Female Reproductive Fluid Increases the Opportunities for Postmating Sexual Selection by Prolonging the Egg Fertilization Window.

AbstractFemale reproductive fluid (the fluid that surrounds the eggs) has attracted increasing attention for its role in fertilization and postmating sexual selection through its effects on sperm traits. Surprisingly, however, only a few studies have investigated the effects of the female reproductive fluid on the eggs. Yet these effects might offer great potential to affect fertilization dynamics by, for example, increasing the opportunities for postmating sexual selection. Here, we determined whether the female reproductive fluid, by extending the egg fertilization window (the time available for egg fertilization), could also increase the opportunities for multiple paternity. Using the zebrafish (Danio rerio), we first tested the prediction that female reproductive fluid increases the egg fertilization window; then, using a split-brood design with the sperm of two males added at different time points after egg activation, we tested whether the degree of multiple paternity varies in the presence or absence of female reproductive fluid. Our results reveal the potential of female reproductive fluid to increase multiple paternity through its effects on the egg fertilization window, thus broadening our knowledge of how female mechanisms affect postmating sexual selection in externally fertilizing species.

Alternative reproductive tactics in goby fishes of the Caspian Sea.

Here we report on the reproductive morphology and histology of three Gobiidae species (the Caspian monkey goby, Neogobius pallasi; the Caspian goby, Neogobius caspius; and the round goby, Neogobius melanostomus) from the Iranian coastline of the Caspian Sea. Based on ageing, reproductive histology, and internal and external morphological measures, it appears that all three of these goby species have two types of reproductive males, a large courting, territorial, male type and a small cuckolding parasitic male type, a phenomenon known as alternative reproductive tactics (ART). Although ARTs have been reported previously for one of these species, the round goby, all reports stem from its invasive range; ARTs have never been reported before in any fish species in the Caspian Sea. In all three goby species there was a large, older male type, with a wide head, dark body colouration, and a large investment in accessory glands (AG), an organ important for female attraction and parental care. But there was also a small, light, younger male type, with a narrow head, longer urogenital papilla, and little investment in AGs. The Caspian goby were the largest of the three species, and in this species the smaller, lighter, presumably cuckolding male morph was quite rare (only about 5% of the reproductive male population). In contrast, many of the round goby and monkey goby males were the small, lighter parasitic type, making up nearly half the population of reproductive males (48% and 40%, respectively). Round goby and Caspian goby males had a prominent mesorchial gland, a fibrous sheath of pheromone-releasing connective tissue that attaches the testes to the dorsal body wall, but all the monkey goby specimens examined lacked this structure. Although ARTs are well documented across fish species and appear to be particularly common in gobies, our study provides the first evidence for ARTs in goby fishes from the Caspian Sea.

Power scaling of normal-dispersion continuum generation using higher-order modes in microstructured optical fibers.

The use of a higher-order HE12-like mode to produce weak normal dispersion over a substantial wavelength range in a microstructured optical fiber is investigated numerically. It is shown that the effective area, and thereby the pulse energy, can in this way be scaled by an order of magnitude compared to using the fundamental mode in a single-mode fiber. Multimode nonlinear simulations indicate that nonlinear mode coupling will not disturb single-mode operation in the HE12 mode at least up to the threshold where polarization modulation instability sets in.

Scaling properties of guided acoustic-wave Brillouin scattering in single-mode fibers.

We investigate guided acoustic-wave Brillouin scattering (GAWBS) in single-mode optical fibers. By treating the discrete GAWBS spectrum as a continuum, we propose a closed-form formula to evaluate the GAWBS variance due to radial modes, showing its dependence on the inverse of the fiber effective area. The formula is checked against an experimental validation at variable signal power. The almost flat experimental results with power suggest that GAWBS dominates stimulated electrostriction. We also compare GAWBS with the Kerr effect showing their common grounds and their main differences. The phase noise characteristics of the nonlinear interference induced by GAWBS is investigated, showing that in ultra-long links GAWBS can be safely taken as a circular white noise. The theoretical results can be used for quick estimations of the GAWBS penalty with any fiber effective area. In particular, we estimated a GAWBS penalty on the signal-to-noise ratio (SNR) of 0.5 dB after 6000 km with fibers of effective area 150 µm2.

Black goby territorial males adjust their ejaculate's characteristics in response to the presence of sneakers.

In many species, males can rapidly adjust their ejaculate performance in response to changing levels of sperm competition, an ability that is probably mediated by seminal fluid adaptive plasticity. In the black goby, Gobius niger, territorial males attach viscous ejaculate trails to the nest roof, from which sperm are slowly released into the water during the long-lasting spawning events. Sneaker males release their sperm in the vicinity of the nest, and territorial males try to keep them at a distance by patrolling their territory. We show here that territorial males' ejaculate trails released a higher proportion of their sperm in the presence of a single sneaker, but this proportion decreased when there were three sneakers, an effect that is most likely mediated by a change in the seminal fluid composition. Field observations showed that when multiple sneaking attempts occurred, territorial males spent more time outside the nest, suggesting that ejaculation rate and territory defence are traded-off. Altogether, these results suggest that the adjustment of sperm release from the ejaculate may be strategic, guaranteeing a more continuous concentration of the territorial male's sperm in the nest, although at a lower level, when he is engaged in prolonged territory defence outside the nest.

A Systematic Review of Procedural Outcomes in Patients With Proximal Common Carotid or Innominate Artery Disease With or Without Tandem Ipsilateral Internal Carotid Artery Disease.

OBJECTIVE: To establish 30 day and mid term outcomes in patients treated for significant stenoses affecting the proximal common carotid artery (CCA) or innominate artery (IA) with/without tandem disease of the ipsilateral internal carotid artery (ICA). METHODS: Systematic review of early and mid term outcomes in 1 969 patients from 77 studies (1960-2017) who underwent: (i) hybrid open retrograde angioplasty/stenting of the IA/proximal CCA plus carotid endarterectomy (CEA) in patients with tandem disease of the ipsilateral proximal ICA (n = 700); (ii) isolated open surgery to the IA or proximal CCA (no CEA) (n = 686); or (iii) an isolated endovascular approach to IA or proximal CCA stenoses (no CEA) (n = 583). RESULTS: In the hybrid group with tandem disease (66% involving proximal CCA), the 30 day death/stroke was 3.3%, with a late ipsilateral stroke rate of 3.3% at a median six years follow up. Late re-stenosis was 10.5% for proximal CCA/IA and 4.1% for the ICA. In the isolated open surgery group (78% involving the IA), the 30 day death/stroke was 7%, with a late ipsilateral stroke rate of 1% at a median 12 years follow up. Late re-stenosis within aortic bypasses was 2.6%. In the isolated endovascular group (52% IA, 47% proximal CCA), the majority of procedures were done percutaneously (84%), with a 30 day death/stroke rate of 1.5%. Late ipsilateral stroke was 1% at a median four years follow up, with a re-stenosis rate of 9%. CONCLUSION: Procedural risks were higher following isolated open surgical interventions involving the proximal CCA/IA, compared with proximal lesions treated by isolated angioplasty/stenting, or in tandem with CEA. This higher morbidity/mortality may, however, reflect a greater proportion of innominate (vs. proximal CCA) lesions in open surgical series, changes in patient selection, time dependent evolution of medical interventions, and publication bias. The available data were limited and related to very different patient groups and management strategies spanning 57 years. Caution is raised, particularly for open surgery IA and CCA surgery, and for any procedures in asymptomatic patients. In symptomatic patients, the data cautiously support an "endovascular first" strategy for isolated proximal CCA/IA lesions and a hybrid approach for tandem proximal CCA/IA and ICA stenoses.

The reliability and feasibility of non-contrast adenosine stress cardiovascular magnetic resonance T1 mapping in patients on haemodialysis.

BACKGROUND: Identifying coronary artery disease (CAD) in patients with end-stage renal disease (ESRD) is challenging. Adenosine stress native T1 mapping with cardiovascular magnetic resonance (CMR) may accurately detect obstructive CAD and microvascular dysfunction in the general population. This study assessed the feasibility and reliability of adenosine stress native T1 mapping in patients on haemodialysis. METHODS: The feasibility of undertaking rest and adenosine stress native T1 mapping using the single-shot Modified Look-Locker inversion recovery (MOLLI) sequence was assessed in 58 patients on maintenance haemodialysis using 3 T CMR. Ten patients underwent repeat stress CMR within 2 weeks for assessment of test-retest reliability of native T1, stress T1 and delta T1 (ΔT1). Interrater and intrarater agreement were assessed in 10 patients. Exploratory analyses were undertaken to assess associations between clinical variables and native T1 values in 51 patients on haemodialysis. RESULTS: Mean age of participants was 55 ± 15 years, 46 (79%) were male, and median dialysis vintage was 21 (8; 48) months. All patients completed the scan without complications. Mean native T1 rest, stress and ΔT1 were 1261 ± 57 ms, 1297 ± 50 ms and 2.9 ± 2.5%, respectively. Interrater and intrarater agreement of rest T1, stress T1 and ΔT1 were excellent, with intraclass correlation coefficients (ICC) > 0.9 for all. Test-retest reliability of rest and stress native T1 were excellent or good (CoV 1.2 and 1.5%; ICC, 0.79 and 0.69, respectively). Test-retest reliability of ΔT1 was moderate to poor (CoV 27.4%, ICC 0.55). On multivariate analysis, CAD, diabetes mellitus and resting native T1 time were independent determinants of ΔT1 (ß = - 0.275, p = 0.019; ß = - 0.297, p = 0.013; ß = - 0.455; p < 0.001, respectively). CONCLUSIONS: Rest and adenosine stress native T1 mapping is feasible and well-tolerated amongst patients with ESRD on haemodialysis. Although rater agreement of the technique is excellent, test-retest reliability of ΔT1 is moderate to poor. Prospective studies should evaluate the relationship between this technique and established methods of CAD assessment and association with outcomes.

A Systematic Review and Meta-Analysis of the Presentation and Surgical Management of Patients With Carotid Body Tumours.

OBJECTIVES: The aim was to determine the mode of presentation and 30 day procedural risks in 4418 patients with 4743 carotid body tumours (CBTs) undergoing surgical excision. METHODS: This is a systematic review and meta-analysis of 104 observational studies. RESULTS: Overall, 4418 patients with 4743 CBTs were identified. The mean age was 47 years, with the majority being female (65%). The commonest presentation was a neck mass (75%), of which 85% were painless. Dysphagia, cranial nerve injury (CNI), and headache were present in 3%, while virtually no one presented with a transient ischaemic attack (0.26%) or stroke (0.09%). The majority (97%) underwent excision, but only 21% underwent pre-operative embolisation. Overall, 27% were Shamblin I CBTs; 44% were Shamblin II; and 29% were Shamblin III. The mean 30 day mortality was 2.29% (95% CI 1.79-2.93). The mean 30 day stroke rate was 3.53% (95% CI 2.91-4.29), while the mean 30 day CNI rate was 25.4% (95% CI 24.5-31.22). The prevalence of persisting CNI at 30 days was 11.15% (95% CI 8.42-14.64). Twelve series (544 patients) correlated 30 day stroke with Shamblin status. Shamblin I CBTs were associated with a 1.89% stroke rate (95% CI 0.92-3.82), increasing to 2.71% (95% CI 1.43-5.07) for Shamblin II CBTs and 3.99% (95% CI 2.34-6.74) for Shamblin III tumours. Twenty-six series (1075 patients) correlated CNI rates with Shamblin status: 3.76% (95% CI 2.62-5.35) for Shamblin I CBTs, 14.14% (95% CI 11.94-16.68) for Shamblin II, and 17.10% (95% CI 14.82-19.65) for Shamblin III tumours. The prevalence of neck haematoma requiring re-exploration was 5.24% (95% CI 3.45-7.91). The proportion of patients with a neck haematoma requiring re-exploration was not reduced by pre-operative embolisation (5.92%; 95% CI 2.56-13.08) vs. no embolisation (5.82%; 95% CI 2.76-11.88). Pre-operative embolisation did not reduce drainage losses (639 mL vs. 653 mL). CONCLUSIONS: This is the largest meta-analysis of outcomes after CBT excision. Procedural risks associated with tumour excision were considerable, especially with Shamblin III tumours where 4% suffered a peri-operative stroke and 17% suffered a CNI.

Theory of thermo-optic instabilities in dual-core fiber amplifiers.

A coupled-mode theory for nonlinear mode coupling by the thermo-optic effect, originally developed for single-core fiber amplifiers, is applied to the case of dual-core amplifiers. It is shown that a non-phase-matched coupling term, which is usually irrelevant in single-core amplifiers, can strongly affect the mode stability when the coupling length between supermodes exceeds a few centimeters. The phase-mismatched coupling can lead to a strongly reduced instability threshold and static deformation effects for a range of intermediate coupling lengths.

Seminal fluid enhances competitiveness of territorial males' sperm in a fish with alternative male reproductive tactics.

The most common adaptation to sperm competition in males is represented by an increase in the sperm number and/or quality released at mating, to raise their probability of egg fertilization. However, rapidly mounting evidence highlights that seminal fluid may directly influence the competitive fertilization success of a male by affecting either own and/or rival sperm performance. In the black goby, Gobius niger, an external fertilizer with guard-sneaker mating tactics and high sperm competition level, sneaker ejaculates contain less seminal fluid and more sperm, that are also of better quality, than those of territorial males. However, territorial males gain a higher paternity success inside natural nests. Here, we ask whether the seminal fluid can contribute to the reproductive success of territorial males by enhancing their sperm performance and/or by decreasing that of sneaker males. Using sperm and seminal fluid manipulation and in vitro fertilization tests, we found that own seminal fluid influences the velocity and fertilization ability of sperm only in territorial males, making them as fast as those of sneakers and with a similar fertilization rate. Moreover, both sneaker and territorial sperm remain unaffected by the seminal fluid of rival males. Thus, black goby males respond to the different level of sperm competition faced by differential allocation of sperm and non-sperm components of the ejaculate, with sneakers primarily investing in sperm of intrinsic high quality and territorial males relying on the effect of seminal fluid to increase the lower intrinsic quality of their sperm.

Thermal modeling of gain competition in Yb-doped large-mode-area photonic-crystal fiber amplifier.

We propose a new model for gain competition effects in high-power fiber amplifiers, which accounts for the thermal effects of heat load on the doped core overlap of the propagating light field. The full-vectorial nature of the fiber modes is modeled by an embedded finite-element method modal solver, and the temperature profile is calculated by a simple and efficient radial heat propagation solver. The model is applied to a Yb³âº-doped LPF45 air-clad photonic-crystal fiber amplifier for coand counter-propagating pumping setups, showing gain competition in conditions of severe heat load.

Clinical Validation of Carotid-Femoral Pulse Wave Velocity Measurement Using a Multi-Beam Laser Vibrometer: The CARDIS Study.

BACKGROUND: Carotid-femoral pulse wave velocity (cfPWV) is the gold standard for noninvasive arterial stiffness assessment, an independent predictor of cardiovascular disease, and a potential parameter to guide therapy. However, cfPWV is not routinely measured in clinical practice due to the unavailability of a low-cost, operator-friendly, and independent device. The current study validated a novel laser Doppler vibrometry (LDV)-based measurement of cfPWV against the reference technique. METHODS: In 100 (50 men) hypertensive patients, cfPWV was measured using applanation tonometry (Sphygmocor) and the novel LDV device. This device has 2 handpieces with 6 laser beams each that simultaneously measure vibrations from the skin surface at carotid and femoral sites. Pulse wave velocity is calculated using ECG for the identification of cardiac cycles. An ECG-independent method was also devised. Cardiovascular risk score was calculated for patients between 40 and 75 years old using the WHO risk scoring chart. RESULTS: LDV-based cfPWV correlated significantly with tonometry (r=0.86, P<0.0001 ECG-dependent [cfPWVLDV_ECG] and r=0.80, P<0.001 ECG-independent [cfPWVLDV_w/oECG] methods). Bland-Altman analysis showed nonsignificant bias (0.65 m/s) and acceptable SD (1.27 m/s) between methods. Intraobserver coefficient of variance for LDV was 4.7% (95% CI, 3.0%-5.5%), and interobserver coefficient of variance was 5.87%. CfPWV correlated significantly with CVD risk (r=0.64, P<0.001; r=0.41, P=0.003; and r=0.37, P=0.006 for tonometry, LDV-with, and LDV-without ECG, respectively). CONCLUSIONS: The study demonstrates clinical validity of the LDV device. The LDV provides a simple, noninvasive, operator-independent method to measure cfPWV for assessing arterial stiffness, comparable to the standard existing techniques. REGISTRATION: URL: https://clinicaltrials.gov/study/NCT03446430; Unique identifier: NCT03446430.

A multimodal approach to diagnosis of neuromuscular neosporosis in dogs.

BACKGROUND: Early diagnosis of neosporosis in dogs is challenging. OBJECTIVES: To evaluate the feasibility of a compound multimodal testing approach for diagnosing in dogs neuromuscular and combined forms of neosporosis. ANIMALS: A total of 16 dogs diagnosed with solely neuromuscular neosporosis or with a combination of neuromuscular and central nervous system neosporosis. METHODS: Retrospective review of clinical signs, laboratory findings, treatment, and outcome with focus on the diagnostic utility of different tests. Development of a chromogenic in situ hybridization (ISH) assay for the identification of Neospora caninum in paraffin-embedded muscle samples. RESULTS: 13/16 dogs had only neuromuscular signs of neosporosis, 3/16 had disease signs with concomitant central nervous system (CNS) involvement. Serology was performed in 15/16, with 10/15 showing titers >1 : 160 at admission. PCR on muscle samples detected N. caninum DNA in 11/16. Immunohistochemistry (IHC) detected N. caninum in 9/16 and ISH in 9/16. Histopathology revealed inflammatory myopathy in 10/16, necrotizing myopathy in 5/16, borderline changes in 1/16 and tachyzoites in 9/16. In 4 cases, N. caninum infection was confirmed with all 5 diagnostic methods, 3 cases with 4, 2 with 3, 6 with 2, and 1 animal with 1. CONCLUSIONS AND CLINICAL IMPORTANCE: Diagnosis of N. caninum infection should rely on a multimodal diagnostic approach and negativity of 1 single test should not allow for exclusion. Serology in combination with direct parasite identification via histopathology, DNA via PCR, or both modalities, appears a reliable diagnostic approach.

Tactic-specific differences in seminal fluid influence sperm performance.

Seminal fluid often makes up a large part of an ejaculate, yet most empirical and theoretical studies on sperm competition have focused on how sperm characteristics (number and quality) affect fertilization success. However, seminal fluid influences own sperm performance and may potentially influence the outcome of sperm competition, by also affecting that of rivals. As a consequence males may be expected to allocate their investment in both sperm and seminal fluid in relation to the potential level of competition. Grass goby (Zosterisessor ophiocephalus) is an external fertilizer with guard-sneaker mating tactics, where sperm competition risk varies according to the tactic adopted. Here, we experimentally manipulated grass goby ejaculates by separately combining sperm and seminal fluid from territorial and sneaker males. While sperm of sneaker and territorial males did not differ in their performance when they interacted with their own seminal fluid only, sperm of sneakers increased their velocity and fertilization rate in the presence of territorial males' seminal fluid. By contrast, sneaker males' seminal fluid had a detrimental effect on the performance of territorial males' sperm. Sperm velocity was unaffected by the seminal fluid of males employing the same tactic, suggesting that seminal fluid's effect on rival-tactic sperm is not based on a self/non-self recognition mechanism. Our findings show that cross interactions of sperm and seminal fluid may influence the fertilization success of competing ejaculates with males investing in both sperm and seminal fluid in response to sperm competition risk.

MERTK missense variants in three patients with retinitis pigmentosa.

BACKGROUND: MERTK (MER proto-oncogene, tyrosine kinase) is a transmembrane protein essential in regulating photoreceptor outer segment phagocytosis. Biallelic mutations in MERTK cause retinal degeneration. Here we present the retinal phenotype of three patients with missense variants in MERTK. MATERIALS AND METHODS: All patients underwent a full clinical examination, fundus photography, short-wavelength fundus autofluorescence and optical coherence tomography imaging. Two patients also underwent Goldmann visual field testing and electroretinography was undertaken for the third patient. Molecular genetic testing was undertaken using next generation or whole-exome sequencing with all variants confirmed by Sanger sequencing. RESULTS: The first patient was a 29-year-old female heterozygous for a missense variant (c.1133C>T, p.Thr378 Met) and a nonsense variant (c.1744_1751delinsT, p.Ile582Ter) in MERTK. The second patient was a 26-year-old male homozygous for a c.2163T>A, p.His721Gln variant in MERTK. The third patient was an 11-year-old female heterozygous for a deletion of exons 5-19 and a missense variant (c.1866 G>C, p.Lys622Asn) in MERTK. Reduced night vision was the initial symptom in all patients. Fundoscopy revealed typical signs of retinitis pigmentosa (RP) with early-onset macular atrophy. All three MERTK missense variants affect highly conserved residues within functional domains, have low population frequencies and are predicted to be pathogenic in silico. CONCLUSIONS: We report three missense variants in MERTK and present the associated phenotypic data, which are supportive of non-syndromic RP. MERTK is a promising candidate for viral-mediated gene replacement therapy. Moreover, one variant represents a single nucleotide transition, which is theoretically targetable with CRISPR-Cas9 base-editing.

Correlation Between Fundus Autofluorescence Pattern and Retinal Function on Microperimetry in Choroideremia.

Purpose: In patients with choroideremia, it is not known how smooth and mottled patterns on short-wavelength fundus autofluorescence (AF) imaging relate to retinal function. Methods: A retrospective case-note review was undertaken on 190 patients with choroideremia at two specialist centers for retinal genetics. Twenty patients with both smooth and mottled zones on short-wavelength AF imaging and concurrent mesopic microperimetry assessments were included. Mean retinal sensitivities within the smooth and mottled zones were compared between choroideremia patients, and identical points on mesopic microperimetry collected from 12 age-matched controls. Longitudinal analyses were undertaken at 2 and 5 years in a subset of patients. Results: In patients with choroideremia, mean retinal sensitivities at baseline were significantly greater in the smooth zone (26.1 ± 2.0 dB) versus the mottled zone (20.5 ± 4.2 dB) (P < 0.0001). Mean retinal sensitivities at baseline were similar in the smooth zone between choroideremia patients and controls (P = 0.054) but significantly impaired in the mottled zone in choroideremia compared to controls (P < 0.0001). The rate of decline in total sensitivity over 5 years was not significant in either the smooth or mottled zone in a small subset of choroideremia patients (n = 7; P = 0.344). Conclusions: In choroideremia, retinal sensitivity as determined by microperimetry correlates with patterns on AF imaging: retinal function in the smooth zone, where the retinal pigment epithelium is anatomically preserved, is similar to controls, but retinal sensitivity in the mottled zone is impaired. Translational Relevance: Patterns on AF imaging may represent a novel, objective outcome measure for clinical trials in choroideremia as a surrogate for retinal function.

Hybrid Ytterbium-doped large-mode-area photonic crystal fiber amplifier for long wavelengths.

A large-mode-area Ytterbium-doped photonic crystal fiber amplifier with build-in gain shaping is presented. The fiber cladding consists of a hexagonal lattice of air holes, where three rows are replaced with circular high-index inclusions. Seven missing air holes define the large-mode-area core. Light confinement is achieved by combined index and bandgap guiding, which allows for single-mode operation and gain shaping through distributed spectral filtering of amplified spontaneous emission. The fiber properties are ideal for amplification in the long wavelength regime of the Ytterbium gain spectrum above 1100 nm, and red shifting of the maximum gain to 1130 nm is demonstrated.

Prevalence, clinical features, and outcome of intervertebral disc extrusion associated with extensive epidural hemorrhage in a population of French Bulldogs compared to Dachshunds.

Intervertebral disc extrusion associated with extensive epidural hemorrhage (DEEH) is a well-documented pathological condition in veterinary medicine. This retrospective study aimed to evaluate the prevalence and clinical features of DEEH in a population of French Bulldogs affected by intervertebral disc extrusion (n=75), compare the findings with those from a group of Dachshunds (n=98) and identify possible predictive factors of DEEH and outcomes in surgically treated patients. The study showed that the prevalence of DEEH observed in Dachshunds (11.2% [95% confidence interval [CI]: 5.7-19.2%]) was significantly lower than that observed in French Bulldogs (41.3% [95% CI: 30.1-53.3%]). The multiple logistic regression model highlighted that the patients presenting with an acute onset of clinical signs (>24 hr) (odds ratio [OR]: 13.08; 95% CI: 4.63-37.03, P=0.00), presence of clinical signs progression (OR: 5.04; P=0.01), and French Bulldogs (OR: 5.15; 95% CI: 1.71-15.54, P=0.00) were at increased risk of developing DEEH. Secondary analysis showed that patients with DEEH were at an increased risk of being non-ambulatory at discharge (OR: 3.43; P=0.017). Overall, the surgically treated patients had favorable outcomes.

Microfabrication of polymer microneedle arrays using two-photon polymerization.

Three dimensional (3D) printing technology has pushed state-of-the-art manufacturing towards more advanced processing methods through its ability to produce complex computer-designed 3D structures in a wide range of materials. Two-photon polymerization applied to the fabrication of ultraprecise 3D microstructures is one of the various innovative approaches to cutting-edge 3D printing. The integration of an ultrashort pulsed laser source and an appropriate photoresist has made it an attractive candidate for advanced photonics and biomedical applications. This paper presents the development of 3D solid microneedle arrays as a novel transdermal drug delivery system via two-photon polymerization in a single manufacturing step. Through a series of experiments, the best fabrication parameters are identified. Finite element simulations are then performed to investigate the interaction between a single microneedle and human skin. The results of this study highlight the influence of fabrication parameters such as laser power, scanning speed, hatch distance and layer height on the structural resolution and fabrication time of microneedles, as well as human skin deformation caused through application of force to a single polymer microneedle.