Continuity of primary care for type 2 diabetes and hypertension and its association with health outcomes and disease control: insights from Central Vietnam.

BACKGROUND: Vietnam is undergoing a rapid epidemiological transition with a considerable burden of non-communicable diseases (NCDs), especially hypertension and diabetes (T2DM). Continuity of care (COC) is widely acknowledged as a benchmark for an efficient health system. This study aimed to determine the COC level for hypertension and T2DM within and across care levels and to investigate its associations with health outcomes and disease control. METHODS: A cross-sectional study was conducted on 602 people with T2DM and/or hypertension managed in primary care settings. We utilized both the Nijmegen continuity of care questionnaire (NCQ) and the Bice - Boxerman continuity of care index (COCI) to comprehensively measure three domains of COC: interpersonal, informational, and management continuity. ANOVA, paired-sample t-test, and bivariate and multivariable logistic regression analysis were performed to examine the predictors of COC. RESULTS: Mean values of COC indices were: NCQ: 3.59 and COCI: 0.77. The proportion of people with low NCQ levels was 68.8%, and that with low COCI levels was 47.3%. Primary care offered higher informational continuity than specialists (p < 0.01); management continuity was higher within the primary care team than between primary and specialist care (p < 0.001). Gender, living areas, hospital admission and emergency department encounters, frequency of health visits, disease duration, blood pressure and blood glucose levels, and disease control were demonstrated to be statistically associated with higher levels of COC. CONCLUSIONS: Continuity of primary care is not sufficiently achieved for hypertension and diabetes mellitus in Vietnam. Strengthening robust primary care services, improving the collaboration between healthcare providers through multidisciplinary team-based care and integrated care approach, and promoting patient education programs and shared decision-making interventions are priorities to improve COC for chronic care.

Effectiveness, safety and utilization of cobimetinib and vemurafenib in patients with BRAF V600 mutant melanoma with and without cerebral metastasis under real-world conditions in Germany: the non-interventional study coveNIS.

Cobimetinib/vemurafenib combination therapy is approved for treatment of adults with unresectable or metastatic BRAF V600 mutated malignant melanoma (mM). The non-interventional post-authorisation safety study coveNIS collected real-world data on cobimetinib/vemurafenib treatment focussing on overall survival (OS), safety and utilization. MM patients with brain metastases are usually excluded from clinical studies. coveNIS observed 2 cohorts: mM patients without (Cohort A) and with cerebral metastases (Cohort B), aiming to close the data gap for the latter population. A direct comparison of the 2 cohorts was not intended. The primary effectiveness objective was OS; the safety objective was the incidence of all and of serious adverse events (AEs). Secondary objectives included progression-free survival (PFS), time to development of cerebral metastasis (Cohort A) and time to central nervous system relapse (Cohort B). All statistical analyses were descriptive. Between 2017 and 2021, 95 patients were included (Cohort A: 54, Cohort B: 41 patients) at 32 sites in Germany. Median OS was 21.6 months in Cohort A, 7.4 months in Cohort B. Median PFS was 6.9 months in Cohort A, 5.2 months in Cohort B. The proportion of patients experiencing any AEs was 83.3% (Cohort A) and 87.8% (Cohort B). The two most common AEs in Cohort A were 'diarrhoea' (37%), 'vomiting' (20.4%) and 'pyrexia' (20.4%); in Cohort B 'diarrhoea' (36.6%) and 'fatigue' (22%). In conclusion, the OS rates in Cohort A and Cohort B of coveNIS are in line with the OS data from other trials with BRAF/MEK inhibitors for mM. No new safety signals were observed.

Robust preimplantation genetic testing of the common F8 Inv22 pathogenic variant of severe hemophilia A using a highly polymorphic multi-marker panel encompassing the paracentric inversion.

BACKGROUND: Hemophilia A (HEMA) is an X-linked bleeding disorder caused by reduced/absent coagulation factor VIII expression, as a result of pathogenic variants in the F8 gene. Preimplantation prevention of HEMA should ideally include direct pathogenic F8 variant detection, complemented by linkage analysis of flanking markers to identify the high-risk F8 allele. Linkage analysis is particularly indispensable when the pathogenic variant cannot be detected directly or identified. This study evaluated the suitability of a panel of F8 intragenic and extragenic short tandem repeat markers for standalone linkage-based preimplantation genetic testing for monogenic disorder (PGT-M) of the Inv22 pathogenic variant, an almost 600 kb paracentric inversion responsible for almost half of all severe HEMA globally, for which direct detection is challenging. METHODS: Thirteen markers spanning 1 Mb and encompassing both F8 and the Inv22 inversion interval were genotyped in 153 unrelated females of Viet Kinh ethnicity. RESULTS: All individuals were heterozygous for ≥ 1 marker, ~ 90% were heterozygous for ≥ 1 of the five F8 intragenic markers, and almost 98% were heterozygous for ≥ 1 upstream (telomeric) and ≥ 1 downstream (centromeric) markers. A prospective PGT-M couple at risk of transmitting F8 Inv22 were fully informative at four marker loci (2 intra-inversion, 1 centromeric, 1 telomeric) and partially informative at another five (2 intra-inversion, 3 centromeric), allowing robust phasing of low- and high-risk haplotypes. In vitro fertilization produced three embryos, all of which clearly inherited the low-risk maternal allele, enabling reliable unaffected diagnoses. A single embryo transfer produced a clinical pregnancy, which was confirmed as unaffected by amniocentesis and long-range PCR, and a healthy baby girl was delivered at term. CONCLUSION: Robust and reliable PGT-M of HEMA, including the common F8 Inv22 pathogenic variant, can be achieved with sufficient informative intragenic and flanking markers.

Mental health and its determinants among adolescents living in families with separated or divorced parents in an urban area of Vietnam.

BACKGROUND: We assessed the prevalence of stress, anxiety, and depression among adolescents living in families with separated or divorced parents in Hue City, Vietnam and identified factors associated with these conditions. METHODS: This cross-sectional study enrolled 309 adolescents, aged 12 to 17 years, living in families with separated or divorced parents in Hue City, Vietnam. The depression anxiety stress scale-21 (DASS-21) was used to measure stress, anxiety, and depression. Predictors of overall and individual mental health problems were identified using ordered and binary logistic regression, respectively. RESULTS: The DASS-21 scale revealed a 49.2% prevalence of stress, while anxiety and depression had s prevalence rates of 61.5%. Among participants, 42.4% experienced all 3 mental health issues. Several factors were identified as significant predictors of mental health problems, including poor to average economic status (adjusted odds ratio [aOR], 2.00; 95% confidence interval [CI], 1.21-3.31; p=0.007); being in high school (aOR, 5.02; 95% CI, 2.93-8.60; p<0.001); maternal occupation of teacher, healthcare professional, or official (aOR, 2.39; 95% CI, 1.13-5.03; p=0.022); longer duration of family separation or divorce (aOR, 1.24; 95% CI, 1.05-1.45; p=0.009); living with one's mother (aOR, 1.69; 95% CI, 1.03-2.76; p=0.04); alcohol consumption (aOR, 1.70; 95% CI, 0.99-2.92; p=0.050); and being bullied (aOR, 5.33; 95% CI, 1.10-25.69; p=0.037). Most of these factors were associated with stress, anxiety, and depression. Additionally, smoking was associated with stress. CONCLUSION: Adolescents with separated or divorced parents were at increased risk of stress, anxiety, and depression. The findings of this study provide important implications for prevention programs.

Mechanism of Friedel-Crafts Acylation Using Metal Triflate in Deep Eutectic Solvents: An Experimental and Computational Study.

In this paper, we develop a method for Friedel-Crafts acylation using metal triflate in deep eutectic solvents. Various metal triflates were tested and provided good to excellent yields of corresponding ketone products. The density functional theory calculation revealed the metal effects on the formation of active intermediate acylium triflate as well as the acidic condition. The metal triflate in the deep eutectic solvent can be recovered and reused with a little loss in the catalytic activity.

Calculation of binding affinity of JAK1 inhibitors via accurately computational estimation.

Janus kinase 1 (JAK1) is a tyrosine kinase that is involved in the initiation of responses to a number of different cytokine receptor families. The JAK1-dependent pathway is a therapeutic target, and several JAK inhibitors have been developed thanks to intensive research. However, since the ATP binding sites of JAK family members are quite alike, JAK1 inhibitors can thus be less selective, resulting in unanticipated adverse effects. Despite this, minor variations in the ATP-binding site have been extensively used to find a variety of small compounds with different inhibitory properties. Stronger binding affinity of JAK1 inhibitors is believed to be able to reduce the negative effects, leading to better treatment results. Therefore, a thorough computational search that can effectively identify ligands with extremely high binding affinity for JAK1 to serve as promising inhibitors is required. Here, a method combining steered-molecular dynamic (SMD) simulations with a modified linear interaction energy (LIE) model has been developed to evaluate the binding affinities of known JAK1 inhibitors. The correlation coefficient between the estimated and experimental values was 0.72 and a root-mean-square error was 0.97 kcal•mol-1, revealing that the SMD/LIE method can precisely and quickly predict the binding free energies of JAK1 inhibitors. Furthermore, three marine fungus-derived compounds, namely hansforesters E, hansforesters G and tetroazolemycins B, were identified to be particularly promising JAK1 inhibitors, accordingly. These findings show that the SMD/LIE method has a lot of promise for in silico screening of possible JAK1 inhibitors from a vast number of compounds that are now accessible.Communicated by Ramaswamy H. Sarma.

Genetic diversity and population structure of Cinnamomum balansae Lecomte inferred by microsatellites.

Cinnamomum balansae Lecomte (Lauraceae), an economically important forest tree, is distributed in the tropical forests of central and northern Vietnam, which has been threatened in recent decades due to the destruction of its habitat and over-exploitation. The genetic diversity and population structure of the species have not been fully evaluated. We used a set of 15 microsatellites to analyze 161 adult trees from 9 different populations, representing the geographical distribution of C. balansae. Ninety-two different alleles were identified. Here our results showed a low genetic diversity level with an average H o = 0.246 and H e = 0.262, and a high level of genetic differentiation (F ST = 0.601). The bottleneck tests indicated evidence of a reduction in the population size of the two populations (TC and CP). Additionally, all three clustering methods (Bayesian analysis, principal coordinate analysis, and Neighbor-joining tree) were identified in the two genetic groups. The Mantel test showed a significant positive correlation between genetic distance and geographic distance (R 2 = 0.7331). This study will provide a platform for the conservation of C. balansae both in ex-situ and in-situ plans.

Attachment of zebra and quagga mussel adhesive plaques to diverse substrates.

Like marine mussels, freshwater zebra and quagga mussels adhere via the byssus, a proteinaceous attachment apparatus. Attachment to various surfaces allows these invasive mussels to rapidly spread, however the adhesion mechanism is not fully understood. While marine mussel adhesion mechanics has been studied at the individual byssal-strand level, freshwater mussel adhesion has only been characterized through whole-mussel detachment, without direct interspecies comparisons on different substrates. Here, adhesive strength of individual quagga and zebra mussel byssal plaques were measured on smooth substrates with varying hydrophobicity-glass, PVC, and PDMS. With increased hydrophobicity of substrates, adhesive failures occurred more frequently, and mussel adhesion strength decreased. A new failure mode termed 'footprint failure' was identified, where failure appeared to be adhesive macroscopically, but a microscopic residue remained on the surface. Zebra mussels adhered stronger and more frequently on PDMS than quagga mussels. While their adhesion strengths were similar on PVC, there were differences in the failure mode and the plaque-substrate interface ultrastructure. Comparisons with previous marine mussel studies demonstrated that freshwater mussels adhere with comparable strength despite known differences in protein composition. An improved understanding of freshwater mussel adhesion mechanics may help explain spreading dynamics and will be important in developing effective antifouling surfaces.

Postmarketing Safety Monitoring After Influenza Vaccination Using a Mobile Health App: Prospective Longitudinal Feasibility Study.

BACKGROUND: For the safety monitoring of vaccinations postlicensure, reports of adverse events after immunization (AEFIs) are crucial. New technologies such as digital mobile apps can be used as an active approach to capture these events. We therefore conducted a feasibility study among recipients of the influenza vaccination using an app for assessment of the reporting of AEFIs. OBJECTIVE: The goal of the research was to determine factors influencing adherence to and correct use of a newly developed app for individuals to report AEFI for 3 months using regular reminder functions, to identify determinants of AEFI occurrence and define reported AEFI types. METHODS: We developed the app (SafeVac) and offered it to recipients of the influenza vaccination in 3 occupational settings in fall 2018. In this prospective longitudinal feasibility study, data on AEFIs were generated through SafeVac for 3 months. Using logistic and Cox regression, we assessed associations between app adherence, correct app entry, AEFIs, and sociodemographic parameters. RESULTS: Of the individuals who logged into SafeVac, 61.4% (207/337) used the app throughout a 3-month period. App use adherence was negatively associated with female sex (odds ratio [OR] 0.47; CI 0.25-0.91) and correct app entry was negatively associated with older age (OR 0.96; CI 0.93-0.99) and lower education (OR 0.31; CI 0.13-0.76). AEFI occurrence was associated with female sex (hazard ratio 1.41; CI 1.01-1.96) and negatively with older age (hazard ratio 0.98; CI 0.97-0.99). The most common AEFIs reported were injection site pain (106/337), pain in extremity (103/337), and fatigue/asthenia (73/337). CONCLUSIONS: Digital AEFI reporting was feasible with SafeVac and generated plausible results for this observation period and setting. Studies directly comparing SafeVac with conventional passive reporting schemes could determine whether such digital approaches improve completeness, timeliness, and sensitivity of vaccine vigilance. Further studies should evaluate if these results are transferable to other vaccinations and populations and if introduction of such a tool has an influence on vaccination readiness and therefore vaccine safety.

De novo assembly and Transcriptome characterization of an endemic species of Vietnam, Panax vietnamensis Ha et Grushv., including the development of EST-SSR markers for population genetics.

BACKGROUND: Understanding the genetic diversity in endangered species that occur inforest remnants is necessary to establish efficient strategies for the species conservation, restoration and management. Panax vietnamensis Ha et Grushv. is medicinally important, endemic and endangered species of Vietnam. However, genetic diversity and structure of population are unknown due to lack of efficient molecular markers. RESULTS: In this study, we employed Illumina HiSeq™ 4000 sequencing to analyze the transcriptomes of P. vietnamensis (roots, leaves and stems). Raw reads total of 23,741,783 was obtained and then assembled, from which the generated unigenes were 89,271 (average length = 598.3191 nt). The 31,686 unigenes were annotated in different databases i.e. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, Nucleotide Collection (NR/NT) and Swiss-Prot for functional annotation. Further, 11,343 EST-SSRs were detected. From 7774 primer pairs, 101 were selected for polymorphism validation, in which; 20 primer pairs were successfully amplified to DNA fragments and significant amounts of polymorphism was observed within population. The nine polymorphic microsatellite loci were used for population structure and diversity analyses. The obtained results revealed high levels of genetic diversity in populations, the average observed and expected heterozygosity were HO = 0.422 and HE = 0.479, respectively. During the Bottleneck analysis using TPM and SMM models (p < 0.01) shows that targeted population is significantly heterozygote deficient. This suggests sign of the bottleneck in all populations. Genetic differentiation between populations was moderate (FST = 0.133) and indicating slightly high level of gene flow (Nm = 1.63). Analysis of molecular variance (AMOVA) showed 63.17% of variation within individuals and 12.45% among populations. Our results shows two genetic clusters related to geographical distances. CONCLUSION: Our study will assist conservators in future conservation management, breeding, production and habitats restoration of the species.

Oil-Infused Silicone Prevents Zebra Mussel Adhesion.

The remarkable underwater adhesion capacity of the invasive freshwater mussel species Dreissena polymorpha (zebra mussel) causes extensive damage each year. The adhesive interface between the substrate surface and the mussels' adhesive plaques plays a key role in zebra mussel biofouling. Silicone-oil-infused polydimethylsiloxane (iPDMS), an omniphobic material in the class of liquid-infused slippery surfaces, has been shown to develop a uniform, microscale, antifouling surface oil layer, which we hypothesized would be effective against zebra mussel fouling. iPDMS substrates with varying levels of oil saturation were tested for their ability to disrupt mussel adhesion by characterizing zebra mussel reattachment in a simulated freshwater environment for 3 days. On fully saturated iPDMS samples or those near full saturation, zebra mussels showed no reattachment, compared to 41% reattachment on PDMS controls (no oil infusion). For lower saturation levels, the frequency of reattachment was decreased relative to PDMS controls. Mussel detachment forces decreased in iPDMS as compared to PDMS, and adhesive failures occurred more frequently with higher iPDMS saturations. Surface analysis of the subsaturated iPDMS substrates showed incomplete coverage of the surface oil layer. After 3 days of immersion in artificial freshwater, subsaturated iPDMS substrates showed a decrease in slipperiness (measured by water slide angle), whereas in fully saturated iPDMS, the slipperiness was unchanged, despite no observed oil loss in either group. The decrease in slipperiness is attributed to microfouling of the subsaturated substrates, consistent with incomplete surface oil layer coverage, and supports the notion that full oil layer coverage is required for effective antifouling properties. Employing iPDMS as an antifouling coating shows promise against freshwater mussel adhesion, and this work further aids in understanding the antifouling mechanism of iPDMS and the role of the plaque-substrate interface in freshwater mussel adhesion.

Monitoring Fetal Heart Rate during Labor: A Comparison of Three Methods.

The purpose of the study was to compare the accuracy of a noninvasive fetal heart rate monitor with that of ultrasound, using a fetal scalp electrode as the gold standard, in laboring women of varying body habitus, throughout labor and delivery. Laboring women requiring fetal scalp electrode were monitored simultaneously with the investigational device (noninvasive fetal ECG), ultrasound, and fetal scalp electrode. An algorithm extracted the fetal heart rate from the noninvasive fetal ECG signal. Each noninvasive device recording was compared with fetal scalp electrode with regard to reliability by positive percent agreement and accuracy by root mean squared error. Seventy-one women were included in this analysis. Positive percent agreement was 83.4 ± 15.4% for noninvasive fetal ECG and 62.4 ± 26.7% for ultrasound. The root mean squared error compared with fetal scalp electrode-derived fetal heart rate was 4.8 ± 2.0 bpm for noninvasive fetal ECG and 14.3 ± 8.2 bpm for ultrasound. The superiority of noninvasive fetal ECG was maintained for stages 1 and 2 of labor and increases in body mass index. Compared with fetal scalp electrode-derived fetal heart rate, noninvasive fetal ECG is more accurate and reliable than ultrasound for intrapartum monitoring for stages 1 and 2 of labor and is less affected by increasing maternal body mass index. This confirms the results of other workers in this field.

Monitoring Uterine Activity during Labor: Clinician Interpretation of Electrohysterography versus Intrauterine Pressure Catheter and Tocodynamometry.

Objective The aim of this article was to compare clinical interpretation of uterine activity tracings acquired by tocodynamometry and electrohysterography with the gold standard, intrauterine pressure. Study Design Using data from a previous study, subjects who had simultaneous monitoring with all three uterine activity devices were included in this study. These were parturients who required intrauterine pressure catheter (IUPC) placement for obstetric indication. A Web-based application displayed scrolling 30-minute segments of uterine activity. Two blinded obstetricians and two blinded obstetric nurses independently reviewed the segments, marking uninterpretable segments and the peak of each contraction. Interpretability was compared using positive percent agreement. False positives are contractions marked in the noninvasive strip that have no corresponding contraction in the IUPC strip. False negatives are the reverse. Results A total of 135 segments, acquired during either Stage 1 (active labor) or Stage 2 (pushing), from 105 women, were included in this analysis. For all four observers, both interpretability and sensitivity of electrohysterography exceeded that of tocodynamometry (p < 0.0001). This remained true for the obese population (96 segments). Conclusion Compared with the IUPC, electrohysterography is more sensitive and provides tracings that are more often interpretable than tocodynamometry for intrapartum monitoring; electrohysterography is also less affected by increasing maternal body mass index.

Monitoring uterine activity during labor: a comparison of 3 methods.

OBJECTIVE: Tocodynamometry (Toco; strain gauge technology) provides contraction frequency and approximate duration of labor contractions but suffers frequent signal dropout, necessitating repositioning by a nurse, and may fail in obese patients. The alternative invasive intrauterine pressure catheter (IUPC) is more reliable and adds contraction pressure information but requires ruptured membranes and introduces small risks of infection and abruption. Electrohysterography (EHG) reports the electrical activity of the uterus through electrodes placed on the maternal abdomen. This study compared all 3 methods of contraction detection simultaneously in laboring women. STUDY DESIGN: Upon consent, laboring women were monitored simultaneously with Toco, EHG, and IUPC. Contraction curves were generated in real-time for the EHG, and all 3 curves were stored electronically. A contraction detection algorithm was used to compare frequency and timing between methods. Seventy-three subjects were enrolled in the study; 14 were excluded due to hardware failure of 1 or more of the devices (n = 12) or inadequate data collection duration (n = 2). RESULTS: In comparison with the gold-standard IUPC, EHG performed significantly better than Toco with regard to the Contractions Consistency Index (CCI). The mean CCI for EHG was 0.88 ± 0.17 compared with 0.69 ± 0.27 for Toco (P < .0001). In contrast to Toco, EHG was not significantly affected by obesity. CONCLUSION: Toco does not correlate well with the gold-standard IUPC and fails more frequently in obese patients. EHG provides a reliable noninvasive alternative, regardless of body habitus.

Spatiotemporal electrohysterography patterns in normal and arrested labor.

OBJECTIVE: The purpose of this study was to investigate the spatiotemporal patterns of uterine electrical activity in normal and arrested labors. STUDY DESIGN: From a database of electrohysterograms, 12 subjects who underwent cesarean delivery for active-phase arrest were each matched with 2 vaginally delivered controls. Using 30-minute segments of the electrohysterogram during the arrest, or the same dilation in controls, the center of uterine electrical activity was derived. The vertical motion of this center of uterine activity was determined for each contraction and the frequencies of movement patterns analyzed. RESULTS: Predominantly upward movement of the center of uterine activity (longer and/or stronger contraction at the fundus) was more common with normal dilation (P = .003). Receiver operating characteristic curve analysis gave an area under the curve of 0.91 for predicting outcome (vaginal vs cesarean delivery). CONCLUSION: There is a significant correlation between upward movement of the center of uterine activity (fundal dominance) and current labor progress.

Monitoring contractions in obese parturients: electrohysterography compared with traditional monitoring.

OBJECTIVE: To compare electrohysterogram-derived contractions with both tocodynamometry and intrauterine pressure monitoring in obese laboring women. METHODS: From a large database of laboring patients with electrohysterogram monitoring, obese subjects were selected in whom data were recorded for at least 30 minutes before and after intrauterine pressure catheter placement for obstetric indication. Using a contraction detection algorithm, the relationship between the methods was determined with regard to both frequency and contraction duration. RESULTS: Of the 25 subjects (median body mass index 39.6 [25th percentile 36.5, 75th percentile 46.3]), seven underwent amniotomy at the time of intrauterine pressure catheter placement. Tocodynamometry identified 248 contractions compared with 336 by electrohysterography, whereas intrauterine pressure catheter monitoring identified 319 contractions compared with 342 by electrohysterography. Using the Contractions Consistency Index, electrohysterogram contraction detection correlated better with the intrauterine pressure catheter (0.94+/-0.06) than with tocodynamometry (0.77+/-0.25), P=.004. Electrohysterogram-derived contraction lengths closely approximated those calculated from the intrauterine pressure catheter signal. CONCLUSION: Contraction monitoring routinely is employed for managing labor, and tocodynamometry may be unreliable in obese parturients. In the obese women in this study, the electrohysterogram-derived contraction pattern correlated better with the intrauterine pressure catheter than tocodynamometry. Electrohysterography may provide another noninvasive means of monitoring labor, particularly for those women in whom tocodynamometry is inadequate.

Topical application of povidone-iodine solution (Betadine) in the management of giant omphaloceles.

Giant omphaloceles, especially if they contain liver tissue, remain the greatest challenge to pediatric surgeons for the coverage of the huge defect. Various reconstructive techniques have been described in the literature, each with advantages and disadvantages. Standard treatment has been placement of a Silastic silo to allow gradual return of abdominal organs to the abdomen with its limited space. The worst complication of silo placement is infection of the fascia with disruption of the suture line. When fascial infection occurs, closure of the abdominal wall is very difficult or impossible. In this report, the authors describe their experience in treating 5 patients with giant omphaloceles, between 1999 and 2003, utilizing an abs orbable synthetic mesh (polyglactin 910-Vicryl) for abdominal closure and topical application of povidone-iodine 10/100 solution (Betadine) to prevent infection. All patients had perfect results with the simple postoperative care, early oral feeding and were discharged after 2 months of hospitalization with complete skin coverage.