Cleavable Amphiphilic Biocides with Ester-Bearing Moieties: Aggregation Properties and Antibacterial Activity.

The rise of multidrug-resistant bacterial infections and the dwindling supply of newly approved antibiotics have emerged as a grave threat to public health. Toward the ever-growing necessity of the development of novel antimicrobial agents, herein, we synthesized a series of cationic amphiphilic biocides featuring two cationic headgroups separated by different hydrophobic spacers, accompanied by the inclusion of two lipophilic tails through cleavable ester functionality. The detailed aggregation properties offered by these biocides were investigated by small-angle neutron scattering (SANS) and conductivity. The critical micellar concentration of the biocides and the size and shape of the micellar aggregates differed with variation of pendant and spacer hydrophobicity. Furthermore, the aggregation number and size of the micelles were found to vary with changing concentration and temperature. These easily synthesized biocides exhibited potent antibacterial properties against various multidrug-resistant bacteria. The optimized biocides with minimum hematotoxicity and potent antibacterial activity against methicillin-resistant Staphylococcus aureus and Acinetobacter baumannii exhibited rapid killing kinetics against planktonic bacteria. Also, these membrane-active agents were able to eradicate preformed biofilms. The enzymatic and acidic degradation profile further offered proof of gradual degradation. Collectively, these cleavable amphiphilic biocides demonstrated excellent potency for combating the multidrug-resistant bacterial infection.

Small molecular adjuvants repurpose antibiotics towards Gram-negative bacterial infections and multispecies bacterial biofilms.

Gram-negative bacterial infections pose a significant challenge due to two major resistance elements, including the impermeability of the outer membrane and the overexpression of efflux pumps, which contribute to antibiotic resistance. Additionally, the coexistence of multispecies superbugs in mixed species biofilms further complicates treatment, as these infections are refractory to most antibiotics. To address this issue, combining obsolete antibiotics with non-antibiotic adjuvants that target bacterial membranes has shown promise in combating antibacterial resistance. However, the clinical translation of this cocktail therapy has been hindered by the toxicity associated with these membrane active adjuvants, mainly due to a limited understanding of their structure and mechanism of action. Towards this goal, herein, we have designed a small molecular adjuvant by tuning different structural parameters, such as the balance between hydrophilic and hydrophobic groups, spatial positioning of hydrophobicity and hydrogen bonding interactions, causing moderate membrane perturbation in bacterial cells without any toxicity to mammalian cells. Moderate membrane perturbation not only enhances the internalization of antibiotics, but also increases the intracellular concentration of drugs by hampering the efflux machinery. This revitalises the efficacy of various classes of antibiotics by 32-512 fold, without inducing toxicity. The leading combination not only exhibits potent bactericidal activity against A. baumannii biofilms but also effectively disrupts mature multispecies biofilms composed of A. baumannii and methicillin-resistant Staphylococcus aureus (MRSA), which is typically resistant to most antibiotics. Importantly, the combination therapy demonstrates good biocompatibility and excellent in vivo antibacterial efficacy (>99% reduction) in a skin infection model of A. baumannii. Interestingly, A. baumannii shows reduced susceptibility to develop resistance against the leading combination, underscoring its potential for treating multi-drug resistant infections.

Inference for covariate-adjusted time-dependent prognostic accuracy measures.

Evaluating the prognostic performance of candidate markers for future disease onset or progression is one of the major goals in medical research. A marker's prognostic performance refers to how well it separates patients at the high or low risk of a future disease state. Often the discriminative performance of a marker is affected by the patient characteristics (covariates). Time-dependent receiver operating characteristic (ROC) curves that ignore the informativeness of the covariates will lead to biased estimates of the accuracy parameters. We propose a time-dependent ROC curve that accounts for the informativeness of the covariates in the case of censored data. We propose inverse probability weighted (IPW) estimators for estimating the proposed accuracy parameters. We investigate the performance of the IPW estimators through simulation studies and real-life data analysis.

Investigation of Paracetamol Entrapped Nanoporous Silica Nanoparticles in Transdermal Drug Delivery System.

An effort was made to administer paracetamol drug through transdermal patch, as no such formulation of this drug has been developed yet. The primary cause for the lack of such formulations is paracetamol's poor aqueous solubility. As a result, the current research concentrated on preparing nanomedicines, or drug-loaded nanoparticles, for delivery via transdermal formulations. Nanoparticles can improve the solubility of weakly aqueous soluble or even aqueous insoluble drugs by changing the crystalline structure of loaded medicines to an amorphous state and serving as drug permeation boosters. Silica nanoparticles (SNPs) were synthesized through sol-gel technique to achieve the aforementioned goal. DLS data revealed that the average particle size was around 100-200 nm, which was sufficient to penetrate the skin barrier. XRD analysis showed that the SNPs were amorphous, and the drug molecules lost their crystallinity after encapsulation into the nanoparticles, causing the enhancement of dissolution of drug molecules in physiological pH (pH-7.4). Different kinetic models were employed for the ex vivo dissolution data to evaluate the suitable kinetic model followed by the drug release in both burst and sustained phase. In vivo analgesic study was executed on mice applying each of the transdermal formulations to examine the performances of the patches.

Concurrent Infection with SARS-CoV-2 and Orientia tsutsugamushi during the COVID-19 Pandemic in the Maldives.

The COVID-19 pandemic was the worst public-health crisis in recent history. The impact of the pandemic in tropical regions was further complicated by other endemic tropical diseases, which can cause concurrent infections along with COVID-19. Here, we describe the clinical course of a patient with concurrent COVID-19 and scrub typhus infection. The patient's de-identified clinical data were retrieved retrospectively. The patient had progressive breathlessness at the time of presentation and was hospitalized for COVID-19. Respiratory examination revealed dyspnea, tachypnea, and coarse crepitations bilaterally over the entire lung field. Oxygenation was impaired, and a PaO2/FiO2 ratio of 229 suggested acute respiratory distress syndrome. Laboratory tests indicated leukocytosis, thrombocytopenia, ferritinemia, hypoalbuminemia, and transaminitis. Upon revaluation for persistent fever, physical examination revealed an eschar in the right antecubital fossa. Serology further confirmed scrub typhus, with IgM and IgG antibody positivity. A remarkable clinical recovery was achieved with doxycycline. The COVID-19 pandemic might have masked endemic tropical diseases. Clinicians working in endemic regions must always consider common tropical diseases that may present as a co-infection, as in our case. Travel and exposure history are critical guides for narrowing down a differential diagnosis. Early diagnosis and treatment can prevent complications.

Examining the Systemic Bioavailability of Cannabidiol and Tetrahydrocannabinol from a Novel Transdermal Delivery System in Healthy Adults: A Single-Arm, Open-Label, Exploratory Study.

INTRODUCTION: Transdermal cannabinoids may provide better safety and bioavailability profiles compared with other routes of administration. This single-arm, open-label study investigated a novel topical transdermal delivery system on the pharmacokinetics of cannabidiol (CBD) and tetrahydrocannabinol (THC). METHODS: Participants were 39.5 ± 7.37 years old and healthy, based on a review by the Medical Director. Blood was collected pre-dose and 10, 20, 30, and 45 min, and 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 h after topical application of 100 mg CBD:100 mg THC. Psychoactive effects were assessed prior to each timepoint. Area-under-the-curve (AUC0-12 h), maximum concentration (Cmax), time to maximum concentration (Tmax), area-under-the-curve to infinity (AUCI), terminal elimination rate constant (λ), terminal half-life (t½), and absorption rate constant (ka) were measured individually for CBD and THC. Safety was assessed by clinical chemistry, hematology, and adverse events. RESULTS: AUC0-12 h for CBD and THC was 3329.8 ± 3252.1 and 2093.4 ± 2090.6 pg/mL/h, with Cmax of 576.52 ± 1016.18 and 346.57 ± 776.85 pg/mL, respectively. Tmax for CBD and THC was 8 h, ranging from 2.5 h to 12 h and 10 min to 12 h, respectively. AUCI for CBD and THC was 6609.2 ± 7056.4 and 3721.0 ± 3251.7 pg/mL/h, with t1/2 of 5.68 ± 1.5 and 5.38 ± 1.25 h, respectively. CBD was absorbed at a faster rate compared with THC (123.36 ± 530.97 versus 71.5 ± 1142.19 h-1) but with similar λ (0.12 ± 0.029 versus 0.13 ± 0.03 h-1). No psychoactive effects were reported. Transdermal cannabinoid delivery was safe and well tolerated in the population studied. CONCLUSION: To our knowledge, this is the first pharmacokinetic study in humans that demonstrated CBD and THC entering systemic circulation via transdermal administration . This study represents an important contribution to understanding the pharmacokinetics of transdermal cannabinoids. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier-NCT05121506 (November 16, 2021).

Acute pancreatitis in pregnancy following COVID-19 vaccine: a case report.

BACKGROUND: Since the approval of the Pfizer-BioNTech (BNT162b2) mRNA vaccine for COVID-19 infection, a few adverse effects have been reported. Acute pancreatitis has been reported in a few patients. However, there is currently no research showing a direct relationship between the vaccine and acute pancreatitis. Here, we report a case of acute pancreatitis following Pfizer vaccination in a young healthy pregnant woman without any known risk factors. To our knowledge, this is the first case report of possible vaccine-induced pancreatitis in a pregnant woman. CASE PRESENTATION: The patient, a 24-year-old South-Asian female, at 31 weeks of gestation, presented with severe epigastric pain radiating to the back and worsening on lying supine, associated with nausea and vomiting. She was diagnosed with acute pancreatitis with a serum lipase level of 4376 U/L and an ultrasound showing features of pancreatitis. The patient received her first dose of the Pfizer vaccine 1 week prior to these symptoms. Detailed evaluation did not show any etiological cause of pancreatitis. The patient had a spontaneous vaginal delivery and the baby was shifted to the neonatal intensive care unit in a stable condition. A computed tomography scan postpartum (day 2) demonstrated acute interstitial edematous pancreatitis. The patient was managed conservatively in the intensive care unit and discharged home in a stable condition. CONCLUSION: This report highlights the importance of a detailed history and evaluation, and the close monitoring of any patient presenting with abdominal pain after vaccination. Acute pancreatitis can be fatal if not picked up early.

Perinatal arsenic exposure-induced sustained microglial activation leads to impaired cognitive response in BALB/c mice.

Arsenic is infamous for its adverse health effects worldwide. It is known to induce cognitive impairment in experimental model animals and children in the arsenic-affected area. Although the effect of arsenic on neuronal health is well studied, but the involvement of the brain immune component, microglia, has not been well explored. The present study is focused on examining the role of microglia in arsenic-induced cognitive impairment. We have used balb/c mice for the study. Pregnant dams were gavaged with sodium arsenite (0.38 mg/kg body weight) from gestational day 5 (GD5) till postnatal day 22 (PND22). Mice were sacrificed on PND 7, 14, 22 and isolated brains were used for various assays. The study reveals that perinatal arsenic exposure keeps the microglia activated and skews them towards the M1 phenotype. Increased microglial proliferation, ROS, NO, higher levels of proinflammatory cytokines and chemokines were observed in the arsenic exposed group. Enhanced phagocytosis and phagocytic receptor TREM2, along with decreased expression of SNAP25 and PSD95, were correlated for enhanced neuronal pruning leading to impaired learning and memory response. Taken together, the study reveals an association between arsenic exposure and altered cognitive response where enhanced neuronal pruning by arsenic-activated microglia plays an important role in developing mice.

Photo-Crosslinked Antimicrobial Hydrogel Exhibiting Wound Healing Ability and Curing Infections In Vivo.

With the increasing focus on healthcare research in the current times, therapeutic and biomaterial interventions for healing of wounds and mitigation of wound-associated infections have seen expedited progress. Conventional approaches consist of release-active gels, which demonstrate leaching of antimicrobials, such as antibiotics, metal ions, etc. However, these systems suffer from the disadvantages of burst release, reservoir exhaustion, and associated toxicity. In this report, intrinsically antimicrobial hydrogel (HyDex) is developed by one-pot UV crosslinking of methacrylated dextran, polyethylene glycol diacrylate, and cationic lipophilic methacrylate with varied hydrophobic chain, which displays broad-spectrum antimicrobial activity, hemostatic ability, and rapid wound closure efficacy. The optimized hydrogel exhibits potent antimicrobial efficacy against multidrug-resistant Gram-positive and Gram-negative bacteria as well as against pathogenic fungus Candida albicans. The HyDex hydrogel shows rapid arrest of bleeding in mice liver puncture model. The hydrogel kills carbapenem-resistant Acinetobacter baumannii in a murine model of burn wound infection with >99% reduction in bacterial burden. Furthermore, this hydrogel displays significant reduction in inflammatory responses, with accelerated wound healing in rat deep wound model. Collectively, these results imply the excellent promise held by lead hydrogel to be developed for tackling deep tissue wounds, notorious infections, and resulting inflammatory responses.

Minocycline reverses developmental arsenic exposure-induced microglia activation and functional alteration in BALB/c mice.

Arsenic activates microglia and exerts bystander effects on neuron. The present study is focused to test whether minocycline, a second generation antibiotic, can reverse the effect of developmental arsenic exposure on microglial activation and function. Pregnant Balb/c dams were gavaged with sodium arsenite (0.38 mg/kg bd wt) from gestational day 5 (GD5) till post natal day 21 (PND21) and then one group of pups continued till PND59 with arsenic gavage. Minocycline (33 mg/kg bd wt) was administered intraperitoneally two weeks till sacrifice, every alternate day. Mice were sacrificed on PND22 and PND60 and used for various assays. Primary microglial were isolated (ex vivo microglia) from experimental animals and used to measure reactive oxygen species (ROS), nitric oxide (NO), cytokine production and phagocytosis. The whole brain lysate was used for western blot analysis of microglial marker CD68 and synaptic marker, post synaptic density protein 95 (PSD95). For real-time PCR analysis of triggering receptor expressed on myeloid cells 2 (TREM2) and PSD95, RNA isolated from whole brain was used. The study reveals that minocycline administration reversed arsenic-induced increased expression of CD68, ROS, NO, cytokine production, phagocytosis and TREM2 expression. Arsenic-induced reduced expression of PSD95 protein was reversed by minocycline, although the mRNA of PSD95 was unaltered among different groups. Finally, we have checked the learning and memory response of the experimental animals using Y-maze test to correlate the arsenic-induced altered level of synaptic protein. Taken together, the present study finds minocycline to reduce arsenic-induced microglial activation and function which in turn reverses the arsenic-induced impaired learning and memory response.

Emotional distress in COVID-19 patients in Maldives.

BACKGROUND AND OBJECTIVES: Researchers are exploring the epidemiology, clinical characteristics, treatment, vaccination and the challenges faced by healthcare authorities. However less focus is being paid towards the impact of COVID-19 on mental health of the patients. This study is a cross-sectional study, measuring the prevalence of emotional distress among patients with COVID-19 in the Maldivian population. METHODS: This study was conducted in Maldivian nations above 18 of age with COVID-19 who were admitted in isolation facilities. Patients who were on treatment for any other chronic medical conditions, severe and critical COVID-19 disease were excluded. This study was conducted over a period of 2 months by administering a local translated version of DASS21 questionnaire. RESULTS: The total of 195 patients were included in this study. The mean age of the patients was 40 (CI at 95% 38-42) years. The respondents were 48.7% men and 51.3% women. Overall, 9% of patients with COVID-19 had depression while 23% of patients had anxiety and 12% of the patients had stress. There was a statistically significant relationship between gender and depression, anxiety and stress (p < 0.01). Symptomatic cases had a significantly higher level of stress than asymptomatic patients (p < 0.05), but no significant association was observed with symptomatic status and anxiety or depression. CONCLUSION: The management of patients with COVID-19 should be multi-disciplinary with special focus on the mental wellbeing of our patients. We should aim to establish proper communication with the patients in order to identify emotional distress and provide appropriate mental health care.

MicroRNA-129-5p-regulated microglial expression of the surface receptor CD200R1 controls neuroinflammation.

CD200R1 is an inhibitory surface receptor expressed in microglia and blood macrophages. Microglial CD200R1 is known to control neuroinflammation by keeping the microglia in resting state, and therefore, tight regulation of its expression is important. CCAAT/enhancer-binding protein ß (CEBPß) is the known regulator of CD200R1 transcription. In the present study, our specific intention was to find a possible posttranscriptional regulatory mechanism of CD200R1 expression. Here we investigated a novel regulatory mechanism of CD200R1 expression following exposure to an environmental stressor, arsenic, combining in silico analysis, in vitro, and in vivo experiments, as well as validation in human samples. The in silico analysis and in vitro studies with primary neonatal microglia and BV2 microglia revealed that arsenic demethylates the promoter of a microRNA, miR-129-5p, thereby increasing its expression, which subsequently represses CD200R1 by binding to its 3'-untranslated region and shuttling the CD200R1 mRNA to the cytoplasmic-processing body in mouse microglia. The role of miR-129-5p was further validated in BALB/c mouse by stereotaxically injecting anti-miR-129. We found that anti-miR-129 reversed the expression of CD200R1, as well as levels of inflammatory molecules IL-6 and TNF-α. Experiments with a CD200R1 siRNA-induced loss-of-function mouse model confirmed an miR-129-5p→CD200R1→IL-6/TNF-α signaling axis. These main findings were replicated in a human cell line and validated in human samples. Taken together, our study revealed miR-129-5p as a novel posttranscriptional regulator of CD200R1 expression with potential implications in neuroinflammation and related complications.

Skin cancer margin detection using nanosensitive optical coherence tomography and a comparative study with confocal microscopy.

Excision biopsy and histology represent the gold standard for morphological investigation of the skin, in particular for cancer diagnostics. Nevertheless, a biopsy may alter the original morphology, usually requires several weeks for results, is non-repeatable on the same site and always requires an iatrogenic trauma. Hence, diagnosis and clinical management of diseases may be substantially improved by new non-invasive imaging techniques. Optical Coherence Tomography (OCT) is a non-invasive depth-resolved optical imaging modality based on low coherence interferometry that enables high-resolution, cross-sectional imaging in biological tissues and it can be used to obtain both structural and functional information. Beyond the resolution limit, it is not possible to detect structural and functional information using conventional OCT. In this paper, we present a recently developed technique, nanosensitive OCT (nsOCT), improved using broadband supercontinuum laser, and demonstrate nanoscale sensitivity to structural changes within ex vivo human skin tissue. The extended spectral bandwidth permitted access to a wider distribution of spatial frequencies and improved the dynamic range of the nsOCT. Firstly, we demonstrate numerical and experimental detection of a few nanometers structural difference using the nsOCT method from single B-scan images of phantoms with sub-micron periodic structures, acting like Bragg gratings, along the depth. Secondly, our study shows that nsOCT can distinguish nanoscale structural changes at the skin cancer margin from the healthy region in en face images at clinically relevant depths. Finally, we compare the nsOCT en face image with a high-resolution confocal microscopy image to confirm the structural differences between the healthy and lesional/cancerous regions, allowing the detection of the skin cancer margin.

Acalculous Cholecystitis in a Young Adult with Scrub Typhus: A Case Report and Epidemiology of Scrub Typhus in the Maldives.

Scrub typhus is a neglected tropical disease predominantly occurring in Asia. The causative agent is a bacterium transmitted by the larval stage of mites found in rural vegetation in endemic regions. Cases of scrub typhus frequently present as acute undifferentiated febrile illness, and without early diagnosis and treatment, the disease can develop fatal complications. We retrospectively reviewed de-identified data from a 23-year-old woman who presented to an emergency department with complaints of worsening abdominal pain. On presentation, she appeared jaundiced and toxic-looking. Other positive findings on abdominal examination were a positive Murphey's sign, abdominal guarding and hepatosplenomegaly. Magnetic resonance cholangiopancreatography demonstrated acalculous cholecystitis. Additional findings included eschar on the medial aspect of the left thigh with inguinal regional lymphadenopathy. Further, positive results were obtained for immunoglobulins M and G, confirming scrub typhus. The workup for other infectious causes of acute acalculous cholecystitis (AAC) detected antibodies against human herpesvirus 4 (Epstein-Barr virus), suggesting an alternative cause of AAC. Whether that represented re-activation of the Epstein-Barr virus could not be determined. As other reports have described acute acalculous cholecystitis in adult scrub typhus patients, we recommend doxycycline to treat acute acalculous cholecystitis in endemic regions while awaiting serological confirmation.

Macromolecular Nanotherapeutics and Antibiotic Adjuvants to Tackle Bacterial and Fungal Infections.

The escalating rise in the population of multidrug-resistant (MDR) pathogens coupled with their biofilm forming ability has struck the global health as nightmare. Alongwith the threat of aforementioned menace, the sluggish development of new antibiotics and the continuous deterioration of the antibiotic pipeline has stimulated the scientific community toward the search of smart and innovative alternatives. In near future, membrane targeting antimicrobial polymers, inspired from antimicrobial peptides, can stand out significantly to combat against the MDR superbugs. Many of these amphiphilic polymers can form nanoaggregates through self-assembly with superior and selective antimicrobial efficacy. Additionally, these macromolecular nanoaggregrates can be utilized to engineer smart antibiotic-delivery system for on-demand drug-release, exploiting the infection site's micoenvironment. This strategy substantially increases the local concentration of antibiotics and reduces the associated off-target toxicity. Furthermore, amphiphilc macromolecules can be utilized to rejuvinate obsolete antibiotics to tackle the drug-resistant infections. This review article highlights the recent developments in macromolecular architecture to design numerous nanostructures with broad-spectrum antimicrobial activity, their application in fabricating smart drug delivery systems and their efficacy as antibiotic adjuvants to circumvent antimicrobial resistance. Finally, the current challenges and future prospects are briefly discussed for further exploration and their practical application in clinical settings.

Power-laws in dog behavior may pave the way to predictive models: A pattern analysis study.

Apparently random events in nature often reveal hidden patterns when analyzed using diverse and robust statistical tools. Power law distributions, for example, project diverse natural phenomenon, ranging from earthquakes to heartbeat dynamics into a common platform of self-similarity. Animal behavior in specific contexts has been shown to follow power law distributions. However, the behavioral repertoire of a species in its entirety has never been analyzed for the existence of such underlying patterns. Here we show that the frequency-rank data of randomly sighted behaviors at the population level of free-ranging dogs follow a scale-invariant power law behavior. It suggests that irrespective of changes in location of sightings, seasonal variations and observer bias, datasets exhibit a conserved trend of scale invariance. The data also exhibits robust self-similarity patterns at different scales which we extract using multifractal detrended fluctuation analysis. We observe that the probability of consecutive occurrence of behaviors of adjacent ranks is much higher than behaviors widely separated in rank. The findings open up the possibility of designing predictive models of behavior from correlations existing in true time series of behavioral data and exploring the general behavioral repertoire of a species for the presence of syntax.

Coronavirus disease 2019 and dengue: two case reports.

BACKGROUND: The pandemic of this century has overwhelmed the healthcare systems of affected countries, and all resources have been diverted to coronavirus disease 2019. At the onset, coronavirus disease 2019 can present as any other acute febrile undifferentiated illness. In tropical regions, clinicians are increasingly challenged to differentiate these febrile illnesses without the use of diagnostics. With this pandemic, many of these tropical diseases are neglected and go underreported. Dengue is holoendemic in the Maldives, and dengue viruses circulate throughout the year. Reports about coinfections with dengue virus and severe acute respiratory syndrome coronavirus 2 are scarce, and the outcome and the dynamics of the disease may be altered in the presence of coinfection. We have described the clinical manifestation and serial laboratory profile, and highlighted the atypical findings uncommon in dengue infection. CASE PRESENTATION: Case 1 was a 39-year old Asian male, presented on day 6 of dengue infection with warning signs. Reverse transcription polymerase chain reaction for severe acute respiratory syndrome coronavirus 2 that was done as per hospital protocol was found to be positive. Case 2 was a 38-year old Asian male, was admitted on day 5 of illness with symptoms of acute respiratory infection with positive reverse transcription polymerase chain reaction for severe acute respiratory syndrome coronavirus 2. Evaluation of progressive leukopenia and thrombocytopenia showed positive dengue serology. CONCLUSION: Clinicians must be conscientious when working on the differential diagnosis of possible tropical diseases in cases of coronavirus disease 2019, specifically, when patients develop hemoconcentration, thrombocytopenia, and transaminitis with elevated expression of aspartate higher than alanine transaminase, which is frequently observed in dengue infection. Caution must be taken during the administration of intravenous fluids when treating patients with coronavirus disease 2019 and dengue coinfection, as coronavirus disease 2019 patients are more prone to develop pulmonary edema. Timely diagnosis and appropriate management are essential to avoid the devastating complications of severe forms of dengue infection. It is important to repeat and reconfirm the dengue serology in coronavirus disease 2019 patients to avoid false positivity. Diligence and care must be taken not to neglect other endemic tropical diseases in the region during the present pandemic.

COVID-19 and emergencies in patients with diabetes: two case reports.

BACKGROUND: Maldives reported its first Coronavirus disease 2019 (COVID-19) case on March 7th, 2020. Since then more than 9400 positive cases and 33 deaths have been reported. Recently studies have shown that COVID-19 patients with diabetes had a poor prognosis and a higher mortality rate when compared to the non-diabetic patients. Poorly controlled diabetic patients had a higher incidence of complications like diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) which might have been precipitated by COVID-19. DKA and HHS are potentially lethal but preventable conditions. During this pandemic, although cases of uncontrolled diabetes are frequently reported, there is scarcity in reporting of cases with diabetic emergencies. CASE PRESENTATION: Case 1 was a 53-year old Asian male, admitted on Day 10th of illness with DKA with acute kidney injury, and Moderate COVID-19. Case 2 was a 72-year old Asian male, admitted with mild COVID-19 who developed HHS with acute kidney injury on day 9 of illness. Both patients were managed conservatively in intensive care unit, with intravenous fluids and insulin. CONCLUSION: Clinicians should focus on close monitoring of diabetic patients with COVID-19, to prevent diabetic emergencies like DKA and HHS. It is important to aggressively manage these conditions for a favorable outcome.

Vocal imitation between mothers and infants.

The aim of the present mixed cross-sectional and longitudinal study was to observe and describe some aspects of vocal imitation in natural mother-infant interaction. Specifically, maternal imitation of infant utterances was observed in relation to the imitative modeling, mirrored equivalence, and social guided learning models of infant speech development. Nine mother-infant dyads were audio-video recorded. Infants were recruited at different ages between 6 and 11 months and followed for 3 months, providing a quasi-longitudinal series of data from 6 through 14 months of age. It was observed that maternal imitation was more frequent than infant imitation even though vocal imitation was a rare maternal response. Importantly, mothers used a range of contingent and noncontingent vocal responses in interaction with their infants. Mothers responded to three-quarters of their infant's vocalizations, including speech-like and less mature vocalization types. The infants' phonetic repertoire expanded with age. Overall, the findings are most consistent with the social guided learning approach. Infants rarely imitated their mothers, suggests a creative self-motivated learning mechanism that requires further investigation.

Inference about time-dependent prognostic accuracy measures in the presence of competing risks.

BACKGROUND: Evaluating a candidate marker or developing a model for predicting risk of future conditions is one of the major goals in medicine. However, model development and assessment for a time-to-event outcome may be complicated in the presence of competing risks. In this manuscript, we propose a local and a global estimators of cause-specific AUC for right-censored survival times in the presence of competing risks. METHODS: The local estimator - cause-specific weighted mean rank (cWMR) - is a local average of time-specific observed cause-specific AUCs within a neighborhood of given time t. The global estimator - cause-specific fractional polynomials (cFPL) - is based on modelling the cause-specific AUC as a function of t through fractional polynomials. RESULTS: We investigated the performance of the proposed cWMR and cFPL estimators through simulation studies and real-life data analysis. The estimators perform well in small samples, have minimal bias and appropriate coverage. CONCLUSIONS: The local estimator cWMR and the global estimator cFPL will provide computationally efficient options for assessing the prognostic accuracy of markers for time-to-event outcome in the presence of competing risks in many practical settings.