Systematic review and meta-analysis of COVID-19 vaccines safety, tolerability, and efficacy among HIV-infected patients

ObjectiveTo conduct a comprehensive systematic review and meta-analysis of all recommended SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) vaccines in people living with HIV (PLWH), as well as an overview of the safety, tolerability, and efficacy of the vaccines in PLWH. MethodsWe searched six databases, Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Medline, Medrxiv, Global research on COVID-19 database, and Google Scholar for studies investigating the effects of SARS-CoV-2 vaccines on PLWH. Results of the association were summarised by SARS-CoV IgG seroconversion and level, vaccines efficacy and tolerability. A meta-analysis was performed for studies, using random-effects model and a pooled RR with 95% CI was reported. ResultsTwenty-three of the 1052 studies screened met the inclusion criteria. The review included 28, 246 participants among whom 79.55% (22,469/28, 246) were PLWH with median CD4 [≥] 200 cells/{micro}L. The pooled estimate of SARS-CoV-2 IgG seroconversion and positive neutralizing antibodies after the second vaccination dose between PLWH vs HIV negative were RR 0.95 (95%CI: 0.92 - 0.99, P = 0.006) and 0.88 (95%CI: 0.82- 0.95, P = 0.0007), respectively. The mean difference of IgG antibodies level (BAU/ml) was found higher in mRNA vaccines MD -1444.97 (95%CI: -1871.39, -1018.55). PLWH with CD4 less than 500 cells/ {micro}l had 15% risk reduction of neutralizing antibodies response compared to those with CD4 [≥] 500 cells/{micro}l (P = 0.003). The SARS-CoV-2 vaccine effectiveness was 65% (95%CI: 56%-72%, P <0.001) among vaccinated compared to unvaccinated PLWH. PLWH with CD4 count <350 cells/{micro}l had lower vaccine effectiveness compared to CD4 count [≥] 350 cells/{micro}l with 59% vs 72%, respectively. Vaccine tolerability was the same between PLWH and HIV negatives. ConclusionAccording to our findings, PLWH with CD4 [≥] 200 cells/{micro}L had lower immunogenicity and antigenicity in COVID-19 vaccines than HIV negatives. Additional doses of SARS-CoV- 2 vaccination are needful in PLWH.

Sensor array for wireless remote monitoring of carbon dioxide and methane near carbon sequestration and oil recovery sites.

Carbon sequestration and enhanced oil recovery are two important geochemical applications currently deployed using carbon dioxide (CO2), a prevalent greenhouse gas. Despite the push to find ways to use and store excess CO2, the development of a large-area monitoring system is lacking. For these applications, there is little literature reporting the development and testing of sensor systems capable of operating in remote areas without maintenance and having significantly low cost to allow their deployment across a large land area. This paper presents the design and validation of a low-cost solar-power distributed sensing architecture using a wireless mesh network integrated, at selective nodes, into a cellular network. This combination allows an "internet of things" approach in remote locations and the integration of a large number of sensor units to monitor CO2 and methane (CH4). This system will allow efficient large area monitoring of both rare catastrophic leaks along with the common micro-seepage of greenhouse gas near carbon sequestration and oil recovery sites. The deployment and testing of the sensor system was performed in an open field at Oklahoma State University. The two-tear network functionality and robustness were determined from a multi-year field study. The reliability of the system was benchmarked by correlating the measured temperature, pressure, and humidity measurement by the network of devices to existing weather data. The CO2 and CH4 gas concentration tracked their expected daily and seasonal cycles. This multi-year field study established that this system can operate in remote areas with minimal human interactions.

[Long-term effects of dibenzazepines on metabolic parameters: retrospective comparison of carbamazepine, oxcarbazepine and eslicarbazepine acetate in the real world]. / Efectos a largo plazo de las dibenzacepinas sobre los parámetros metabólicos: comparación retrospectiva de carbamacepina, oxcarbacepina y acetato de eslicarbacepina en el mundo real.

INTRODUCTION: Although carbamazepine (CBZ) has strong enzyme-inducing properties, oxcarbazepine (OXC) and eslicarbazepine acetate (ESL) are thought to have a milder effect. These drugs are known to have effects on lipid metabolism and may cause hyponatremia and changes in blood cell counts and liver function tests. AIM: To compare the long-term effects of three antiepileptic drugs (CBZ, OXC and ESL) on these variables. PATIENTS AND METHODS: Retrospective cohort study of consecutive patients treated with CBZ, OXC or ESL. Natremia, lipid concentrations, blood cell counts and liver function tests were compared before, during and at the end of the study period. RESULTS: A total of 292 patients were included. Of these, 143 were treated with CBZ, 55 with OXC and 94 with ESL. CBZ showed a greater impact on lipid metabolism, while OXC was correlated with lower mean sodium levels and a higher frequency of hyponatremia. Lifestyle recommendations related to diet, physical activity and water intake were helpful in overcoming these side effects. No other statistically significant differences were detected. CONCLUSIONS: While CBZ showed a greater impact on lipid metabolism, OXC displayed a higher frequency of hyponatremia. Lifestyle recommendations may be helpful in overcoming these side effects. No other statistically significant differences were found.

TITLE: Efectos a largo plazo de las dibenzacepinas sobre los parámetros metabólicos: comparación retrospectiva de carbamacepina, oxcarbacepina y acetato de eslicarbacepina en el mundo real.Introducción. Aunque la carbamacepina (CBZ) tiene fuertes propiedades de inducción enzimática, se cree que la oxcarbacepina (OXC) y el acetato de eslicarbacepina (ESL) ejercen un efecto más leve. Se sabe que estos fármacos tienen efectos sobre el metabolismo lipídico, pueden causar hiponatremia y cambios en el recuento de células sanguíneas y en las pruebas de función hepática. Objetivo. Comparar los efectos a largo plazo de tres medicamentos antiepilépticos (CBZ, OXC y ESL) en estas variables. Pacientes y métodos. Estudio de cohorte retrospectivo de pacientes consecutivos tratados con CBZ, OXC o ESL. La natremia, las concentraciones de lípidos, el recuento de células sanguíneas y las pruebas de función hepática se compararon antes, durante y al final del período de estudio. Resultados. Se incluyó a 292 pacientes. De ellos, 143 fueron tratados con CBZ, 55 con OXC y 94 con ESL. La CBZ mostró un mayor impacto en el metabolismo de los lípidos, mientras que la OXC se correlacionó con niveles medios de sodio más bajos y una frecuencia mayor de hiponatremia. Las recomendaciones de estilo de vida relacionadas con la dieta, la actividad física y la ingesta de agua fueron útiles para superar estos efectos secundarios. No se detectaron otras diferencias estadísticamente significativas. Conclusiones. Mientras que la CBZ mostró un mayor impacto en el metabolismo de los lípidos, la OXC mostró una mayor frecuencia de hiponatremia. Las recomendaciones de estilo de vida pueden ser útiles para superar estos efectos secundarios. No se encontraron otras diferencias estadísticamente significativas.

Precision and Limits of Detection for Selected Commercially Available, Low-Cost Carbon Dioxide and Methane Gas Sensors.

The performance of a sensor platform for environmental or industrial monitoring is sensitive to the cost and performance of the individual sensor elements. Thus, the detection limits, accuracy, and precision of commercially available, low-cost carbon dioxide and methane gas concentration sensors were evaluated by precise measurements at known gas concentrations. Sensors were selected based on market availability, cost, power consumption, detection range, and accuracy. A specially constructed gas mixing chamber, coupled to a precision bench-top analyzer, was used to characterize each sensor during a controlled exposure to known gas concentrations. For environmental monitoring, the selected carbon dioxide sensors were characterized around 400 ppm. For methane, the sensor response was first monitored at 0 ppm, close to the typical environmental background. The selected sensors were then evaluated at gas concentrations of several thousand ppm. The determined detection limits accuracy, and precision provides a set of matrices that can be used to evaluate and select sensors for integration into a sensor platform for specific applications.

A Critical Comparison of 3D Experiments and Simulations of Tricalcium Silicate Hydration.

Advances in nano-computed X-ray tomography (nCT), nano X-ray fluorescence spectrometry (nXRF), and high-performance computing have enabled the first direct comparison between observations of three-dimensional nanoscale microstructure evolution during cement hydration and computer simulations of the same microstructure using HydratiCA. nCT observations of a collection of triclinic tricalcium silicate (Ca3SiO5) particles reacting in a calcium hydroxide solution are reported and compared to simulations that duplicate, as nearly as possible, the thermal and chemical conditions of those experiments. Particular points of comparison are the time dependence of the solid phase volume fractions, spatial distributions, and morphologies. Comparisons made at 7 h of reaction indicate that the simulated and observed volumes of Ca3SiO5 consumed by hydration agree to within the measurement uncertainty. The location of simulated hydration product is qualitatively consistent with the observations, but the outer envelope of hydration product observed by nCT encloses more than twice the volume of hydration product in the simulations at the same time. Simultaneous nXRF measurements of the same observation volume imply calcium and silicon concentrations within the observed hydration product envelope that are consistent with Ca(OH)2 embedded in a sparse network of calcium silicate hydrate (C-S-H) that contains about 70 % occluded porosity in addition to the amount usually accounted as gel porosity. An anomalously large volume of Ca(OH)2 near the particles is observed both in the experiments and in the simulations, and can be explained as originating from the hydration of additional particles outside the field of view. Possible origins of the unusually large amount of observed occluded porosity are discussed.

Linking Inuit Knowledge and Public Health for Improved Child and Youth Oral Health in NunatuKavut.

The oral health of Inuit children in Canada has been identified as a public health crisis. Although efforts are being made to identify and address ways to deal with this crisis, current policy and program approaches are largely entrenched within the prevailing paradigm of dental science to the exclusion of Indigenous people's understandings of health. This article reports qualitative findings of a larger study aimed at identifying, understanding, and addressing rates of oral disease among children living in NunatuKavut, a cluster of small, coastal Inuit communities located in southern Labrador, Canada. Through 18 focus groups with youth (n = 86), caregivers (n = 22), and interviews with key informant (n = 13), this study begins to elucidate southern Inuit understandings of oral health. Theorized using Two-Eyed Seeing, an Indigenous approach to balancing both Indigenous and non-Indigenous understandings of the world, the findings reported here reveal 3 themes, each of which is crosscut by historical and contemporary dimensions: 1) (w)holistic conceptualizations of health are essential to good oral health, 2) achieving optimal oral health is prohibitive for Inuit communities, and 3) community-engaged oral health service delivery is needed. Our recommendations have implications for improved oral public health service delivery for Inuit communities, in that the inclusion of Inuit perspectives on oral health should form an instrumental element of oral public health service delivery. Knowledge Transfer Statement: The results of this study may be used by clinicians and oral health educators to inform approaches to oral health service delivery within the context of Indigenous communities. It may also be used by policymakers to recognize how historical and contemporary issues of colonization relate to the formation of oral health-related policies.

The plastic crystalline A15 phase of dimethylaminoalane, [N(CH3)2-AlH2]3.

A plastic crystalline phase of dimethylaminoalane has been discovered at T > 332 K. The phase transitions solid - plastic phase - liquid are fully reversible. The plastic crystalline phase exhibits a cubic unit cell, space group Pm3[combining macron]n, in which the dimethylaminoalane molecules rotate and adopt a structural arrangement reminiscent of the A15 phase.

[Clinical guidelines for infantile-onset Pompe disease]. / Guia clinica de la enfermedad de Pompe infantil.

Infantile-onset Pompe disease has a fatal prognosis in the short term unless it is diagnosed at an early stage and enzyme replacement therapy is not started as soon as possible. A group of specialists from different disciplines involved in this disease have reviewed the current scientific evidence and have drawn up an agreed series of recommendations on the diagnosis, treatment and follow-up of patients. We recommend establishing enzyme treatment in any patient with symptomatic Pompe disease with onset within the first year of life, with a clinical and enzymatic diagnosis, and once the CRIM (cross-reactive immunological material) status is known.

TITLE: Guia clinica de la enfermedad de Pompe infantil.La enfermedad de Pompe infantil tiene un pronostico fatal a corto plazo si no se diagnostica precozmente ni se inicia un tratamiento enzimatico sustitutivo lo antes posible. Un grupo de especialistas de las diferentes disciplinas involucradas en esta enfermedad ha revisado la evidencia cientifica actual y ha elaborado por consenso una serie de recomendaciones para el diagnostico, el tratamiento y el seguimiento de los pacientes. Se recomienda instaurar tratamiento enzimatico en todo paciente con enfermedad de Pompe sintomatica de comienzo en el primer año de vida, con diagnostico clinico y enzimatico, y una vez conocido el estado CRIM (material inmunologico con reactividad cruzada).

Direct Measurements of 3D Structure, Chemistry and Mass Density During the Induction Period of C3S Hydration.

The reasons for the start and end of the induction period of cement hydration remain topic of controversy. One long-standing hypothesis is that a thin metastable hydrate forming on the surface of cement grains significantly reduces the particle dissolution rate; the eventual disappearance of this layer re-establishes higher dissolution rates at the beginning of the acceleration period. However, the importance, or even the existence, of this metastable layer has been questioned because it cannot be directly detected in most experiments. In this work, a combined analysis using nano-tomography and nano-X-ray fluorescence makes the direct imaging of early hydration products possible. These novel X-ray imaging techniques provide quantitative measurements of 3D structure, chemical composition, and mass density of the hydration products during the induction period. This work does not observe a low density product on the surface of the particle, but does provide insights into the formation of etch pits and the subsequent hydration products that fill them.

Direct three-dimensional observation of the microstructure and chemistry of C3S hydration.

Disagreements about the mechanisms of cement hydration remain despite the fact that portland cement has been studied extensively for over 100 years. One reason for this is that direct observation of the change in microstructure and chemistry are challenging for many experimental techniques. This paper presents results from synchrotron nano X-ray tomography and fluorescence imaging. The data show unprecedented direct observations of small collections of C3S particles before and after different periods of hydration in 15 mmol/L lime solution. X-ray absorption contrast is used to make three dimensional maps of the changes of these materials with time. The chemical compositions of hydration products are then identified with X-ray fluorescence mapping and scanning electron microscopy. These experiments are used to provide insight into the rate and morphology of the microstructure formation.

SPECT de perfusión, SISCOM y PET 18F-FDG en la valoración del paciente epiléptico fármaco-resistente candidato a cirugía de epilepsia / Perfusion SPECT, SISCOM and PET 18F-FDG in the assessment of drug- refractory epilepsy patients candidates for epilepsy surgery

Objetivos. La SPECT de perfusión ictal-interictal, subtraction ictal SPECT coregistered to MRI (SISCOM) y 18F-FDG-PET (interictal), desempeñan un papel fundamental en la valoración prequirúrgica del paciente epiléptico fármaco-resistente. Los objetivos de este trabajo fueron establecer la reproducibilidad del análisis visual de la SPECT y SISCOM y la capacidad de la SPECT, SISCOM y PET en la identificación del foco epileptógeno. Material y métodos. Se realizó una SPECT 99mTc-HMPAO (ictal-interictal) y SISCOM (Analyze 7.0) en 47 pacientes epilépticos fármaco-resistentes (24 M, 19-60 años). En 13 pacientes se repitió el SISCOM utilizando el programa FocusDET. El análisis de las imágenes fue realizado por 2 observadores. Se valoró la reproducibilidad utilizando el índice Kappa. Los resultados conjuntos de la SPECT, SISCOM y PET, en 16 pacientes, fueron comparados con la localización del área resecada y el seguimiento clínico poscirugía (escala de Engel) o con la estereo-EEG. Resultados. Grado de acuerdo interobservador de la SPECT 91% índice Kappa 0,86. Grado de acuerdo interobservador SISCOM Analyze 7.0 82%, índice Kappa 0,80. El Analyze 7.0 mostró un elevado número de resultados no concluyentes, superior al del análisis visual. El SISCOM FocusDET mostró un grado de acuerdo interobservador 92% con un índice Kappa 0,87 y menor número de resultados no concluyentes que el Analyze. La valoración conjunta SPECT, SISCOM y PET permitió identificar 87% focos epileptógenos: 79% temporales, 26% parieto-temporales y 7% frontales. Conclusión. La SPECT ictal-interictal y el SISCOM mostraron una elevada reproducibilidad. La valoración conjunta de la SPECT ictal-interictal, SISCOM y PET permitió mejorar la rentabilidad diagnóstica de la valoración individualizada (AU)

Aims. Brain perfusion SPECT (ictal-interictal), SPECT images and subtraction ictal SPECT coregistered to MRI (SISCOM) and 18F-FDG-PET (interictal), play an important role in the pre-surgical diagnosis of patients with medically refractory epilepsy. This study aimed to establish: the reproducibility of visual ictal-interictal SPECT and SISCOM analysis altogether with the capacity of SPECT, SISCOM and PET to determine the epileptogenic zone. Material and methods. 99mTc-HMPAO SPECT ictal-interictal and SISCOM (Analyze 7.0) were performed on 47 refractory epilepsy patients (24 F, 19-60 yrs). In 13 patients, SISCOM was also performed using a new program (Focus DET). Ictal-interictal SPECT and SISCOM images were analysed independently by two nuclear medicine physicians (observer 1 and 2). Kappa concordance coefficient was used to evaluate the reproducibility. In sixteen patients, SPECT, SISCOM and PET findings were compared with the resected area during the surgery, and surgical outcome using Engel scale or with the stereo EEG-(SEEG). Results. The ictal-interictal SPECT interobserver agreement was 91%, Kappa index 0.86, SISCOM (Analyze 7.0) interobserver agreement percentage was 82%, Kappa index 0.80, Analyze 7.0 showed a higher inconclusive results than visual SPECT analysis. SISCOM FocusDET interobserver agreement was 92%, Kappa index 0.87, with lower inconclusive results than Analyze 7.0. SPECT, SISCOM and PET combined findings identified 87% seizure onset zone: 79% temporal, 26% parieto-temporal and 7% frontal. Conclusions. Ictal-interictal SPECT and SISCOM showed a high reproducibility in this sample of patients with drug-refractory epilepsy. SPECT,SISCOM and PET combined findings improved detection of epileptogenic zone in comparison with the individual assessment (AU)

Assessing long-term effects of eslicarbazepine acetate on lipid metabolism profile, sodium values and liver function tests.

INTRODUCTION: Older dibenzazepines with a carboxamide substitution have been demonstrated to cause deleterious effects on lipid metabolism profile, as well as frequent hyponatremia. The aim of our study is to assess the effects of eslicarbazepine acetate, a novel AED, on lipid metabolism profile, sodium values and liver function tests, as well as to compare them with previous effects of carbamazepine and oxcarbazepine. METHODS: This report describes a retrospective cohort study of 108 patients who were treated with eslicarbazepine. Of these patients, 52% had switched to eslicarbazepine from prior treatment with carbamazepine or oxcarbazepine. Laboratory values concerning lipid metabolism profile, liver function tests and sodium were assessed before and after beginning/switching treatment. Patients who began treatment or whose treatment for dyslipidemia was modified during the study period were excluded from the analysis. Co-medications that could impact lipid metabolism profile, sodium or hepatic function were kept stable during the study period. RESULTS: The mean total cholesterol of the entire group decreased significantly from prior pathological to normal values after beginning/switching treatment. The percentage of patients with pathological values decreased. Patients switching from prior carboxamides also showed significant reductions in mean LDL and triglycerides. Patients beginning treatment without prior carboxamides did not develop dyslipidemia after titration. A tendency for an increased percentage of patients with hyponatremia was detected in both groups. CONCLUSIONS: Compared with older carboxamides, eslicarbazepine acetate exhibits a safer profile related to lipid metabolism. No relevant changes were detected in liver function tests. Consequently, a vascular risk factor could be avoided in patients with chronic epilepsy, while hyponatremia still needs to be ruled out. Prospective studies are still needed.

Perfusion SPECT, SISCOM and PET (18)F-FDG in the assessment of drug- refractory epilepsy patients candidates for epilepsy surgery.

AIMS: Brain perfusion SPECT (ictal-interictal), SPECT images and subtraction ictal SPECT coregistered to MRI (SISCOM) and (18)F-FDG-PET (interictal), play an important role in the pre-surgical diagnosis of patients with medically refractory epilepsy. This study aimed to establish: the reproducibility of visual ictal-interictal SPECT and SISCOM analysis altogether with the capacity of SPECT, SISCOM and PET to determine the epileptogenic zone. MATERIAL AND METHODS: (99m)Tc-HMPAO SPECT ictal-interictal and SISCOM (Analyze 7.0) were performed on 47 refractory epilepsy patients (24 F, 19-60 yrs). In 13 patients, SISCOM was also performed using a new program (Focus DET). Ictal-interictal SPECT and SISCOM images were analysed independently by two nuclear medicine physicians (observer 1 and 2). Kappa concordance coefficient was used to evaluate the reproducibility. In sixteen patients, SPECT, SISCOM and PET findings were compared with the resected area during the surgery, and surgical outcome using Engel scale or with the stereo EEG-(SEEG). RESULTS: The ictal-interictal SPECT interobserver agreement was 91%, Kappa index 0.86, SISCOM (Analyze 7.0) interobserver agreement percentage was 82%, Kappa index 0.80, Analyze 7.0 showed a higher inconclusive results than visual SPECT analysis. SISCOM FocusDET interobserver agreement was 92%, Kappa index 0.87, with lower inconclusive results than Analyze 7.0. SPECT, SISCOM and PET combined findings identified 87% seizure onset zone: 79% temporal, 26% parieto-temporal and 7% frontal. CONCLUSIONS: Ictal-interictal SPECT and SISCOM showed a high reproducibility in this sample of patients with drug-refractory epilepsy. SPECT,SISCOM and PET combined findings improved detection of epileptogenic zone in comparison with the individual assessment.

EEG extreme delta brush: An ictal pattern in patients with anti-NMDA receptor encephalitis.

INTRODUCTION: The anti-NMDA receptor (NMDAr) encephalitis-associated syndrome includes neuropsychiatric symptoms, impaired consciousness, seizures, autonomic instability, and hypoventilation. The electroencephalographic (EEG) activity throughout the course of the disease has still not been well documented. We reviewed electroclinical data of patients with NMDAr encephalitis to characterize their EEG and its clinical correlation. MATERIAL AND METHODS: We retrospectively identified 16 patients with NMDAr encephalitis from 8 Spanish medical centers, 15 of whom underwent video-EEG in the acute phase. RESULTS: In 15 patients (11 females, median age: 37.4, range: 14-87 years), seizures occurred in 9 (60%) and status epilepticus (SE) in 5 (33.3%). Magnetic resonance imaging (MRI) was abnormal in 10 (66.6%), and CSF (cerebrospinal fluid) was normal in 3 and abnormal in 12, with positive PCR (polymerase chain reaction) for Mycoplasma pneumoniae (1/15) and herpes simple virus (1/15). An ovarian teratoma was found in 1 patient and other malignancies (small cell lung carcinoma) in 1 patient. The EEG was abnormal in the acute phase in 14/15 (93.3%). Extreme delta brush (EDB) was observed in 5 (33.3%), and the presence of EDB was associated with SE in all cases. Rhythmic delta activity without EDB was observed in 5 (33.3%), while excessive beta activity was present in 4 (26.6%). Extreme delta brush can follow a pattern of well-characterized electroclinical seizures. CONCLUSIONS: Almost invariably, patients with NMDAr encephalitis had abnormal EEG. The presence of EDB, which can follow a pattern of well-characterized electroclinical seizures, in our patients was associated with seizures and SE. These findings suggest that EDB could be an evolutive pattern of an SE in NMDAr encephalitis. This article is part of a Special Issue entitled "Status Epilepticus".

Borohydrides: from sheet to framework topologies.

The five novel compounds ALiM(BH4)4 (A = K or Rb; M = Mg or Mn) and K3Li2Mg2(BH4)9 crystallizing in the space groups Aba2 and P2/c, respectively, represent the first two-dimensional topologies amongst homoleptic borohydrides. The crystal structures have been solved, refined and characterized by synchrotron X-ray powder diffraction, neutron powder diffraction and solid-state DFT calculations. Minimal energies of ordered models corroborate crystal symmetries retrieved from diffraction data. The layered Li-Mg substructure forms negatively charged uninodal 4-connected networks. It is shown that this connectivity cannot generate the long sought-after, bimetallic Li-Mg borohydrides without countercations when assuming preferred coordination polyhedra as found in Mg(BH4)2 and LiBH4. The general properties of the trimetallic compound series are analogous with the anhydrous aluminosilicates. Additionally, a relationship with zeolites is suggested, which are built from three-dimensional Al-Si-O networks with a negative charge on them. The ternary metal borohydride systems are of interest due to their potential as novel hydridic frameworks and will allow exploration of the structural chemistry of light-metal systems otherwise subject to eutectic melting.