Efficacy and safety of a sodium-glucose co-transporter-2 inhibitor versus placebo as an add-on therapy for people with type 2 diabetes inadequately treated with metformin and a dipeptidyl peptidase-4 inhibitor: a systematic review and meta-analysis of randomised controlled trials.

AIMS: To conduct a systematic review and meta-analysis to assess the efficacy, safety and tolerability of sodium-glucose co-transporter-2 inhibitors vs placebo as add-on therapy after metformin and dipeptidyl peptidase-4 inhibitor dual therapy in type 2 diabetes. METHODS: This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO registration number: CRD42018099398). A search was conducted via PubMed, www.clinicaltrials.gov and Cochrane Central Register of Controlled Trials of relevant randomised controlled trials up until 14 August 2020 that compared sodium-glucose co-transporter-2 inhibitors vs placebo as add-on therapy after metformin and dipeptidyl peptidase-4 inhibitor therapy. A random-effects model was used. RESULTS: Six randomised controlled trials (1661 participants) met the inclusion criteria. Compared with placebo, sodium-glucose co-transporter-2 inhibitor treatment, as add-on to metformin and dipeptidyl peptidase-4 inhibitor therapy, was associated with a significant reduction in HbA1c level [mean difference -8 mmol/mol, 95% CI -10, -6 (-0.7%, 95% CI -0.9, -0.6); P < 0.00001], in fasting plasma glucose level [mean difference -1.70 mmol/l, 95% CI -1.91, -1.49; P < 0.00001], in weight (mean difference -1.76 kg, 95% CI -2.04, -1.48; P < 0.00001) and in blood pressure (systolic blood pressure: mean difference -3.6 mmHg, 95% CI -4.8, -2.4; P < 0.00001; diastolic blood pressure: mean difference -1.5 mmHg; 95% CI -2.4, -0.6; P = 0.002). Genital mycotic infections (odds ratio 7.37, 95% CI 3.06, 17.76; P < 0.00001) were more common with sodium-glucose co-transporter-2 inhibitors, but there was no significant statistical difference in urinary tract infections (odds ratio 1.16, 95% CI 0.63, 2.13; P = 0.64), in hypoglycaemia (odds ratio 1.36, 95% CI 0.61, 3.04; P = 0.45), or in discontinuation rates due to adverse events (odds ratio 1.52, 95% CI 0.78, 2.97; P = 0.22) between the two groups. CONCLUSIONS: In comparison with placebo, add-on therapy with a sodium-glucose co-transporter-2 inhibitor is significantly more efficacious in lowering HbA1c , fasting plasma glucose and weight in people with type 2 diabetes following inadequate glycaemic control with metformin and a dipeptidyl peptidase-4 inhibitor. The rate of discontinuation due to adverse events was similar despite higher risk of genital mycotic infections.

The Prevalence and Management of Metabolic Acidosis of Chronic Kidney Disease

Aim Emerging evidence supports initiating oral sodium bicarbonate (OSB) at a serum bicarbonate (HCO3) level of less than 22mmol/L. We look to identify the prevalence of metabolic acidosis of chronic kidney disease (MA-CKD) and its management with OSB at a regional university hospital. Methods Retrospective data was collected using the national electronic renal database (eMED) to identify chronic kidney disease (CKD) patients with MA-CKD over a one-year period. Results One-hundred and forty-four patients were identified with CKD, of which 131 (89%) were tested for HCO3. MA-CKD was present in 44 patients (34%), all had eGFR< 30ml/min/1.73m2, 7 (16%) were prescribed OSB, 7(16%) OSB was contraindicated, and 37 (84%) patients managed with dietary input only. Mean HCO3 level at initiation in OSB group was 18.3±1mmol/L compared to 19.4±1.4mmol/L in dietary input only group which was statistically significant (p<0.05). Conclusion A high burden of advanced CKD was found in the regional nephrology centre, with one third of patients demonstrating MA-CKD. Majority had dietary input only. Further awareness and consensus need to be established on the benefits of treating MA-CKD with OSB.

Platynosomum fastosum-induced chronic intrahepatic cholangitis and Spirometra spp. infections in feral cats from Grand Cayman.

The occurrence of platynosomiasis and intestinal sparganosis is described in feral cats from Grand Cayman, Cayman Islands. Spirometra spp. was observed within the intestine of 18.18% (10/55) of cats; 1.18% (1/55) of cats demonstrated gross and histological manifestation of parasitism by Platynosomum fastosum, but 14.5% (8/55) of cats had the characteristic pathological manifestations of P. fastosum-induced intrahepatic cholangitis without the concomitant presence of the intraductal trematode. Combined parasitism (Spirometra spp. and P. fastosum) was observed in 9.09% (5/55) of feral cats. Significant pathological findings were only associated with the hepatic fluke, P. fastosum, and were grossly characterized by moderate hepatomegaly with enlarged and dilated bile ducts. Examples of cestodes with morphological features characteristic of Spirometra spp. were observed within the small intestine without any associated pathological lesion. The histopathological evaluation of liver fragments revealed chronic intrahepatic cholangitis with and without the associated intraductal trematode, and was characterized by marked periductal fibrosis, adenomatous proliferation of bile duct epithelium, dilation of intrahepatic bile ducts and portal accumulations of inflammatory cells. The occurrence of the cestode in feral cats coupled with factors that are unique to Grand Cayman makes this island the ideal location for sporadic cases of human sparganosis.

The impact of COVID-19 pandemic on blood supplies and transfusion services in Eastern Mediterranean Region.

BACKGROUND: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has spurred a global health crisis. The safety and supply of blood during this pandemic has been a concern of blood banks and transfusion services as it is expected to adversely affect blood system activities. We aim to assess the situation in the Eastern Mediterranean Region (EMR) during the first months of the pandemic. MATERIALS AND METHODS: A survey was designed to address blood supply, transfusion demand, and donor management during the coronavirus disease-19 (COVID-19) pandemic. Medical directors of different blood banks were invited to participate. RESULTS: A total of 16 centers participated with representation from 15/19 countries in the region. In total, 75% were from national blood banks. Most centres had a decrease in the blood supply, ranging from 26-50%. Representatives from 14 countries (93.3%) believed that public fear has contributed to a decrease in donations. Most centres (n=12, 75%) had a reduction in transfusion demand, while those who did not, reported heavy involvement in treating patients with underlying haemoglobinopathies and haematological malignancies. Half of the centres activated their contingency plans. Four centres had to alter the blood donor eligibility criteria to meet demands. All centres implemented donor deferral criteria in relation to SARS-CoV-2, but were variable in measures to mitigate the risk of donor and staff exposure. CONCLUSION: Blood services in the region faced variable degrees of blood shortages. We summarize lessons learnt during this pandemic for the blood banks to consider to plan, assess, and respond proportionately to future similar pandemics.

Acquired reactive perforating collagenosis: a clinicopathologic study of 15 cases from Saudi Arabia.

BACKGROUND: Perforating dermatoses include a family of disease characterized by transepidermal elimination of collagen. Despite being described many years ago in association with systemic disease, it is still clinically misdiagnosed. OBJECTIVE: A retrospective clinical and pathologic review that will increase clinical and pathologic diagnostic awareness of this entity and explore associated systemic disease. PATIENTS AND METHODS: In this report, we present from Saudi Arabia for the first time details of a series of patients seen at the King Abdulaziz Medical City, WR, Jeddah, Saudi Arabia, during the period 2002-2009. RESULTS: The study revealed 15 histologically confirmed cases of acquired reactive perforating collagenosis (ARPC). Patients were predominantly adult females with a mean age of 54 years. The lesions were pruritic, predominantly multiple, erythematous excoriated papules and umblicated nodules centrally crusted with an average duration of 6 months, involving the extremities with or without the trunk in 12 patients. Associated systemic disease included diabetes mellitus in 12 patients and chronic renal failure on dialysis in 8 patients. The provisional clinical differential diagnosis included perforating collagenosis in only eight patients. CONCLUSION: ARPC is not uncommon in Saudi Arabia. The noduloulcerative lesions involve predominantly the extremities, and diabetes mellitus is the most common associate. It is hoped that this article will increase awareness for recognition of this entity to start appropriate therapy.

Invasive infection in a young immunocompetent soldier caused by Scytalidium dimidiatum.

Scytalidium dimidiatum is mainly responsible for human skin and nail infections but the mould has also been reported for invasive infections in immunocompromised individuals. We report a young immunocompetent individual diagnosed with invasive non-traumatic Scytalidium dimidiatum infection involving the left orbital cavity and maxillary sinus.

Computationally efficient fully-automatic online neural spike detection and sorting in presence of multi-unit activity for implantable circuits.

BACKGROUND: Spike sorting is a basic step for implantable neural interfaces. With the growing number of channels, the process should be computationally efficient, automatic,robust and applicable on implantable circuits. NEW METHOD: The proposed method is a combination of fully-automatic offline and online processes. It introduces a novel method for automatically determining a data-aware spike detection threshold, computationally efficient spike feature extraction, automatic optimal cluster number evaluation and verification coupled with Self-Organizing Maps to accurately determine cluster centroids. The system has the ability of unsupervised online operation after initial fully-automatic offline training. The prime focus of this paper is to fully-automate the complete spike detection and sorting pipeline, while keeping the accuracy high. RESULTS: The proposed system is simulated on two well-known datasets. The automatic threshold improves detection accuracies significantly( > 15%) as compared to the most common detector. The system is able to effectively handle background multi-unit activity with improved performance. COMPARISON: Most of the existing methods are not fully-automatic; they require supervision and expert intervention at various stages of the pipeline. Secondly, existing works focus on foreground neural activity. Recent research has highlighted importance of background multi-unit activity, and this work is amongst the first efforts that proposes and verifies an automatic methodology to effectively handle them as well. CONCLUSION: This paper proposes a fully-automatic, computationally efficient system for spike sorting for both single-unit and multi-unit spikes. Although the scope of this work is design and verification through computer simulations, the system has been designed to be easily transferable into an integrated hardware form.

In vivo cytokine profiles in patients with kala-azar. Marked elevation of both interleukin-10 and interferon-gamma.

The immunological mechanisms underlying the susceptibility to disseminated visceral parasitism of mononuclear phagocytes in patients with kala-azar remain undefined. Resistance and susceptibility are correlated with distinct patterns of cytokine production in murine models of disseminated leishmanial disease. To assess lesional cytokine profiles in patients with kala-azar, bone marrow aspirates were analyzed using a quantitative reverse transcriptase PCR technique to amplify specific mRNA sequences of multiple Th1-, Th2-, and/or macrophage-associated cytokines. Transcript levels of IL-10 as well as IFN-gamma were significantly elevated in patients with active visceral leishmaniasis; IL-10 levels decreased markedly with resolution of disease. These findings suggest that IL-10, a potent, pleiotropic suppressor of all known microbicidal effector functions of macrophages, may contribute to the pathogenesis of kala-azar by inhibiting the cytokine-mediated activation of host macrophages that is necessary for the control of leishmanial infection.

Epidemiological Trends of Cutaneous Leishmaniasis in Al-Madinah Al-Munawarah Province, Western Region of Saudi Arabia.

OBJECTIVE: To investigate the epidemiological trends of cutaneous leishmaniasis (CL) in Al-Madinah Al-Munawarah, western region of KSA. MATERIALS AND METHODS: Four hundred and sixty-seven parasitologically confirmed CL cases attending Al-Meeqat Hospital, Al-Madinah, during 2012-2015, were included in this study. RESULTS: Both Saudi and non-Saudi nationals were infected, with the highest infection rate being among Saudis (68.7%). Males were more affected than females as 86.9% of the total CL cases were males. Moreover, CL was prevalent in all age groups with higher frequency among young adults and adolescents (23.1% and 22.7%, respectively). Interestingly, almost all the patients in the adolescent and child age groups were Saudis (96.2% and 93.5%, respectively). Considering geographical distribution, the highest percentage of the cases (40.5%) were from the northern parts of Al-Madinah province while the eastern parts reported the least infection rate (7.3%). Few cases (2.5%) were supposed to encounter the infection abroad. Additionally, the frequency of infection was found to follow a seasonal distribution. Regarding treatment, pentostam, ketoconazole, or cryotherapy were the treatment options usually used. CONCLUSION: CL is prevalent in Al-Madinah Al-Munawarah area and new foci are being introduced. Thus, detailed studies with large surveillances regarding vector and reservoir hosts in and around the area are needed.

6-thioguanine as a cause of toxic veno-occlusive disease of the liver.

Lesions of hepatic veno-occlusive disease were found in the needle biopsy specimen of one patient suffering from chronic granulocytic leukaemia and in the liver at necropsy of a second patient suffering from acute myeloid leukaemia. The treatment included administration of 6-thioguanine which was the only relevant compound used in the first patient and which was combined with cytosine arabinoside in the second patient.

Appendicular schistosomiasis: a cause of clinical acute appendicitis?

The role of schistosomes in the pathologenesis of acute appendicitis in an endemic area was investigated. Of 1600 appendicectomies received in our laboratory, 26 showed appendiceal schistosomiasis, which prompted what we believe to be the first detailed histopathological evaluation of all appendices with schistosomal infestation, without prior knowledge of the clinical and operative diagnoses. The results suggest that there are two types of schistosomal appendicitis, each with distinct clinicopathological features and different pathogenetic mechanisms. They could be called obstructive and granulomatous schistosomal acute appendicitis, respectively.

Congenital kala-azar and leishmaniasis in the placenta.

During an epidemic of visceral leishmaniasis in the Sudan, two cases of congenital kala-azar were seen. The first child, whose mother had contracted kala-azar in southern Sudan, was born in Khartoum, where no transmission of leishmaniasis is currently occurring. At seven months, the child had fever, lymphadenopathy, and hepatosplenomegaly; leishmania parasites were detected in the bone marrow. The child died and an autopsy showed leishmania parasites in all tissues including the lungs, kidneys, and thymus. In the second case, parasites were found in the placenta of a five-month-old fetus. These two cases demonstrate the importance of follow-up of infants born to mothers with leishmaniasis.

The treatment of kala-azar in the Sudan with sodium stibogluconate: a randomized trial of three dosage regimens.

In a randomized study in the Sudan, 3 different regimens of sodium stibogluconate were compared in patients with parasitologically confirmed kala-azar (visceral leishmaniasis): 10 mg/kg for 30 d (38 patients), 20 mg/kg for 30 d (29 patients), and 20 mg/kg for 15 d (37 patients). Treatment failures were defined as death, partial response, relapse, or the development of post-kala-azar dermal leishmaniasis. The hazard ratio for failure of 20 mg/kg for 30 d vs. 10 mg/kg for 30 d 2.1 (95% confidence interval [CI] = 0.6, 7.6) and for 20 mg/kg for 15 d vs. 10 mg/kg for 30 d it was 1.7 (95% CI = 0.5, 6.1). No significant difference was detected between the 3 regimens in the rate of return to normal of haematological criteria, regression of spleen size, or weight gain. After 15 d treatment parasite clearance with 20 mg/kg for 30 d and 20 mg/kg for 15 d was more profound than with 10 mg/kg for 30 d (P < 0.05), but the difference was no longer present at the end of treatment. Further investigation of the effectiveness of short, intensive treatment regimens in the treatment of kala-azar is warranted.

Kala-azar in displaced people from southern Sudan: epidemiological, clinical and therapeutic findings.

Six hundred and ninety-three patients with kala-azar were seen in Khartoum, Sudan, from January 1989 to February 1990. They were almost exclusively from the Nuer tribe, originating from the western Upper Nile province in southern Sudan, an area not known previously to be endemic for kala-azar. Because of the civil war in southern Sudan no treatment was available locally and massive migration to northern Sudan occurred; many died on the way. All age groups were affected; there was a slight male preponderance (56%). In the clinical presentation, marked generalized lymphadenopathy was prominent (84%). Splenomegaly was absent in 4% of cases. Patients usually showed anaemia, leucopenia and/or thrombocytopenia. 623 patients were treated with sodium stibogluconate, 10 mg/kg for 30 d; relapse occurred in 4% and death in 12%. Latterly, 70 patients were treated with sodium stibogluconate at 2 x 10 mg/kg for 15 d, with relapse in 6% and death in 6%. The difference between the 2 regimens in the number of relapses and deaths was not significant. The outbreak may have been caused by a combination of factors: the introduction of the parasite from an endemic area to a non-immune population, the presence of malnutrition caused by loss of cattle and unavailability of other food sources, and possibly an ecological change in favour of the sandfly vector.

Direct agglutination test for diagnosis and sero-epidemiological survey of kala-azar in the Sudan.

132 patients with suspected kala-azar (visceral leishmaniasis) were included in a prospective study to compare the performance of the direct agglutination test (DAT) with smears of lymph node, bone marrow and splenic aspiration. A titre greater than 1:3200 was considered positive. 67 patients provided positive smears and 65 were smear-negative. Compared with the results obtained from smears, the sensitivity of the DAT was 94% and its specificity 72%. Of 18 patients who were negative by smears but positive by DAT, 3 were treated on strong clinical suspicion of kala-azar and responded well to therapy. One other patient had post-kala-azar dermal leishmaniasis. Of the remaining 14, 8 were tested with the leishmanin skin test; 6 gave a positive result, suggesting past or sub-clinical infection. In 4 smear-positive patients, the DAT was negative; in 2 of these, the test remained negative during 6 months' follow-up. In a sero-epidemiological survey in a camp for displaced people, 30 of 600 sampled individuals gave a positive DAT. Of these, 11 had been treated for kala-azar; 4 others were leishmanin positive. The DAT is a useful screening test (sensitivity 94%; predictive value of a negative test 92%), but it does not differentiate between past kala-azar, sub-clinical infection and active disease.

Post kala-azar dermal leishmaniasis in the Sudan: clinical features, pathology and treatment.

The clinical features, pathology, immune responses, diagnosis and treatment of post kala-azar dermal leishmaniasis (PKDL) in the Sudan are described and discussed. The disease is characterized by maculopapular or nodular lesions on the face, limbs or trunk. Lesions appear during or within months after the treatment of visceral leishmaniasis, but in 2 of 19 patients there was no previous history of kala-azar. PKDL may be confused with leprosy both clinically and pathologically. Similarities and differences between the 2 diseases are discussed. Unlike visceral leishmaniasis, the peripheral lymphoid cells of patients with PKDL respond to Leishmania antigen and some are leishmanin positive. The response to intravenous sodium stibogluconate (20 mg/kg for 30 d) was reasonably good but some patients required repeated or more prolonged treatment. Ketoconazole in a dose of 10 mg/kg daily for 4 weeks had no effect on PKDL.

Kala-azar: a comparative study of parasitological methods and the direct agglutination test in diagnosis.

In a comparative study 88 patients were diagnosed as suffering from kala-azar (visceral leishmaniasis) using 3 parasitological methods simultaneously. Splenomegaly was absent in 4 cases. In 84 patients with splenomegaly, splenic aspiration appeared to be the most sensitive method (96.4%), followed by bone marrow aspiration (70.2%) and lymph node aspiration (58.3%). There was no relation between titres in the direct agglutination test and parasite load as determined by the number of parasitological methods which were positive or parasite density in splenic aspirates. Splenic aspiration and bone marrow aspiration were compared as an assessment of cure in kala-azar. In 6 (13%) of 46 patients tested, parasites were found, all by splenic aspiration. Bone marrow showed parasites in one of these. The literature with regard to parasitological investigations before and after treatment is reviewed.

Extraspinal meningioma. Case report.

A case of ectopic extraspinal meningioma is reported which presented as a tumor at the back of the neck of a 51-year-old woman. This neoplasm was of considerable size and arose extradurally in the region of the C-2 nerve root, with its main bulk lying almost totally outside the spinal canal in the right suboccipital region. Total resection was accomplished in two stages, with no evidence of recurrence after 1 year. The rarity of such cases prompted this report.

Anti-filarial effects of nine quinoline-containing drugs on adult filariae in vitro.

The potencies and efficacies of 9 quinoline-containing anti-malarials including chloroquine, (bis)desethylchloroquine, SN6911, SN12108, amodiaquine, CN-2999-2K, primaquine, quinacrine, and quinine were examined in vitro against adult female Brugia pahangi. Parasite motility and lactate excretion were measured as indicators of drug effects. All of the agents tested showed time-dependent increases in potency over a 24-72-hr incubation period. SN12108 was the most potent at 72 hr, reducing motility by greater than or equal to 50% (IC50) at 1.0 x 10(-7) M. Chloroquine (IC50 2.3 x 10(-6) M), desethylchloroquine (IC50 7.0 x 10(-6) M), quinacrine (IC50 1.9 x 10(-6) M), and quinine (IC50 1.5 x 10(-5) M) were the least potent. All of the drugs caused time-dependent decreases in lactate excretion, except quinine; decreases were found to be dose dependent. A high correlation (r greater than 0.85) was seen between time-dependent effects on motility and lactate excretion. The effects of chloroquine (10 microM) on motility were also examined in female Acanthocheilonema viteae, Dirofilaria immitis, Onchocerca volvulus, and male Onchocerca gutturosa. Dirofilaria immitis was less sensitive to chloroquine than B. pahangi; A. viteae was equally sensitive. Species of Onchocerca were the most sensitive parasites studied. Adult O. gutturosa and O. volvulus were affected by 10 microM chloroquine within 4-6 hr; motility was reduced by 80% within 24 hr. Although the mechanism of anti-filarial activity of the quinoline-containing drugs is not known, their in vitro activity against a variety of adult filariae at clinically relevant concentrations, as well as differential sensitivity seen between the different filariae examined, warrants further study of these compounds.