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Background: Biallelic variants in POLR1C are associated with POLR3-related leukodystrophy (POLR3-HLD), or 4H leukodystrophy (Hypomyelination, Hypodontia, Hypogonadotropic Hypogonadism), and Treacher Collins syndrome (TCS). The clinical spectrum of POLR3-HLD caused by variants in this gene has not been described. Methods: A cross-sectional observational study involving 25 centers worldwide was conducted between 2016 and 2018. The clinical, radiologic and molecular features of 23 unreported and previously reported cases of POLR3-HLD caused by POLR1C variants were reviewed. Results: Most participants presented between birth and age 6 years with motor difficulties. Neurological deterioration was seen during childhood, suggesting a more severe phenotype than previously described. The dental, ocular and endocrine features often seen in POLR3-HLD were not invariably present. Five patients (22%) had a combination of hypomyelinating leukodystrophy and abnormal craniofacial development, including one individual with clear TCS features. Several cases did not exhibit all the typical radiologic characteristics of POLR3-HLD. A total of 29 different pathogenic variants in POLR1C were identified, including 13 new disease-causing variants. Conclusions: Based on the largest cohort of patients to date, these results suggest novel characteristics of POLR1C-related disorder, with a spectrum of clinical involvement characterized by hypomyelinating leukodystrophy with or without abnormal craniofacial development reminiscent of TCS.
Background: SMA is a neurodegenerative disease caused by biallelic deletion/mutation of the survival motor neuron (SMN1) gene. In the phase 1 trial (NCT02122952), SMN GRT onasemnogene abeparvovec (AVXS-101) improved outcomes of 15 symptomatic SMA1 patients (3 at a lower dose [cohort 1] and 12 at the proposed therapeutic dose [cohort 2]). This report describes long-term follow-up study design and data from the phase 1 study. Methods: Patients in the phase 1 study could rollover into a long-term follow-up study (NCT03421977). The primary objective is to collect long-term safety data (serious adverse events, hospitalizations, and adverse events of special interest). Annual follow-up will occur for 15 years. Additionally, patient record transfers from local clinician(s) will be requested. Safety assessments include medical history and record review, physical examination, clinical laboratory evaluation, and pulmonary assessments. Efficacy assessments include physical examination to assess developmental milestones. Results: As of September 27, 2018, the oldest patients are 59.2 (cohort 1) and 52.1 (cohort 2) months old and free of permanent ventilation. Preliminary data, including survival and developmental milestones, will be presented. Conclusions: Patients treated with a one-time dose of AVXS-101 continue to gain strength, develop, and achieve new milestones, demonstrating a long-term, durable response.
A mother's nutritional choices while pregnant may have a great influence on her baby's development in the womb and during infancy. There is evidence that what a mother eats during pregnancy interacts with her genes to affect her child's susceptibility to poor health outcomes including childhood obesity, pre-diabetes, allergy and asthma. Furthermore, after what an infant eats can change his or her intestinal bacteria, which can further influence the development of these poor outcomes. In the present paper, we review the importance of birth cohorts, the formation and early findings from a multi-ethnic birth cohort alliance in Canada and summarise our future research directions for this birth cohort alliance. We summarise a method for harmonising collection and analysis of self-reported dietary data across multiple cohorts and provide examples of how this birth cohort alliance has contributed to our understanding of gestational diabetes risk; ethnic and diet-influences differences in the healthy infant microbiome; and the interplay between diet, ethnicity and birth weight. Ongoing work in this birth cohort alliance will focus on the use of metabolomic profiling to measure dietary intake, discovery of unique diet–gene and diet–epigenome interactions, and qualitative interviews with families of children at risk of metabolic syndrome. Our findings to-date and future areas of research will advance the evidence base that informs dietary guidelines in pregnancy, infancy and childhood, and will be relevant to diverse and high-risk populations of Canada and other high-income countries.
The mechanisms underlying both depressive and anxiety disorders remain poorly understood. One of the reasons for this is the lack of a valid, evidence-based system to classify persons into specific subtypes based on their depressive and/or anxiety symptomatology. In order to do this without a priori assumptions, non-parametric statistical methods seem the optimal choice. Moreover, to define subtypes according to their symptom profiles and inter-relations between symptoms, network models may be very useful. This study aimed to evaluate the potential usefulness of this approach.
A large community sample from the Canadian general population (N = 254 443) was divided into data-driven clusters using non-parametric k-means clustering. Participants were clustered according to their (co)variation around the grand mean on each item of the Kessler Psychological Distress Scale (K10). Next, to evaluate cluster differences, semi-parametric network models were fitted in each cluster and node centrality indices and network density measures were compared.
A five-cluster model was obtained from the cluster analyses. Network density varied across clusters, and was highest for the cluster of people with the lowest K10 severity ratings. In three cluster networks, depressive symptoms (e.g. feeling depressed, restless, hopeless) had the highest centrality. In the remaining two clusters, symptom networks were characterised by a higher prominence of somatic symptoms (e.g. restlessness, nervousness).
Finding data-driven subtypes based on psychological distress using non-parametric methods can be a fruitful approach, yielding clusters of persons that differ in illness severity as well as in the structure and strengths of inter-symptom relationships.
Introduction: The number of seniors presenting to emergency departments after a fall is increasing. Head injury concerns in this population often leads to a head CT scan. The CT rate among physicians is variable and the reasons for this are unknown. This study examined the role of patient characteristics and country of practice in the decision to order a CT. Methods: This study used a case-based survey of physicians across multiple countries. Each survey included 9 cases pertaining to an 82-year old man who falls. Each case varied in one aspect compared to a base case (aspirin, warfarin, or rivaroxaban use, occipital hematoma, amnesia, dementia, and fall with no head trauma). For each case, participants indicated how “likely” they were to order a head CT scan, measured on a 100-point scale. A response of 80 or more was defined a priori as ‘likely to order a CT scan’. The survey was piloted among emergency residents for feedback on design and comprehension, and was published in French and English. Recruitment was through the Canadian Association of Emergency Physicians, Twitter and CanadiEM. For each case we compared the proportion of physicians who were ‘likely to scan’ with relative to the base case. We also compared the proportion of participants who were ‘likely to scan’ each case in the USA, UK and Australia, relative to Canada. Results: Data was collected from 484 respondents (Canada-308, USA-64, UK-67, Australia-27, and 18 from other countries). Social media distribution limited our ability to estimate of the response rate. Physicians were most likely to scan in the anticoagulation cases (90% likely to order a scan compared to 36% for the base case (p = <0.001)). Other features associated with increased scans were occipital hematoma (48%), multiple falls (68%), and amnesia (68%) (all p < 0.005). Compared to Canada, US physicians were more likely to order CT scans for all cases (p = <0.05). Compared to Canada, UK physicians were significantly less likely to order CT for patients in every case except in the patient with amnesia. Finally, Australian physicians differed from Canada only for the occipital hematoma case where they were significantly more likely to order CT scan. Conclusion: Anticoagulation, amnesia and a history of multiple falls appear to drive the ordering a head CT scan in elderly patients who had fallen. We observed variations in practice between countries. Future clinical decision rules will likely have variable impact on head CT scan rates depending on baseline practice variation.
Introduction: The Canadian population is aging and an increasing proportion of emergency department (ED) patients are seniors. ED visits among seniors are frequently instigated by a fall at home. Some of these patients develop intracranial hemorrhage (ICH) because of falling. There has been little research on the frequency of ICH in elderly patients who fall, and on which clinical factors are associated with ICH in these patients. The aim of this study was to identify the incidence of ICH, and the clinical features which are associated with ICH, in seniors who present to the ED having fallen. Methods: This was a prospective cohort study conducted in three EDs. Patients were included if they were age >65 years, and presented to the ED within 48 hours of a fall on level ground, off a bed/chair/toilet or down one step. Patients were excluded if they fell from a height, were knocked over by a vehicle or were assaulted. ED physicians recorded predefined clinical findings (yes/no) before any head imaging was done. Head imaging was done at the ED physician's discretion. All patients were followed for 6 weeks (both by telephone call and chart review at 6 weeks) for evidence of ICH. Associations between baseline clinical findings and the presence of ICH were assessed with multivariable logistic regression. Results: In total, 1753 patients were enrolled. The prevalence of ICH was 5.0% (88 patients), of whom 74 patients had ICH on the ED CT scan and 14 had ICH diagnosed during follow-up. 61% were female and the median age was 82 (interquartile range 75-88). History included hypertension in 76%, diabetes in 29%, dementia in 27%, stroke/TIA in 19%, major bleeding in 11% and chronic kidney disease in 11%. 35% were on antiplatelet therapy and 25% were on an anticoagulant. Only 4 clinical variables were independently associated with ICH: bruise/laceration on the head (odds ratio (OR): 4.3; 95% CI 2.7-7.0), new abnormalities on neurological examination (OR: 4.4; 2.4-8.1), chronic kidney disease (OR: 2.4; 1.3-4.6) and reduced GCS from baseline (OR: 1.9; 1.0-3.4). Neither anticoagulation (OR: 0.9; 0.5-1.6) nor antiplatelet use (OR: 1.1; 0.6-1.8) appeared to be associated with ICH. Conclusion: This prospective study found a prevalence of ICH of 5.0% in seniors after a fall, and that bruising on the head, abnormal neurological examination, abnormal GCS and chronic kidney disease were predictive of ICH.
Introduction: There is an evidence-practice gap between guidelines for diagnosing pulmonary embolism (PE) and emergency physician practice. Computed tomography (CT) scanning is being overused to exclude PE in Canadian emergency departments (EDs) and current guidelines do not fit well with the ED model of patient care. There is a lack of research on patient opinions on PE testing, and a poor physician understanding of patient-specific goals in the ED. We are addressing this by conducting patient interviews to identify patient-specific values and opinions on PE testing in the ED. These will be used to develop patient-centered educational tools which physicians and patients can use to discuss the decision to order a CT PE scan. The aim of this study is to identify patient expectations and priorities on PE testing in the ED. Methods: This qualitative study uses constructivist grounded theory to analyze patient values and opinions on PE testing in ED patients from two hospitals. Participants are screened by monitoring the ED patient tracker. If a patient is being tested for PE, they are approached and consented by a researcher to take part in a 30-minute semi-structured interview. Each interview is transcribed verbatim and independently analyzed by four researchers using constant comparative coding. The researchers meet weekly to compare codes and agree on common coding terms. The codes are grouped into themes, and the interview script is modified to maximize information on emerging themes. From this, major themes with associated subthemes will be derived, each representing an opportunity, barrier or value which must be addressed in our new patient education tools. We have performed 23 interviews and expect to reach theme saturation at 30 interviews. Full results will be available by the 2019 CAEP conference. Results: From the patient interviews conducted so far, we have mapped four major themes: patient satisfaction comes from addressing their primary concern (for example, their pain); patients expect individualized care; patients prefer imaging over clinical examination when testing for PE; and patients expect 100% confidence from their ED physician when given a diagnosis. Conclusion: These four domains will be used to create a new patient-centered approach to PE testing in the ED which will include physician education, patient information and organizational changes to patient processing. This study incorporates evidence-based medicine with ethical and social implications to improve patient outcomes.
The Centro de Laseres Pulsados in Salamanca, Spain has recently started operation phase and the first user access period on the 6 J 30 fs 200 TW system (VEGA 2) already started at the beginning of 2018. In this paper we report on two commissioning experiments recently performed on the VEGA 2 system in preparation for the user campaign. VEGA 2 system has been tested in different configurations depending on the focusing optics and targets used. One configuration (long focal length
cm) is for underdense laser–matter interaction where VEGA 2 is focused onto a low density gas-jet generating electron beams (via laser wake field acceleration mechanism) with maximum energy up to 500 MeV and an X-ray betatron source with a 10 keV critical energy. A second configuration (short focal length
cm) is for overdense laser–matter interaction where VEGA 2 is focused onto a
thick Al target generating a proton beam with a maximum energy of 10 MeV and temperature of 2.5 MeV. In this paper we present preliminary experimental results.
Recent infection testing algorithms (RITA) for HIV combine serological assays with epidemiological data to determine likely recent infections, indicators of ongoing transmission. In 2016, we integrated RITA into national HIV surveillance in Ireland to better inform HIV prevention interventions. We determined the avidity index (AI) of new HIV diagnoses and linked the results with data captured in the national infectious disease reporting system. RITA classified a diagnosis as recent based on an AI < 1.5, unless epidemiological criteria (CD4 count <200 cells/mm3; viral load <400 copies/ml; the presence of AIDS-defining illness; prior antiretroviral therapy use) indicated a potential false-recent result. Of 508 diagnoses in 2016, we linked 448 (88.1%) to an avidity test result. RITA classified 12.5% of diagnoses as recent, with the highest proportion (26.3%) amongst people who inject drugs. On multivariable logistic regression recent infection was more likely with a concurrent sexually transmitted infection (aOR 2.59; 95% CI 1.04–6.45). Data were incomplete for at least one RITA criterion in 48% of cases. The study demonstrated the feasibility of integrating RITA into routine surveillance and showed some ongoing HIV transmission. To improve the interpretation of RITA, further efforts are required to improve completeness of the required epidemiological data.
Studies investigating the underlying mechanisms of hallucinations in patients with schizophrenia suggest that an imbalance in top-down expectations v. bottom-up processing underlies these errors in perception. This study evaluates this hypothesis by testing if individuals drawn from the general population who have had auditory hallucinations (AH) have more misperceptions in auditory language perception than those who have never hallucinated.
We used an online survey to determine the presence of hallucinations. Participants filled out the Questionnaire for Psychotic Experiences and participated in an auditory verbal recognition task to assess both correct perceptions (hits) and misperceptions (false alarms). A hearing test was performed to screen for hearing problems.
A total of 5115 individuals from the general Dutch population participated in this study. Participants who reported AH in the week preceding the test had a higher false alarm rate in their auditory perception compared with those without such (recent) experiences. The more recent the AH were experienced, the more mistakes participants made. While the presence of verbal AH (AVH) was predictive for false alarm rate in auditory language perception, the presence of non-verbal or visual hallucinations were not.
The presence of AVH predicted false alarm rate in auditory language perception, whereas the presence of non-verbal auditory or visual hallucinations was not, suggesting that enhanced top-down processing does not transfer across modalities. More false alarms were observed in participants who reported more recent AVHs. This is in line with models of enhanced influence of top-down expectations in persons who hallucinate.
The wide geographical distribution and genetic diversity of bat-associated lyssaviruses (LYSVs) across Europe suggest that similar viruses may also be harboured in Italian insectivorous bats. Indeed, bats were first included within the passive national surveillance programme for rabies in wildlife in the 1980s, while active surveillance has been performed since 2008. The active surveillance strategies implemented allowed us to detect neutralizing antibodies directed towards European bat 1 lyssavirus in six out of the nine maternity colonies object of the study across the whole country. Seropositive bats were Myotis myotis, M. blythii and Tadarida teniotis. On the contrary, the virus was neither detected through passive nor active surveillance, suggesting that fatal neurological infection is rare also in seropositive colonies. Although the number of tested samples has steadily increased in recent years, submission turned out to be rather sporadic and did not include carcasses from bat species that account for the majority of LYSVs cases in Europe, such as Eptesicus serotinus, M. daubentonii, M. dasycneme and M. nattereri. A closer collaboration with bat handlers is therefore mandatory to improve passive surveillance and decrypt the significance of serological data obtained up to now.
LiGAPS-Beef (Livestock simulator for Generic analysis of Animal Production Systems – Beef cattle) is a generic, mechanistic model designed to quantify potential and feed-limited growth, which provides insight in the biophysical scope to increase beef production (i.e. yield gap). Furthermore, it enables identification of the bio-physical factors that define and limit growth, which provides insight in management strategies to mitigate yield gaps. The aim of this paper, third in a series of three, is to evaluate the performance of LiGAPS-Beef with independent experimental data. After model calibration, independent data were used from six experiments in Australia, one in Uruguay and one in the Netherlands. Experiments represented three cattle breeds, and a wide range of climates, feeding strategies and cattle growth rates. The mean difference between simulated and measured average daily gains (ADGs) was 137 g/day across all experiments, which equals 20.1% of the measured ADGs. The root mean square error was 170 g/day, which equals 25.0% of the measured ADGs. LiGAPS-Beef successfully simulated the factors that defined and limited growth during the experiments on a daily basis (genotype, heat stress, digestion capacity, energy deficiency and protein deficiency). The simulated factors complied well to the reported occurrence of heat stress, energy deficiency and protein deficiency at specific periods during the experiments. We conclude that the level of accuracy of LiGAPS-Beef is acceptable, and provides a good basis for acquiring insight in the potential and feed-limited production of cattle in different beef production systems across the world. Furthermore, its capacity to identify factors that define or limit growth and production provides scope to use the model for yield gap analysis.
Effective treatment of maternal antenatal depression may ameliorate adverse neurodevelopmental outcomes in offspring. We performed two follow-up rounds of children at age 2 and age 5 whose mothers had received either specialized cognitive-behavioural therapy or routine care for depression while pregnant. Of the original cohort of 54 women, renewed consent was given by 28 women for 2-year follow-up and by 24 women for 5-year follow-up. Child assessments at the 2-year follow-up included the Parenting Stress Index (PSI), Bayley Scales of Infant Development (BSID-III) and the Child Behaviour Checklist (CBCL). The 5-year follow-up included the Wechsler Preschool and Primary Scales of Intelligence (WPPSI-III) and again the CBCL. Treatment during pregnancy showed significant benefits for children’s development at age 2, but not at age 5. At 2 years, intervention effects were found with lower scores on the PSI Total score, Parent Domain and Child domain (d=1.44, 1.47, 0.96 respectively). A non-significant trend favoured the intervention group on most subscales of the CBCL and the BSID-III (most notably motor development: d =0.52). In contrast, at 5-year follow-up, no intervention effects were found. Also, irrespective of treatment allocation, higher depression or anxiety during pregnancy was associated with higher CBCL and lower WPPSI-III scores at 5 years. This is one of the first controlled studies to evaluate the long-term effect of antenatal depression treatment on infant neurodevelopmental outcomes, showing some benefit. Nevertheless, caution should be taken interpreting the results because of a small sample size, and larger studies are warranted.
Understanding the rumen microbial ecosystem requires the identification of factors that influence the community structure, such as nutrition, physiological condition of the host and host–microbiome interactions. The objective of the current study was to describe the rumen microbial communities before, during and after a complete rumen content transfer. The rumen contents of one donor cow were removed completely and used as inoculum for the emptied rumen of the donor itself and three acceptor cows under identical physiological and nutritional conditions. Temporal changes in microbiome composition and rumen function were analysed for each of four cows over a period of 6 weeks. Shortly after transfer, the cows showed different responses to perturbation of their rumen content. Feed intake depression in the first 2 weeks after transfer resulted in short-term changes in milk production, methane emission, fatty acid composition and rumen bacterial community composition. These effects were more pronounced in two cows, whose microbiome composition showed reduced diversity. The fermentation metrics and microbiome diversity of the other two cows were not affected. Their rumen bacterial community initially resembled the composition of the donor but evolved to a new community profile that resembled neither the donor nor their original composition. Descriptive data presented in the current paper show that the rumen bacterial community composition can quickly recover from a reduction in microbiome diversity after a severe perturbation. In contrast to the bacteria, methanogenic communities were more stable over time and unaffected by stress or host effects.
The role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for serum 25-hydroxyvitamin D (25(OH)D)–pulmonary function association. We conducted the largest cross-sectional meta-analysis of the 25(OH)D–pulmonary function association to date, based on nine European ancestry (EA) cohorts (n 22 838) and five African ancestry (AA) cohorts (n 4290) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Data were analysed using linear models by cohort and ancestry. Effect modification by smoking status (current/former/never) was tested. Results were combined using fixed-effects meta-analysis. Mean serum 25(OH)D was 68 (sd 29) nmol/l for EA and 49 (sd 21) nmol/l for AA. For each 1 nmol/l higher 25(OH)D, forced expiratory volume in the 1st second (FEV1) was higher by 1·1 ml in EA (95 % CI 0·9, 1·3; P<0·0001) and 1·8 ml (95 % CI 1·1, 2·5; P<0·0001) in AA (Prace difference=0·06), and forced vital capacity (FVC) was higher by 1·3 ml in EA (95 % CI 1·0, 1·6; P<0·0001) and 1·5 ml (95 % CI 0·8, 2·3; P=0·0001) in AA (Prace difference=0·56). Among EA, the 25(OH)D–FVC association was stronger in smokers: per 1 nmol/l higher 25(OH)D, FVC was higher by 1·7 ml (95 % CI 1·1, 2·3) for current smokers and 1·7 ml (95 % CI 1·2, 2·1) for former smokers, compared with 0·8 ml (95 % CI 0·4, 1·2) for never smokers. In summary, the 25(OH)D associations with FEV1 and FVC were positive in both ancestries. In EA, a stronger association was observed for smokers compared with never smokers, which supports the importance of vitamin D in vulnerable populations.
In Belgium, it is mandatory to report Shiga toxin-producing Escherichia coli (STEC) infections to the health inspection authorities. To facilitate the decision making regarding infection control measures, information about the risk factors for the development of the haemolytic uremic syndrome (HUS) can be helpful. We performed statistical analyses on a dataset of 411 Belgian STEC strains. Demographic and clinical patient characteristics as well as phenotypical and genotypical STEC strain characteristics were taken into account. Multivariate logistic regression models indicated that age categories ⩽5, 6–12 and ⩾75; the stx2 gene; and the eae gene were significant HUS development risk determinants. The stx2a subtype had the highest risk (OR 29.6, 95% CI 7.0–125.1), while all stx1 subtypes encompassed a significant lower risk (OR 0.3, 95% CI 0.1–0.5). Presence of the stx1 gene without stx2 encompassed a lower risk than the combined presence of stx1 and stx2, or stx2 solely. Based on these results, we propose a new virulence typing algorithm that will enable the National Reference Centre to provide the physicians and health inspection authorities with a risk classification for the development of HUS. We believe this will contribute to a more efficient STEC infection control management in Belgium.
Measurements in the infrared wavelength domain allow direct assessment of the physical state and energy balance of cool matter in space, enabling the detailed study of the processes that govern the formation and evolution of stars and planetary systems in galaxies over cosmic time. Previous infrared missions revealed a great deal about the obscured Universe, but were hampered by limited sensitivity.
SPICA takes the next step in infrared observational capability by combining a large 2.5-meter diameter telescope, cooled to below 8 K, with instruments employing ultra-sensitive detectors. A combination of passive cooling and mechanical coolers will be used to cool both the telescope and the instruments. With mechanical coolers the mission lifetime is not limited by the supply of cryogen. With the combination of low telescope background and instruments with state-of-the-art detectors SPICA provides a huge advance on the capabilities of previous missions.
SPICA instruments offer spectral resolving power ranging from R ~50 through 11 000 in the 17–230 μm domain and R ~28.000 spectroscopy between 12 and 18 μm. SPICA will provide efficient 30–37 μm broad band mapping, and small field spectroscopic and polarimetric imaging at 100, 200 and 350 μm. SPICA will provide infrared spectroscopy with an unprecedented sensitivity of ~5 × 10−20 W m−2 (5σ/1 h)—over two orders of magnitude improvement over what earlier missions. This exceptional performance leap, will open entirely new domains in infrared astronomy; galaxy evolution and metal production over cosmic time, dust formation and evolution from very early epochs onwards, the formation history of planetary systems.
Effective integrated weed management in agricultural landscapes depends on the ability to identify and manage processes that drive weed dynamics. The current study reports the effects of grazing management and crop rotation strategies on the seedbank and emerged weed flora in an integrated crop-livestock system (ICLS) experiment during a 12-year period under no-tillage in sub-tropical southern Brazil. During winter, Italian ryegrass cover crops were grazed by sheep: grazing management treatments included two stocking methods (continuous and rotational) and two forage allowances (10 and 20 kg of herbage dry matter available per 100 kg animal live weight). During summer, the crop rotation treatments involved either soybean-maize or soybean-soybean in succession with winter-grazed cover crops. The treatments were part of a factorial randomized complete block design. Treatment effects were evaluated on the weed seedbank and emerged weed flora populations during winter-grazed cover crop and summer crop growth as well as during the harvest phase. The current results demonstrate that crop rotation and grazing management exhibited interactive effects on the determination of weed outcomes in an ICLS. However, overall, compared with moderate forage allowance, high forage allowance during the winter-grazed cover crop caused lower emerged weed flora in subsequent crops (20% reduction during crop growth and 90% reduction at crop harvest) and 48% reduction in seedbank size. High forage allowance promoted more residue from winter-grazed cover crop biomass, which remained during the summer crop phases and probably resulted in a physical barrier to weed emergence.