS: In 2016, nusinersen became the first disease-modifying medication approved by the U.S. Food and Drug Administration (FDA) for spinal muscular atrophy (SMA). With the later availability of risdiplam in 2020, individuals now have the option of switching from nusinersen to risdiplam. Limited published data exist to inform this decision. This study aims to evaluate the perceptions and experiences of adult participants and parents of minor participants who previously received nusinersen and switched to risdiplam for the treatment of SMA. METHODS: Institutional Review Board (IRB) approval was obtained from the Wake Forest IRB prior to the initiation of this study. A cross-sectional, observational study, with qualitative and quantitative data gathered via questionnaire and medical record review, was performed. Inclusion criteria included (1) prior diagnosis of SMA, (2) previous treatment with nusinersen, and (3) change to treatment with risdiplam. No participants were excluded based on age. RESULTS: Fourteen participants-eight adults and six children-were enrolled in the study. Respondents noted improvements in physical function with each medication. Overall, respondents reported worse satisfaction with the method of delivery of the intrathecally delivered nusinersen compared to the orally-delivered risdiplam, but no respondent reported negative overall satisfaction with either medication. A majority (78.6%) of respondents reported that switching from nusinersen to risdiplam was the correct decision. DISCUSSION: These results suggest that most patients are satisfied when switching from nusinersen to risdiplam, with the method of delivery being a primary factor.

A machine-learning approach to map landscape connectivity in Aedes aegypti with genetic and environmental data.

Mapping landscape connectivity is important for controlling invasive species and disease vectors. Current landscape genetics methods are often constrained by the subjectivity of creating resistance surfaces and the difficulty of working with interacting and correlated environmental variables. To overcome these constraints, we combine the advantages of a machine-learning framework and an iterative optimization process to develop a method for integrating genetic and environmental (e.g., climate, land cover, human infrastructure) data. We validate and demonstrate this method for the Aedes aegypti mosquito, an invasive species and the primary vector of dengue, yellow fever, chikungunya, and Zika. We test two contrasting metrics to approximate genetic distance and find Cavalli-Sforza-Edwards distance (CSE) performs better than linearized FST The correlation (R) between the model's predicted genetic distance and actual distance is 0.83. We produce a map of genetic connectivity for Ae. aegypti's range in North America and discuss which environmental and anthropogenic variables are most important for predicting gene flow, especially in the context of vector control.

Tight-focusing parabolic reflector schemes for petawatt lasers.

A comparative study of three different tight-focusing schemes for high-power lasers is performed numerically. Using the Stratton-Chu formulation, the electromagnetic field in the vicinity of the focus is evaluated for a short-pulse laser beam incident upon an on-axis high numerical aperture parabola (HNAP), an off-axis parabola (OAP), and a transmission parabola (TP). Linearly- and radially-polarized incident beams are considered. It is demonstrated that while all the focusing configurations yield intensities above 1023 W/cm2 for a 1 PW incident beam, the nature of the focused field can be drastically modified. In particular, it is shown that the TP, with its focal point behind the parabola, actually converts an incoming linearly-polarized beam into an m = 2 vector beam. The strengths and weaknesses of each configuration are discussed in the context of future laser-matter interaction experiments. Finally, a generalization of NA calculations up to 4π-illumination is proposed through the solid angle formulation, providing a universal way to compare light cones from any kind of optics.

ENDOGENOUS ENDOPHTHALMITIS ASSOCIATED WITH INJECTION DRUG USE COMPARED WITH OTHER ETIOLOGIES.

PURPOSE: To compare features of endogenous endophthalmitis associated with injection drug use (IDU) to endogenous endophthalmitis from other etiologies. METHODS: The authors retrospectively collected data on patients with endogenous endophthalmitis due to IDU or other causes from three academic tertiary care centers over a six-year period. Differences in presenting characteristics, culture results, treatment, and visual acuity were compared between groups. RESULTS: Thirty-eight patients (34%) had IDU-associated endogenous endophthalmitis while 75 patients (67%) had endogenous endophthalmitis from other causes. Compared with patients in the non-IDU group, IDU patients were significantly younger, more frequently male, had longer duration of symptoms at diagnosis, and were less likely to have bilateral disease ( P < 0.05 for all). Injection drug use patients were less likely to have a systemic infection source identified (29% vs. 71%, P < 0.001) or have positive cultures (47% vs. 80%, P < 0.001). The IDU group was less likely to be admitted to the hospital (71% vs. 92%, P = 0.005) and less likely to receive treatment with intravenous antimicrobials (55% vs. 83%, P = 0.003). Visual acuity did not significantly differ between groups. CONCLUSION: Endophthalmitis related to IDU presents in younger patients with less comorbidities and frequently without positive cultures or an identifiable systemic source; therefore, a high index of suspicion is needed to identify this disease.

Effect of water temperature on frog virus 3 disease in hatchery-reared pallid sturgeon Scaphirhynchus albus.

Ranaviruses are large double-stranded DNA viruses within the genus Ranavirus (family Iridoviridae) that are being detected with increasing frequency among aquacultured and wild fishes. In the USA, multiple sturgeon hatcheries have experienced ranavirus epizootics resulting in significant morbidity and mortality in young-of-year (YOY). Significant economic losses have resulted from repeated outbreaks of frog virus 3 (FV3), the type species for the genus Ranavirus, in YOY pallid sturgeon Scaphirhynchus albus reared at a hatchery within the Missouri River Basin. Water temperature and stocking density are known to influence the severity of ranavirus disease in ectothermic vertebrates. To determine the effect of water temperature on ranavirus disease in hatchery-raised S. albus, we conducted FV3 challenges at 2 temperatures (17 and 23°C) and compared cumulative survival over a 28 d study period. A mean (±SE) survival rate of 57.5 ± 13.2% was observed in replicate tanks of sturgeon maintained at 23°C, whereas no mortality was observed among sturgeon maintained at 17°C. In a second challenge study, we compared the effect of water temperature on disease progression by regularly sampling fish over the study period and evaluating lesions by histopathology and in situ hybridization, and by assessing viral titer and load in external and internal tissues using virus isolation and qPCR, respectively. Results suggest that temperature manipulation may be an effective mitigation strategy that sturgeon hatcheries can employ to minimize ranavirus-associated disease.

Genetic evidence for the origin of Aedes aegypti, the yellow fever mosquito, in the southwestern Indian Ocean.

Aedes aegypti is among the best-studied mosquitoes due to its critical role as a vector of human pathogens and ease of laboratory rearing. Until now, this species was thought to have originated in continental Africa, and subsequently colonized much of the world following the establishment of global trade routes. However, populations of this mosquito on the islands in the southwestern Indian Ocean (SWIO), where the species occurs with its nearest relatives referred to as the Aegypti Group, have received little study. We re-evaluated the evolutionary history of Ae. aegypti and these relatives, using three data sets: nucleotide sequence data, 18,489 SNPs and 12 microsatellites. We found that: (a) the Aegypti Group diverged 16 MYA (95% HPD: 7-28 MYA) from its nearest African/Asian ancestor; (b) SWIO populations of Ae. aegypti are basal to continental African populations; (c) after diverging 7 MYA (95% HPD: 4-15 MYA) from its nearest formally described relative (Ae. mascarensis), Ae. aegypti moved to continental Africa less than 85,000 years ago, where it recently (<1,000 years ago) split into two recognized subspecies Ae. aegypti formosus and a human commensal, Ae. aegypti aegypti; (d) the Madagascar samples form a clade more distant from all other Ae. aegypti than the named species Ae. mascarensis, implying that Madagascar may harbour a new cryptic species; and (e) there is evidence of introgression between Ae. mascarensis and Ae. aegypti on Réunion, and between the two subspecies elsewhere in the SWIO, a likely consequence of recent introductions of domestic Ae. aegypti aegypti from Asia.

Interplay of pulse duration, peak intensity, and particle size in laser-driven electron emission from silica nanospheres.

We present the results of a systematic study of photoelectron emission from isolated dielectric nanoparticles (SiO2) irradiated by intense 25 fs, 780 nm linearly polarized laser pulses as a function of particle size (20 nm to 750 nm in diameter) and laser intensity. We also introduce an experimental technique to reduce the effects of focal volume averaging. The highest photoelectron energies show a strong size dependence, increasing by a factor of six over the range of particles sizes studied at a fixed intensity. For smaller particle sizes (up to 200 nm), our findings agree well with earlier results obtained with few-cycle, ∼4 fs pulses. For large nanoparticles, which exhibit stronger near-field localization due to field-propagation effects, we observe the emission of much more energetic electrons, reaching energies up to ∼200 times the ponderomotive energy. This strong deviation in maximum photoelectron energy is attributed to the increase in ionization and charge interaction for many-cycle pulses at similar intensities.

Increasing burden of type 2 diabetes in Navajo youth: The SEARCH for diabetes in youth study.

AIM: SEARCH has recently reported that both prevalence and incidence of youth onset type 2 diabetes (YT2D) increased among most US race/ethnic groups in the early 2000s. This study reports on the incidence (2002-2013) and prevalence (2001, 2009) of YT2D in the Navajo Nation among youth age < 20 years from 2001 to 2013. METHODS: SEARCH sought to identify prevalent YT2D cases in 2001 (N = 75) and 2009 (N = 70) and all incident YT2D cases in three periods: 2002 to 2005 (N = 53), 2006 to 2009 (N = 68), and 2010 2013 (N = 90) in Navajo Nation. Denominators were based on the active Indian Health Service user population for eligible health care facilities. Prevalence (per 100 000) and period-specific incidence rates (per 100 000 person-years) were computed for youth aged 10 to 19 years. Changes in prevalence were tested with a two-sided skew-corrected inverted score test, while changes in incidence were tested with Poisson regression. RESULTS: YT2D prevalence was high but stable in 2001 and 2009, overall [146.6 (116.8, 184.0) vs 141.5 (112.0, 178.8), P = .65) and in all subgroups. In contrast, incidence rates increased particularly between the second and third periods overall and in most subgroups by age and by sex. CONCLUSIONS: These data confirm the high burden of YT2D among Navajo youth and suggest an increasing risk in more recent years. However, recent improvements in obesity reduction in this population demonstrate optimism for potential reductions in YT2D in Navajo Nation.

Heat stress assessment during intermittent work under different environmental conditions and clothing combinations of effective wet bulb globe temperature (WBGT).

This study examined whether different combinations of ambient temperature and relative humidity for the effective wet bulb globe temperature, in conjunction with two different levels of clothing adjustment factors, elicit a similar level of heat strain consistent with the current threshold limit value guidelines. Twelve healthy, physically active men performed four 15-min sessions of cycling at a fixed rate of metabolic heat production of 350 watts. Each trial was separated by a 15-min recovery period under four conditions: (1) Cotton coveralls + dry condition (WD: 45.5 °C dry-bulb, 15% relative humidity); (2) Cotton coveralls + humid condition (WH: 31 °C dry-bulb, 84% relative humidity); (3) Protective clothing + dry condition (PD: 30 °C dry-bulb, 15% relative humidity); and (4) Protective clothing + humid condition (PH: 20 °C dry-bulb, 80% relative humidity). Gloves (mining or chemical) and headgear (helmet or powered air-purifying respirator) were removed during recovery with hydration ad libitum. Rectal temperature (Tre), skin temperature (Tsk), physiological heat strain (PSI), perceptual heat strain (PeSI), and body heat content were calculated. At the end of the 2-hr trials, Tre remained below 38 °C and the magnitude of Tre elevation was not greater than 1 °C in all conditions (WD: 0.9, WH: 0.8, WH: 0.7, and PD: 0.6 °C). However, Tsk was significantly increased by approximately 2.1 ± 0.8 °C across all conditions (all p ≤ 0.001). The increase in Tsk was the highest in WD followed by PD, WH, and PH conditions (all p ≤ 0.001). Although PSI and PeSI did not indicate severe heat strain during the 2-hr intermittent work period, PSI and PeSI were significantly increased over time (p ≤ 0.001). This study showed that core temperature and heat strain indices (PSI and PeSI) increased similarly across the four conditions. However, given that core temperature increased continuously during the work session, it is likely that the American Conference of Governmental Industrial Hygienist's TLV® upper limit core temperature of 38.0 °C may be surpassed during extended work periods under all conditions.

Recent History of Aedes aegypti: Vector Genomics and Epidemiology Records.

Aedes aegypti bears the common name "the yellow fever mosquito," although, today, it is of more concern as the major vector of dengue, chikungunya, and, most recently, Zika viruses. In the present article, we review recent work on the population genetics of this mosquito in efforts to reconstruct its recent (approximately 600 years) history and relate these findings to epidemiological records of occurrences of diseases transmitted by this species. The two sources of information are remarkably congruent. Ae. aegypti was introduced to the New World 400-550 years ago from its ancestral home in West Africa via European slave trade. Ships from the New World returning to their European ports of origin introduced the species to the Mediterranean region around 1800, where it became established until about 1950. The Suez Canal opened in 1869 and Ae. aegypti was introduced into Asia by the 1870s, then on to Australia (1887) and the South Pacific (1904).

Umbilical temperature correlation with core and skin temperatures at rest, in the heat and during physical activity.

PURPOSE: to determine the correlation of umbilical temperatures (Tumb) with simultaneously recorded chest wall temperature (Tchest) and rectal temperature (Trectal) in adults during rest, heat exposure and exercise. METHODS: A total of 28 healthy men, wearing different types of clothing (athletic garb, a spandex full body heating garment, firefighter bunker gear) had average and peak umbilical, chest wall and rectal temperature measurements taken during sedentary temperature stabilisation stages, heat exposure periods and active exercise phases. RESULTS: Curvilinear relationships were noted between Tchest and Tumb compared with Trectal and their association became noticeably positive and linear at approximately 35.5 °C. Polynomial regression analysis of Trectal with linear and quadratic forms of Tchest and Tumb indicated an overall R2 of 0.657 and 0.767, respectively. Bivariate analysis of a restricted data set (where Tchest and Tumb ≥35.5°), indicated that Tumb was significantly associated with Trectal (raverage = 0.710, p <0.001; rpeak = 0.841, p <0.001) and Tchest was also significantly associated with Trectal, but less so (raverage = 0.570, p <0.001; rpeak = 0.699, p <0.001). CONCLUSIONS: the umbilicus offers a non-invasive, peripheral site for measurement of temperature that more closely correlated with body core temperature than Tchest when core temperature was ≥35.5 °C.

Powered air-purifying respirator use in healthcare: Effects on thermal sensations and comfort.

Twelve subjects wore an N95 filtering facepiece respirator (N95 FFR), one tight-fitting full facepiece powered air-purifying respirator (PAPR), two loose-fitting PAPRs, and one elastomeric/PAPR hybrid for 1 hr each during treadmill walking at 5.6 km/hr while undergoing physiological and subjective response monitoring. No significant interaction (p ≥ .05) was noted between the five respirators in heart rate, respiratory rate, oxygen saturation, transcutaneous carbon dioxide, and perceptions of breathing effort or discomfort, exertion, facial heat, and overall body heat. Respirator deadspace heat/humidity were significantly greater for the N95 FFR, whereas tympanic forehead skin temperatures were significantly greater for the hybrid PAPR. Temperature of the facial skin covered by the respirator was equivalent for the N95 FFR and hybrid PAPR, and both were significantly higher than for the other three PAPRs. Perception of eye dryness was significantly greater for a tight-fitting full facepiece PAPR than the N95 FFR and hybrid PAPR. At a low-moderate work rate over 1 hr, effects on cardiopulmonary variables, breathing perceptions, and facial and overall body heat perceptions did not differ significantly between the four PAPRs and a N95 FFR, but the tight-fitting, full facepiece PAPR increased perceptions of eye dryness. The two loose-fitting PAPRs and the full facepiece tight-fitting PAPR ameliorated exercise-induced increases in facial temperature, but this did not translate to improved perception of facial heat and overall body heat.

Global genetic diversity of Aedes aegypti.

Mosquitoes, especially Aedes aegypti, are becoming important models for studying invasion biology. We characterized genetic variation at 12 microsatellite loci in 79 populations of Ae. aegypti from 30 countries in six continents, and used them to infer historical and modern patterns of invasion. Our results support the two subspecies Ae. aegypti formosus and Ae. aegypti aegypti as genetically distinct units. Ae. aegypti aegypti populations outside Africa are derived from ancestral African populations and are monophyletic. The two subspecies co-occur in both East Africa (Kenya) and West Africa (Senegal). In rural/forest settings (Rabai District of Kenya), the two subspecies remain genetically distinct, whereas in urban settings, they introgress freely. Populations outside Africa are highly genetically structured likely due to a combination of recent founder effects, discrete discontinuous habitats and low migration rates. Ancestral populations in sub-Saharan Africa are less genetically structured, as are the populations in Asia. Introduction of Ae. aegypti to the New World coinciding with trans-Atlantic shipping in the 16th to 18th centuries was followed by its introduction to Asia in the late 19th century from the New World or from now extinct populations in the Mediterranean Basin. Aedes mascarensis is a genetically distinct sister species to Ae. aegypti s.l. This study provides a reference database of genetic diversity that can be used to determine the likely origin of new introductions that occur regularly for this invasive species. The genetic uniqueness of many populations and regions has important implications for attempts to control Ae. aegypti, especially for the methods using genetic modification of populations.

Comparison of estimated core body temperature measured with the BioHarness and rectal temperature under several heat stress conditions.

Monitoring and measuring core body temperature is important to prevent or minimize physiological strain and cognitive dysfunction for workers such as first responders (e.g., firefighters) and military personnel. The purpose of this study is to compare estimated core body temperature (Tco-est), determined by heart rate (HR) data from a wearable chest strap physiology monitor, to standard rectal thermometry (Tre) under different conditions. Tco-est and Tre measurements were obtained in thermoneutral and heat stress conditions (high temperature and relative humidity) during four different experiments including treadmill exercise, cycling exercise, passive heat stress, and treadmill exercise while wearing personal protective equipment (PPE). Overall, the mean Tco-est did not differ significantly from Tre across the four conditions. During exercise at low-moderate work rates under heat stress conditions, Tco-est was consistently higher than Tre at all-time points. Tco-est underestimated temperature compared to Tre at rest in heat stress conditions and at a low work rate under heat stress while wearing PPE. The mean differences between the two measurements ranged from -0.1 ± 0.4 to 0.3 ± 0.4°C and Tco-est correlated well with HR (r = 0.795 - 0.849) and mean body temperature (r = 0.637 - 0.861). These results indicate that, the comparison of Tco-est to Tre may result in over- or underestimation which could possibly lead to heat-related illness during monitoring in certain conditions. Modifications to the current algorithm should be considered to address such issues.

Effects of codon usage on gene expression: empirical studies on Drosophila.

For most amino acids, more than one codon can be used. Many hypotheses have been put forward to account for patterns of uneven use of synonymous codons (codon usage bias) that most often have been indirectly tested primarily by analyses of patterns. Direct experimental tests of effects of synonymous codon usage are available for unicellular organisms, however empirical data addressing this problem in multicellular eukaryotes are sparse. We have developed a flexible transfecting plasmid that allows us to empirically test the effects of different codons on transcription and translation and present data from Drosophila. We could detect no significant effects of codon usage on transcription. With regard to translation, optimal codons (most used) produce higher levels of protein expression compared to non-optimal codons if the effect of difference in thermodynamic stability of secondary structure of the 5' mRNA ribosome-binding site is controlled for. These results are consistent with what has been found in bacteria and thus expand the generality of these principles to multicellular eukaryotes.

Effect of external airflow resistive load on postural and exercise-associated cardiovascular and pulmonary responses in pregnancy: a case control study.

BACKGROUND: Facial coverings (e.g., balaclavas, niqabs, medical/surgical masks, respirators, etc.), that impose low levels of airflow resistive loads, are worn by millions of pregnant women worldwide, but little data exist addressing their impact on pregnancy-associated cardiovascular and pulmonary responses. METHODS: 16 pregnant and 16 non-pregnant women were monitored physiologically (heart rate, blood pressure, mean arterial pressure, total peripheral resistance, stroke volume, cardiac output, oxygen saturation, transcutaneous carbon dioxide, fetal heart rate) and subjectively (exertion) for 1 h of mixed sedentary postural activity (sitting, standing) and moderate exercise (bicycle ergometer) with and without wearing N95 filtering facepiece respirators with filter resistive loads of 94.1 Pa (9.6 mm H2O) - 119.6 Pa (12.2 mm H2O) pressure. RESULTS: The external airflow resistive loads were associated with increases in diastolic pressure (p = 0.004), mean arterial pressure (p = 0.01), and subjective exertion score (p < 0.001) of all study subjects. No significant differences were noted with the external resistive loads between the pregnant and non-pregnant groups for any cardiovascular, pulmonary and subjective variable over 1 h. CONCLUSIONS: Low external airflow resistive loads, during combined sedentary postural activity and moderate exercise over 1 h, were associated with increases in the diastolic and mean arterial pressures of all study subjects, but pregnancy itself was not associated with any significant differences in physiologic or subjective responses to the external airway resistive loads utilized in the study.

Effect of wearing an N95 respirator on infrared tympanic membrane temperature measurements.

To determine the impact of wearing an N95 filtering facepiece respirator (N95 FFR) on tympanic temperature measurements. TMT measurements, with and without wearing an N95 filtering facepiece respirator (N95 FFR) were obtained at the onset and termination of 1 h of treadmill exercise in 21 subjects, and at staggered time intervals (0, 20, 40, 60 min) during combined sedentary activity and exercise of another 46 subjects, to determine any effect on TMT. A total of 877 TMT measurements were obtained that demonstrated a mean TMT increase of 0.05 °C in the first study group (p = 0.04) and a 0.19 °C decrease in the second study group (p < 0.001) with the wearing of an N95 FFR, both of which were lower than controls. Wearing an N95 FFR for 1 h, at different levels of activity, results in significantly lower TMT values than not wearing an N95 FFR, but the magnitude of the changes would likely have minimal clinical significance.

Effect of Pregnancy Upon Facial Anthropometrics and Respirator Fit Testing.

Workers required to wear respirators must undergo additional respirator fit testing if a significant change in body weight occurs. Approximately 10% of working women of reproductive age will be pregnant and experience a significant change in weight, yet the effect of pregnancy-associated weight gain on respirator fit is unknown. Cephalo-facial anthropometric measurements and quantitative fit testing of N95 filtering facepiece respirators (N95 FFR) of 15 pregnant women and 15 matched, non-pregnant women were undertaken for comparisons between the groups. There were no significant differences between pregnant and non-pregnant women with respect to cephalo-facial anthropometric measurements or N95 FFR quantitative fit tests. Healthy pregnant workers, who adhere to the recommended weight gain limits of pregnancy, are unlikely to experience an increase in cephalo-facial dimensions that would mandate additional N95 FFR fit testing above that which is normally required on an annual basis.

Microhabitat partitioning of Aedes simpsoni (Diptera: Culicidae).

Yellow fever virus is a reemerging infection responsible for widespread, sporadic outbreaks across Africa. Although Aedes aegypti (L.) is the most important vector globally, in East Africa, epidemics may be vectored by Aedes bromeliae (Theobald), a member of the Aedes simpsoni (Theobald) species complex. The Ae. simpsoni complex contains 10 subspecies, of which Ae. bromeliae alone has been incriminated as a vector of yellow fever virus. However, morphological markers cannot distinguish Ae. bromeliae from conspecifics, including the sympatric and non-anthropophilic Aedes lilii (Theobald). Here, we used three sequenced nuclear markers to examine the population structure of Ae. simpsoni complex mosquitoes collected from diverse habitats in Rabai, Kenya. Gene trees consistently show strong support for the existence of two clades in Rabai, with segregation by habitat. Domestic mosquitoes segregate separately from forest-collected mosquitoes, providing evidence of habitat partitioning on a small spatial scale (< 5 km). Although speculative, these likely represent what have been described as Ae. bromeliae and Ae. lilii, respectively. The observation of high levels of diversity within Rabai indicates that this species complex may exhibit significant genetic differentiation across East Africa. The genetic structure, ecology, and range of this important disease vector are surprisingly understudied and need to be further characterized.