INTRODUCTION:

Malaria is a dangerous, perhaps fatal disease that is carried by mosquitoes and brought on by a parasite. Until it was eradicated by numerous disease-control programmes in the late 1940s, malaria posed a serious health danger in the United States. A high fever and chills are among the flu-like symptoms that the sickness displays.

The parasite disease known as malaria, which is spread by the Anopheles mosquito and causes acute, life-threatening illness, is a serious danger to global health. An estimated 125 million travellers per year and two billion residents of the 90 endemic countries are at risk of catching malaria. The multistage lifecycle of the Plasmodium parasite causes the recognisable cyclical fevers.

Most persons get rapid symptom relief with prompt treatment; nevertheless, serious consequences, such as cerebral malaria, severe malarial anaemia, coma, or death, may happen.

The most effective antimalarial therapeutic and chemoprophylactic regimens are determined by the patient's demographics, susceptibility, and geographic location. Years after exposure, latent or reactivating infections may be discovered.¹

The malaria life cycle requires the following three components:

1. The parasite begins its life cycle in the Anopheles mosquito, which also carries it.

2. The parasite (Plasmodium) has numerous subspecies, each of which causes symptoms of varying severity and responds to various medications.

3. The parasite first makes its way to a person's liver, where it can develop and grow. Red blood cells are then infected and killed as it circulates in the bloodstream.

During a blood meal, the mosquito vector transfers the Plasmodium spp. parasite to the host in the sporozoite stage. Sporozoites enter liver cells within 30 to 60 minutes, when they multiply and divide into merozoites. Merozoites are released into the bloodstream when an infected liver cell bursts, starting the disease's symptomatic asexual reproductive stage in which they invade red blood cells.

Figure 1: The Plasmodium spp. life cycle.

Four to eight days after the initial red blood cell invasion, symptoms appear. Within the red blood cells, the merozoites replicate for 36–72 hours (from red blood cell invasion to haemolysis). Therefore, fever develops every 36–72 hours in synchronous infections (infections that result from a single infectious bite), when the infected red blood cells lyse and release endotoxins en masse.^2,3

Additionally, the hypnozoite stage of Plasmodium vivax and Plasmodium ovale can be reached in the liver. Red blood cells that produce merozoites can infiltrate other red blood cells, where they can continue to multiply, or, in some situations, they can develop into gametocytes that are either male or female.^4,5 It has been demonstrated that the transcription factor AP2-G (not depicted) controls the decision to commit to gametocytogenesis. The mosquito vector consumes the concentrated gametocytes in the skin capillaries during a subsequent blood meal. Each male gametocyte undergoes three rounds of mitosis in the mosquito's gut, producing eight microgametes; the female gametocyte develops into a macrogamete. The male macrogamete is sought after by the male microgamete, which is a motile form with flagella.

The male macrogamete is sought after by the male microgamete, which is a motile form with flagella. A diploid zygote is created when the male and female gametocytes unite, and it grows into an ookinete, which leaves the gut through the epithelium3 as an oocyst. Oocysts go through replication cycles and develop into sporozoites, which go from the mosquito's abdomen to the salivary glands. So, 7–10 days after ingesting blood containing gametocytes, the mosquito may be "armed" and capable of transmitting Plasmodium spp. to another person by her bite.

Drugs that block the red blood cell stage are necessary for the treatment of the symptomatic stage of the disease. Compounds that inhibit the formation of gametocytes or their development in the mosquito (including drugs that kill mosquitoes feeding on blood) are transmission-blocking agents. Drugs that prevent Plasmodium spp. invasion or proliferation in the liver have prophylactic activity. In the case of hypnozoites, merozoite invasion of red blood cells can be postponed by months or years. the number of days before symptoms become noticeable. By species, gametogenesis lasts a different amount of time. Temperature has a significant impact on how quickly sporozoites develop inside the mosquito's digestive tract. Adapted from Ref. by Macmillan Publishers Ltd.2,3 with permission.

The intensity of Plasmodium spp. infection effects varies by species and host variables, such as host immunity, which is related to the extent of prior parasite exposure.^6,7 Most cases of malaria are categorised as asymptomatic, simple, or severe (complicated)8 (Box 1). Low-grade fever, trembling chills, muscle aches, and, in youngsters, stomach issues are typical early symptoms. These symptoms can appear suddenly (in paroxysms), then worsen to include excessive sweating, a temperature, and fatigue. Following the haemolysis of Plasmodium spp.-infected red blood cells, paroxysmal malaria symptoms appear. Severe anaemia and other signs of multi-organ damage, including brain malaria, are symptoms of severe malaria, which is frequently fatal. 9 (Box 1) (Box 1). The presence of parasites in capillaries that are in the red blood cell stage is what causes severe malaria consequences, which result in microvascular obstruction. This primer focuses on recent advancements in diagnostics, novel therapies (drugs and vaccines), chemoprotection, and chemoprevention, as well as our understanding of malaria pathogenesis in relation to parasite and vector biology.^7-9

History and Physical:

The primary sign of malaria is fever; fever, particularly persistent fever lasting seven days or longer in a patient who lives in or has recently visited an endemic area, is highly suspect and should trigger assessment. Adults may have headache, malaise, weakness, stomach pain, upper respiratory symptoms, and muscle aches; more severe cases may result in jaundice, disorientation, convulsions, and black urine. ¹² Lethargy, malaise, abdominal discomfort, nausea, vomiting, and diarrhoea are common in children; more severe cases might result in somnolence, seizures, and coma. ¹²

The location of residence, recent travel, use of chemoprophylaxis, exposures (such as sick contacts, freshwater, caves, farm/wild animals, insects/arthropods), HIV status, history of a current or recent pregnancy, history of G6PD deficiency, history of sickle cell disease, history of anaemia, history of blood or other cancers, and history of previous malaria infections are all crucial questions to ask when taking a patient's history (including successful or failed treatments).A feverish, unwell-appearing patient with suspected hepatosplenomegaly, icterus, jaundice, pallor, or evidence of dehydration may be discovered during the physical examination. In severe situations, hemodynamic instability, sleepiness, or coma may be present, especially in people who also have a concurrent bacterial infection or adrenal insufficiency brought on by malaria. P. falciparum infection is more likely to cause a severe presentation. ¹²

Etiology:

Human infection is possible with five different Plasmodium species: P. falciparum, P. ovale, P. vivax, P. malariae, and P. knowlesi. 13 During a blood meal, the female Anopheles mosquito consumes gametes that develop into sporozoites and multiply in the intestine. Saliva carrying sporozoites is discharged into a human host's bloodstream during successive bloodmeals. In less than an hour, sporozoites enter the liver, infiltrate the hepatocytes, and then quickly split to become merozoites. Organisms reenter the bloodstream and infiltrate erythrocytes during an active infection. 14 Plasmodia grow from immature trophozoites (ring stage) to either mature trophozoites or gametocytes within erythrocytes by consuming haemoglobin (CDC Malaria 2019). The reproduction of mature trophozoites results in the formation of schizonts, which damage the integrity of the erythrocyte cell membrane and cause capillary endothelial adhesion and cell lysis (CDC Malaria 2019). Malaria can remain untreated for 2 to 24 months. Infections with P. vivax and P. ovale may exhibit "latent schizogony," in which dormant intrahepatic parasites (hypnozoites) persist until reactivation months to years later.

Toxin-induced IFN-gamma and TNF-alpha production is the basis for pathogenesis.¹⁴ Monocyte and macrophage phagocytosis within the splenic red pulp dominates the innate immune response. IFN-gamma and TNF-alpha-induced class flipping of CD4-positive cells is the basis for the development of adaptive immunity14. The severity and timing of symptoms are determined by parasitemia; symptoms typically appear at 0.002% parasitemia in people who have never been exposed to parasites and at 0.2% parasitemia in those who have. ¹ A severe infection often has a 5% parasitemia. ¹⁴

Epidemiology:

Every year, 40% of the world's population travels to or lives in areas where malaria is prevalent. Western and sub-Saharan Africa are home to P. falciparum, which has the greatest morbidity and fatality rates of all the Plasmodia species. South Asia, the Western Pacific, and Central America all contain P. vivax. Sub-Saharan Africa is home to P. ovale and P. malariae. Southeast Asia contains P. knowlesi. ¹² Annually, there are up to 500 million cases of malaria and 1.5–2.7 million fatalities. In Africa, 90% of fatalities take place. Children under the age of five, pregnant women, and disease-unaware people, such as refugee populations in Central and Eastern Africa, nonimmune civilian and military travellers, and immigrants going back to their country of origin are those most at danger. ¹¹ Ten thousand to thirty thousand travellers who visit endemic regions each year contract malaria; of them, one percent will pass away from the disease's consequences. ^11,12 It is anticipated that the prevalence of malaria would grow due to changing weather patterns and rising average global temperatures; a rise of 3 degrees Celsius is predicted to result in an increase of 50–80 million cases of malaria.

Pathophysiology:

The time from incubation to symptom onset varies depending on the species: P. falciparum takes 8 to 11 days, P. vivax takes 8 to 17 days, P. ovale takes 10 to 17 days, P. malariae takes 18 to 40 days (but it may take up to several years), and P. knowlesi takes 9 to 12 days. The classic "malarial paroxysm" of rigours, several hours of fever, diaphoresis, and return to normal body temperature (P. vivax infection establishes a 48-hr cycle) is created by the periodicity of the Plasmodium lifecycle, though this is less common seen today due to quick identification and treatment.

Evaluation:

Blood cultures, urinalysis, chest radiographs, thick and thin blood smears, a complete blood count, a comprehensive metabolic panel, a coagulation panel, and thick and thin blood smears are among the initial tests used to assess undifferentiated fever in stable patients who may have been exposed to malaria. A lactate level, arterial blood gas analysis, and lumbar puncture may also be recommended in individuals with altered mental status when cerebral malaria is suspected.¹²

A complete blood count in malaria patients indicates thrombocytopenia in 60–70% of cases and anaemia in varied degrees in 29% of adults and 78% of children.¹² Due to the invasion of all aged erythrocytes and capillary and splenic erythrocyte sequestration as a result of reduced flexibility and cytoadherence, anaemia is more severe in P. falciparum. With P. vivax and P. malariae, anaemia is often moderate because these two parasites prefer to invade reticulocytes and older erythrocytes, respectively. A thorough metabolic panel may identify renal disease due to glomerular damage, hepatocellular injury secondary to parasite invasion, indirect hyperbilirubinemia due to hemolysis, electrolyte abnormalities secondary to intracellular content release, and concurrent dehydration. A panel for coagulation may.¹² demonstrate coagulopathy raising concerns about the possibility of bleeding in patients with severe thrombocytopenia or liver disease.

A microscopic assessment of Giemsa-stained thick and thin smears of a free-flowing venipuncture blood sample serves as the gold standard for diagnosing malaria.¹² To prevent missing low-level parasitemia or "delicate ring formations," the examination with oil immersion must be conducted at 100- and 1000-times magnification. The number of organisms per high powered field is used to determine the parasitemia's severity. Differential microscopic features of infected erythrocytes serve as a guide for speciation

· When P. falciparum is in the ring stage, it takes the appearance of a "purple spot with a thin ring," a "purple spot with a distorted body," a "ring with a huge purple spot," a "purple spot with a thick body," and when P. knowlesi, a "purple spot (or spots) with an amorphous thick ring."¹⁵

· The trophozoite stage is characterised by "a bigger spot [growing] around a smaller spot" in P. falciparum, "a misshapen circle [containing] an extended spot," "a circle (occasionally with small corners) that contains a purple spot with undefined shapes," "a basket or band-shaped [without a] spot," and "a purple branched spot" in P. vivax, P. ovale, and P. malariae.¹⁵

· P. falciparum's schizont stage is undefined, whereas in P. vivax, it manifests as "not defined purple specks inside a circle;" in P. malariae as "diffuse purple spots around a darker area," in P. knowlesi as "defined purple spots [that are] easy to count," and in P. ovale as "more than one spot inside an oval circle (occasionally with narrow corners). ¹⁵

· The gametocyte stage is "banana [or] sausage-shaped" in P. falciparum, "an extended, big spot" in P. vivax, "a row of accumulated spots" in P. ovale, "a big stained spot that almost fill[s] the circle," a "big spot that contains small spots" in P. malariae, and "a big spot that contains big spots" in P. knowlesi.¹⁵

As infected erythrocytes may become intravascularly sequestered, a negative first smear does not necessarily rule out malaria; if clinical suspicion of malaria is high, smears must be repeated in 12 and 24 hours. Monocytes and neutrophils may also contain the malarial pigment, which can appear on blood smears, especially in those with cerebral malaria.

Rapid diagnostic testing (RDT), microhematocrit centrifugation, and polymerase chain reaction are other diagnostic techniques (PCR). RDTs that identify the parasite antigens lactate dehydrogenase, aldolase, and histidine-rich protein-2 are increasingly used to identify P. falciparum infections. 16 Although microscopy is still advised at the time of presentation and after 12 and 24 hours, sensitivities are becoming close to 100%. The only P. falciparum species may be detected by RDTs, the parasite burden cannot be quantified, and false-positive results might arise weeks after infection because of persisting blood antigens. Infected erythrocytes are isolated by microhematocrit centrifugation, which then binds to acridine in the collection tube to make the parasites glow. The detection and speciation of low-level parasitemia are both aided by PCR.

Complicated or severe malaria:

This occurs when malaria affects different body systems.

· every anemia (due to destruction of red blood cells)

· Kidney failure

· Cerebral malaria -- seizures, unconsciousness, abnormal behavior, or confusion

· Low blood sugar (in pregnant women after treatment with quinine)

· Cardiovascular collapse

Malaria facts:

In 2016, there were more than 215 million cases of malaria worldwide.

· Although there has been a significant decline in deaths since 2000 due to increased prevention and control measures, there has been an increase from 2015 to 2016.

· The World Health Organization estimates that 445,000 people died of malaria in 2016, with the majority being young children in sub-Saharan Africa.

· Approximately 1,700 Americans are diagnosed with malaria each year in the United States, often travellers coming back from endemic regions.

· Up until disease-control initiatives eliminated it during the 1920s–1940s, malaria posed a significant threat to public health in the United States. The CDC's early efforts were largely devoted to managing and eradicating malaria in the United States.

Malaria Prevention:

Malaria, a potentially fatal infection spread by the bite of a female Anopheles mosquito, is a concern for many tourists visiting tropical regions. Malaria affects more than 100 nations, however it is most prevalent in Africa.

Is malaria contagious?

Since malaria is a mosquito-borne illness, it cannot be passed from one person to another (with the exception of pregnant women, as will be discussed below), but it can spread in some situations without a mosquito. This happens infrequently and is typically discovered when congenital malaria is transmitted from a pregnant mother to her unborn child, through blood transfusions, or when intravenous drug users share needles. Malaria is not thought to be infectious from person to person, with the exception of the aforementioned diseases.

What is the incubation period for malaria?

It takes between seven and thirty days after the mosquito bite for symptoms to manifest (incubation period). P. vivax typically takes 10–17 days to incubate, but it can take much longer (up to a year, and very infrequently even 30 years!). Typically, P. falciparum has a brief incubation period (10-14 days). Similar to P. vivax, other Plasmodium species that cause malaria have incubation times.

What causes malaria? What are the types of malaria?

Parasites of the genus Plasmodium cause malaria. Although there are many species of the malaria parasite Plasmodium, only five infect humans and cause malaria.

Plasmodium falciparum:

found in tropical and subtropical areas; major contributor to deaths from severe malaria

P. vivax: found in Asia and Latin America; has a dormant stage that can cause relapses

P. ovale: found in Africa and the Pacific islands

P. malariae: worldwide; can cause a chronic infection

P. knowlesi: found throughout Southeast Asia; can rapidly progress from an uncomplicated case to a severe malaria infection

What are the signs and symptoms of malaria?

There are many different symptoms of malaria. The incubation period, which begins seven to thirty days after the infected mosquito bites, typically lasts seven to fifteen days.

Malaria is categorized as either uncomplicated or complicated (severe) by medical professionals.

Fever and chills, headaches, nausea and vomiting, and general weakness and body aches are the most common signs of simple malaria.

The standard description of a malaria attack is a six- to 12-hour phase of coldness and shivering followed by fever and headaches, followed by a stage of sweating and exhaustion (which is rarely observed) (sometimes divided into the cold and hot stage).

Because of how vague these symptoms are, it's critical to determine whether the patient has malaria risk factors (usual travel in endemic areas).

Complicated or severe malaria:

When malaria affects several bodily systems, this happens:

Kidney failure; severe anaemia (red blood cell depletion); convulsions; unconsciousness; aberrant behaviour; or confusion; cerebral malaria; cardiovascular collapse; low blood sugar (in pregnant women after treatment with quinine)

What specialists treat malaria?

Your primary care physician (paediatrician, family physician, or internal medicine) as well as infectious disease experts can treat malaria.

How is malaria diagnosed by doctors?

Malaria symptoms might resemble those of numerous other illnesses, such as influenza or viral syndrome. Therefore, it's crucial to ask if there have been any recent trips to an endemic region or other potential exposures.

By examining a blood sample from an infected patient under a microscope (blood smear) and determining whether the parasite is present, doctors can determine with certainty that the patient has malaria. To help identify the parasite, the blood from the patients is prepared on a slide and stained with a particular dye. The most often used and acknowledged test is this one.

There are various rapid diagnostic tests (antigen tests) that can provide the diagnosis in a short period of time. After a positive test, a blood smear examination is advised.

What is the treatment for malaria?

The medical team must choose the best antimalarial medication(s) in addition to supportive care to treat malaria. The choice will be based on a number of variables, such as the particular species of parasite found, the severity of the symptoms, and the determination of treatment resistance based on the patient's travels.

Depending on the aforementioned factors, doctors may provide the drug as a tablet or an intravenous antimalarial.

The most commonly used medications are:

· chloroquine (Aralen)

· doxycycline (Vibramycin, Oracea, Adoxa, Atridox)

· quinine (Qualaquin)

· mefloquine (Lariam)

· atovaquone/proguanil (Malarone),

· artemether/lumefantrine (Coartem), and

· Primaquine phosphate (Primaquine).

What is the prognosis of malaria?

The prognosis of malaria is very excellent if it is detected early and the proper antimalarials are accessible and administered.

Each year, malaria causes more than 400,000 fatalities worldwide. Sub-Saharan African small children make up the majority of the victims. Death is frequently brought on by a lack of access to or availability of therapy.

The species that frequently causes the most difficulties and has a high fatality rate if left untreated is P. falciparum.

Even with treatment, cerebral malaria, a P. falciparum complication, has a 20% fatality rate.

Is there a malaria vaccine?

There isn't a commercial malaria vaccine on the market right now. The majority of efforts are presently focused on a P. falciparum vaccine because of the diversity of Plasmodium species and the fact that P. falciparum is the most deadly parasite. The most advanced option for a workable vaccination is RTS,S/ASO1.

RTS,S/ASO1 underwent a phase 3 trial, the findings of which were reported in 2015. The pilot programme is being supported by the WHO in numerous sub-Saharan nations.

How can malaria be avoided?

There are various measures involved in preventing malaria.

Assess whether malaria is a problem in the destination first (CDC malaria information by country table). Additionally, this table will list the drugs that should be used as chemo-prophylaxis.

If chemo-prophylaxis is suggested, talk to a medical expert about the suggested treatments to see if they are appropriate. Take into account any existing medical conditions, pharmacological combinations with regularly taken prescription medications, and the potential negative effects of the suggested medication.

Because no treatment is 100% successful, avoiding mosquito bites is of utmost importance. The following should be among these precautions:

· Sleeping beneath a bed net: This should extend from the head of the bed to the floor. When coated with an insecticide, these nets work best.

· Clothes: Wearing clothing that covers the majority of exposed flesh and wearing shoes with laces helps lower the chance of being bitten. All clothing should be tucked in, and to prevent exposure around the ankles, pants should be tucked into socks. Further reducing the risk of bites is the application of insecticides on clothing.

· Spray insect repellent on all skin that is exposed.

CONCLUSION:

Numerous thousands of deaths from malaria are avoidable. People can easily recover from this illness with prompt and effective therapy. Symptom delays should be reported to healthcare professionals because they are probable. It is crucial to notify the CDC of any malaria cases in the US as well.

ACKNOWLEDGEMENT:

I Would like to express my special thanks of gratitude to my Prof. Dr. Anuj Nautiyal SGRR University, Dehradun. who gave me the golden opportunity to do this Review article on “MALARIA”, Who also helped me in completing my review article.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

ABBREVIATIONS:

IV: Intravenous, RDT: Rapid Diagnostic Testing

MIN: Minutes, HR: Hour, WHO: World Health Organaization.

REFERENCE:

1. Garcia LS. Malaria. Clin Lab Med. 2010Mar; 30(1):93-129. doi: 10.1016/j.cll.2009.10.001, PMID20513543.

2. Wijesekera SK, Carter R, Rathnayaka L, Mendis KN. A malaria parasite toxin associated with Plasmodium vivax paroxysms. Clin ExpImmunol. 1996; 104(2):221-7. doi: 10.1046/j.1365-2249.1996.07699.x, PMID 8625512.

3. Annan Z, Durand P, Ayala FJ, Arnathau C, Awono-Ambene P, Simard F, Razakandrainibe FG, Koella JC, Fontenille D, Renaud F. Population genetic structure of Plasmodium falciparum in the two main African vectors. Anopheles gambiae and Anopheles funestus. Proc Natl AcadSci USA. 2007; 104(19):7987-92. doi: 10.1073/pnas.0702715104, PMID 17470800.

4. Baker DA. Malaria gametocytogenesis. Mol Biochem Parasitol. 2010; 172(2):57-65. doi: 10.1016/j.molbiopara.2010.03.019, PMID 20381542.

5. Waters AP. Epigenetic roulette in blood stream Plasmodium: gambling on sex. PLOS Pathog. 2016; 12(2):e1005353. doi: 10.1371/journal.ppat.1005353, PMID 26866803.

6. Wassmer SC. Investigating the pathogenesis of severe malaria: a multidisciplinary and cross-geographical approach. Am J Trop Med Hyg. 2015; 93(3); Suppl:42-56. doi: 10.4269/ajtmh.14-0841, PMID 26259939.

7. Wassmer SC, Grau GE. Severe malaria: what’s new on the pathogenesis front? IntJParasitol. 2017; 47(2-3):145-52. doi: 10.1016/j.ijpara.2016.08.002, PMID 27670365.

8. World Health Organization. Severe malaria. Trop Med Int Health. 2014; 19; Suppl 1:7-131. doi: 10.1111/tmi.12313_2, PMID 25214480.

9. Dondorp AM, Day NP. The treatment of severe malaria. TransRSocTropMedHyg. 2007; 101(7):633-4. doi: 10.1016/j.trstmh.2007.03.011, PMID 17434195

10. Bernabeu M, Smith JD. EPCR and malaria severity: the center of a perfect storm. Trends Parasitol. 2017; 33(4):295-308. doi: 10.1016/j.pt.2016.11.004, PMID 27939609. Reviews the molecular basis of parasite sequestration in the tissues, which leads to the obstruction of the microvasculature and severe disease, and discusses the key role of EPCR in these processes.

11. López Del Prado GR, Hernán García C, Moreno Cea L, Fernández Espinilla V, Muñoz Moreno MF, Delgado Márquez A, Polo Polo MJ, Andrés García I. Malaria in developing countries. JInfectDevCtries. 2014Jan15; 8(1):1-4. doi: 10.3855/jidc.4610, PMID24423706.

12. Fletcher TE, Beeching NJ.Malaria. JR Army Med Corps. 2013Sep; 159(3):158-66. doi: 10.1136/jramc-2013-000112, PMID 24109136.

13. Mayer RC, Tan KR, Gutman JR. Safety of atovaquone-Proguanil during pregnancy. JTravelMed. 2019Jun1; 26(4). doi: 10.1093/jtm/tay138, PMID30544231.

14. Carlton JM. Malaria parasite evolution in a test tube. Science. 2018Jan12; 359(6372):159-60. doi: 10.1126/science.aar4189, PMID29326260.

15. Ortiz-Ruiz A, Postigo M, Gil-Casanova S, Cuadrado D, Bautista JM, Rubio JM, Luengo-Oroz M, Linares M. Plasmodium species differentiation by non-expert on-line volunteers for remote malaria field diagnosis. MalarJ. 2018Jan30; 17(1):54. doi: 10.1186/s12936-018-2194-8, PMID29378588.

16. Mathison BA, Pritt BS. Update on Malaria Diagnostics and testutilization. JClinMicrobiol. 2017Jul; 55(7):2009-17. doi: 10.1128/JCM.02562-16, PMID28404673.

Received on 21.01.2023 Modified on 21.02.2023

Asian J. Res. Pharm. Sci. 2023; 13(2):154-160.

DOI: 10.52711/2231-5659.2023.00027