Search

The discovery that the commercial rubber antidegradant 6PPD reacts with ozone (\ce{O3}) to produce a highly toxic quinone (6PPDQ) spurred a significant research effort into non-toxic alternatives. Identification of non-toxic alternatives has been hampered by lack of a detailed understanding of the mechanism of protection that 6PPD affords rubber compounds against ozone. Herein, we report high-level density functional theory studies into early steps of rubber and PPD ($p$-phenylenediamine) ozonation, identifying key steps that contribute to the antiozonant activity of PPDs. In this, we establish that our density functional theory approach can achieve chemical accuracy for many ozonation reactions, which are notoriously difficult to model. Using adiabatic energy decomposition analysis, we examine and dispel the notion that one-electron charge transfer initiates ozonation in these systems, as is sometimes argued. Instead, we find direct interaction between \ce{O3} and PPD carbon atoms is kinetically accessible, and that this motif is more significant than interactions with PPD nitrogens. The former pathway results in a hydroxylated PPD intermediate, which reacts further with \ce{O3} to afford 6PPD hydroquinone and, ultimately, 6PPDQ. This mechanism directly links the toxicity of 6PPDQ to the antiozonant function of 6PPD. These results have significant implications for development of alternative antiozonants, which are discussed.

Introduction Cross sectional therapeutic drug monitoring (TDM) data mining introduces new opportunities for the investigation of medication treatment effects to find optimal therapeutic windows. Medication discontinuation has been proven useful as an objective surrogate marker to assess treatment failure. This study aimed to investigate the treatment effects of escitalopram and pharmacokinetic influences on blood levels using retrospectively assessed data from a TDM database. Methods Data was collected from 134 patients longitudinally treated with escitalopram for whom TDM was requested to guide drug therapy. Escitalopram metabolism was estimated by the log-transformed dose-corrected concentrations and compared within subpopulations differing in age, gender, renal function, smoking status, body mass index, and comedication. Results Patients with a depressive episode who were treated with escitalopram and discontinued the treatment within the hospital stay showed lower serum concentrations compared to patients who continued escitalopram treatment with a concentration of 15 ng/mL separating both groups. Variability was high between individuals and factors influencing blood levels, including dose, sex, and age. Comedication that inhibits cytochrome P450 (CYP) 2C19 isoenzymes were further found to influence escitalopram pharmacokinetics independent of dose, age or sex. Discussion Medication switch is a valuable objective surrogate marker to assess treatment effects under real-world conditions. Of note, treatment discontinuation is not always a cause of insufficient response but may also be related to other factors such as medication side effects. TDM might not only be useful in addressing these issues but titrating drug concentrations into the currently recommended reference range for escitalopram will also increase response in non-responders and avoid treatment failure in underdosed patients.

Este ensayo se centra en las superposiciones y coincidencias biográficas, sociales, culturales y literarias que existen entre la vida y la obra de dos grandes escritores del siglo xx, el novelista irlandés James Joyce (1882-1941) y el poeta peruano César Vallejo (1892-1938). Aunque nunca se conocieron, ambos vivieron en París durante las décadas de 1920 y 1930; y aunque tampoco leyeron los escritos del otro, se encuentran similitudes sorprendentes entre sus obras respectivas. Los dos compartían una relación angustiosa con el catolicismo, también se involucraron en la política de izquierda, y estaban fascinados por las posibilidades creativas de los juegos de palabras (ambos son conocidos por su amplio uso de neologismos). Esto llevó tanto a Joyce como a Vallejo a confiar en el «oído» —más que en el «ojo»— al escribir sus obras maestras. Finalmente, sus obras demuestran una coincidencia en el uso de ciertos tópicos, tales como el enfoque en el contraste entre la comunicación oral y la producción anal, y la exploración de lo absurdo y la paradoja (el círculo cuadrado, el mundo al revés y el «sonido» del silencio).

The use of videoconferencing has increased during the pandemic, creating prolonged exposure to self-image. This research aimed to investigate whether eating disorder (ED) risk was associated with videoconferencing performance for work or study and to explore whether the use of safety behaviors and self-focused attention mediated the relationship between ED risk and perceived control over performance anxiety, impaired engagement, or avoidance of videoconferencing for work or study.In 2020, an online survey was distributed within Australia to those aged over 18 years via academic and social networks, measuring: use of videoconferencing for work/study, demographics, ED risk, safety behaviors for appearance concerns, self-focused attention, perceived control over performance anxiety, perceived engagement impairment, and avoidance of videoconferencing. A total of 640 participants (77.3% female, M245 participants (38.7%) were considered at-risk for EDs (SCOFF 2). Those at-risk reported significantly more safety behaviors, self-focused attention, impaired engagement, and avoidance, plus lower perceived control over performance anxiety than those not at-risk. Multiple mediation models found the effects of ED risk on control over performance anxiety, impaired engagement, and avoidance were partially mediated by safety behaviors and self-focused attention.Our cross-sectional findings suggest videoconferencing for work/study-related purposes is associated with performance anxiety, impaired engagement, and avoidance among individuals at-risk for EDs. Poorer videoconferencing outcomes appear more strongly related to social anxiety variables than ED status. Clinicians and educators may need to provide extra support for those using videoconferencing.Because videoconferencing often involves seeing your own image (via self-view) we wondered whether the appearance concerns experienced by those with eating disorders (EDs) might interfere with the ability to focus on or to contribute to work/study videoconferencing meetings. We found that although those with EDs experience more impairments in their videoconferencing engagement/contribution, these were linked just as strongly to social anxiety as they were to appearance concerns.

The selective serotonin reuptake inhibitor escitalopram (ESC) is indicated for the treatment of major depressive disorder (MDD) and of generalized anxiety disorder (GAD). Monitoring of blood levels (BLs) is strongly indicated due to ESC’s high interindividual pharmacokinetic variability. The aim of this study was to analyse clinical efficacy and pharmacokinetic influences on ESC BLs, in patients with depressive disorder alone and with comorbid alcohol or benzodiazepine use disorder. Data were collected from patients treated under naturalistic conditions for whom Therapeutic Drug Monitoring (TDM) was requested to guide antidepressant drug therapy and analysed retrospectively. Particular emphasis was given to patients with alcohol or benzodiazepine use disorder. Responders according to the clinical global impression (CGI) scale were compared with nonresponders for their ESC blood level (BL). The patient sample included 344 patients from 16 psychiatric hospitals in Germany. Influencing factors that could explain 22% of ESC BLs were dose, sex and age. Variability was high between individuals, and doses up to 40 mg were common in real-world settings. Patients treated with ESC monotherapy who responded showed a trend towards higher BLs compared to nonresponders with a concentration of 15 ng/mL separating both groups. Pathological changes in liver function (indicated by elevated GGT in combination with an AST/ALT ratio ≥ 1) resulted in higher dose-corrected ESC concentrations. Influencing factors that could explain 22% of ESC blood levels were dose, sex, and age. Our findings confirm the currently recommended lower threshold level and support the need for standard TDM analyses in everyday clinical practice. The ICD 10 diagnosis alcohol dependence alone does not lead to pharmacokinetic changes in the metabolism of ESC, but altered liver function does.

To evaluate whether contralateral limb strength represents a dynamic, rather than static, data point after anterior cruciate ligament reconstruction (ACL-R).Patients who underwent isolated ACL-R at a single institution were identified. Patients completed an institutional Lower-Extremity Assessment Protocol (LEAP) testing protocol at 6 and 9 months postoperatively. Extension strength and flexion strength of the ipsilateral and contralateral limbs and limb symmetry index (LSI) were compared between the 6- and 9-month testing outcomes. Subgroup analysis compared patients demonstrating less than or greater than 10% change in contralateral limb flexion and extension strength between 6 and 9 months postoperatively.A total of 144 subjects were included in this study. On average, contralateral limb flexion and extension strength increased 2-4% between 6 and 9 months postoperatively. However, the contralateral limb increased10% from 6 to 9 months in extension and flexion strength in 35/144 (24.3%) and 55/144 (38.2%) of patients, respectively. The cohort with10% change between 6 and 9 months had significantly weaker contralateral extension and flexion strength at 6 months compared to the cohort that demonstrated10% change (extension: 2.00 vs 2.39;A large percentage of patients demonstrate significant changes in their contralateral limb flexion and extension strength between 6 and 9 months postoperatively that result from an initial contralateral limb strength deficit. This may limit the utility of the contralateral limb as a control for comparison to the operative extremity during return to sport assessment.

Full list of authors: Jorstad, S. G.; Marscher, A. P.; Raiteri, C. M.; Villata, M.; Weaver, Z. R.; Zhang, H.; Dong, L.; Gomez, J. L.; Perel, M., V; Savchenko, S. S.; Larionov, V. M.; Carosati, D.; Chen, W. P.; Kurtanidze, O. M.; Marchini, A.; Matsumoto, K.; Mortari, F.; Aceti, P.; Acosta-Pulido, J. A.; Andreeva, T.; Apolonio, G.; Arena, C.; Arkharov, A.; Bachev, R.; Bonnoli, G.; Borman, G. A.; Bozhilov, V; Carnerero, M., I; Damljanovic, G.; Ehgamberdiev, S. A.; Elsasser, D.; Frasca, A.; Gabellini, D.; Grishina, T. S.; Gupta, A. C.; Hagen-Thorn, V. A.; Hallum, M. K.; Hart, M.; Hasuda, K.; Hemrich, F.; Hsiao, H. Y.; Ibryamov, S.; Irsmambetova, T. R.; Ivanov, D., V; Joner, M. D.; Kimeridze, G. N.; Klimanov, S. A.; Knoett, J.; Kopatskaya, E. N.; Kurtanidze, S. O.; Kurtenkov, A.; Kuutma, T.; Larionova, E. G.; Leonini, S.; Lin, H. C.; Lorey, C.; Mannheim, K.; Marino, G.; Minev, M.; Mirzaqulov, D. O.; Morozova, D. A.; Nikiforova, A. A.; Nikolashvili, M. G.; Ovcharov, E.; Papini, R.; Pursimo, T.; Rahimov, I; Reinhart, D.; Sakamoto, T.; Salvaggio, F.; Semkov, E.; Shakhovskoy, D. N.; Sigua, L. A.; Steineke, R.; Stojanovic, M.; Strigachev, A.; Troitskaya, Y., V; Troitskiy, I. S.; Tsai, A.; Valcheva, A.; Vasilyev, A. A.; Vince, O.; Waller, L.; Zaharieva, E.; Chatterjee, R., Blazars are active galactic nuclei (AGN) with relativistic jets whose non-thermal radiation is extremely variable on various timescales1,2,3. This variability seems mostly random, although some quasi-periodic oscillations (QPOs), implying systematic processes, have been reported in blazars and other AGN. QPOs with timescales of days or hours are especially rare4 in AGN and their nature is highly debated, explained by emitting plasma moving helically inside the jet5, plasma instabilities6,7 or orbital motion in an accretion disc7,8. Here we report results of intense optical and γ-ray flux monitoring of BL Lacertae (BL Lac) during a dramatic outburst in 2020 (ref. 9). BL Lac, the prototype of a subclass of blazars10, is powered by a 1.7 × 108 MSun (ref. 11) black hole in an elliptical galaxy (distance = 313 megaparsecs (ref. 12)). Our observations show QPOs of optical flux and linear polarization, and γ-ray flux, with cycles as short as approximately 13 h during the highest state of the outburst. The QPO properties match the expectations of current-driven kink instabilities6 near a recollimation shock about 5 parsecs (pc) from the black hole in the wake of an apparent superluminal feature moving down the jet. Such a kink is apparent in a microwave Very Long Baseline Array (VLBA) image. © 2022 Springer Nature Limited., The research reported here is based on work supported in part by US National Science Foundation grants AST-2108622 and AST-2107806, and NASA Fermi GI grants 80NSSC20K1567, 80NSSC21K1917 and 80NSSC21K1951; by Shota Rustaveli National Science Foundation of Georgia under contract FR-19-6174; by the Bulgarian National Science Fund of the Ministry of Education and Science under grants DN 18-10/2017, DN 18-13/2017, KP-06-H28/3 (2018), KP-06-H38/4 (2019) and KP-06-KITAJ/2 (2020), and by National RI Roadmap Project D01-383/18.12.2020 of the Ministry of Education and Science of the Republic of Bulgaria; by JSPS KAKENHI grant #19K03930 of Japan; by the Ministry of Education, Science and Technological Development of the Republic of Serbia (contract 451-03-9/2021-14/200002) and observing grant support from the Institute of Astronomy and Rozhen NAO BAS through the bilateral joint research project ‘Gaia Celestial Reference Frame (CRF) and fast variable astronomical objects’; by the Agenzia Spaziale Italiana (ASI) through contracts I/037/08/0, I/058/10/0, 2014-025-R.0, 2014-025-R.1.2015 and 2018-24-HH.0 to the Italian Istituto Nazionale di Astrofisica (INAF). H.Z. is supported by the NASA Postdoctoral Program at Goddard Space Flight Center, administered by ORAU. M.V.P. is partially supported by the Russian Foundation for Basic Research grant 20-02-00490. G.B. acknowledges support from the State Agency for Research of the Spanish MCIU through the ‘Center of Excellence Severo Ochoa’ award to the Instituto de Astrofísica de Andalucía (SEV-2017-0709) and from the Spanish ‘Ministerio de Ciencia e Innovacíon’ (MICINN) through grant PID2019-107847RB-C44. M.D.J. thanks the Brigham Young University Department of Physics and Astronomy for continued support of the extragalactic monitoring programme under way at the West Mountain Observatory. R.C. thanks ISRO for support under the AstroSat archival data utilization programme and BRNS for support through a project grant (sanction no. 57/14/10/2019-BRNS). The measurements at the Hans Haffner Observatory, Hettstadt, Germany, were supported by Baader Planetarium, Mammendorf, Germany. This study was based (in part) on observations conducted using the 1.8-m Perkins Telescope Observatory (PTO) in Arizona, USA, which is owned and operated by Boston University. These results made use of the Lowell Discovery Telescope (LDT) at Lowell Observatory. Lowell Observatory is a private, non-profit institution dedicated to astrophysical research and public appreciation of astronomy, and operates the LDT in partnership with Boston University, the University of Maryland and the University of Toledo. This paper is partly based on observations made with the IAC-80 operated on the island of Tenerife by the Instituto de Astrofisica de Canarias in the Spanish Observatorio del Teide and on observations made with the LCOGT telescopes, one of whose nodes is located at the Observatorios de Canarias del IAC on the island of Tenerife in the Observatorio del Teide. This paper is partly based on observations made with the Nordic Optical Telescope, owned in collaboration by the University of Turku and Aarhus University, and operated jointly by Aarhus University, the University of Turku and the University of Oslo, representing Denmark, Finland and Norway, the University of Iceland and Stockholm University at the Observatorio del Roque de los Muchachos, La Palma, Spain, of the Instituto de Astrofisica de Canarias. The VLBA is an instrument of the NRAO, USA. The NRAO is a facility of the National Science Foundation operated under cooperative agreement by Associated Universities, Inc.

Cemented endoprosthetic reconstruction after resection of primary bone sarcomas has been in common use for decades. Although multiple studies have reported the survivorship of primary endoprostheses, implant survivorship after revision surgery is less well established. Given that earlier advances in systemic therapy improved survival of patients with sarcoma, the usage of revision endoprostheses can be expected to increase and, as such, understanding revision implant survivorship will help to inform patient and surgeon expectations. Additionally, as new implants are developed that allow alternative reconstruction options, a normative dataset establishing accurate expectations for revision cemented endoprostheses is a critical benchmark by which to measure progress.(1) What is the implant survivorship free of all-cause revision for primary and revision cemented distal femoral replacements (DFRs) used in the treatment of malignant or benign tumors? (2) What are the most common indications for revision of primary and revision DFRs in an oncology population with mean follow-up of more than 10 years? (3) How does the indication for revision of a primary DFR affect the subsequent risk for and type of revision DFR complication? (4) What patient, tumor, or implant characteristics are associated with improved survivorship free of revision in cemented DFRs used in patients treated initially for primary malignant or benign tumors?This was a retrospective, comparative study using our institution's longitudinally-maintained database of 806 cemented endoprostheses starting in 1980 and assessed through December 31, 2018. In all, 365 DFRs were inserted during this time, but 14% (51 of 365) were placed for nonprimary bone tumors and 1% (5 of 365) were cementless reconstructions, leaving 309 cemented DFRs. Seventy-one percent (218 of 309) were primary implants and 29 percent (91 of 309) were revision implants (used to revise a prior DFR in all patients). During this time period, our strong bias was to use cemented stems and, thus, nearly all of our patients had cemented stems. Six percent (13 of 218) of primary DFRs were implanted more than 2 years before the study end; however, they lacked 2 years of follow-up data and, thus, were considered lost to follow-up, leaving 205 implants in the primary DFR analysis group. Only the first revision after primary DFR revision surgery was included in the revision cohort analysis. Thirty-two percent (29 of 91) of revision DFRs were second or more revision patients and were excluded, leaving 62 implants in the revision analysis group. Most patients in both groups were men (57% [117 of 205] for primary and 71% [44 of 62] for revision) who had been diagnosed with osteosarcoma (75% [153 of 205] and 73% [45 of 62] for primary and revision, respectively). The primary cohort had mean age of 26 ± 16 years with a mean follow-up of 136 ± 122 months, and the revision cohort had mean age of 31 ± 13 years (p = 0.02) with 141 ± 101 months of follow-up. Study endpoints included all-cause implant revision and cause-specific revision for soft tissue complications, aseptic loosening, structural complications (defined as periprosthetic or implant fracture), infection, or tumor progression. Planned surgery for implant lengthening procedures was excluded. Implant survivorship free from all-cause revision was calculated using a competing risk (cumulative incidence) estimator with death as a competing risk. A log-rank test using chi-square analysis was used to evaluate the differences in implant survivorship between primary DFRs and first revisions. The cause-specific incidences of implant revision were tabulated for primary and revision DFRs. Cox regression analysis investigated the odds of subsequent all-cause revision surgery for revision cemented DFRs based on the primary implant complication. A binary logistic regression analysis using age, gender, indication for revision, tumor type, infection, perioperative chemotherapy, and radiation was performed to identify factors associated with a second DFR reoperation. Relative effect sizes are reported as ORs.The revision DFR cohort had a shorter mean survival to all-cause revision than the primary cohort (mean 10 years [95% CI 7 to 12] versus 18 years [95% CI 15 to 20]; p0.001). The most common complications necessitating revision for revision implants were periprosthetic or implant fracture in 37% (23 of 62) and aseptic loosening in 15% (9 of 62), and the type of primary implant complication was not associated with risk of subsequent all-cause revision surgery for revision implants. Stem diameter less than 15 mm was associated with repeat all-cause revision in cemented revision DFRs after controlling for resection length, stem length, implant fabrication (custom or modular), and presence of a porous collar (OR 4 [95% CI 1 to 17]; p = 0.03). No other parameters that we explored, including patient age, gender, chemoradiation history, or primary tumor diagnosis, were associated with repeat revision surgery.Understanding modifiable factors that can improve revision DFR survival is critical to achieving long-term limb salvage for patients with tumors around the knee. Our data suggest that utilizing implants with the largest possible stems-or at a minimum increasing the stem size over the primary implant-is important to revision cemented DFR survivorship and is an important part of our revision practice. Improving revision implants' resistance to aseptic loosening through designs that resist torsion (a common mode of cemented fixation failure)-such as with the use of custom cross-pin fabrication-may be one method to improve survivorship. Another will be improved implant metallurgy that is resistant to fatigue fracture. Next steps may include understanding the optimal ratio of femoral diaphyseal width to implant diameter in patients where anatomic constraints preclude the insertion of cemented stems 15 mm or more in diameter.Level IV, therapeutic study.

Arthrogenic muscle inhibition (AMI) is a common impairment in individuals who sustain an anterior cruciate ligament (ACL) injury. The AMI causes decreased muscle activation, which impairs muscle strength, leading to aberrant movement biomechanics. The AMI is often resistant to traditional rehabilitation techniques, which leads to persistent neuromuscular deficits following ACL reconstruction. To better treat AMI following ACL injury and ACL reconstruction, it is important to understand the specific neural pathways involved in AMI pathogenesis, as well as the changes in muscle function that may impact movement biomechanics and long-term structural alterations to joint tissue. Overall, AMI is a critical factor that limits optimal rehabilitation outcomes following ACL injury and ACL reconstruction. This review discusses the current understanding of the: (1) neural pathways involved in the AMI pathogenesis following ACL injury; (2) consequence of AMI on muscle function, joint biomechanics, and patient function; and (3) development of posttraumatic osteoarthritis. Finally, the authors review the evidence for interventions specifically used to target AMI following ACL injury.

Afforestation, as one of the major drivers of land cover change, has the potential to provide a wide range of ecosystem services (ES). Aside from carbon sequestration, it can improve hydrological regulation by increasing soil water storage capacity and reducing surface water runoff. However, afforested areas are rarely studied at the appropriate time scale to determine when changes in soil hydrological processes occur as the forest grows. This study investigates the seasonal soil moisture and temperature dynamics, as well as the event-based responses to precipitation events and dry periods between a mature and juvenile forest ecosystem over a 5-year time period. Generally, soil moisture was higher in the juvenile forest than in the mature forest, indicating less physiological water demand. However, following the 2018 drought, soil moisture dynamics in the growing juvenile plantation began to match those of the mature forest, owing to canopy development and possibly also to internal resilience mechanisms of the young forest to external perturbations. On the other hand, soil temperature dynamics in the juvenile plantation followed air temperature patterns closely, indicating lower thermal regulation capacity compared to the mature forest. While our findings reveal that an aggrading juvenile plantation achieves mature forest soil moisture dynamics at an early stage, well before maturity, this was not the case for soil temperature. Our results shed light on long-term trends of seasonal and event-based responses of soil moisture and temperatures in different-aged forest systems, which can be used to inform future assessments of hydrological and ecosystem responses to disturbances and forest management.

During development, early-life stress (ELS) impairs cognition, learning, and emotional regulation, in part by disrupting neural circuitry in regions underlying these higher-order functions. In addition, our recent work indicates that ELS also alters simple sensory perception: ELS impaired auditory perception and neural encoding of short gaps in sounds, which are essential for vocal communication. The combination of higher-order and basic sensory disruption suggests that ELS is likely to affect both the perception and interpretation of communication signals. We tested this hypothesis by measuring behavioral responses to conspecific vocalizations (those emitted by other gerbils) in ELS and untreated Mongolian gerbils. Because stress effects often differ by sex, we separately examined females and males. To induce ELS, pups were intermittently maternally separated and restrained from post-natal days (P) 9–24, a time window when the auditory cortex is most sensitive to external disruption. We measured the approach responses of juvenile (P31–32) gerbils to two types of conspecific vocalizations: an alarm call, which is emitted to alert other gerbils of a potential threat, and the prosocial contact call, which is emitted near familiar gerbils, especially after separation. Control males, Control females, and ELS females approached a speaker emitting pre-recorded alarm calls, while ELS males avoided this source, suggesting that ELS affects the response to alarm calls in male gerbils. During playback of the pre-recorded contact call, Control females and ELS males avoided the sound source, while Control males neither approached nor avoided, and ELS females approached the sound. These differences cannot be accounted for by changes in locomotion or baseline arousal. However, ELS gerbils slept more during playback, suggesting that ELS may reduce arousal during vocalization playback. Further, male gerbils made more errors than females on a measure of working memory, but the sex difference of cognition in this context may stem from novelty aversion rather than impaired memory. These data indicate that ELS influences behavioral responses to ethologically relevant communication sounds in a sex-specific manner, and are among the first to demonstrate an altered response to auditory stimuli following ELS. Such changes may arise from differences in auditory perception, cognition, or a combination of factors, and suggest that ELS may affect auditory communication in human adolescents.

Diamondback terrapins (Malaclemys terrapin) are sexually dimorphic generalist turtles that inhabit salt marshes and estuaries along the Atlantic and Gulf coasts of the United States. On October 29th, 2012, Hurricane Sandy made landfall in New Jersey, USA, directly impacting terrapin populations inhabiting central and southern Barnegat Bay. To examine potential food web mediated impacts to the terrapin population and their foraging dynamics we examined carbon and nitrogen stable isotope values collected from terrapin tissues (2011, 2015, 2019) and resource taxa (2015, 2019) within Barnegat Bay. Isotopic analysis revealed that mature females had lower carbon and higher nitrogen values than immature females and males with almost no isotopic niche overlap, whereas males and immature females had statistically similar values with overlapping niches. Terrapins and resources collected from island habitats contained higher carbon and nitrogen values than those from mainland habitats, with little overlap in niche between habitats. There were no significant temporal variations detected in either carbon or nitrogen values from terrapins between years, or within each habitat pre- and post-Hurricane Sandy. These findings suggest long-term terrapin foraging dynamics have remained relatively stable, signifying resilience to disturbance events within the study site.