Children with acute lymphoblastic leukemia (ALL) are at a risk of developing influenza-related complications. Approximately 10% of influenza-infected children with ALL or other types of cancer need intensive care, and 5% of them eventually die.th day. On the 20th day of this phase, she was admitted to our department with fever, mucositis, tachypnea, abdominal pain, and diarrhea. In September 2009, a 14-year-old boy (case 2) who, according to acute lymphoblastic leukemia intercontinental Berlin-Frankfürt-Münster protocol 2002, was categorized in the high-risk (HR) group, received the induction (Protocol I) phase of therapy without severe complications. On the 7th day of the HR-1 course, he manifested fever and strong, tiring cough, followed by strong mucositis. Chemotherapy had to be interrupted in both children.We report 2 children with ALL and the swine-origin influenza A virus infection. Diagnosing influenza in them was a challenge. Medical records of these children were reviewed for demographic, clinical, and laboratory data. Patients were hospitalized in the Department of Pediatric Hematology, Oncology, and Transplantology of the Medical University of Lublin, Poland. Case 1 involved a 2-year-old girl who, according to acute lymphoblastic leukemia intercontinental Berlin-Frankfürt-Münster protocol 2009, started chemotherapy in July 2015. She was categorized in the intermediate risk group and received the induction and consolidation phase of the therapy without severe complications. The reinduction therapy was administered in the outpatient department till the 15Respiratory viral infections, causing pneumonia, occurred in both patients during anticancer treatment. Initially, the real-time polymerase chain reaction test for the swine-origin influenza A was negative in both patients, which delayed the diagnosis. Additionally, bacterial, and fungal complications were also observed.Both patients received oseltamivir twice a day, a broad-spectrum antibiotic, antifungal drug, and granulocyte colony growth factor.The disease progressed quickly, and our patients subsequently died.We speculated that early antiviral treatment can help in the better management of patients in the HR group. It is also important to minimize influenza morbidity and mortality by vaccinating family members, using empiric therapy, providing immediate antiviral therapy, and educating parents about hygiene measures. A global pandemic caused by the swine influenza A (H1N1) virus was reported in 2009. The virus infects the upper and lower respiratory tract causing symptoms mediated by the production of interferons and cytokines. Real-time polymerase chain reaction (RT-PCR) has the highest sensitivity and specificity for the test. Diagnostic difficulties may occur in immunocompromised patients and during multipathogenic infections.,2 Additional complications of influenza include: bacteremia, affecting 16.5% of the children, and less common fungal pneumonias or hemophagocytic lymphohistiocytosis (HLH).,4,5 Antiviral treatment is recommended (preferably within 48 hour) for patients with confirmed or suspected flu having serious infection or an increased risk of complications. Influenza in children with cancer causes a significant delay in chemotherapy in 20% to 80% of the patients (average treatment interruptions of ≥3 week), which in turn affects the prognosis. Approximately 10% of influenza-infected children with ALL or other types of cancer need intensive care, and death occurs in eventually 5% of the patients.,3Children with acute lymphoblastic leukemia (ALL) are particularly at a risk of influenza-associated complications. Respiratory viral infections, causing respiratory failure, pneumonia, and need for ventilatory support, occur in 10% to 20% of the patients during cancer therapy.We report 2 patients with ALL and the swine-origin influenza A  was <20 000/μL; she showed a good response to steroids, as on day 8 the blast count in peripheral blood was <1000/μL; myelogram on day 15 had 2.4% blasts and minimal residual disease was 1.94%; myelogram on day 33 had 4.8% blasts). She received the induction (Protocol I) and consolidation (Protocol M) phase of therapy without any severe complications. The reinduction therapy was administered in the outpatient department till day 15. Chemotherapy was well tolerated. On day 20 of this phase, she was admitted to our department due to fever, mucositis, tachypnea, abdominal pain, and diarrhea. Laboratory and microbiological data are presented in a time-dependent manner in Table Aspergillus fumigatus deoxyribonucleic acid by using the PCR method. Infection with the AH1N1 virus was confirmed only in the BAL fluid, and 45 mg oseltamivir was administered daily. This was continued for 2 weeks without any effect. Due to the progression of clinical symptoms, respiratory pathogens, and A fumigatus deoxyribonucleic acid tests were repeated, and the AH1N1 test was positive in both the blood and BAL that time. CT showed that manifestations persisted with additional pulmonary cavities. Therefore, amantadine sulfate was administered with oseltamivir. After 4 weeks of therapy, CT presented massive progression in the changes and enlargement of the pulmonary cavities . He received the induction (Protocol I) phase of therapy without severe complications. On the 7th day of the HR-1 course, fever, and a strong, tiring cough occurred, followed by strong mucositis. Chemotherapy had to be interrupted. Laboratory and microbiological data are presented in a time-dependent manner in Table The child was diagnosed with B-cell precursor common positive ALL with infiltration of the central nervous system (pleocytosis of 145/μL), and according to ALL IC-BFM 2002, treatment was started in September 2009.3,8The influenza virus, particularly AH1N1, is well known to become lethal in ALL children undergoing chemotherapy. This virus spreads easily in pediatric oncology departments from both visitors and health care workers.th week of treatment for HLH.Yöntem Y et al reported that 8 out of the 98 children who received chemotherapy for leukemia were diagnosed with the pandemic H1N1 infection. In our study, 2 out of 8 patients had a fatal course (25%) of which 1 developed pneumonia and acute respiratory distress syndrome, and the other developed HLH and died due to secondary infection in the 6In another study, authors reported 10 patients with a median age of 7 years who suffered from ALL and were treated for influenza in an institution. They were all treated with oseltamivir. H1N1 RT-PCR of the nasopharyngeal aspirate was carried out whenever influenza was suspected. Oseltamivir was generally given empirically without awaiting microbiological confirmation, except in the first patient in whom the treatment began after 5 days following fever. No deaths were reported. Two patients under intensive chemotherapy developed pneumonia and 1 required ventilatory support. ALL patients under maintenance treatment developed a mild disease.When the first patient had infection, influenza was not reported in the hospital, neither among patients nor the staff. It is highly probable that the child was infected at home, even though the parents did not have information that someone was sick in their surroundings. The girl was undergoing intensive steroid treatment and chemotherapy, which were significant risk factors. Despite bacterial, viral, and fungal tests, it was difficult to diagnose an AH1N1 viral infection. Only the BAL fluid specimen confirmed viral infection. Antiviral treatment was applied after 48 hours from the appearance of first clinical symptoms. The additional complications of influenza comprised bacterial and fungal infections The presence of the virus in the blood in the next test confirmed the ineffectiveness of antiviral treatment.In 2009, when the second patient developed an infection, WHO  declared H1N1 influenza as a pandemic. The patient was the first to have flu diagnosed in our clinic at that time. Next, 5 out of the 25 cancer children and 1 doctor contracted pneumonia caused by AH1N1. Our patient received an aggressive course of chemotherapy, and therefore progression of infection was very quick. Like the previous child, only BAL tested positive. Oseltamivir was administered after 9 days from the initiation of clinical symptoms. Immediately, the remaining children and the doctor with clinical symptoms were given empiric antiviral therapy . All patients responded well to the treatment. In these individuals, the nasopharyngeal aspirates confirmed (PCR) the AH1N1 infection.In the analyzed patients, the tests were negative, which delayed the diagnosis. The reason could be severe mucositis in both children. In our opinion, patients with mucositis, serious clinical symptoms, and negative nasopharyngeal swab test results should undergo BAL analysis. We speculate that early empirical antiviral treatment could produce better results in HR groups.Most studies show a link between immunosuppression and the development of influenza-associated pneumonia. Unfortunately, because of immunosuppression, vaccines, such as the seasonal influenza vaccine, hold very little benefit for immunosuppressed children. Therefore, it is important to minimize influenza morbidity and mortality by using empiric therapy and early initiation of antiviral therapy and educating parents about hygiene measures. The education and vaccination of families and medical staff dealing with immunocompromised patients is of utmost importance.JZ, ML, AZP, KD were responsible for the study design. ML, AZP, KD collected the clinical data.JZ analysed the data interpreted the data, wrote, and supervised the paper. All authors read and approved the final manuscript.


Olives’ consumption produces copious agricultural byproducts that have accompanied humanity for millennia, but the increasing worldwide production complicates its management. Most wastes are generated during olive oil production in form of olive stones and other lignocellulosic derivatives. Industrial processes of chemical or physical nature to recover economically compounds from biomass residues are costly, difficult, and non-environmentally friendly. Cellulose, hemicellulose, and lignin biopolymers are the principal components of olive stones, which present interesting qualities as lignocellulosic fillers in polymeric composites. This review will summarize examples of composites based on thermoplastic polymers, such as polystyrene (PS), polylactide (PLA), polyvinyl chloride (PVC), polypropylene (PP), and polycaprolactone (PCL); thermosetting resins  and acrylonitrile butadiene rubber/devulcanized waste rubber (NBR/DWR) blends focusing on the fabrication procedures, characterization, and possible applications. Finally, thanks to the wide disparity in polymer matrix types, the variability in applications is important, from adsorption to mechanical enhancement, showing the easiness and benefit of olive stone integration in many materials. The olive tree is considered one of the first trees cultivated in human history, with implications for religion (Greek mythology and the Old Testament) and social life of our ancestors. For example, the olive plant has been a symbol of peace and friendship since Ancient Greece, when the Olympic Games winners were honored with a garland of olive branches .Olea europea L. is edible. The modern olive tree is believed to have appeared about 5000 years ago in Mesopotamia. The Phoenicians were responsible for their initial spreading along the Mediterranean coast and, later, the Greeks and Roman Empire. The Romans used olive oil in many applications, and the olive oil trade was a major commercial success that increased the trade routes. During the following centuries, the olive-derived industry continued being increasingly important up to our day [Although more than 30 olive trees species are known, only the  our day .The basic oil obtention procedure consisted of squeezing olives in stone mortars and collecting the olive paste in pots. Then, with the addition of hot water, the oil was easily separated from the solid mixture, because it remained on the surface due to its lower density in relation to water. Later, the methodology was improved with the use of different technologies. The improvement in the rushing and application of pressure with new devices pressing systems, such as millstone crushers for the crushing, presses, and hydraulic enhanced the oil extraction step before phase separation, in the so-called traditional milling method. Finally, in the modern three-phase oil removal system, industrial decanters based on centrifugation, a heating process , and a further residue oil purification with hexane or other reagents can be used .The growth of olive tree plantations, the industrialization of agriculture, and the extraction procedures have significantly increased the production of olives worldwide in recent decades. The European Union (EU) is the main producer, consumer, and exporter of olive oil, accounting for 80% and consuming 70% of the world’s production. Although the production of the EU leads the world market, production in other regions is rapidly rising. Only nine member countries  are responsible for about 5 million hectares of olive cultivation, ~3.3 million olive growers, and an average production of ~16 million metric tons, the majority for olive oil production. As shown in With the evolution of technology over time, the efficiency of production methods has increased significantly and, consequently, the production of waste has become increasingly expressive. According to the literature, the main byproducts of olive processing are: (a) Solid: Pomace (crushed stones and detritus of the pulp), twigs and leaves, (b) liquid: Fine olive pulp, unrecoverable oil, olive juice and water, named olive mill wastewater (OMWW), and (c) gaseous: Fumes generated in the malaxation step and other machinery involved processes . TherefoIt is estimated that, with the most modern technology available, one ton of olives is responsible for 0.6 ton of olive mill solid residue. Many of these residues are used in the production of electrical and/or thermal energy, because the costs associated with the dispersed location of small/medium farms/properties or any advanced technological solution that implies complex chemical treatments become prohibitive for alternative solutions. Considering that reducing the cost of technology or transforming waste into value-added materials are difficult options, physical and chemical processes have been studied, especially at level of olive mill wastewater (OMWW) . MoreoveIn order to overcome this problem, literature also reports studies in which lignocellulosic materials derived from olive residues are used as fillers for polymer-based composites, because biocomposites have been gaining more and more approval since the oil crisis. This proposed solution is similar to that used in composites, where synthetic fibers are replaced by natural fibers due to their biodegradability, abundance, low density, low cost, and they are non-abrasive ,10,11,12Regardless of the benefits previously reported, the fact that forests are decreasing, especially in developed countries, leads to the use of other agricultural byproducts or agro-waste to reinforce polymer-based composites ,17,18. T6 m3 are produced annually worldwide. In addition to the large quantities of OMWW produced, its high-polluting power due to high biochemical oxygen demand (BOD), chemical oxygen demand (COD), total solids, organic carbon, and slightly acidic character of OMWW promotes a severe negative impact on the soil, agriculture, water quality, environment, and public health [−3) and calculated costs per ton of olive oil (€ × ton−1) around 0.05–6.82€ × m−3 and 1.5–67.5€ × ton−1, respectively [Olive mill wastewater (OMWW) resulting from the oil extraction process is the main waste, and it is estimated that values around 5.4 × 10c health ,20,21. Ic health ,23. Therc health . The maic health  and revic health , while Ac health  analyzedc health  natural c health . For exaectively .The olive stone, resulting from the olive oil extraction and pitted table olive industries, is another residue with high environmental and economic interest. It is probably the residue produced in the olive fruit industrial sector with the greatest commercial interest due to its chemical/physical properties and combustion heat. In this context, because the olive stone is a lignocellulosic material , the literature reports several studies with methods of recovering lignocellulosic material or biomass for production of solid, liquid, or gas biofuel. In addition, other compounds with high added value can be obtained for other uses, which are synthesized in Regarding the possible applications mentioned above, the present manuscript will focus mainly on composite materials reinforced with olive stones, as bio-filler, in order to report its influence on the mechanical performance of such materials. Basically, in addition to intending to add value to a renewable bio-product from an economic point of view, it also aims to minimize the negative effects on the environment of certain polymers by promoting clean technologies and recycled products. For example, products such as panels, sandwich panels, tubes, or profiles, among others, can be produced by extrusion or injection technologies ,28. HoweThe olive fruit as a structure can be divided into three parts: (a) The skin also labeled as epicarp, (b) the pulp, flesh, or mesocarp, and (c) the stone or endocarp . The skiThe olive stone without seed can be recovered by filtration of solid waste from the olive oil industry, while the whole olive stone (stone and seed) is obtained by separation of the pulp in the pitted table olive industry. According to Rodriguez et al. , the 20023–C33 alkanes, polyunsaturated acids, sugars, polysaccharides, and amino acids can be detected [3–EtOH) is showed in Olives are a lignocellulosic biomass of varying chemical composition, but essentially formed by lignin, cellulose, and hemicellulose, in addition to proteins and fats . For exadetected . A list In addition to its main use being as biomass and fuel, olive stones are useful thanks to their physical properties and useful chemical components . The thr12 tons per year. Cellulose can appear in plants in pure form, but is usually accompanied by hemicellulose and lignin. Depending on the type of plant, the amount of cellulose varies enormously, for example, in jute (45–60 wt.%) and bamboo (40–55 wt.%).Natural cellulose is a renewable natural polymer that exists in all algae and plants, and in some marine creatures and microorganisms that can synthesize the biopolymer. Cellulose is the most common macromolecules in the world, because it represents 30 to 40% of the wood content or 65% in bast plants, which represents a global production of ≈1.5 × 106H10O5)n is the chemical formula, n is the number of glucoses and the degree of polymerization (chain length), and many of the cellulose properties depend on that length. Furthermore, the number of glucose units varies according to the species of plant, from 300 to 10,000 units. Cellulose is formed by bundles of nano-fibrils, each of which is formed by 60% of crystallites and the rest by random amorphous domains. Each cellulose chain has many crystallites and disordered amorphous parts linked together by 1,4-β-glycosidic bonds. D-glucopyranose is the repetitive unit in this stereo-regular and linear polysaccharide.Chemically, cellulose presents a multi-level complex structure, and several types of cellulose are known, from Cellulose I to IV. Cellulose I is the natural cellulose, cellulose II is regenerated cellulose, and III and IV can be obtained by chemical treatments .  than cellulose . NormallIn lignocellulosic compounds, cell walls can be regarded as composites, because they are formed by fibers (cellulose), matrices , and a variety of fillers (water and many organic compounds). The properties of lignocellulosic materials vary enormously between different plant species because they present important heterogeneity in their internal structures: Plant anatomy, cells, tissues, and organs. Since fibers or bundles are part of natural lignocellulose, the final mechanical behavior is governed by the chemical composition, internal architecture, and order of the bio-compounds .Due to the increasing interest in eco-friendly and bio-based composites with better performance, the use of lignocellulosic fillers is being increased. Natural fibers and powders, in addition to their biodegradability and renewability, have the advantage of being cheaper, lighter, and more resistant per unit mass than the typical inorganic fillers  .It is well known that the characteristics of nanocomposites are affected by the properties of their elements and by their interfacial and morphological characteristics. The use of reinforcing phase materials arises from natural and renewable sources in polymer composites have important advantages. The main qualities of lignocellulosic fillers in polymeric composites are: (a) Low cost, (b) low density, (c) renewable origin, (d) wide variability of structures, (e) chemically reactive surface, (f) relative high elastic modulus and strength, (g) relative easiness to degrade lignocellulosic composites by combustion (in comparison with inorganic fillers), (h) high sound attenuation capability, and (i) decrease in the machinery wear (because biobased resources are non-abrasive) ,39.There are examples of lignocellulosic fillers of multiple origins, such as sugar cane bagasse, jute, sisal, or wood. These materials from biomass can be introduced into various polymers of different natures. There are examples in thermoplastic polymers, such as poly(vinyl chloride (PVC), poly(lactic acid) (PLA), poly(ethylene) (PE), or poly(propylene) (PP); thermosetting resins, such as polyesters or epoxy resins, and rubbers (elastomers), as shown in The main goal of this section is to study the state of the art of using olive stone powder residues as lignocellulosic fillers in thermoplastic polymers and rubbers. Polymeric matrices of polystyrene, polylactide, polyvinyl chloride, polypropylene, and poly(ε-caprolactone) were used to prepare composites filled with olive powder. These materials will be analyzed in terms of their mechanical, thermal, rheological properties as well as other complementary characteristics .Hamida et al.  studied 3) and sawdust, with size between 0 to 0.25 mm. In terms of tensile strength, except for the composite filled with CaCO3, all the others showed a decrease with increasing filler content. It was also possible to observe that the composite reinforced with olive stone, independently of the filler content, was the one that presented the lowest tensile strength. Similar behavior was observed for elongation at break, where for all fillers this property decreased with increasing the filler content. Therefore, some degree of stiffness was exhibited in all filled composites, leading to a more fragile material. In fact, authors obtained an increase in stiffness with higher filler contents, which explains the lower stress at break caused by the premature rupture of specimens containing organic fillers. Regarding the impact strength, authors found that fillers worsen this property, regardless of its concentration, due to poor adhesion with the nonpolar matrix. While the inorganic fillers show the best results, the olive stones present the best performance among the organic loads. Finally, a significant increase in the heat deflection temperature (HDT) was observed with the increasing of the filler content for all composites, and the values obtained are in good agreement with those reported for the elastic modulus. It was noted that the lowest value was obtained with fillers of olive stones.La Mantia et al.  studied Koutsomitopoulou et al.  studied Perinović et al.  studied g around 75 °C with a position being insensitive to the filler content.Naghmouchi et al.  studied Naghmouchi et al. ,48 studiTasdemir et al. ,50 produ2 and CH3 groups) and the peaks in the spectrum are visible at 2916 cm−1 (CH2), 2959 cm−1 (CH3), 2841 cm−1 (CH2), 1460 cm−1 (CH2), 1376 cm−1 (CH3), 1357 cm−1 (CH2–CH), 1328 cm−1 (CH2–CH), 1302 cm−1, 1224 cm−1, 1260 cm−1, 1170 cm−1, and 1153 cm−1 (CH3), (CH2), and (CH), respectively. Regarding the PP Fourier transform infrared spectroscopy (FTIR) spectra, it was possible to report one peak at about 1550 cm−1 bands due to the lignocellulosic bonds after an added 15% ratio of olive pits, and a linear correlation was also observed between the olive pits amount and the peak intensity of lignocellulosic material. In this context, the addition of the olive pit particles did not distort the spectrum, however, a decrease of 5% occurred in the intensities in the 2916 cm−1 (CH2), 2959 cm−1 (CH3), 2841 cm−1 (CH2), and 1376 cm−1 (CH3) regions. The carbon–hydrogen bonds were physically affected by the amount of olive pit particles, therefore, and due to the differently sized particles, the peak intensity changed. Authors also analyzed the manufactured composites’ surfaces morphology, and it was noticed that the PP with 0 to 15 wt.% presented a homogeneous and smooth surface structure. Cracks and air bubbles were not found in all specimens with filler content on that range. However, a rougher and more irregular surface was reported in the PP filled by 20 wt.% of olive pit particles composite. In addition, authors used the SEM analysis to conclude that the addition of olive pit particles to the PP matrix did not cause a deformation on the surface and that, in addition to the filler being well dispersed into the matrix, there was a good adhesion between filler and matrix. Finally, to study the evaluation of the oxidative stability, authors preformed Oxygen Induction Time (OIT) tests on the manufactured composites. It was noticed that the OIT’s value of neat PP was 1.15 min, however, when 20 wt.% of olive pit particles were added to the PP, the OIT value reached 30.1 min. Through OIT’s data, the PP without the reinforcement was not able to effectively protect the material against thermo-oxidative conditions, nevertheless, when the olive pit was added to the polymer, the OIT values increased significantly. The results also indicated that the material reinforced with olive pit powder was more resistant to high temperatures than neat PP. From the thermal gravimetric (TGA) tests, the thermal characteristics of the composites showed that increasing the olive pit powder content, for a given temperature, the decomposition rate decreased. In this context, increasing the temperature from 200 °C to 800 °C, the weight losses were 99.4% for neat PP, 96.7% for 5.0 wt.% PP/olive pit composite, 94.9% for 10.0 wt.% PP/olive pit composite, 89.5% for 15.0 wt.% PP/olive pit composite, and 87.2% for 20.0 wt.% PP/olive pit composite. Therefore, with the addition of the olive pit powder, the decomposition behavior did not change, but the curves shifted to higher temperatures, showing, in this case, that the olive stone particles improved the thermal stability of PP in relation to untreated PP. Lastly, authors observed that the olive pit particle–treated PP composite provided higher storage modulus than the untreated one due to the better interfacial adhesion between the olive pit particles and the polymeric matrix. For all tested specimens, the storage modulus decreased with the increase of temperature. The results of the dynamic mechanical analysis (DMA) demonstrated that the storage modulus of the composite increased with the addition of olive pit particle. Regarding the loss modulus of the manufactured composites, the effect of the filler was similar to the storage modulus—it increased with the addition of olive pits. With these results, authors could conclude that, with the increase in olive pit content, the damping properties of composites improved.Gümüş et al.  producedHejna et at.  used oliFrom the SEM analysis, authors observed that the largest filler particles were observed for PCL/WB composites. Therefore, due to its size, high porosity, and absence of strong interfacial interactions, this group of materials showed the least compatibility among all. Consequently, a noticeable drop in tensile strength and elongation at break was observed. On the other hand, compared to OS and DS fillers, the addition of WB resulted in a higher decrease in tensile strength, which can be explained by the lower content of polysaccharides  that enhances the interfacial interactions with the matrix due to the large number of polar groups. In addition, WB has a higher protein content, which can act as plasticizers in the PCL matrix. Furthermore, this explains the highest elongation at break of PCL/WB composites.Regarding the composites with higher filling contents, they showed significant dependence on the type of filling. Therefore, the reduction in mechanical performance was instead associated to the disturbance of matrix integrity and limitation of PCL chains mobility. The stiffening of the material, expressed by increasing the modulus, was due to the incorporation of lignocellulosic fillers. This was related to the mobility of the PCL chains limited by filler particles and potential interactions between the PCL carbonyl group and polar groups present on the surface of applied fillers.g between composites with different fillers. In this context, materials containing lignocellulosic fillers exhibited significantly higher Tg values  compared to neat poly(ε-caprolactone). The lowest Tg values were associated to PCL/WB materials due to the existence of amino acids, which increase the PCL’s ability to flow under stress. Regarding the water uptake values, it was observed that the composites containing WB were characterized by a water absorption more than 50% higher than the PCL/OS and PCL/DS materials.Authors confirmed that the addition of these fillers into poly(ε-caprolactone) matrix resulted in increased hardness. The PCL/OS composites showed the most significant increase in hardness, from 50.2 for neat PCL to 52.8, 54.7, and 56.7 °Sh D, respectively, for 10, 30, and 50 pbw of filler. For materials containing WB, the lowest values of hardness were found (around 5% lower than for PCL/OS composites). Finally, these authors observed some differences in TThe application of lignocellulosic fillers to thermosetting resins was considered an attractive alternative to increase the properties of such materials or to add new capabilities . Phenol-2 atmosphere. The adsorption ability of the prepared samples was compared with two commercial activated carbons. As chemical materials for testing, two phenols were chosen: M-nitrophenol and p-nitrophenol, because they are common in water purification and they can work as model-substance in the porous structure of the adsorptive materials. For comparison, all materials were grounded and sifted to obtain diameters less than 63 µm, and then the samples were mixed with an aqueous solution (0.032 g/L) that contained one of the organic pollutants and, after different intervals of time, they were analyzed.Simitzis et al.  preparedIt was observed that the pores of the laboratory samples were different from the commercial ones. The olive derived resemble charcoals treated with steam, retaining the wood morphology. In addition, the influence of the sample and grains shape and size in the adsorption was found. The adsorption capacity was higher for the samples having the shape of small cylinder grains in relation to the corresponding powdered samples. The adsorption of the different organic compounds on activated carbons followed the Freundlich-equation or the Langmuir-equations. Results showed very good adsorption of phenol, 3-nitrophenol, or 4-nitrophenol from aqueous solution in the carbonaceous materials by activation and in the commercial ones. The adsorption capability of the three phenols examined in the pulverized materials followed this order: P-nitrophenol > m-nitrophenol > phenol.2. First, the furnace was heated to 1000 °C at a rate of 4 °C/min, followed by an isotherm for 10 min, cooled to room temperature and, finally, kept under vacuum. In addition, the pyrolysis residues were activated with steam at 930 °C. The adsorption properties of the materials (C20 and C20a) and a commercial activated carbon (CC) were investigated based on the adsorption of pentane and nitrogen capability. The adsorption capacity and the surface area were determined following the Brunauer–Emmett–Teller (BET) and Dubinin–Radushkevich–Kaganer (DRK) equations. The pore volume was measured as micropore volume employing the Dubinin–Radushkevich (DR) equation and using the Kelvin equation as cumulative pore volume. In this context, the results obtained that the adsorption properties measured based on the adsorption of nitrogen and pentane, i.e., pore volume, surface area, and adsorption capacity, followed the next sequence: C20a > CC > C20. The activated materials C20a and CC were principally microporous and in the Brunauer classification for nitrogen adsorption were part of the type I isotherms. However, the material C20 contained part of microporosity and mesoporosity, which explains being part of types I and II. The DR equation could be applied for the adsorption of nitrogen in all materials in the region of the relative pressure P/P0 = 0.005–0.3 [In another study published by the same authors , they co.005–0.3 .2. Adsorption of dyes requires pores 65 times larger than the particles, i.e., 20 to 500 Å. The results determined that C1 had a high content of mesopores that favored the methylene blue adsorption. The others, mesopores and micropores, facilitated the adsorption of the dye and vapors, respectively [Similar studies involving the same material (novolac resin and olive stone biomass in proportions 20:80 (wt.%:wt.%) were developed by Simitzis et al.  but, in ectively . In summSfyrakis et al.  studied 2. In this study, two phenol–formaldehyde resins were synthesized (Resol and Novolac). In the first resin, Resol, a 2.5:1 formaldehyde-to-phenol ratio was used to obtain the Re resin sample. The second type of resin, Novolac, two formaldehyde-to-phenol mole ratios were used, 1:1 and 1:1.22, to yield the No1 and No2 resin samples, respectively. Incorporating potassium chloride (KCl) to the Re and No1 cured resins, the carbon precursors were prepared. The cured resins were impregnated with KCl at room temperature (ReKCla and No1KCla precursors) or boiled with a saturated KCl solution (ReKClb and No1KClb precursors). Nevertheless, the No2 cured resin was used as additive to the olive stones in a 80:20 wt., with a proportion of OS:resin. This blend was then mixed with hexamethylenetetramine (28.6%) and heated at 170 °C for 30 min (No2OS precursor). The precursors were then carbonized in a horizontal furnace under a nitrogen flow rate of 50 mL.min−1. Prepared at room temperature, the ReKCla and No1KCla precursors were carbonized at 600 °C and produced ReKCla-600 and No1KCla-600 carbonized samples. Prepared at a boiling temperature, the ReKClb and No1KClb precursors were carbonized at 1000 °C and produced ReKClb-1000 and No1KClb-1000 carbonized samples. Lastly, the No2OS precursor was carbonized at 1000 °C to obtain the No2OS-1000 carbonized sample. It was reported that the interaction between temperature (T) and burn-off (B) was detected in the experimental region under consideration. At high activation temperatures (T > 700 °C for ReKCla-600 and T > 810 °C for No1KCla-600), authors reported that CO2 uptake decreased with the increase in burn-off. However, at low temperatures, the burn-off had not significantly influenced CO2 uptake. Moreover, over the temperature range studied and in the absence of interaction, the effect of burn-off was low or null. Authors used the response surface methodology (RSM) to evaluate the combined effect of activation temperature and burn-off degree on the CO2 capture capacity of phenol–formaldehyde resin and olive stone-based activated carbons. In the experimental region studied, the activation parameters do not similarly influence the capture capacity of all the evaluated materials. Therefore, these authors concluded that No1KCla-600 reached a maximum CO2 capture capacity of 9.3 wt.% at an activation temperature of 809 °C and a burn-off of 22%. The CO2 adsorption capacity values (at 35 °C and atmospheric pressure) of a mixture of this type of resin (20 wt.%) with olive stones (80 wt.%) were similar to those of commercial activated carbons (7.3–9.3 wt.%). Furthermore, for samples No1KClb-1000 and No2OS-1000, the greatest CO2 uptakes  were achieved at 800 and 942 °C, respectively, regardless of the burn-off degree. They reported that great potential as adsorbents for CO2 capture at atmospheric pressure was showed by activated carbons derived from the Novolac phenol–formaldehyde resin type and from OS [Gil et al.  produced from OS .Elsahli et al.  produced3, particle density around 1.39%, size dimensions 3.65%, permeability 12.70 mD, and the total Fungi and bacteria account were Absent (cfu/g). These results demonstrated the potential of olive stones in the manufacture of agglomerated panels with adequate mechanical and physical properties.These particleboards using olive stone waste were characterized according to European standards, and most of the results were in accordance with the requirements of American, British, and European standards. For example, considering the particleboard 80:20 wt.%:wt.%, the results showed a porosity around 14.21%, particle size of 22.06 cmGharbi et al.  producedCompared to neat resin, composites with 10, 30, 40, and 55 wt.% of ONF exhibited flexural modulus around 1.36, 1.9, 2.07, and 2.51 times higher, respectively. However, the same composites with a silane treatment exhibited flexural modulus around 1.45, 2.2, 2.5, and 2.8 times higher, denoting a significant improvement with the silane-based treatment.Regarding flexural strength, The improvement of interfacial adhesion after silane modification was evaluated by dynamic mechanical analysis (DMA) and SEM observations. From Authors also studied the water absorption properties and observed that the water content increased rapidly in the first absorption phase, followed by a gradual decrease until reaching the saturation plateau after about 1 month of immersion into water. However, the water absorption increased for higher contents of ONF, but when the fillers were treated, the water absorption decreased. For example, the maximum water absorption decreased from around 9% to about 5%, considering composites with 40 wt.% of untreated and treated ONF, respectively. The increase in interfacial adhesion between the filler and the matrix, as well as the improvement in the wetting of the ONF particles by the polymer, are the causes of this reduction. Another reason that contributes to the decrease in the water sensitivity of the composite is the decrease in the hydrophilic character of the filler, after treatment with MRPS.f = 7, 14, 27 and 44% of olive pit’s powder). After being subjected to thermal shock cycling conditions in the temperature range from −27 °C to +80 °C, the specimens were properly characterized. Normally, when the filler content increases, the strength of particulate polymers decreases due to the creation of aggregates, however, for the manufactured materials, only a small decrease in the flexural strength has been reported for larger filler-volume fractions. On the other hand, the addition of olive pit powder to the neat resin led to an increase in the flexural modulus. In this case, they observed that the flexural modulus increased with the fillers content, reaching a maximum value of around 48%, compared to neat resin, with a Vf = 44% of olive pit powder. These benefits result from the good adhesion between filler and matrix, as reported in the SEM micrographs obtained by the authors. In addition, to predict the modulus and compare the predicted values with the experimental ones, authors used the modulus predictive model (MPM). It was found that the degree of adherence and degree of dispersion were k = 0.357 and λ = 0.355, respectively, in addition to excellent repeatability, because the experimental deviations were less than 3%. Therefore, the modulus variation with the reinforcement content can be effectively predicted with the modulus predictive model (MPM). On the other hand, to predict the modulus variation as a function of the number of thermal shock cycles, and different filler contents, the residual property model (RPM) was used. However, different damage mechanisms occurred within the materials, due to their heterogeneous nature and very dissimilar expansion/contraction behavior from the constituents, which resulted in the degradation of their physical and mechanical properties. Therefore, for application of RPM, P∞ was obtained for composites with Vf = 7, 14 and 27% of olive pit powder, from the experimental flexural modulus at 200 cycles, and for composites with Vf = 44% at 100 cycles. P0 was obtained from the experimental flexural modulus of virgin composites. The temperature range of thermal shock cycling, ΔT, was 107 °C. The experimental results and respective predictions showed a good agreement between them, in most cases. However, the flexural modulus of the materials produced remained almost unchanged, even under the hostile environment, for all the cases studied.Papanicolaou et al.  studied In another study, Papanicolaou et al.  developef, it remained almost constant.Finally, in another study, Papanicolaou et al.  producedErkliğ et al.  studied The highest benefit obtained in terms of tensile strength was achieved for 5 wt.% of OP particles, evidencing an improvement of 16.6% compared to composites with neat resin (from 319.5 MPa to 372.65 MPa), while the flexural strength reached an improvement of 35.5% (from 465.56 MPa to 630.9 MPa). It was also found that the addition of particles promoted an increase in maximum elongation at the break point, however, the addition of OP particles above 5%  impaired chemical compatibility and charge transfer between the matrix and the particles. In terms of damping ratio, the highest value was obtained for 10% by weight of OP particles, a value that was about 70% higher than that obtained for composites with neat resin. Finally, the maximum storage modulus was reached for 10 wt.% of OP filler, evidencing an improvement of 74.2% in relation to the value obtained for composites with neat resin. This is a consequence of the good chemical compatibility between the OP particles and the epoxy resin and, in addition, the incorporation of the particles contributed to the increase in the dissipated energy.Mohammed et al.  studied Finally, rubbers have great commercial success due to their excellent chemical and mechanical behavior, such as resistance to crack propagation, elasticity, or flexibility. Rubbers can be of synthetic or natural origin, but both after the vulcanization process are being used in a multitude of products, such as gloves or tires .Khalil et al.  investigb), this mechanical property increased with the addition of DWR to NBR up to 20% of DWR. However, in blend 70/30 NBR/DWR, Eb values decreased due to the good compatibility of DWR with NBR, as previously revealed for the tensile strength. Finally, the modulus increased to DWR levels between 10 and 30%, reaching the maximum to 30%, but values above 30% of DWR led to its decrease. Therefore, as 70/30 NBR/DWR showed the best results for tensile properties, authors used this combination for further investigations and added various OSW concentrations (between 5 to 40 phr). Authors observed that the tensile strength (TS) decreases with the addition of 10% DWR to the NBR, however, for higher DWR contents, this property increases systematically, reaching maximum values for 30% DWR. This increase was attributed to the nature of NBR as non-crystallizing, with low gum strength. With the addition of 40%, a further decrease in TS was observed. In terms of elongation at break (Eb) values decreased for both fillers, although the composites filled with OSWT showed the lowest values.It is possible to observe that the tensile strength increases with the increase of olive stones waste (OSW) up to 10 phr, for both untreated and treated fillers, but, posteriorly, this value decreased until reaching the maximum concentration (40 phr). In addition, when compared with OSW, and for the same concentration, composites with treated olive stone waste (OSWT) showed better values for tensile strength (TS). The composite with 10 phr OSW/OSWT achieved the highest tensile strength due to the presence of hydroxyl (OH) groups, because olive stones waste has a hydrophilic nature. The interaction of these groups with the NBR nitrile group increased the TS values, however, there was a reduction in the TS to values above 10 phr due to the agglomeration of the fillers. Nevertheless, when increasing the OSW content, the elongation at break  at room temperature, and the results are shown in Finally, A review of all published works was presented in the previous section, where the benefits obtained from the olive pits are reported in detail. Therefore, this section intends to summarize all the benefits reported and, for this purpose, Olive oil has been a fundamental product for Mediterranean countries and culture. Initially obtained by traditional and few ecological methods, they have been gradually transformed and, nowadays, they are industrialized processes of high technology . HoweverThe olive fruit presents three identifiable sections: Skin, pulp, and stone. After the olive oil manufacturing process, from all residues, the olive stone is the most abundant. In addition, the table olive industry also participates with a large amount of this waste. This residue is considered a lignocellulosic material, the most available in the biosphere, which is formed by three chemical compounds: Cellulose, hemicellulose, and lignin. Basically, cellulose is a chain of glucose molecules connected by β(1→4)-linkers. Hemicellulose is formed by various types of sugars of 5- and 6-carbons; and lignin is synthesized by polymerization of three phenolic molecules. All three chemical compounds are organized in supramolecular structures during millions of years of natural evolution, presenting a complex organization into microfibrils that integrate structural stability in the plant cell walls. However, the great structural and chemical stability of lignocellulosic biomass hinders possible treatments as waste. Nevertheless, using chemical and/or physical treatments to purify and separate the individual components of the biomass allow them to be transformed into different molecules for the chemical industry. Although viable, these processes are difficult, expensive, and present environmental problems .Therefore, there is an interest in direct applications and without any complex treatment. In this context, taking advantage of the benefits of lignocellulose, the literature reports its integration into polymers  in form of fillers ,28. In tIn this context, and in general, literature review shows an increase in the elastic modulus with the olive stone content, while the tensile strength and elongation at break decrease. Similar behavior is observed for the same properties obtained in the bending mode, but this loading mode is shown to be much more sensitive to the interfacial properties. Both tensile and bending strength decrease due to the insufficient adhesion between fillers/matrix and, when the volume fraction increases, more interfaces and cavities are formed in the composite ,71,72. ITherefore, from the present review, it is clear that polymeric composites based on olive stone fillers have a high potential in a wide spectrum of engineering applications. At the same time, it seems clear that additional efforts must be made to understand the mechanical behavior (fracture and fatigue behavior) of these materials with a view to their application in engineering.-The various studies carried out with different types of polymer matrices demonstrate the interest of the scientific community in the reuse of olive stone residues in polymeric composites;-Resins filled with fillers based in olive stones present higher modulus than neat polymers, but the strength is affected by the filler content. This drawback does not provide applications for structural applications, but it is a promising solution for non-structural applications. For this purpose, studies covering the fracture and fatigue behavior are expected due to their absence in the literature;-The developed studies reveal that the mechanical properties depend on the filler/matrix interface. The functionalization of the olive stone particles with functionalization or coupling agents showed significant improvements, however, for each type of polymeric matrix, the functionalization agent must be different due to its distinct polarity and physical-chemical interactions. In this context, a complete study on the best functionalization agent and an optimized experimental procedure is highly recommended and should be a priority in future studies;-Olive stone residues constitute a cheap and useful source for reinforcing composites, however, several challenges must still be overcome. Therefore, more research is needed to achieve structural properties and, at same time, to valorize the olive oil industry.From this review about olive stones as a filler for polymer-based composites, several conclusions can be drawn, especially for future works:


Supplemental Digital Content is available in the text Many smartphone users experience pain in the thumb/wrist. This pain can be due to certain types of hand injuries as well as inflammation of the extensor pollicis brevis and the abductor pollicis longus tendon sheaths, known as De Quervain tenosynovitis. The objective of this study was to evaluate the association between smartphone addiction and wrist/thumb pain and to determine the severity of the pain, as well as to calculate the prevalence of De Quervain tenosynovitis among medical students at King Abdulaziz University (KAU) in Jeddah.A total of 387 medical students were enrolled. The smartphone addiction scale-short version (SAS-SV) was used to divide participants into the smartphone addict group and non-addict group. Both groups completed the self-administered patient-rated wrist and hand evaluation (PRWHE) questionnaire to evaluate wrist/hand pain. The Finkelstein test was administered to those who reported pain in the thumb/wrist.P = .036).Two hundred fifty-seven (66.4%) participants were smartphone addicts; 74 (19.1%) had a positive Finkelstein test. There was a significant correlation between smartphone addiction and high PRWHE scores , furthermore a correlation between heavy smartphones usage and hand pain was found which indicates that heavy usage of these devices can cause subclinical effects on the human hand. Currently, many conditions of behavioral addictions are very common, for example, compulsive buying, internet addiction, eating disorders, and gambling.–6 Smartphone functions represent great potential for applications in medical education, as they allow doctors and students to access resources efficiently to support better decision making at the point-of-care.–10 Despite their benefits, excessive use could result in various physical effects such as neck or wrist pain, and may be associated with disturbances of sleep and anxiety.,12Many smartphone users experience pain in the thumb/wrist, but whether those who develop pain are smartphone addicts or not has not been evaluated. Previous studies showed that using electronic devices or other devices that involve frequent use and movement of the thumb will lead to increasing load on the thumb, and therefore a higher prevalence of musculoskeletal disorders.In previous studies, there is a clear lack of research investigating this topic, and none of the previous investigations have been performed in Saudi Arabia. The aim of this study, therefore, was to evaluate the association between smartphone addiction and thumb/wrist pain and to determine the severity of the pain, as well as to calculate the prevalence of De Quervain tenosynovitis among medical students at King Abdulaziz University (KAU) in Jeddah.2 Since no recent, accurate data were available, the prevalence was taken at 50%, with a 95% confidence interval and 5% marginal error. Study participants were recruited according to their academic year, and an equal percentage was obtained from each year. Men and women were divided equally among the academic year groups. All students between the ages of 18 and 25 years who owned a smartphone and use it for >2 hours daily were included. Individuals with a history of hand surgery or inflammatory arthritis were excluded.A cross-sectional survey (level IV evidence) was conducted in May 2016. Participants were selected from undergraduate medical students at KAU, Jeddah, KSA. By using the standard formula to calculate sample size by prevalence, the calculated sample size was 385.α and confirmatory factor analysis were applied to test the questionnaire.The smartphone addiction scale short-version (SAS-SV) was translated by The Research unit in the English Language Institute at KAU. The English Language Institute is fully accredited by the United States based Commission for English Language Program Accreditation (CEA). Forward and backward translation was applied. In order to test the validity and reliability of the Arabic version, we administered the Arabic version to 100 students. We then administered the English version to the same students. Cronbach  SAS-SV was originally developed from an older version termed the smartphone addiction scale (SAS). It consists of 10 questions that are based on a self-reporting system with a Likert scale of 6 points . A cut-off value was reported as 31 for men and 33 for women.SAS-SV was used to divide participants into the smartphone addict or non-addict groups according to their scores. The PRWHE-A was designed to assess pain and functional difficulties of the wrist and hand. It is a self-reported questionnaire that consists of 15 items. It is further divided into 2 subscales, the pain subscale (5 items) and function subscale (10 items). Each item is analyzed with a numerical scale (0–10) where (0) means no pain and (10) means the worst pain ever felt. The scoring system is calculated by adding the functional scores and dividing them by 2, then adding the pain scores to give a total of 100 points. Lower scores indicate better function and less pain.Pain was assessed using the Arabic version of the patient-rated wrist and hand evaluation (PRWHE-A).,18For those who had experienced pain in the thumb or wrist of the dominant hand, the Finkelstein test was performed. The participants were asked to clench a fist with the thumb inside, and the examiner passively deviates it to the ulnar side; tenderness was checked at the radial styloid.U test was used for comparison of non-parametric data between groups. A P value <.05 was considered significant.Informed written consent was obtained from the participants. This study was approved by the Institutional Review Board of KAU  before conducting the survey. Data entry and analysis were conducted via SPSS  version 24. Categorical variables are expressed as frequency or proportion. Continuous variables are expressed as median and interquartile range after testing the normality of the distribution using the Kolmogorov–Smirnov test for non-normally distributed data. The chi-square test was used to determine the association between categorical variables. The Mann–Whitney 3P < .001 for all items. A reliability analysis was carried out concerning the knowledge part of the questionnaire, comprising 10 items. Cronbach α showed the questionnaire to reach high reliability, α = 0.890. Most items appeared to be worthy of retention, resulting in a decrease in the alpha if deleted, as shown in Table The total number of participants in this study was 387, with a response rate of 84%, including 204 (52.3%) men and 183 (47.7%) women . The chi-square of independence was calculated comparing the frequency of a positive Finkelstein test in smartphone addicts and non-smartphone addicts; the P value was not significant (χ2 (1) = 3.028, P = .082).According to the SAS-SV results, 257 66.4%) participants were considered to be smartphone addicts, while 130 (33.6%) were deemed to be non-addicts. In total, 20.4% of participants reported pain in the thumb/wrist, but only 74 (19.1%) participants had a positive Finkelstein test, including 22 (10.8%) men and 52 (28.4%) women. The Mann–Whitney % partici4 Another study in Switzerland reported that 97.6% of adolescents own smartphones.The aim of this study was to evaluate the association between smartphone addiction and wrist/thumb pain and to determine the severity of the pain, as well as to calculate the prevalence of De Quervain tenosynovitis among medical students at KAU in Jeddah. There has been a rapid increase in smartphone use due to its multiple benefits, to the point that it has become a necessity. One study including 6 Asian countries showed that 62% of adolescents own smartphones. In a study from Riyadh, 76% of participants showed a moderate to high risk of smartphone and internet addiction. A German study enrolling resident doctors found that 27.1% were smartphone addicts. This study found that the use of smartphones was necessary to communicate with their families during the long hours of duty. An Indian meta-analysis found that the percentage of smartphone addicts ranged from 39% to 44%, and reported that smartphone usage is increasing because it is becoming a fundamental way to spend free time. People who are addicted to smartphones will probably have physical and psychosocial problems as well as internet addiction.The results of the SAS-SV revealed that the majority of the participants were addicts (66.4%). The prevalence of smartphone addiction has been rising throughout the world. In Switzerland, the prevalence of smartphone addiction among adolescents was reported to be 16.9%.,6,25 In the current study, 20.4% of all participants reported pain in the thumb/wrist. In a study from China, 43.4% of participants experienced thumb/wrist pain due to the use of different electronic devices. In a study from Pakistan, 42% of adolescents reported pain in the thumb/wrist due to smartphone use.Many adolescents report various musculoskeletal disorders due to the use of electronic devices.P < .05). The median total pain and disability score of the PRWHE-A for addicts was 8.00 with an interquartile range of 0 to 20, meaning that the total score for the majority of addicts (75%) was ≤20. The median total pain and disability score of the PRWHE-A for non-addicts was 4.25 with an interquartile range of 0 to 13. Since the severity of the pain for those with thumb/wrist pain while using a smartphone and electronic devices has not been previously established, we compared our data with similar results reported using the PRWHE for different hand and wrist disorders. In Switzerland, the mean score of pain and disability was 11 for individuals with a distal radial fracture (DRF) after 6 months’ follow-up. In Canada, the mean score of pain and disability was 13.5 for those with DRF after 1 year follow-up. Usually, patients with DRF experience some mild pain and stiffness in this follow-up period.,27Our study found a significant correlation between smartphone addiction and thumb/wrist pain .P > .05). There are other potential causes of thumb/wrist pain, including the extensor pollicis longus in the third dorsal compartment, flexor pollicis longus, thenar eminence, and median nerve; additionally, other clinical and subclinical changes could be involved due to mobile phone use, as discussed and demonstrated by ultrasound in recent studies.,32Although we found that thumb/wrist pain was associated with smartphone addiction, there was no significant association between smartphone addiction and Finkelstein test results  for English editing, manuscript style and structure, and technical review.The authors thank Min Kwon, Fatmah N. Hasani, and Hussam Rajab for assisting and providing the questionnaires used in this research and Abdulmalik Abumohssin for comments and revisions that greatly improved the manuscript. They would like to thank Editage (Conceptualization: Ayman Baabdullah, Diyaa Bokhary, Yousof Kabli, Omar Saggaf, Motaz Daiwali, Amre Hamdi.Data curation: Ayman Baabdullah, Diyaa Bokhary, Yousof Kabli, Omar Saggaf, Motaz Daiwali, Amre Hamdi.Formal analysis: Ayman Baabdullah, Amre Hamdi.Investigation: Ayman Baabdullah, Diyaa Bokhary, Yousof Kabli, Omar Saggaf, Motaz Daiwali, Amre Hamdi.Methodology: Ayman Baabdullah, Diyaa Bokhary, Yousof Kabli, Omar Saggaf, Motaz Daiwali, Amre Hamdi.Project administration: Ayman Baabdullah, Diyaa Bokhary, Yousof Kabli, Motaz Daiwali, Amre Hamdi.Resources: Amre Hamdi.Supervision: Ayman Baabdullah, Diyaa Bokhary, Amre Hamdi.Validation: Ayman Baabdullah, Omar Saggaf, Amre Hamdi.Visualization: Amre Hamdi.Writing – original draft: Ayman Baabdullah, Diyaa Bokhary, Yousof Kabli, Omar Saggaf, Motaz Daiwali, Amre Hamdi.Writing – review & editing: Ayman Baabdullah, Diyaa Bokhary, Yousof Kabli, Omar Saggaf, Motaz Daiwali, Amre Hamdi.Ayman Baabdullah orcid: 0000-0002-5784-0241.


Although several studies have reported increased mortality risk with early menopause, there were no studies examining the relationship between age at menopause and mortality in Japan. The goal of this analysis is to investigate the relationship between age at menopause and all-cause mortality among the Japanese.Study subjects were 4,683 postmenopausal females in the Jichi Medical School Cohort Study, a population-based prospective study. Baseline data were obtained by questionnaire and health checkups between April 1992 and July 1995 in 12 rural areas in Japan. Main outcome measures were all-cause mortality derived from death certificates up to December 31, 2002. Cox’s proportional hazard models were used to analyze the association of age at menopause with mortality.A total of 215 deaths were observed during the average of 9.2 year follow-up period. After adjusting for age, systolic blood pressure, serum total cholesterol level, serum high density lipoprotein cholesterol level, history of diabetes mellitus, body mass index, smoking habits, alcohol drinking habits, marital status, study area, and types of menopause, the hazard ratios  of all-cause mortality were 2.10 (1.07-4.11), 0.68 (0.36-1.26), 0.94 (0.68-1.30), and 1.17 (0.63-2.20) for females with a menopause at ages younger than 40 years, 40-44, 50-54, and 55 or older, respectively, relative to those with menopause at age 45-49 years.Our data suggest that menopause aged younger than 40 years increases the risk of death from all causes among the Japanese. On the other hand, some epidemiologic studies reported that later menopause increased the risk of breast cancer13,14 and endometrial and ovarian cancer,15,16 and many studies reported that HRT also increased the risk of breast cancer.12,17Menopause occurs by loss of ovarian function and subsequent deficiency of endogenous estrogens. Relationship between age at menopause and mortality is mainly explained by deficiency of endogenous estrogens. Many epidemiologic studies indicated that an early natural menopause increased the risk of ischemic heart disease.18-21 In other words, mortality of those with menopause at young age was higher than the mortality of those with menopause at old age. To our knowledge, all previous studies were conducted in Western countries, and there was no study in Japan.There were some studies examining the relationship between age at menopause and all-cause mortality. Most previous reports have found inverse relationship between age at menopause and all-cause mortality.The purpose of this study was to examine the relationship between age at menopause and all-cause mortality in the Japanese population.22 The baseline data were obtained between April 1992 and July 1995 in 12 rural areas in Japan. Mass screening examinations for cardiovascular diseases have been conducted since 1983 in accordance with the Health and Medical Service Law for the Aged of 1982, and we used this system to collect the data. The subjects for the mass screening examinations were residents aged 40-69 years in 8 areas, and were 30 years and older in one area. Subjects for other age groups were included in 3 areas. In each community, a local government office sent personal invitations to all the subjects by mail.We used the data set of the Jichi Medical School Cohort Study, which is a population-based prospective study investigating risk factors for cardiovascular diseases starting in 1992.2. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured with a fully automated sphygmomanometer, BP203RV-II . Serum total cholesterol and high density lipoprotein (HDL) cholesterol were also measured with standard methods, as reported previously.22Health checkup was carried out in each community. Body mass index (BMI) was calculated as weight (kg) / height (m)Information about medical history and sociodemographic characteristics was obtained by trained interviewers using a standardized questionnaire. Smoking status was judged as current smoking, ex-smoking, or never smoking, and alcohol drinking status was judged as current drinking, ex-drinking, or never drinking. Females were asked about the age at menopause and the type of menopause . We did not show the definition of the word of menopause, and we did not ask about HRT use.A total of 12,490 subjects  participated in the mass screening and the response rate for the residents who underwent a basic medical checkup was about 99%. The proportion of people who actually underwent a medical checkup for the total population was 65.4%. Written informed consent for the study was obtained individually for the responders of the mass screening, and 95 responders  rejected to join the study. Therefore, 12,395 subjects  who were 19-93 years of age agreed to participate in the study. For our purpose, we identified 4,848 females with data of age at menopause, and we excluded those who reported a previous history of myocardial infarction , stroke , and malignant neoplasms . A total of 4,683 females aged between 36 and 89 years remained.Causes of death were identified using death certificates, which were collected at the respective local public health centers with permission from the Ministry of Internal Affairs and Communications. The people who moved out of the communities during the observation period were followed up until the date of the emigration. Data on emigration of the study subjects were obtained every year from their municipal governments.Age at menopause was categorized into <40 years, 40-44 years, 45-49 years, 50-54 years, and 55+ years. The reference group was females who were 45-49 years at menopause.® software version 11.0. Descriptive parameters are shown as mean, standard deviation or proportion (%). We compared characteristics between the groups by one-way analyses of variance or the chi-square tests. Cox’s proportional hazard models were used to calculate hazard ratios of mortality for age at menopause after adjusting for age, SBP, serum total cholesterol level, HDL cholesterol level, history of diabetes mellitus, BMI, smoking habits, alcohol drinking habits, marital status, study area, and type of menopause, which were considered to be potential confounding factors. Among the potential confounding factors that we obtained as the baseline data about blood pressure, we used SBP only in the multivariate analyses to avoid the co-linearity.Statistical analysis was performed using the SPSSThis study was approved by the Institutional Review Board of Jichi Medical School for ethical issues.The total observed person-years were 43,152, and the mean follow-up period±standard deviation (SD) was 9.2±1.6 years. The mean age±SD was 61.0±6.7 at baseline data collection. There were 215 deaths (4.6%) during the study period. Of these, 93 died of malignant neoplasms, 29 of heart diseases, 29 of stroke, and 64 of other diseases. The mean age±SD at menopause were 48.3± 4.8; 80% of females had their menopause between 45 and 54 years of age. Baseline characteristics in relation to each category of age at menopause are shown in To eliminate the influence of potentially preexisting subclinical diseases, we repeated analyses excluding those who died within 2 years after the baseline examination, and the results were essentially unchanged (data not shown).We investigated the association between reported age at menopause and all-cause mortality using data from the Jichi Medical School Cohort Study, a population-based cardiovascular cohort study. The present study did not show an inverse relationship between age at menopause and all-cause mortality, but comparing females with early menopause (<40 years) with those who experience menopause when they were 45-49 years old, the former group has significantly higher all-cause mortality.18 studying in a breast cancer screening cohort comprising 12,134 postmenopausal Dutch females followed for average of 17 years, a later menopause was associated with a decreased all-cause mortality risk, showing a linear trend. Jacobsen et al19 reported there was a weak inverse relationship between age at natural menopause and all-cause mortality in a cohort of 19,731 Norwegian postmenopausal females followed for average of 37 years. Cooper et al20 also reported an inverse relationship between age at natural menopause and all-cause mortality in the National Health and Examination Survey Epidemiologic Follow-up Study followed up 3,191 postmenopausal females during a 4-year period. Jacobsen et al21 studied the relationship between age at natural menopause and all-cause mortality in a cohort of 6,182 California Seventh-Day Adventist females who reported a natural menopause followed for average of 13 years. The result was same as above.There were several epidemiologic studies examining the relationship between age at menopause and all-cause mortality. According to Ossewaarde et al18-21 Premature ovarian failure (POF) or premature menopause refers to development of amenorrhoea due to cessation of ovarian function before the age of 40 years. POF occurs in 1% of females.23-25 In our study, limiting natural menopause, 1.1% of females reported to menopause <40 years, same as former studies, and they had significantly higher risk of death than those reported to menopause 45-49 years. A wide spectrum of pathogenic mechanisms may lead to the development of POF including chromosomal,26 genetic,27,28 autoimmune,29,30 metabolic,31 infectious,32-34 and iatrogenic causes.35,36 It may result in the higher mortality on early menopausal females.The average age for menopause is approximately 49 years in previous studies in Western countries.1-4 fewer calcifications in the aorta,37 and less extensive atherosclerosis38 in females with later menopause. In contrast, later menopause has been related to increased risk of breast cancer,13,14 endometrial and ovarian cancer.15,16 We analyzed cause specific mortality, but no significant relationship was seen in any category. That was because the number of deaths in our analysis was too small to draw firm conclusions about specific causes of death. We cannot explain why our result did not show an inverse relationship between age at menopause and all-cause mortality, especially why females who had menopause 40-44 years had lower mortality, though it was not significant, than those who had menopause 45-49. All the previous studies were conducted in Western countries in which major cause of death is cardiovascular disease. On the other hand, major cause of death was malignant neoplasms in Japan. It may influence our result. To clarify these questions, cause specific mortality will be useful. We are going to analyze cause specific mortality after extending the follow-up period.Observational studies have shown a reduced risk of cardiovascular disease,19-21 Ossewaarde et al18 reported type of menopause  did not affect the associations between age at menopause and cause specific mortality. Some other factors except ovarian function may influence the association between age at menopause and mortality.In our study, the multivariate-adjusted hazard ratios of those with surgical menopause at younger age were higher (though not significantly) than those with surgical menopause at older age. Although we did not ask whether both ovaries were still present or not, we excluded those who had a history of malignant neoplasms from the subject of our study. Therefore, many females who had surgical menopause may have both ovaries. We did not know why the younger group had higher mortality. The subjects of many previous studies were limited only natural menopause, the relationship between surgical menopause and mortality in not well known.Our current data suggested that those with menopause at young age have a high risk of mortality. Although the cause-specific analyses are required, health management, such as an intensive health check-up system, may be useful for such females.The strong points of our research are as follows. First, to our knowledge, our report was the first in Japan. Second, we adjusted for possible confounding factors such as age, SBP, serum total cholesterol level, serum HDL cholesterol level, history of diabetes mellitus, BMI, smoking habits, alcohol drinking habits, marital status, and study area, and conducted this research with an adequately accurate method of measurement. Accordingly, we aimed at thorough unification of the methodology, such as blood pressure measurement and blood testing. In order to eliminate variation arising from individual techniques, the same automatic sphygmomanometer was used in all the areas. Furthermore, the blood samples were analyzed at a single trusted laboratory using the same method of measurement.39,40 Second, we did not ask about HRT use. However, there are few females who take HRT in Japan, and we think the influence of HRT was small.There are three limitations in our study. First, this study makes biased reporting of age at menopause unlikely. However, as demonstrated in previous reports, self-reported age at menopause and type of menopause are reasonably valid and reproducible.The final limitation is that those who were before menopause at the baseline data collection were excluded from our data analyses. This restriction might lead a selection bias, which is that we observed only those whose age at menopause was relatively younger. However, the results were not so different in the analyses with subjects aged 55 years and older; most of them were considered menopausal condition.In conclusion, our data indicated that menopause aged younger than 40 years increases the risk of death from all causes among Japanese.