Arcsine Laws of Light.

We demonstrate that the time-integrated light intensity transmitted by a coherently driven resonator obeys Lévy's arcsine laws-a cornerstone of extreme value statistics. We show that convergence to the arcsine distribution is algebraic, universal, and independent of nonequilibrium behavior due to nonconservative forces or nonadiabatic driving. We furthermore verify, numerically, that the arcsine laws hold in the presence of frequency noise and in Kerr-nonlinear resonators supporting non-Gaussian states. The arcsine laws imply a weak ergodicity breaking which can be leveraged to enhance the precision of resonant optical sensors with zero energy cost, as shown in our companion manuscript [V. G. Ramesh et al., companion paper, Phys. Rev. Res. (2024).PPRHAI2643-1564]. Finally, we discuss perspectives for probing the possible breakdown of the arcsine laws in systems with memory.

The progression of doxorubicin-induced intestinal mucositis in rats.

Chemotherapy-induced intestinal mucositis is a severe side effect contributing to reduced quality of life and premature death in cancer patients. Despite a high incidence, a thorough mechanistic understanding of its pathophysiology and effective supportive therapies are lacking. The main objective of this rat study was to determine how 10 mg/kg doxorubicin, a common chemotherapeutic, affected jejunal function and morphology over time (6, 24, 72, or 168 h). The secondary objective was to determine if the type of dosing administration (intraperitoneal or intravenous) affected the severity of mucositis or plasma exposure of the doxorubicin. Morphology, proliferation and apoptosis, and jejunal permeability of mannitol were examined using histology, immunohistochemistry, and single-pass intestinal perfusion, respectively. Villus height was reduced by 40% after 72 h, preceded at 24 h by a 75% decrease in proliferation and a sixfold increase in apoptosis. Villus height recovered completely after 168 h. Mucosal permeability of mannitol decreased after 6, 24, and 168 h. There were no differences in intestinal injury or plasma exposure after intraperitoneal or intravenous doxorubicin dosing. This study provides an insight into the progression of chemotherapy-induced intestinal mucositis and associated cellular mucosal processes. Knowledge from this in vivo rat model can facilitate development of preventive and supportive therapies for cancer patients.

Exceptional Precision of a Nonlinear Optical Sensor at a Square-Root Singularity.

Exceptional points (EPs)-spectral singularities of non-Hermitian linear systems-have recently attracted interest for sensing. While initial proposals and experiments focused on enhanced sensitivities neglecting noise, subsequent studies revealed issues with EP sensors in noisy environments. Here we propose a single-mode Kerr-nonlinear resonator for exceptional sensing in noisy environments. Based on the resonator's dynamic hysteresis, we define a signal that displays a square-root singularity reminiscent of an EP. However, our sensor has crucial fundamental and practical advantages over EP sensors: the signal-to-noise ratio increases with the measurement speed, the square-root singularity is easily detected through intensity measurements, and both sensing precision and information content of the signal are enhanced around the singularity. Our sensor also overcomes the fundamental trade-off between precision and averaging time characterizing all linear sensors. All these unconventional features open up new opportunities for fast and precise sensing using hysteretic resonators.

Spontaneous Symmetry Breaking in a Coherently Driven Nanophotonic Bose-Hubbard Dimer.

We report on the first experimental observation of spontaneous mirror symmetry breaking (SSB) in coherently driven-dissipative coupled optical cavities. SSB is observed as the breaking of the spatial or mirror Z_{2} symmetry between two symmetrically pumped and evanescently coupled photonic crystal nanocavities, and manifests itself as random intensity localization in one of the two cavities. We show that, in a system featuring repulsive boson interactions (U>0), the observation of a pure pitchfork bifurcation requires negative photon hopping energies (J<0), which we have realized in our photonic crystal molecule. SSB is observed over a wide range of the two-dimensional parameter space of driving intensity and detuning, where we also find a region that exhibits bistable symmetric behavior. Our results pave the way for the experimental study of limit cycles and deterministic chaos arising from SSB, as well as the study of nonclassical photon correlations close to SSB transitions.

Cannabis exposure during adolescence: A uniquely sensitive period for neurobiological effects.

Adolescence is a crucial developmental period where neural circuits are refined and the brain is especially vulnerable to external insults. The endocannabinoid (eCB) system undergoes changes during adolescence which affect the way in which it modulates the development of other systems, in particular dopamine circuits, which show protracted development into adolescence. Given the rise of cannabis use by adolescents and young people, as well as variants containing increasingly higher concentrations of THC, it is now crucial to understand the unique effects of adolescent exposure to cannabis on the developing brain and it might shape future adult vulnerabilities to conditions such as psychosis, schizophrenia, addiction and more. Here we discuss the development of the eCB system across the lifespan, how CB1 receptors modulate dopamine release and potential neurobiological and behavioral effects of adolescent THC exposure on the developing brain such as alterations in excitatory/inhibitory balance during this developmental period.

Extremely Broadband Stochastic Resonance of Light and Enhanced Energy Harvesting Enabled by Memory Effects in the Nonlinear Response.

We report the first observation of non-Markovian stochastic resonance (SR), and we discover that memory effects in the nonlinearity extremely enlarge the SR bandwidth. Our experimental system is an oil-filled microcavity which, driven by a continuous wave laser, has memory in its nonlinear optical response. Modulating the cavity length while adding noise to the driving laser, we observe a peak in the transmitted signal-to-noise ratio as a function of the noise variance. Through simulations, we reproduce our observations and extrapolate that the SR bandwidth could be ∼3000 times larger in our cavity than in a Kerr-nonlinear cavity. Experiments evidencing this memory-enhanced bandwidth across two decades are presented. As an extension of our results, we numerically demonstrate an order-of-magnitude enhancement in energy harvesting thanks to a nonlinearity with memory.

Universal Scaling in the Dynamic Hysteresis, and Non-Markovian Dynamics, of a Tunable Optical Cavity.

We investigate, experimentally and theoretically, the dynamics of a laser-driven cavity with noninstantaneous effective photon-photon interactions. Scanning the laser-cavity frequency detuning at different speeds across an optical bistability, we find a hysteresis area that is a nonmonotonic function of the speed. In the limit of fast scans comparable to the memory time of the interactions, we demonstrate that the hysteresis area decays following a universal power law with scaling exponent -1. We further demonstrate a regime of non-Markovian dynamics emerging from white noise. This regime is evidenced by peaked distributions of residence times in the metastable states of our system. Our results offer new perspectives for exploring the physics of scaling, universality, and metastability, in non-Markovian regimes using arrays of bistable optical cavities with low quality factors, driven by low laser powers, and at room temperature.

Evaluation of drug permeability calculation based on luminal disappearance and plasma appearance in the rat single-pass intestinal perfusion model.

The rat single-pass intestinal perfusion (SPIP) model is commonly used to investigate gastrointestinal physiology and membrane drug transport. The SPIP model can be used with the intestinal segment inside or outside the abdomen. The rats can also be treated with parecoxib, a selective cycloxygenase-2 inhibitor that has been shown to affect some intestinal functions following abdominal surgery, such as motility, epithelial permeability, fluid flux and ion transport. However, the impact of extra-abdominal placement of the intestinal segment in combination with parecoxib on intestinal drug transport has not been investigated. There is also uncertainty how well intestinal permeability determinations based on luminal drug disappearance and plasma appearance correlate in the rat SPIP model. The main objective of this rat in vivo study was to investigate the effect of intra- vs. extra-abdominal SPIP, with and without, pretreatment with parecoxib. The effect was evaluated by determining the difference in blood-to-lumen 51Cr-EDTA clearance, lumen-to-blood permeability of a cassette-dose of four model compounds (atenolol, enalaprilat, ketoprofen, and metoprolol), and water flux. The second objective was to compare the jejunal permeability values of the model drugs when determined based on luminal disappearance or plasma appearance. The study showed that the placement of the perfused jejunal segment, or the treatment with parecoxib, had minimal effects on membrane permeability and water flux. It was also shown that intestinal permeability of low permeability compounds should be determined on the basis of data from plasma appearance rather than luminal disappearance. If permeability is calculated on the basis of luminal disappearance, it should preferably include negative values to increase the accuracy in the determinations.

Testicular tissue cryopreservation: 8 years of experience from a coordinated network of academic centers.

STUDY QUESTION: Is it feasible to disseminate testicular tissue cryopreservation with a standardized protocol through a coordinated network of centers and provide centralized processing/freezing for centers that do not have those capabilities? SUMMARY ANSWER: Centralized processing and freezing of testicular tissue from multiple sites is feasible and accelerates recruitment, providing the statistical power to make inferences that may inform fertility preservation practice. WHAT IS KNOWN ALREADY: Several centers in the USA and abroad are preserving testicular biopsies for patients who cannot preserve sperm in anticipation that cell- or tissue-based therapies can be used in the future to generate sperm and offspring. STUDY DESIGN, SIZE, DURATION: Testicular tissue samples from 189 patients were cryopreserved between January 2011 and November 2018. Medical diagnosis, previous chemotherapy exposure, tissue weight, and presence of germ cells were recorded. PARTICIPANTS/MATERIALS, SETTING, METHODS: Human testicular tissue samples were obtained from patients undergoing treatments likely to cause infertility. Twenty five percent of the patient's tissue was donated to research and 75% was stored for patient's future use. The tissue was weighed, and research tissue was fixed for histological analysis with Periodic acid-Schiff hematoxylin staining and/or immunofluorescence staining for DEAD-box helicase 4, and/or undifferentiated embryonic cell transcription factor 1. MAIN RESULTS AND THE ROLE OF CHANCE: The average age of fertility preservation patients was 7.9 (SD = 5) years and ranged from 5 months to 34 years. The average amount of tissue collected was 411.3 (SD = 837.3) mg and ranged from 14.4 mg-6880.2 mg. Malignancies (n = 118) were the most common indication for testicular tissue freezing, followed by blood disorders (n = 45) and other conditions (n = 26). Thirty nine percent (n = 74) of patients had initiated their chemotherapy prior to undergoing testicular biopsy. Of the 189 patients recruited to date, 137 have been analyzed for the presence of germ cells and germ cells were confirmed in 132. LIMITATIONS, REASONS FOR CAUTION: This is a descriptive study of testicular tissues obtained from patients who were at risk of infertility. The function of spermatogonia in those biopsies could not be tested by transplantation due limited sample size. WIDER IMPLICATIONS OF THE FINDINGS: Patients and/or guardians are willing to pursue an experimental fertility preservation procedure when no alternatives are available. Our coordinated network of centers found that many patients request fertility preservation after initiating gonadotoxic therapies. This study demonstrates that undifferentiated stem and progenitor spermatogonia may be recovered from the testicular tissues of patients who are in the early stages of their treatment and have not yet received an ablative dose of therapy. The function of those spermatogonia was not tested. STUDY FUNDING/COMPETING INTEREST(S): Support for the research was from the Eunice Kennedy Shriver National Institute for Child Health and Human Development grants HD061289 and HD092084, the Scaife Foundation, the Richard King Mellon Foundation, the Departments of Ob/Gyn & Reproductive Sciences and Urology of the University of Pittsburgh Medical Center, United States-Israel Binational Science Foundation (BSF), and the Kahn Foundation. The authors declare that they do not have competing financial interests.

Cervical cancer screening decentralized policy adaptation: an African rural-context-specific systematic literature review.

BACKGROUND: Worldwide, nearly 570,000 women are diagnosed with cervical cancer each year, with 85% of new cases in low- and middle-income countries. The African continent is home to 35 of 40 countries with the highest cervical cancer mortality rates. In 2014, a partnership involving a rural region of Senegal, West Africa, was facing cervical cancer screening service sustainability barriers and began adapting regional-level policy to address implementation challenges. OBJECTIVE: This manuscript reports the findings of a systematic literature review describing the implementation of decentralized cervical cancer prevention services in Africa, relevant in context to the Senegal partnership. We report barriers and policy-relevant recommendations through Levesque's Patient-Centered Access to Healthcare Framework and discuss the impact of this information on the partnership's approach to shaping Senegal's regional cervical cancer screening policy. METHODS: The systematic review search strategy comprised two complementary sub-searches. We conducted an initial search identifying 4272 articles, then applied inclusion criteria, and ultimately 19 studies were included. Data abstraction focused on implementation barriers categorized with the Levesque framework and by policy relevance. RESULTS: Our findings identified specific demand-side (clients and community) and supply-side (health service-level) barriers to implementation of cervical cancer screening services. We identify the most commonly reported demand- and supply-side barriers and summarize salient policy recommendations discussed within the reviewed literature. CONCLUSIONS: Overall, there is a paucity of published literature regarding barriers to and best practices in implementation of cervical cancer screening services in rural Africa. Many articles in this literature review did describe findings with notable policy implications. The Senegal partnership has consulted this literature when faced with various similar barriers and has developed two principal initiatives to address contextual challenges. Other initiatives implementing cervical cancer visual screening services in decentralized areas may find this contextual reporting of a literature review helpful as a construct for identifying evidence for the purpose of guiding ongoing health service policy adaptation.

The foot fillet flap for ischial pressure sore reconstruction: A new indication.

INTRODUCTION: The main cause of ischial pressure sores in paraplegic patients is prolonged sitting without pressure relief. These wounds are subject to recurrence and may need repeated reconstruction with local flaps. When all options are exhausted, the total thigh flap is the last resort. Disarticulation of the hip joint impairs stability even when sitting and causes subsequently very high discomfort. In this manuscript, we describe an alternative to the total thigh flap to avoid hip disarticulation: the foot fillet flap. MATERIALS & METHODS: This study was performed on four patients at the department of Plastic & Reconstructive Surgery of the Ghent University Hospital, Belgium. Inclusion criteria were the following: paraplegic patients affected by recurrent pressure sores, exhaustion of all local options and adequate vascular status of the lower extremities. RESULTS: All patients were kept in an air-fluidized bed for two weeks and progressed well during their post-operative course. Healing time varied from 12 to 29 days and suction drains were removed after 15 days as in any standard pressure sore flap. Hospital stay varied from 18 to 42 days. CONCLUSION: The pedicled foot fillet flap is a valuable alternative to the total thigh flap. Coverage of large, recurrent, pressure sores in the ischial, trochanteric or sacral region is ideal due to the thick glabrous plantar skin, shock-absorbing fibrofatty subcutaneous tissue and underlying muscles provided by the sole of the foot. Furthermore, coxofemoral disarticulation, mandatory in a total thigh flap, that leads to instability while sitting, is avoided.

[Conservative treatment of atraumatic femoral head necrosis]. / Konservative Therapie der atraumatischen Hüftkopfnekrose.

BACKGROUND: Femoral head necrosis is a progressive disease that can progress within a relatively short time. Therefore, an early and clear diagnosis including stage classification and treatment is necessary to prevent or delay the onset of the femoral head and joint destruction. TREATMENT: In addition to the identification of possible risk factors and treatment, the question of the available treatment options arises. The present article deals with conservative treatment options and presents the published results in the sense of the currently available evidence and against the background of the S3 guideline on atraumatic femoral head necrosis. The results of physical therapy, drug therapy (iloprost and bisphosphonates ), electrotherapy, shockwave therapy, etc. are presented. In the early stages of femoral head necrosis with low expansion, alendronate gives positive results. Iloprost is also a successful conservative treatment option in the early stages of atraumatic femoral head necrosis (ARCO I and II). In stages ARCO III and IV, Ilomedin is no longer indicated. Anticoagulants, such as enoxaparin, have demonstrated an arthroprotective effect.

The genetic basis for most patients with pustular skin disease remains elusive.

BACKGROUND: Rare variants in the genes IL36RN, CARD14 and AP1S3 have been identified to cause or contribute to pustular skin diseases, primarily generalized pustular psoriasis (GPP). OBJECTIVES: To better understand the disease relevance of these genes, we screened our cohorts of patients with pustular skin diseases [primarily GPP and palmoplantar pustular psoriasis (PPP)] for coding changes in these three genes. Carriers of single heterozygous IL36RN mutations were screened for a second mutation in IL36RN. METHODS: Coding exons of IL36RN, CARD14 and AP1S3 were sequenced in 67 patients - 61 with GPP, two with acute generalized exanthematous pustulosis and four with acrodermatitis continua of Hallopeau. We screened IL36RN and AP1S3 for intragenic copy-number variants and 258 patients with PPP for coding changes in AP1S3. Eleven heterozygous IL36RN mutations carriers were analysed for a second noncoding IL36RN mutation. Genotype-phenotype correlations in carriers/noncarriers of IL36RN mutations were assessed within the GPP cohort. RESULTS: The majority of patients (GPP, 64%) did not carry rare variants in any of the three genes. Biallelic and monoallelic IL36RN mutations were identified in 15 and five patients with GPP, respectively. Noncoding rare IL36RN variants were not identified in heterozygous carriers. The only significant genotype-phenotype correlation observed for IL36RN mutation carriers was early age at disease onset. Additional rare CARD14 or AP1S3 variants were identified in 15% of IL36RN mutation carriers. CONCLUSIONS: The identification of IL36RN mutation carriers harbouring additional rare variants in CARD14 or AP1S3 indicates a more complex mode of inheritance of pustular psoriasis. Our results suggest that, in heterozygous IL36RN mutation carriers, there are additional disease-causing genetic factors outside IL36RN.

Females drive asymmetrical introgression from rare to common species in Darwin's tree finches.

The consequences of hybridization for biodiversity depend on the specific ecological and evolutionary context in which it occurs. Understanding patterns of gene flow among hybridizing species is crucial for determining the evolutionary trajectories of species assemblages. The recently discovered hybridization between two species of Darwin's tree finches (Camarhynchus parvulus and C. pauper) on Floreana Island, Galápagos, presents an exciting opportunity to investigate the mechanisms causing hybridization and its potential evolutionary consequences under conditions of recent habitat disturbance and the introduction of invasive pathogens. In this study, we combine morphological and genetic analysis with pairing observations to explore the extent, direction and drivers of hybridization and to test whether hybridization patterns are a result of asymmetrical pairing preference driven by females of the rarer species (C. pauper). We found asymmetrical introgression from the critically endangered, larger-bodied C. pauper to the common, smaller-bodied C. parvulus, which was associated with a lack of selection against heterospecific males by C. pauper females. Examination of pairing data showed that C. parvulus females paired assortatively, whereas C. pauper females showed no such pattern. This study shows how sex-specific drivers can determine the direction of gene flow in hybridizing species. Furthermore, our results suggest the existence of a hybrid swarm comprised of C. parvulus and hybrid birds. We discuss the influence of interspecific abundance differences and susceptibility to the invasive parasite Philornis downsi on the observed hybridization and recommend that the conservation of this iconic species group should be managed jointly rather than species-specific.

Effects of ovarian fluid and genetic differences on sperm performance and fertilization success of alternative reproductive tactics in Chinook salmon.

In many species, sperm velocity affects variation in the outcome of male competitive fertilization success. In fishes, ovarian fluid (OF) released with the eggs can increase male sperm velocity and potentially facilitate cryptic female choice for males of specific phenotypes and/or genotypes. Therefore, to investigate the effect of OF on fertilization success, we measured sperm velocity and conducted in vitro competitive fertilizations with paired Chinook salmon (Oncorhynchus tshawytscha) males representing two alternative reproductive tactics, jacks (small sneaker males) and hooknoses (large guarding males), in the presence of river water alone and OF mixed with river water. To determine the effect of genetic differences on fertilization success, we genotyped fish at neutral (microsatellites) and functional [major histocompatibility complex (MHC) II ß1] markers. We found that when sperm were competed in river water, jacks sired significantly more offspring than hooknoses; however, in OF, there was no difference in paternity between the tactics. Sperm velocity was significantly correlated with paternity success in river water, but not in ovarian fluid. Paternity success in OF, but not in river water alone, was correlated with genetic relatedness between male and female, where males that were less related to the female attained greater paternity. We found no relationship between MHC II ß1 divergence between mates and paternity success in water or OF. Our results indicate that OF can influence the outcome of sperm competition in Chinook salmon, where OF provides both male tactics with fertilization opportunities, which may in part explain what maintains both tactics in nature.

Critical review of the addition of tumor treating fields (TTFields) to the existing standard of care for newly diagnosed glioblastoma patients.

Since 2005, the standard of care for patients with newly diagnosed glioblastoma (GBM) has consisted of maximal resection followed by radiotherapy plus daily temozolomide (TMZ), followed by maintenance TMZ. In patients selected for clinical trials, median overall survival (OS) and progression-free survival (PFS) with this regimen is 15-17 months and 6-7 months, respectively. There have been various, largely unsuccessful attempts to improve on this standard of care. With the FDA approval of the tumor-treating fields (TTFields) device, Optune, for recurrent GBM (2011), and the more recent EF-14 interim trial results and approval for newly diagnosed GBM patients, several questions have arisen. A roundtable of experts was convened at the 2015 ASCO meeting to engage in an open conversation and debate of the EF-14 results presented at that meeting and their implications for neuro-oncology practice and clinical research. In October 2015, subsequent to the roundtable discussion, TTFields received FDA approval for newly diagnosed GBM.

[Compliance of osteoporosis patients with additional specific osteoporosis-training course]. / Compliance der medikamentösen Behandlung der Osteoporosepatienten nach Patientenschulung.

BACKGROUND: In the present study patients with an osteoporotic fracture were examined in order to determine how many patients decided to continue their therapy as outpatients having taken part in osteoporosis training at the Dr. Becker Rhein-Sieg Clinic. PATIENTS AND METHODS: Patients who had previously suffered an osteoporotic fracture and thereafter received inpatient rehabilitation were selected for the study. Patients (n = 95) who had taken part in inpatient rehabilitation after an osteoporotic fracture were approached either via telephone or mail and were then followed up after 6 and 12 months with regard to their adherence to the treatment. RESULTS: From a total of 95 patients, after 6 months 82 % (n = 78) were contacted successfully and included in the study. 68 out of 78 patients (72 %) had continued their medication. After 1 year 76 % of patients (n = 72) were successfully contacted once. Here, 62 % of patients (n = 59) had continued their medication under medical supervision. In the 1­year follow-up period there were eight cases of falls, and one of these resulted in a peripheral fracture, which was treated conservatively. CONCLUSION: Osteoporosis-specific information and osteoporosis training of patients after osteoporotic fracture are important tools to improve the motivation and compliance of patients. One possibility to realize this is osteoporosis-specific training with video presentations and individual care and education of the patients within outpatient or inpatient rehabilitation.

Hemostatic effects of two desogestrel-containing combined oral contraceptive regimens: a multinational, multicenter, randomized, open-label study.

PURPOSE OF INVESTIGATION: To compare the effects of desogestrel (DSG) 150 mcg/ethinyl estradiol (EE) 20 mcg for 21 days followed by either seven days of EE ten mcg (21/7-active) or no treatment (DSG/EE+no Tx) on hemostatic markers. MATERIALS AND METHODS: This was a randomized, multicenter, open-label study that enrolled healthy premenopausal women. Non-inferiority of 21/7-active to DSG/EE+no Tx was determined if the upper limit of the two-sided 95% CI of the mean treatment difference in prothrombin fragment 1+2 (F1+2) over 24 weeks between groups was < 130 pmol/L. RESULTS: 246 subjects (n = 125, 21/7-active; n = 121, DSG/EE+no Tx) comprised the primary analysis. Mean F1+2 levels increased in both 21/7-active and DSG/EE+no Tx regimens (least square [LS] mean changes +45 pmol/L and +56.8 pmol/L, respectively). LS mean treatment difference was -11.8 pmol/L (95% CI: -54.8, 31.2). CONCLUSION: The effect of adding EE ten mcg to the seven-day hormone-free interval of DSG/EE on F1+2 levels was non-inferior to traditional DSG/EE.

Infrared and Raman screening of seized novel psychoactive substances: a large scale study of >200 samples.

The potential of IR absorption and Raman spectroscopy for rapid identification of novel psychoactive substances (NPS) has been tested using a set of 221 unsorted seized samples suspected of containing NPS. Both IR and Raman spectra showed large variation between the different sub-classifications of NPS and smaller, but still distinguishable, differences between closely related compounds within the same class. In initial tests, screening the samples using spectral searching against a limited reference library allowed only 41% of the samples to be fully identified. The limiting factor in the identification was the large number of active compounds in the seized samples for which no reference vibrational data were available in the libraries rather than poor spectral quality. Therefore, when 33 of these compounds were independently identified by NMR and mass spectrometry and their spectra used to extend the libraries, the percentage of samples identified by IR and Raman screening alone increased to 76%, with only 7% of samples having no identifiable constituents. This study, which is the largest of its type ever carried out, therefore demonstrates that this approach of detecting non-matching samples and then identifying them using standard analytical methods has considerable potential in NPS screening since it allows rapid identification of the constituents of the majority of street quality samples. Only one complete feedback cycle was carried out in this study but there is clearly the potential to carry out continuous identification/updating when this system is used in operational settings.