Prognostic Implications of Diabetic Ketoacidosis in Adults on Long-term Mortality and Diabetes-related Complications.

OBJECTIVES: Diabetic ketoacidosis (DKA) occurring after diabetes diagnosis is often associated with risk factors for other diabetes-related complications. In this study we aimed to determine the prognostic implications of DKA on all-cause mortality and complications in type 1 diabetes (T1D). METHODS: Previously collected data from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study were obtained through the the National Institute of Diabetes and Digestive and Kidney Diseases Central Repository. Using Cox proportional hazards models with time-dependent covariates, we examined age- and sex-adjusted, glycated hemoglobin-adjusted, and fully adjusted associations of DKA with all-cause mortality, cardiovascular disease, microvascular, and acute complications over 34 years. RESULTS: Of the 1,441 study participants, 297 had 488 DKA events. Prior DKA was associated with a higher risk of age- and sex-adjusted all-cause mortality (hazard ratio [HR] 8.28, 95% confidence interval [CI] 3.74 to 18.32, p<0.001), major adverse cardiovascular events (MACEs) (HR 2.05, 95% CI 1.34 to 3.13, p<0.001), and all advanced microvascular and acute complications compared with no prior DKA. Most associations except retinopathy were significant even after adjustment for covariates. In our fully adjusted analysis, prior DKA was associated with a significantly higher risk of subsequent all-cause mortality (HR 9.13, 95% CI 3.87 to 21.50, p<0.001), MACEs (HR 1.66, 95% CI 1.07 to 2.59, p=0.03), advanced kidney disease (HR 2.10, 95% CI 1.00 to 4.22, p=0.049), advanced neuropathy (HR 1.49, 95% CI 1.05 to 2.13, p=0.03), severe hypoglycemia (HR 1.53, 95% CI 1.28 to 1.81, p<0.001), and recurrent DKA (HR 3.24, 95% CI 2.41 to 4.36, p<0.001) compared with person-time without DKA. CONCLUSIONS: DKA is a prognostic marker for diabetes complications, including excess all-cause mortality. Intensified clinical interventions, such as cardiovascular prevention strategies, may be warranted after diagnosis of DKA.

Medication-Induced Hyperglycemia and Diabetes Mellitus: A Review of Current Literature and Practical Management Strategies.

With the increasing global incidence of diabetes mellitus, physicians may encounter more patients with acute and chronic complications of medication-induced hyperglycemia and diabetes. Moreover, medication-induced diabetes may be an important contributing factor to the high rates of diabetes, and recognizing its impact and risk is a critical step in curtailing its effect on the global population. It has long been recognized that multiple classes of medications are associated with hyperglycemia through various mechanisms, and the ability to foresee this and implement adequate management strategies are important. Moreover, different antihyperglycemic medications are better suited to combat the hyperglycemia encountered with different classes of medications, so it is critical that physicians can recognize which agents should be used, and which medications to avoid in certain types of medication-induced hyperglycemia. In this review, we will discuss the evidence behind the main classes of medications that cause hyperglycemia, their mechanism of action, specific agents that are associated with worsened glycemic control, and, most importantly, management strategies that are tailored to each specific class.

A Rare Case of Unilateral Fetal Cataract and Coincidental Polydactyly in Congenital Toxoplasmosis.

Congenital toxoplasmosis is caused by transplacental infection of Toxoplasma gondii during pregnancy. We present a case of a congenital toxoplasma with intracranial calcifications, microcephaly, growth restriction, a unilateral cataract that developed in the third trimester, and a coincidental post-axial-polydactyly. Antenatal imaging findings are important to guide further testing and confirmation of diagnosis, it is important to know all possible associations and prognoses for timely counseling, testing, and intervention. To our knowledge, no case has been published with findings of unilateral cataract in congenital toxoplasmosis and associated coincidental polydactyly. Therefore, we wish to add this case to the current scientific literature.

Use of once-daily oral semaglutide and associated clinical outcomes among adults with type 2 diabetes in routine clinical practice in Canada: A multicentre, prospective real-world study (PIONEER REAL Canada).

AIM: PIONEER REAL Canada examined real-world clinical outcomes associated with the use of once-daily oral semaglutide in adults with type 2 diabetes. MATERIALS AND METHODS: This was a 34- to 44-week, multicentre, prospective, open-label, non-interventional study in adults who were treatment-naive to injectable glucose-lowering medication and initiated oral semaglutide in routine clinical practice. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to the end of the study (EoS). Secondary endpoints assessed at EoS were change from baseline in body weight (BW); the proportion of participants reaching HbA1c levels <7% and the composite endpoints, HbA1c reduction ≥1% point with BW reduction ≥3% and ≥5%; and treatment satisfaction measured using Diabetes Treatment Satisfaction Questionnaires (DTSQ) status and change. Primary analyses were based on the in-study observation period. RESULTS: In total, 182 participants initiated oral semaglutide (mean age, 58.6 years; HbA1c, 8.0%; BW, 93.7 kg). The estimated changes (95% confidence interval) from baseline to EoS in HbA1c and BW were -1.09% points (-1.24, -0.94; p < .0001) and -7.17% (-8.24, -6.11; p < .0001), respectively. At EoS, 53.7% of participants had HbA1c levels <7%; 39.3% and 31.6% reached HbA1c reduction ≥1% point plus BW reduction ≥3% and ≥5%, respectively. Treatment satisfaction significantly increased (DTSQ status, +4.47 points; DTSQ change, 11.83 points; both p < .0001). At EoS, 75.3% of participants remained on oral semaglutide (55.5% received oral semaglutide 14 mg). No new safety signals were identified for oral semaglutide. CONCLUSIONS: In PIONEER REAL Canada, participants treated with oral semaglutide in routine clinical practice experienced clinically relevant reductions in HbA1c and BW and increased treatment satisfaction.

Recent Advances in Graphene-Enabled Materials for Photovoltaic Applications: A Comprehensive Review.

Graphene's two-dimensional structural arrangement has sparked a revolutionary transformation in the domain of conductive transparent devices, presenting a unique opportunity in the renewable energy sector. This comprehensive Review critically evaluates the most recent advances in graphene production and its employment in solar cells, focusing on dye-sensitized, organic, and perovskite devices for bulk heterojunction (BHJ) designs. This comprehensive investigation discovered the following captivating results: graphene integration resulted in a notable 20.3% improvement in energy conversion rates in graphene-perovskite photovoltaic cells. In comparison, BHJ cells saw a laudable 10% boost. Notably, graphene's 2D internal architecture emerges as a protector for photovoltaic devices, guaranteeing long-term stability against various environmental challenges. It acts as a transportation facilitator and charge extractor to the electrodes in photovoltaic cells. Additionally, this Review investigates current research highlighting the role of graphene derivatives and their products in solar PV systems, illuminating the way forward. The study elaborates on the complexities, challenges, and promising prospects underlying the use of graphene, revealing its reflective implications for the future of solar photovoltaic applications.

Morbidity Associated With Distal Tibial Autograft Harvest.

Distal tibial autograft harvesting has been studied in the past, but morbidity at the level of the donor site is unclear. The purpose of this retrospective review is to assess morbidity in distal tibial autograft harvesting associated with foot and ankle arthrodesis procedures. A retrospective analysis was performed utilizing patients treated in the last 13 years at a large, multicenter, academic, tertiary referral, research institution. Included patients were between the ages of 18 and 80 years old. One-hundred and seven patients (39 male; 68 female) underwent ipsilateral distal tibial bone graft (n = 110) harvesting to augment the index procedure. Patients were followed for an average of 11.2 months after surgery (Range: 1-73 months). The incidence rate of distal tibial stress fractures was 4.5%, with an overall postoperative complication rate of 8.2%. Overall, low complication rates associated with distal tibial autograft harvesting were found, supporting the use of the distal tibia as an appropriate site for autograft harvesting in foot and ankle surgery.

IADVL SIG Recalcitrant Dermatophytosis Position Statement on Super Bioavailable Itraconazole.

Itraconazole (ITZ) has been the mainstay of oral antifungal treatment for the current epidemic of recalcitrant dermatophytosis (RD) in India. Recently, a newer formulation of ITZ, super bioavailable itraconazole (SUBA-ITZ), is made available in the market by many pharmaceutical companies. It is important for dermatologists to understand the pharmacokinetic properties of SUBA-ITZ vis-a-vis conventional pellet formulation to use it effectively and safely. Indian Association of Dermatologists, Venereologists and Leprologists (IADVL) has established a special interest group for recalcitrant dermatophytosis (SIG-RD) to strengthen research, continuing medical education, and industry collaboration on the subject. This position statement on SUBA-ITZ by SIG-RD is an attempt to address current pieces of evidence and the position of this new formulation in the management of RD.

Successful implementation of virtual care to overcome the challenges of managing gestational diabetes during the COVID-19 pandemic: a quality improvement project.

At the start of the COVID-19 pandemic, the Jim Pattison Diabetes and Pregnancy (JP DAP) clinic quickly switched from in-person to virtual care for patients with gestational diabetes (GDM) to reduce the risk of viral transmission. Poor glycaemic control in pregnancies increases the risk of maternal-fetal complications and thus women with GDM require education, frequent follow-up and treatment to reduce these risks. Delays in care could potentially result in increased maternal-fetal complications. We conducted a prospective, single-centre quality improvement (QI) study of women with GDM who attended the JP DAP clinic and delivered between 1 September 2019 and 31 March 2021. 2123 singleton pregnancies between 1 September 2019 and 31 March 2021 with GDM were analysed for this study. The time of referral to see the endocrinologist was lower than baseline in the first wave but rose significantly in the second wave. No-shows for appointments increased in the first wave but were lower than baseline after the implementation of time slots. There was no special cause variation for maternal-fetal complications pre pandemic, first wave or during the second wave. A patient satisfaction survey reported that 93% of respondents strongly agreed or agreed with the statement 'I was satisfied with the care provided to me over the telephone appointments'. The GDM education package, online educational videos in Hindi and English and the glucometer smartphone application helped to maintain the time of referral to first endocrinologist appointment in the first wave and therefore were considered an effective substitute for in-person education. Despite the delays in care seen in the second wave, there was no increase in maternal-fetal complications. Our clinic plans to continue using virtual tools for the foreseeable future.

Impact of the TLR4 agonist BECC438 on a novel vaccine formulation against Shigella spp.

Shigellosis (bacillary dysentery) is a severe gastrointestinal infection with a global incidence of 90 million cases annually. Despite the severity of this disease, there is currently no licensed vaccine against shigellosis. Shigella's primary virulence factor is its type III secretion system (T3SS), which is a specialized nanomachine used to manipulate host cells. A fusion of T3SS injectisome needle tip protein IpaD and translocator protein IpaB, termed DBF, when admixed with the mucosal adjuvant double-mutant labile toxin (dmLT) from enterotoxigenic E. coli was protective using a murine pulmonary model. To facilitate the production of this platform, a recombinant protein that consisted of LTA-1, the active moiety of dmLT, and DBF were genetically fused, resulting in L-DBF, which showed improved protection against Shigella challenge. To extrapolate this protection from mice to humans, we modified the formulation to provide for a multivalent presentation with the addition of an adjuvant approved for use in human vaccines. Here, we show that L-DBF formulated (admix) with a newly developed TLR4 agonist called BECC438 (a detoxified lipid A analog identified as Bacterial Enzymatic Combinatorial Chemistry candidate #438), formulated as an oil-in-water emulsion, has a very high protective efficacy at low antigen doses against lethal Shigella challenge in our mouse model. Optimal protection was observed when this formulation was introduced at a mucosal site (intranasally). When the formulation was then evaluated for the immune response it elicits, protection appeared to correlate with high IFN-γ and IL-17 secretion from mucosal site lymphocytes.

A novel investigation using thermal modeling and optimization of waste pyrolysis reactor using finite element analysis and response surface methodology.

The influence of humans on the environment is growing drastically and is pervasive. If this trend continues for a longer time, it can cost humankind, social and economic challenges. Keeping this situation in mind, renewable energy has paved the way as our saviour. This shift will not only help in reducing pollution but will also provide immense opportunities for the youth to work. This work discusses about various waste management strategies and discusses the pyrolysis process in details. Simulations were done keeping pyrolysis as the base process and by varying parameters like feeds and reactor materials. Different feeds were chosen like Low-Density Polyethylene (LDPE), wheat straw, pinewood, and a mixture of Polystyrene (PS), Polyethylene (PE), and Polypropylene (PP). Different reactor materials were considered namely, stainless steel AISI 202, AISI 302, AISI 304, and AISI 405. AISI stands for American Iron and Steel Institute. AISI is used to signify some standard grades of alloy steel bars. Thermal stress and thermal strain values and temperature contours were obtained using simulation software called Fusion 360. These values were plotted against temperature using graphing software called Origin. It was observed that these values increased with increasing temperature. LDPE got the lowest values for stress and stainless steel AISI 304 came out to be the most feasible material for pyrolysis reactor having the ability to withstand high thermal stresses. RSM was effectively used to generate a robust prognostic model with high efficiency, R2 (0.9924-0.9931), and low RMSE (0.236 to 0.347). Optimization based on desirability identified the operating parameters as 354 °C temperature and LDPE feedstock. The best thermal stress and strain responses at these ideal parameters were 1719.67 MPa and 0.0095, respectively.

Mucocele Arising from the Submandibular Gland Presenting as Neck Swelling: A Rare Case Report.

Mucoceles rarely involve major salivary glands. Very few cases involving the submandibular gland have been reported to date. A young male child presented with diffuse, soft, and painless swelling of the left submandibular region. Investigations suggested mucocele of the submandibular salivary gland. The mucocele was excised along with the left submandibular gland. Recovery was uneventful.

Successful Management of Severe Recalcitrant Pemphigus Vulgaris with Lenalidomide.

Pemphigus variants are treated with immunosuppressives and immunomodulators, but often, clinical remission is challenging. We report a case of pemphigus vulgaris (PV) with involvement of skin, oral mucosa, and esophagus, which failed to respond to commonly used drugs but showed a good response to lenalidomide.

A Delphi consensus on the nomenclature and diagnosis of lichen planus pigmentosus and related entities.

BACKGROUND: Although well known in clinical practice, research in lichen planus pigmentosus and related dermal pigmentary diseases is restricted due to lack of consensus on nomenclature and disease definition. AIMS AND OBJECTIVES: Delphi exercise to define and categorise acquired dermal pigmentary diseases. METHODS: Core areas were identified including disease definition, etiopathogenesis, risk factors, clinical features, diagnostic methods, treatment modalities and outcome measures. The Delphi exercise was conducted in three rounds. RESULTS: Sixteen researchers representing 12 different universities across India and Australia agreed to be part of this Delphi exercise. At the end of three rounds, a consensus of >80% was reached on usage of the umbrella term 'acquired dermal macular hyperpigmentation'. It was agreed that there were minimal differences, if any, among the disorders previously defined as ashy dermatosis, erythema dyschromicum perstans, Riehl's melanosis and pigmented contact dermatitis. It was also agreed that lichen planus pigmentosus, erythema dyschromicum perstans and ashy dermatosis did not differ significantly apart from the sites of involvement, as historically described in the literature. Exposure to hair colours, sunlight and cosmetics was associated with these disorders in a significant proportion of patients. Participants agreed that both histopathology and dermatoscopy could diagnose dermal pigmentation characteristic of acquired dermal macular hyperpigmentation but could not differentiate the individual entities of ashy dermatosis, erythema dyschromicum perstans, Riehl's melanosis, lichen planus pigmentosus and pigmented contact dermatitis. LIMITATIONS: A wider consensus involving representatives from East Asian, European and Latin American countries is required. CONCLUSION: Acquired dermal macular hyperpigmentation could be an appropriate conglomerate terminology for acquired dermatoses characterised by idiopathic or multifactorial non-inflammatory macular dermal hyperpigmentation.

Alopecia Areata Complicated by Plica Neuropathica: A Rare Case Report.

Plica neuropathica is a rare scalp condition, which is manifested as a compact mass of scalp hair. Previously, it has been found to be associated with a variety of dermatological disorders. We report a case of 15-year-old female presenting with alopecia areata associated with plica neuropathica.

Development of amino acid-modified biodegradable lipid nanoparticles for siRNA delivery.

The use of siRNA therapeutics to treat cancer is a very promising approach. However, specific delivery of siRNAs to tumors remains a major challenge. The recent success of siRNA delivery to the liver has incentivized the development of biomaterials for siRNA delivery into tumors. Here, we report a new class of amino acid-modified lipids for siRNA delivery to cancer cells. Eight lipids were developed by headgroup modification with histidine and lysine. The lipids were screened in PC3-luciferase stable cells for gene silencing and cellular cytotoxicity study. The best lipid LHHK shows a pKa of 6.08, which is within the optimal pKa range of lipid nanoparticles (LNPs) for siRNA delivery. The LHHK LNP protects siRNA from serum degradation for up to 24 h and shows higher endosomal release and better cellular uptake compared to other lysine-modified lipids in PC3 cells. The LHHK LNP exhibits significant silencing activity of IKKα and IKBKE in prostate cancer and pancreatic cancer, respectively. Moreover, the LHHK LNP encapsulating IKBKE siRNA inhibits cell proliferation of pancreatic cancer cells and suppresses the tumor progression in a pancreatic cancer mouse model. STATEMENT OF SIGNIFICANCE: Lipid nanoparticle (LNP) is a promising platform for siRNA delivery. However, LNP is generally associated with high systemic toxicity. As a result, efficient and biodegradable lipids are highly needed for siRNA-based cancer therapy. Herein, we develop amino acid-modified biodegradable lipids. These lipids show very low cellular toxicity and high transfection efficiency. The best lipid LHHK shows a pKa of 6.08, which is within the optimal pKa range of LNPs for siRNA delivery. The LHHK LNP efficiently silences IKKα and IKBKE in prostate and pancreatic cancer, respectively. Moreover, the LHHK LNP encapsulating IKBKE siRNA inhibits cell proliferation and suppresses tumor growth of pancreatic cancer in vivo. These results suggest that amino acid-modified lipids possess a great potential for siRNA delivery in cancer therapy.

Identifying misconduct-committing officer crews in the Chicago police department.

Explanations for police misconduct often center on a narrow notion of "problem officers," the proverbial "bad apples." Such an individualistic approach not only ignores the larger systemic problems of policing but also takes for granted the group-based nature of police work. Nearly all of police work is group-based and officers' formal and informal networks can impact behavior, including misconduct. In extreme cases, groups of officers (what we refer to as, "crews") have even been observed to coordinate their abusive and even criminal behaviors. This study adopts a social network and machine learning approach to empirically investigate the presence and impact of officer crews engaging in alleged misconduct in a major U.S. city: Chicago, IL. Using data on Chicago police officers between 1971 and 2018, we identify potential crews and analyze their impact on alleged misconduct and violence. Results detected approximately 160 possible crews, comprised of less than 4% of all Chicago police officers. Officers in these crews were involved in an outsized amount of alleged and actual misconduct, accounting for approximately 25% of all use of force complaints, city payouts for civil and criminal litigations, and police-involved shootings. The detected crews also contributed to racial disparities in arrests and civilian complaints, generating nearly 18% of all complaints filed by Black Chicagoans and 14% of complaints filed by Hispanic Chicagoans.

Discovery of Anti-PD-L1 Human Domain Antibodies for Cancer Immunotherapy.

Immunotherapy using monoclonal antibodies targeting the PD-1/PD-L1 interaction has shown enormous success for various cancers. Despite their encouraging results in clinics, antibody-based checkpoint inhibitors have several limitations, such as poor tumor penetration. To address these limitations of monoclonal antibodies, there is a growing interest in developing low-molecular-weight checkpoint inhibitors, such as antibody fragments. Several antibody fragments targeting PD-1/PD-L1 were recently discovered using phage libraries from camel or alpaca. However, animal-derived antibody fragments may elicit unwanted immune responses, which limit their therapeutic applications. For the first time, we used a human domain antibody phage library and discovered anti-human PD-L1 human single-domain antibodies (dAbs) that block the PD-1/PD-L1 interaction. Among them, the CLV3 dAb shows the highest affinity to PD-L1. The CLV3 dAb also exhibits the highest blocking efficacy of the PD-1/PD-L1 interaction. Moreover, the CLV3 dAb significantly inhibits tumor growth in mice implanted with CT26 colon carcinoma cells. These results suggest that CLV3 dAb can be potentially used as an anti-PD-L1 inhibitor for cancer immunotherapy.