Polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes syndrome with dilated cardiomyopathy: A case report

BACKGROUND Polyneuropathy,organomegaly,endocrinopathy,M-protein,skin changes(POEMS)syndrome is a rare paraneoplastic syndrome that encompass multiple systems.The most common clinical symptoms of POEMS syndrome are pro-gressive sensorimotor polyneuropathy,organ enlargement,endocrine disorders,darkening skin,a monoclonal plasma cell proliferative disorder,and lymph node hyperplasia.The organomegaly consists of hepatosplenomegaly and/or lym-phadenopathy;cases of cardiomyopathy are rare.Diagnoses are often delayed because of the atypical nature of the syndrome,exposing patients to possibly severe disability.Therefore,identifying atypical symptoms can improve the prognosis and quality of life among POEMS syndrome patients.lenalidomide and dexamethasone.CONCLUSION When patients with cardiomyopathy have systemic manifestations such as numb limbs and darkening skin,the POEMS syndrome is the most possible diagnosis.

Polyneuropathy organomegaly endocrinopathy M-protein and skin changes syndrome with ascites as an early-stage manifestation:A case report

BACKGROUND Polyneuropathy organomegaly endocrinopathy M-protein and skin changes(POEMS)syndrome is a rare paraneoplastic syndrome caused by a potential plasma cell tumor.The clinical manifestations of POEMS syndrome are diverse.Due to the insidious onset and lack of specific early-stage manifestations,POEMS syndrome is easily misdiagnosed or never diagnosed,leading to delayed treatment.Neurological symptoms are usually the first clinical manifestation,while ascites is a rare symptom in patients with POEMS syndrome.CASE SUMMARY A female patient presented with unexplained ascites as an initial symptom,which is a rare early-stage manifestation of the condition.After 1 year,the patient gradually developed progressive renal impairment,anemia,polyserosal effusion,edema,swollen lymph nodes on the neck,armpits,and groin,and decreased muscle strength of the lower extremities.The patient was eventually diagnosed with POEMS syndrome after multidisciplinary team discussion.Treatment comprised bortezomib+dexamethasone,continuous renal replacement therapy,chest and abdominal closed drainage,transfusions of erythrocytes and platelets,and other symptomatic and supportive treatments.The patient’s condition initially improved after treatment.However,then her symptoms worsened,and she succumbed to the illness and died.CONCLUSION Ascites is a potential early manifestation of POEMS syndrome,and this diagnosis should be considered for patients with unexplained ascites.Furthermore,multidisciplinary team discussion is helpful in diagnosing POEMS syndrome.

Discovering the efficacy and mechanism of Chinese herbal medicine for distal symmetric polyneuropathy via integrating meta-analysis and network pharmacology analysis

Objective Chinese herbal medicine(CHM)has been commonly used in Distal Symmetric Polyneuropathy(DSPN)treatment with satisfactory clinical effects,but the underlying pharmacological mechanism of CHM on DSPN remains unclear.We aimed to identify frequently used clinically effective CHM and its potential pharmacological mechanisms for DSPN by conducting meta-analysis and network pharmacology analysis.Methods We searched both Chinese and English databases from March 1990 to October 2022.Studies that met the inclusion criteria were selected for meta-analysis.After extracting the relevant data,we performed meta-analysis and frequency analysis.The active compounds and predicted targets of high-frequency herbs and DSPN-related targets were extracted from public databases.Then we conducted network construction,Gene Ontology(GO)enrichment,and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis to discover the potential pharmacological mechanisms.Results Sixteen articles were selected for meta-analysis,and nine high-frequency CHMs were identified,including Radix Astragali seu Hedysari,Rhizoma Ligustici,Caulis Spatholobi,Radix Salviae Miltiorrhizae,Radix Paeoniae Alba,Flos Carthami,Radix Notoginseng,Radix Rehmanniae Recens,Rhizoma Corydalis.Fourteen hub targets including STAT3,CTNNB1,MAPK14,SRC,AKT1,TP53,EGFR,JUN,RELA,MAPK1,FOS,CCND1,HSP90AA1,MYC,and ten active compounds including Quercetin,Kaempferol,Luteolin,Apigenin,beta-sitosterol,Stigmasterol,Caffeic Acid,Aeginetic Acid,Vanillin,and Lauric Acid were identified by network analysis.Enrichment analysis showed that the biological process of hub targets included transcriptional regulation,cell proliferation,redox processes,apoptosis processes,ERK1 and ERK2 cascades,hypoxia reactions,MAPK cascades,and inflammatory responses.The main signalling pathways included HIF,TNF,and PI3K-AKT pathways.Conclusion Nine herbs were involved in the clinical therapeutic effect of CHM on DSPN treatment,and they may exert an anti-DSPN effect by regulating cell proliferation,apoptosis,and redox processes.

Demyelinating polyneuropathy and lymphoplasmacytic lymphoma coexisting in 36-year-old man:A case report

BACKGROUND Lymphoplasmacytic lymphoma is a rare non-Hodgkin’s lymphoma,occurring mostly in the elderly.It develops slowly and leads to malignant proliferation of lymphoid line cells in the bone marrow,lymph nodes and spleen.It may also affect nerve roots and meninges;some patients develop sensorimotor polyneuropathy which may precede general symptoms of lymphoma.CASE SUMMARY We present a case of a 36-year-old man diagnosed in 2012 with chronic inflammatory demyelinating polyneuropathy(CIDP),then he was hospitalized in 2019 due to progressive symptoms of heart failure and significant weight loss over the previous four months.Based on clinical and laboratory findings a diagnosis of lymphoplasmacytic lymphoma was suspected and confirmed by bone marrow flow cytometry.There was no improvement in the results of laboratory tests and the patient's condition after immediate implementation of chemotherapy.Patient died on the fifth day of treatment.CONCLUSION While CIDP and malignant disease co-occurrence is rare,it should be suspected and investigated in patients with atypical neuropathy symptoms.

Critical illness polyneuropathy and myopathy:a systematic review

Critical illness polyneuropathy and critical illness myopathy are frequent complications of severe illness that involve sensorimotor axons and skeletal muscles, respectively. Clinically, they manifest as limb and respiratory muscle weakness. Critical illness polyneuropathy/myopathy in isolation or combination increases intensive care unit morbidity via the inability or difficulty in weaning these patients off mechanical ventilation. Many patients continue to suffer from decreased exercise capacity and compromised quality of life for months to years after the acute event. Substantial progress has been made lately in the understanding of the pathophysiology of critical illness polyneuropathy and myopathy. Clinical and ancillary test results should be carefully interpreted to differentiate critical illness polyneuropathy/myopathy from similar weaknesses in this patient population. The present review is aimed at providing the latest knowledge concerning the pathophysiology of critical illness polyneuropathy/myopathy along with relevant clinical, diagnostic, differentiating, and treatment information for this debilitat- ing neurological disease.

CLINICAL AND GENETIC ANALYSIS OF THREE FAMILIES WITH FAMILIAR AMYLOID POLYNEUROPATHY

Objective To study the clinical and genetic features of familiar amyloid polyneuropathy (FAP). Methods Three families of suspected FAP in China mainland and Macao were investigated on aspects of clinical manifestations, histological features, and gene analysis. Results All the 3 families had the clinical features of sensory and motor polyneuropathies, and notable vegetative nerve involvements. Affected cases of one family had ultrasound proved cardiomyopathy. Histological studies showed amyloid deposition in all the biopsy tissues of the affected cases of the 3 families, and anti-transthyretin antisera staining was positive in 3 cases of one family. Gene analysis confirmed that mutation types were amyloidogenic transthyretin (ATTR) Val30Met, Phe33Val, and Gly67Glu in the 3 families respectively. The ATTR Gly67Glu family had a shorter survival time due to the heart involvement compared with the other 2 families. Conclusion FAP is an autosomal dominant inherited disease, with its clinical manifestations related to the type of genetic mutation.

FAMILIAL AMYLOID POLYNEUROPATHY──CLINICAL REPORT OF A FAMILY

This paper reports a familial amyloid polyneuropathy (FAP) family in China. This family being investigated had 69 members of five generations. From the third generation, there have been 16 patients. The age of onset was about 3 to 5 decades. The initial symptoms were autonomic nerve symptoms, such as impotence, dyspepsia and diarrhoea, associated with the sensory loss of lower extremities. As the disease progressed, the upper extremities and motor ability were also involved. The duration of disease course was about 8-10 years, most patients died of infection and cachexia. Sural biopsy in 3 patients had showed positive Congo red staining. From the clinical view, this FAP family is similar to FAP I found in Japan. The true classification, however, should be confirmed by further genetic analysis.

Pericarditis and chronic inflammatory demyelinating polyneuropathy during therapy with pegylated interferon alfa-2a for chronic hepatitis C

We report a case of pericarditis and chronic inflam- matory demyelinating polyneuropathy with biological signs of a lupus-like syndrome due to pegylated interferon alfa-2a therapy during treatment for chronic hepatitis C.The patient developed moderate weakness in the lower limbs and dyspnea.He was hospitalized for congestive heart failure.An electrocardiogram showed gradual ST-segment elevation in leads V1 through V6 without coronary artery disease.A transthoracic cardiac ultrasonographic study revealed moderate pericardial effusion with normal left ventricular function.Anti-DNA antibody and anti-ds DNA IgM were positive.Neu ro logical examination revealed a symmetrical predomina ntly sensory polyneuropathy with impairment of light touch and pin prick in globe and stoking-like distribution.Treatment with prednisolone improved the pericarditis and motor nerve disturbance and the treatment with intravenous immunoglobulin improved the sensory nerve disturbance.

De novo intraocular amyloid deposition after hepatic transplantation in familial amyloidotic polyneuropathy

The familiar amyloid polyneuropathy(FAP) is a rare autosomal-dominant systemic amyloidosis. Amyloid deposition occurs more frequently and extensively in the vitq. The increase in intraocular pressure(IOP) is a result of deposition of transthyretin(TTR) in trabecular meshwork. Rarely, the amyloid deposition in anterior segment can be more exuberant than in posterior segment. A 42 years old man, with FAP(Val30Met mutation), liver transplantation in 1997. He was asymptomatic, without any significant ocular abnormality until 2011. In 2011 he had an episode of pain in right eye(RE). Scalloped pupils, pupillary amyloid deposits and subtle vitreous opacities were detected. The IOP was 40 mmHg in RE and 28 mmHg in left eye(LE) with open angle. Optical coherence tomography detected a temporal superior retinal nerve fiber layer defect in LE and perimetry was normal. Topical timolol was initiated, and brimonidine was subsequently added to improve IOP control, which was achieved with topical medication until last evaluation. No progression occurred since 2011. Actually, with longer life expectancies, there is an increased risk of ocular involvement in FAP, even after liver transplantation. Although rare, a more exuberant amyloid deposition in anterior segment vs posterior segment can occur, and supports an important role of amyloid production in ciliary pigment epithelium in these patients. Medical control of IOP and a stable course are unusual in this secondary glaucoma. Ophthalmologists have an important task in the follow-up of patients and early diagnosis of risk factors for secondary glaucoma, such as scalloped pupils with amyloid deposits.

Conductive hearing loss in chronic inflammatory demyelinating polyneuropathy(CIDP):A case report

Chronic inflammatory demyelinating polyneuropathy(CIDP) is a progressive autoimmune disorder that targets peripheral nerves. It commonly presents with motor-predominant dysfunction and enlargement of cranial nerves. With regards to hearing loss, a few cases of sensorineural loss have been described. We present a novel case of conductive hearing loss caused by a mass on the tympanic segment of the facial nerve in the setting of CIDP.

Effective treatment of polyneuropathy,organomegaly,endocrinopathy,M-protein,and skin changes syndrome with congestive heart failure:A case report

BACKGROUND Polyneuropathy,organomegaly,endocrinopathy,M-protein,and skin changes(POEMS)syndrome is a rare paraneoplastic syndrome caused by a plasma cell proliferative disorder.The syndrome is characterized by elevated plasma cells,platelets,and vascular endothelial growth factor levels.Although heart disease rarely occurs in POEMS syndrome,the death rate increases sharply after heart failure.We report a patient who initially presented with an endocrine disease and developed congestive heart failure related to POEMS syndrome 9 years later.CASE SUMMARY A 23-year-old woman with no history of menstruation and a 9-year history of type I diabetes reported feeling breathless after activities.She could not lie down and rest at night.Three months prior,she experienced pain and increased tension in her left thigh accompanied by tenderness and edema in both lower extremities.The chief complaint upon hospital admission was that blood sugar has increased for more than 9 years,pain in the left thigh,and edema in both legs for more than 2 mo.After a multisystem evaluation,she was diagnosed with POEMS syndrome.Her echocardiogram showed left ventricular dilation with systolic dysfunction,and the left ventricular ejection fraction was only 38%with severely elevated brain natriuretic peptide.She received a combination of dexamethasone and thalidomide for 1 mo,but her symptoms did not improve.Therefore,we added a two-per-week bortezomib injection.After 2 wk,the patient’s heart function had improved significantly.CONCLUSION This case provides information about the treatment of POEMS syndrome with complications and highlights the challenges of developing a standardized treatment.

A prospective, open label, 24-week trial of methylcobalamin in the treatment of diabetic polyneuropathy

Introduction: Vitamin B complex has been used for peripheral neuropathy for a long time and continues to be part of current practice despite lack of strong evidence for its use and its non-inclusion in treatment guidelines. Objective: To determine the clinical and neurophysiological effects of 1500 μgm/day of oral methylcobalamin among subjects with diabetic polyneuropathy. Methodology: We conducted a prospective, open-label study on adult diabetic subjects with polyneuropathy who were given 1500 μgm/day of oral methylcobalamin over 24-weeks. The primary outcome measure was the Toronto Clinical Scoring System (CSS) and secondary measures were Subjective Impression of Change, Clinicians Impression of Change and neurophysiological parameters. Results: Out of forty eight subjects, thirty seven completed treatment and twenty one agreed to have repeat neurophysiologic study post-treatment. At the end of treatment, there was a significant decline in the Toronto CSS score (p < 0.0001) indicating improvement. This was observed across all stages of severity and in any duration of diabetes whether more or less than 10 years. The symptoms that improved compared to baseline and that did not emerge over the course of 24 weeks were tingling (p < 0.03), upper limb symptoms (p < 0.003), ataxia (p < 0.004), and signs of impaired position (P < 0.009) sense, vibration sense (p < 0.0001), pinprick sensation (p < 0.004) and knee reflex (p < 0.004). No significant improvement was seen in the secondary outcomes (both p=0.06) except for ulnar nerve amplitude and distal latency. Conclusion: This 24-week open label study demonstrated that symptoms of diabetic polyneuropathy significantly improved among subjects given methylcobalamin 1500 μgm/day and new symptoms did not emerge over the 24 week observation period. Larger controlled trials are needed to corroborate these findings.

Celiac disease manifested by polyneuropathy and swollen ankles

A 27-year-old male started to have his ankles swollen during his military service. He was examined at a military hospital where electromyoneurography showed the signs of distal sensory-motor polyneuropathy with axon demyelinization and weak myopathic changes, whereas histopathological examination of gastrocnemius muscle biopsy revealed some mild and nonspecific myopathy. Besides, he was found to have subcutaneous ankle tissue edemas and hypertransaminasemia. Due to these reasons, he was dismissed from the military service and examined at another hospital where bone osteodensitometry revealed low bone mineral density of the spine. However, his medical problems were not resolved and after the second discharge from hospital he was desperately seeing doctors from time to time. Finally, at our institution he was shown to have celiac disease (CD) by positive serology (antitissue transglutaminase and antiendomysial antibodies) and small bowel mucosal histopathological examination, which showed total small bowel villous atrophy. Three months after the initiation of gluten-free diet, his ankle edema disappeared, electromyoneurographic signs of polyneuropathy improved and liver aminotransferases normalized. Good knowledge of CD extraintestinal signs and serologic screening are essential for early CD recognition and therapy.

Tailoring of therapy for chronic inflammatory demyelinating polyneuropathy

Chronic inflammatory demyelinating polyneuropathy （CIDP） is a treatable immune-mediated disorder, which causes in its typical form, symmetric proximal and distal weakness with large fibre sensory impairment involving the four limbs. There are currently three main first-line therapeutic options for CIDP. These consist of corticosteroids, immunoglobulins and plasma exchanges （PE） which have all been found effective in a number of trials conducted over the past several years （Van den Bergh and Rajabally, 2013）. No immunosuppressant therapy has shown benefit in CIDP, although they are utilized by many clinicians in various circumstances despite absence of an evidence base.

The Improbable Association between the Herbicide 2,4-D and Polyneuropathy

Isolated case reports have circumstantially linked the use of the herbicide 2.4-dichlorophen-oxyacetic acid (2,4-D) to polyneuropathy. However, a critical review of the literature reveals numerous reasons for doubting a relationship of 2.4-D to polyneuropathy: (1) too few cases given the wide use of the chemical: (2) no valid toxicologic or epidemiologic evidence; (3) the diversity of antecedent illness; (4) an unlikely time sequence of antecedent illness to exposure (pharmacokinetics); (5) the lack of polyneuropathy in medical patients given repetitive doses of 2.4-D; (6) the lack of polyneuropathy in heavily exposed military personnel involved in operation Ranch Hand; (7) the biological properties of 2.4-D which minimize penetration of 2.4-D into the nervous system under normal exposure conditions; and (8) the lack of polyneuropathy in a variety of experimental animal species given 2,4-D by several routes of exposure and at dose levels and durations of exposure many times greater than human applicator exposure. Thus, the weight of evidence indicates that 2.4-D is an unlikely cause of polyneuropathy. 1990 Academic Press. Inc.

HIV-Associated Polyneuropathy in Resource-Limited Settings: Genetic Predisposition and Vitamin Variations

Human immunodeficiency virus-related polyneuropathy remains a painful condition resulting from damaged nerve endings. HIV infection strongly associates with a predominantly polyneuropathy that is attributed to HIV infection itself, or a toxic neuropathy associated with combination antiretroviral therapy (CART). In non-HIV-infected individuals, both deficiency and high intake of vitamins have been associated with polyneuropathy. For that reason, clinicians recommend vitamin supplements before and during CART. Although some, but not all, HIV-related vitamin deficiencies may replete during treatment with CART, it is predictable that high vitamin supplement intakes may contribute to nerve disorders. In resource-limited settings where the diagnosis of polyneuropathy heavily relies on symptoms, data on risk factors for polyneuropathy including vitamin status, alcohol consumption, and co-infections are limited. In addition, studies on genetic influence on the concentration of micronutrients in the blood of long-term users of CART are scarce. Possible sources of high intakes of vitamins could arise from the fact that a number of HIV-infected persons self-medicate. In addition, since HIV-infected individuals have an increased lifespan, relying on symptoms alone to specifically diagnose HIV-associated neuropathies could be a barrier to effective treatment in recourse-poor settings. This paper reviews evidence on single nucleotide polymorphisms (SNPs) with the potential to influence bioavailability of vitamins in HIV-infected patients. Genome-wide association studies have reported SNPs in alkaline phosphatase, fucosyltransferase 2, cubilin, transcobalamin 1, and tumor necrosis factor as potential determinants of various blood levels of vitamin B-6, B-12 and E. As long term CART increasingly become, personalized, future research should focus on SNPs, which influence vitamin blood levels, and with potential to augment long-term treatment with CART.

Distal Sensory Polyneuropathy among HIV Patients in Libreville in Gabon

Distal sensory polyneuropathy (DSP) was more frequent among Human Immunodeficiency Virus (HIV) patients. The reliable tool for its diagnosis is not available everywhere in sub-Saharan Africa. We aimed to estimate the frequency of DSP among HIV patients in Libreville. We’ve conducted a cross-sectional study including all consecutives HIV-patients admitted to the HIV clinic in the University Teaching Hospital of Libreville (Gabon) between 1 May and 31 July 2014. All patients underwent a full neurological examination doing by two neurologists. The diagnosis of DSP was based on Brief Peripheral Neuropathy Screen (BPNS). We also collected the data concerning past medical history, the use of neurotoxic drug, history of disease and data of High Active Antiretroviral Therapy (HAART). The logistic regression was used to study the factors associated with DSP. They were 620 patients aged from 17 to 74 years with the mean age of 42.1 years ± 11.0 years and 570 (91.9%) were on HAART. The mean duration of disease was 57.6 ± 42.5 months. Among the 620 patients 170 fulfilled criteria for DSP, and the overall frequency of DSP was 27.4%. The associated factors in univariate analysis were the age, the occupation, the use of HAART, the HAART option, the stage of the disease, opportunistic disease, alcohol consumption, exposure to isoniazid, diabetes mellitus and the modes of contamination. But in multivariate analysis the associated factors were the stage of disease OR 2.7 [1.2 - 3.7], diabetes mellitus OR 2.4 [1.4 - 5.8] and the use of D4T in HAART OR 1.9 [1.1 - 4.9]. The main symptoms among the patients were burning feet (47.6%), the tingling (40.0%), numbness (27.6%), alteration of ankle reflex (87.6%) and alteration of vibration sensation (27.6%). The DSP was more frequent among HIV patients and could be explained by the duration of the disease, the association with metabolic disease and the use of D4T.

Severe Axonal Peripheral Polyneuropathy Revealing a Systemic Lupus Erythematosus: About One Case

Aim: We report a case of acute and severe sensorimotor peripheral polyneuropathy (with a severe motor damage) revealing a lupus. Case Presentation: A 48-year-old female patient was interned in rheumatology for a chronic polyarthritis. Four days after her hospitalisation, she was presenting a flask distal and proximal tetraparesia, with rapidly progressive installation. Electromyogram showed severe acute axonal sensorimotor polyneuropathy. The antinuclear antibody was positive as the anti-ds-DNA antibodies. The evolution has been unsatisfactory despite the high-dose corticotherapy and the immunosuppressor. Conclusion: Even if it is rare, peripheral neuropathy can be a lupus discovery circumstance.

Frequency of Distal Sensory Polyneuropathy among Diabetics in Parakou in 2012

Background: The distal sensory polyneuropathy (DSP) was more frequent among diabetics, although its determinant was not well known among diabetics in Benin. Objective: We aimed to assess the frequency of DSP and its determinants among diabetics at Parakou. Methods: It was a cross-sectional study carried out from 1 March to 31 August 2012 and included 336 diabetics followed at the diabetes unit of Parakou hospital. The diagnosis of DSP was based on DNS (Diabetic Neuropathy Score) criteria and other criteria. All data concerning the diabetes mellitus were recorded. We used Epi-Info and SPSS 16.0 software to perform analysis. Results: They were 187 females (56.0%) with the mean age of 54.9 ± 10.9 years. 298 patients fulfilled criteria for DSP;the overall prevalence of DSP was 88.7%. The main associated factors in multivariate analysis were treatment duration of diabetes more than 4 years: OR = 36.7 [4.0 - 336.9];the elevated glycaemia: OR = 3.1 [1.4 - 7.1];the activity with high income: OR = 0.2 [0.0 - 0.8];the ethnicity: nagots/fon: OR: 3.7 [1.4 - 12.5]. Conclusion: Those results suggested the high frequency of DSP among diabetics at Parakou.

Physical Exercise as Treatment for Type 2 Diabetes Distal Symmetric Polyneuropathy: A Systematic Review of Randomized and Controlled Studies

Pharmaceuticals targeting the pathogenesis of diabetic distal symmetric polyneuropathy have all failed in clinical trials, limiting recourse to palliative treatments. The American Diabetes Association regards the effectiveness of glycemic control and lifestyle modification therapies on diabetic neuropathies as inconclusive. The objective of this research was to determine if and how physical exercise influences distal symmetric polyneuropathic severity in type 2 diabetes patients. Embase, MEDLINE, and Google Scholar were searched to collect randomized and controlled studies published between January 1, 2012 and April 20, 2020. Titles had to mention diabetes, physical exercise of any type or lifestyle interventions in general, and neuropathy. Abstracts had to indicate satisfaction of PICOS criteria, whereas full-text reviews had to be fully confirmatory. Extracted data was thematically synthesized based primarily on relationships between exercise interventions and effects on distal symmetric polyneuropathic severity outcomes in type 2 diabetes patients. Qualitative analysis scoring criteria objectively mirrored PICO except for the bias and limitation score component, which assessed common markers of validity for randomized trials (as specified in the PRISMA statement). Database searches yielded 379 unique records, 15 of which passed eligibility screening. Thematic synthesis supported exercise as an ameliorative treatment of type 2 diabetes distal symmetric polyneuropathy through improved Michigan Diabetic Neuropathy Scores and increased sural sensory nerve conduction velocity, though efficacy may be limited by neuropathic severity. This is the first systematic review to acquire these results, and to do so within the context of neuropathic severity. This review protocol is registered on PROSPERO (CRD42020181211) at https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020181211