Continuous Glucose Monitoring Use in Clinical Trials for On-Market Diabetes Drugs

To the best of our knowledge, there are no published data on the historical and recent use of CGM in clinical trials of pharmacological agents used in the treatment of diabetes. We analyzed 2,032 clinical trials of 40 antihyperglycemic therapies currently on the market with a study start date between 1 January 2000 and 31 December 2019. According to ClinicalTrials.gov, 119 (5.9%) of these trials used CGM. CGM usage in clinical trials has increased over time, rising from <5% before 2005 to 12.5% in 2019. However, it is still low given its inclusion in the American Diabetes Association’s latest guidelines and known limitations of A1C for assessing ongoing diabetes care.

The availability of reliable continuous glucose monitoring (CGM) systems has proven to be a major innovation in diabetes management and research. Most current CGM systems are approved for 7- to 14-day use and use a wire-tipped glucose oxidase sensor inserted in subcutaneous tissue to monitor glucose concentrations in interstitial fluid. One implanted CGM system is approved for longer-term use (90–180 days); it operates with fluorescence-based technology. CGM sensors record a glucose data point every 1–15 minutes (depending on the system), collecting far more granular data and information on glycemic patterns than self-monitoring of blood glucose (SMBG) alone. Real-time CGM or intermittently scanned CGM systems send data continuously or intermittently to dedicated receivers or smartphones, whereas professional CGM systems provide retrospective data, either blinded or unblinded, for analysis and can be used to identify patterns of hypo- and hyperglycemia. Professional CGM can be helpful to evaluate patients when other CGM systems are not available to the patient or the patient prefers a blinded analysis or a shorter experience with unblinded data.In the 20 years since CGM systems first became available to people with diabetes, technological improvements, particularly pertaining to accuracy and form factor, have made CGM increasingly viable for both patient use and clinical investigation (1,2). Average sensor MARD (mean absolute relative difference; a summary accuracy statistic) has decreased from >20 to <10% (3–10), including two systems that do not require fingerstick calibrations and three that are approved to be used for insulin dosing (11). Concurrently, size, weight, and cost of CGM systems have all decreased, while user-friendliness and convenience have increased (12).To encourage use of CGM-derived data, researchers and clinicians have worked to develop a standard set of glycemic metrics beyond A1C. In 2017, two international groups of leading diabetes clinical and research organizations published consensus definitions for key metrics, including clinically relevant glycemic cut points for hypoglycemia (<70 and <54 mg/dL), hyperglycemia (>180 and >250 mg/dL), and time in range (TIR; 70–180 mg/dL) (13,14).CGM-derived metrics provide far greater precision and granularity than is possible with SMBG or A1C data alone (Table 1), enabling clinicians and investigators to better represent inter- and intraday glycemic differences with metrics such as TIR, glycemic variability, and time in hypoglycemia and hyperglycemia (15). Crucially, CGM also allows for the accurate measurement and detection of nocturnal glycemia (16). The use of these metrics enables a more comprehensive understanding of glycemic management that can facilitate individualized treatment for people with diabetes or prediabetes. Although A1C is a useful estimate of mean glucose over the previous 2–3 months, especially when evaluating population health, it is important to include other glycemic outcomes in clinical trials. Furthermore, there is emerging evidence suggesting that TIR predicts the development of microvascular complications at least as well as A1C (17,18).TABLE 1Benefits of CGM Compared With A1C Alone in Assessing Glycemia

Dietary Aspects to Incorporate in the Creation of a Mobile Image-Based Dietary Assessment Tool to Manage and Improve Diabetes

Diabetes is the seventh leading cause of death in United States. Dietary intake and behaviors are essential components of diabetes management. Growing evidence suggests dietary components beyond carbohydrates may critically impact glycemic control. Assessment tools on mobile platforms have the ability to capture multiple aspects of dietary behavior in real-time throughout the day to inform and improve diabetes management and insulin dosing. The objective of this narrative review was to summarize evidence related to dietary behaviors and composition to inform a mobile image-based dietary assessment tool for managing glycemic control of both diabetes types (type 1 and type 2 diabetes). This review investigated the following topics amongst those with diabetes: (1) the role of time of eating occasion on indicators of glycemic control; and (2) the role of macronutrient composition of meals on indicators of glycemic control. A search for articles published after 2000 was completed in PubMed with the following sets of keywords “diabetes/diabetes management/diabetes prevention/diabetes risk”, “dietary behavior/eating patterns/temporal/meal timing/meal frequency”, and “macronutrient composition/glycemic index”. Results showed eating behaviors and meal macronutrient composition may affect glycemic control. Specifically, breakfast skipping, late eating and frequent meal consumption might be associated with poor glycemic control while macronutrient composition and order of the meal could also affect glycemic control. These factors should be considered in designing a dietary assessment tool, which may optimize diabetes management to reduce the burden of this disease.     

Silencing of xylose isomerase and cellulose synthase by siRNA inhibits encystation in Acanthamoeba castellanii

A key challenge in the successful treatment of Acanthamoeba infections is its ability to transform into a dormant cyst form that is resistant to physiological conditions and pharmacological therapies, resulting in recurrent infections. The carbohydrate linkage analysis of cyst walls of Acanthamoeba castellanii showed variously linked sugar residues, including xylofuranose/xylopyranose, glucopyranose, mannopyranose, and galactopyranose. Here, it is shown that exogenous xylose significantly reduced A. castellanii differentiation in encystation assays (P?<?0.05 using paired t test, one-tailed distribution). Using small interfering RNA (siRNA) probes against xylose isomerase and cellulose synthase, as well as specific inhibitors, the findings revealed that xylose isomerase and cellulose synthase activities are crucial in the differentiation of A. castellanii. Inhibition of both enzymes using siRNA against xylose isomerase and cellulose synthase but not scrambled siRNA attenuated A. castellanii metamorphosis, as demonstrated by the arrest of encystation of A. castellanii. Neither inhibitor nor siRNA probes had any effect on the viability and extracellular proteolytic activities of A. castellanii.     

Photochemotherapeutic Strategy against Acanthamoeba Infections

Acanthamoeba is a protist pathogen that can cause serious human infections, including blinding keratitis and a granulomatous amoebic encephalitis that almost always results in death. The current treatment for these infections includes a mixture of drugs, and even then, a recurrence can occur. Photochemotherapy has shown promise in the treatment of Acanthamoeba infections; however, the selective targeting of pathogenic Acanthamoeba has remained a major concern. The mannose-binding protein is an important adhesin expressed on the surface membranes of pathogenic Acanthamoeba organisms. To specifically target Acanthamoeba, the overall aim of this study was to synthesize a photosensitizing compound (porphyrin) conjugated with mannose and test its efficacy in vitro. The synthesis of mannose-conjugated porphyrin was achieved by mixing benzaldehyde and pyrrole, yielding tetraphenylporphyrin. Tetraphenylporphyrin was then converted into mono-nitrophenylporphyrin by selectively nitrating the para position of the phenyl rings, as confirmed by nuclear magnetic resonance (NMR) spectroscopy. The mono-nitrophenylporphyrin was reduced to mono-aminophenylporphyrin in the presence of tin dichloride and confirmed by a peak at m/z 629. Finally, mono-aminoporphyrin was conjugated with mannose, resulting in the formation of an imine bond. Mannose-conjugated porphyrin was confirmed through spectroscopic analysis and showed that it absorbed light of wavelengths ranging from 425 to 475 nm. To determine the antiacanthamoebic effects of the derived product, amoebae were incubated with mannose-conjugated porphyrin for 1 h and washed 3 times to remove extracellular compound. Next, the amoebae were exposed to light of the appropriate wavelength for 1 h. The results revealed that mannose-conjugated porphyrin produced potent trophicidal effects and blocked excystation. In contrast, Acanthamoeba castellanii incubated with mannose alone and porphyrin alone did not exhibit an antiamoebic effect. Consistently, pretreatment with mannose-conjugated porphyrin reduced the A. castellanii-mediated host cell cytotoxicity from 97% to 4.9%. In contrast, treatment with porphyrin, mannose, or solvent alone had no protective effects on the host cells. These data suggest that mannose-conjugated porphyrin has application for the targeted photodynamic therapy of Acanthamoeba infections and may serve as a model in the development of therapeutic interventions against other eukaryotic infections.     

Gelatin- and Papaya-Based Biodegradable and Edible Packaging Films to Counter Plastic Waste Generation

Most of the food packaging materials used in the market are petroleum-based plastics; such materials are neither biodegradable nor environmentally friendly and require years to decompose. To overcome these problems, biodegradable and edible materials are encouraged to be used because such materials degrade quickly due to the actions of bacteria, fungi, and other environmental effects. In this work, commonly available household materials such as gelatin, soy protein, corn starch, and papaya were used to prepare cost-effective lab-scale biodegradable and edible packaging film as an effective alternative to commercial plastics to reduce waste generation. Prepared films were characterized in terms of Fourier transform infrared spectroscopy (FTIR), water vapor transmission rate (WVTR), optical transparency, and tensile strength. FTIR confirmed the addition of papaya and soy protein to the gelatin backbone. WVTR of the gelatin-papaya films was recorded to be less than 50 g/m²/day. This water vapor barrier was five times better than films of pristine gelatin. The gelatin, papaya, and soy protein films exhibited transparencies of around 70% in the visible region. The tensile strength of the film was 2.44 MPa, which improved by a factor of 1.5 for the films containing papaya and soy protein. The barrier qualities of the gelatin and gelatin-papaya films maintained the properties even after going through 2000 bending cycles. From the results, it is inferred that the prepared films are ideally suitable for food encapsulation and their production on a larger scale can considerably cut down the plastic wastage.     

p38MAPK对轻度热应激大鼠脾脏巨噬细胞免疫功能的影响

目的: 探讨p38MAPK在Bip蛋白介导的体外轻度热应激大鼠巨噬细胞功能改变中的信号作用.方法: p38MAPK抑制剂预处理大鼠脾脏巨噬细胞,将细胞置于41℃恒温箱中,使细胞轻度热应激,1 h后恢复到37℃(抑制组),以未应激(对照组)和41℃热应激1 h后60 min巨噬细胞(应激组)为对照,分别检测3组巨噬细胞吞噬、杀伤、趋化功能,同时检测p38MAPK蛋白和Bip蛋白的表达.结果: p38MAPK抑制剂预处理大鼠脾脏巨噬细胞,与应激组比较,轻度热应激后巨噬细胞吞噬、趋化和杀伤活性明显降低(0.17±0.01 vs 0.74±0.03,33.32±3.55 vs 82.07±5.17,24.20%±2.39% vs 60.80%±4.02%,均P<0.01);应激组p38MAPK蛋白表达明显上调,p38MAPK抑制剂预处理后,抑制组p38 MAPK蛋白表达受到抑制,与应激组比较差异有显著性(p38/β-actin: 2.863±0.794 vs 4.752±1.386,P<0.01);Bip蛋白的表达(Bip/β-act in)也因p38MAPK抑制剂预处理而由应激组的1.270±0.535降至抑制组的1.028±1.061( P<0.05).结论: p38MAPK抑制剂可显著抑制轻度热应激大鼠巨噬细胞吞噬、趋化和杀伤功能以及p38MAPK和Bip蛋白的表达.     

Endometriosis presenting as a urethral diverticulum: a case report

BACKGROUND: Pelvic pain is a common complaint among women of childbearing age. It has an extensive differential diagnosis that at times can make it difficult to determine its etiology. One must therefore rely on the characteristics of the physical examination, symptoms and imaging studies. However, in doing so, one should keep in mind that many diseases mimic one another. Physicians must be careful not to fall into the trap of simply assigning a specific disease to a given group of symptoms. CASE: A 35-year-old woman, gravida 2, para 0020, presented to a clinic complaining of left lower abdominal pain. She had a history of dyspareunia, dysmenorrhea, urinary frequency and numerous urinary tract infections. Previous laparoscopies had been negative for endometriosis. Physical examination demonstrated a 1.5-cm mass left of the midurethra. No pus was expressed through the urethra with cyst massage. Imaging showed a 1.1 x 1.1-cm lesion in the left posterolateral aspect of the urethra consistent with a urethral diverticulum. Uterine adenomyosis was also noted. Although clinical symptoms, physical examination and imaging suggested a urethral diverticulum, a vaginal endometriotic cyst was encountered at surgery. Pathologic evaluation of the surgically excised lesion revealed endometriosis, revealed endometriosis. CONCLUSION: In this case, clinical findings, location and imaging characteristics of a periurethral endometriotic lesion suggested a urethral diverticulum. Endometriosis should be considered in patients with a history of pelvic pain who present with urinary frequency and a periurethral lesion.     

Relative importance of indigenous medicinal plants from Layyah district,Punjab Province,Pakistan

Ethnopharmacological relevance

Ethnomedicinal reports are important for the discovery of new crude drugs from reported medicinal plants with high use value. The current study aimed to document the medicinal flora as well as medicinal knowledge of indigenous plants of local communities from Layyah district, Punjab Province, Pakistan.

Material and methods

Rapid appraisal approach (RAA), semi-structured interviews, group meetings with herbalists, landowners and local people having awareness about the medicinal action of plants were employed to collect the data. Use values (UV) and frequency of citation (FC) were calculated to check the relative importance of plants.

Results and discussions

The current ethnomedicinal study reported 125 medicinal plant species diversified from 106 genus belonging to the 43 different families and Poaceae was the predominant family over others with 16 reported medicinal plants. Wild herbaceous plants were the predominant over other life forms while among plant parts, leaves contributed 32% followed by the stem (27%), fruit and flowers (15%). Allium sativum exhibited the highest use vale (UV) 0.92 while the lowest UV was exhibited by Lasiurus scindicus which was 0.15.

Conclusion

Local communities of district Layyah still have a strong faith on herbal medicines for basic healthcare needs. Indigenous plants having high UV and FC should be subjected to the detailed phytochemical investigations to explore new natural drugs.     

Ecotoxicological risks associated with tannery effluent wastewater

The problem of water pollution acquires greater relevance in the context of a developing agrarian economy like Pakistan. Even though, the leather industry is a leading economic sector in Pakistan, there is an increasing environmental concern regarding tanneries because they produce large amounts of potentially toxic wastewater containing both trivalent and hexavalent chromium, which are equally hazardous for human population, aquaculture and agricultural activities in the area. Therefore, we defined the scope of the present study as to employ different bioassays to determine the eco-toxic potential of tannery effluent wastewater (TW) and its chromium based components, i.e., potassium dichromate (K(2)Cr(2)O(7)) and chromium sulfate Cr(2)(SO(4))(3). Particle-induced X-ray emission (PIXE) analysis of TW was carried out to determine the concentration of chromium in TW and then equal concentrations of hexavalent (K(2)Cr(2)O(7)) and trivalent chromium Cr(2)(SO(4))(3) were obtained for this study. Cytotoxicity assay, artemia bioassay and phytotoxicity assay was utilized to investigate the eco-toxicological potential of different concentrations of TW, K(2)Cr(2)O(7) and Cr(2)(SO(4))(3). All the dilutions of TW, K(2)Cr(2)O(7) and Cr(2)(SO(4))(3) presented concentration dependent cytotoxic effects in these assays. The data clearly represents that among all three tested materials, different dilutions of K(2)Cr(2)O(7) caused significantly more damage (P<0.001) to vero cell, brine shrimp and germination of maize seeds. Interestingly, the overall toxicity effects of TW treated groups were subsequent to K(2)Cr(2)O(7) treated group. Based on biological evidences presented in this article, it is concluded that hexavalent chromium (K(2)Cr(2)O(7)) and TW has got significant eco-damaging potential clearly elaborating that environmental burden in district Kasur is numerous and high levels of chromium is posing a considerable risk to the human population, aquaculture and agricultural industry that can obliterate ecosystem surrounding the tanneries.