Protective effects of a small-molecule inhibitor DDQ against tau-induced toxicities in a transgenic tau mouse model of Alzheimer's disease.

The purpose of our study is to determine DDQ (diethyl (3,4-dihydroxyphenethylamino) (quinolin-4-yl) methylphosphonate)-a newly discovered molecule that has been shown to protect against phosphorylated tau (p-tau) in Alzheimer's disease (AD) pathogenesis. We used a well-studied tau (P301L) transgenic mouse model to achieve our goal. We administered DDQ into 12-month-old Tau mice, at 20 mg/kg body weight intraperitoneally two times per week for 2 months. We also assessed DDQ levels in the blood, skeletal muscle and brain using biochemical and molecular techniques. We investigated the mRNA and protein levels of mitochondrial dynamics, biogenesis, synaptic, p-tau and longevity genes sirtuins in DDQ-treated tau mice using real-time quantitative PCR (q-RT-PCR), immunoblotting and immunofluorescence techniques. Our extensive pharmacodynamics investigations revealed that skeletal muscle had the greatest peak levels of DDQ, followed by serum and brain. Interestingly, DDQ-treated tau mice had higher levels of mitochondrial fusion, biogenesis, synaptic genes and sirtuins than DDQ-untreated tau mice. In addition, DDQ-treated tau mice had lower levels of mitochondrial fission and p-tau than untreated tau mice. The current findings, combined with our prior findings, firmly show that DDQ possesses anti-aging, anti-amyloid-beta and anti-p-tau properties, making it a promising molecule for reducing age-related, amyloid-beta and p-tau-induced synaptic and mitochondrial toxicities in AD.

A phase II trial of nivolumab followed by ipilimumab and nivolumab in advanced non-clear-cell renal cell carcinoma.

OBJECTIVE: To evaluate the efficacy of sequential treatment with ipilimumab and nivolumab following progression on nivolumab monotherapy in individuals with advanced, non-clear-cell renal cell carcinoma (nccRCC). MATERIALS AND METHODS: UNISoN (ANZUP1602; NCT03177239) was an open-label, single-arm, phase 2 clinical trial that recruited adults with immunotherapy-naïve, advanced nccRCC. Participants received nivolumab 240 mg i.v. two-weekly for up to 12 months (Part 1), followed by sequential addition of ipilimumab 1 mg/kg three-weekly for four doses to nivolumab if disease progression occurred during treatment (Part 2). The primary endpoint was objective tumour response rate (OTRR) and secondary endpoints included duration of response (DOR), progression-free (PFS) and overall survival (OS), and toxicity (treatment-related adverse events). RESULTS: A total of 83 participants were eligible for Part 1, including people with papillary (37/83, 45%), chromophobe (15/83, 18%) and other nccRCC subtypes (31/83, 37%); 41 participants enrolled in Part 2. The median (range) follow-up was 22 (16-30) months. In Part 1, the OTRR was 16.9% (95% confidence interval [CI] 9.5-26.7), the median DOR was 20.7 months (95% CI 3.7-not reached) and the median PFS was 4.0 months (95% CI 3.6-7.4). Treatment-related adverse events were reported in 71% of participants; 19% were grade 3 or 4. For participants who enrolled in Part 2, the OTRR was 10%; the median DOR was 13.5 months (95% CI 4.8-19.7) and the median PFS 2.6 months (95% CI 2.2-3.8). Treatment-related adverse events occurred in 80% of these participants; 49% had grade 3, 4 or 5. The median OS was 24 months (95% CI 16-28) from time of enrolment in Part 1. CONCLUSIONS: Nivolumab monotherapy had a modest effect overall, with a few participants experiencing a long DOR. Sequential combination immunotherapy by addition of ipilimumab in the context of disease progression to nivolumab in nccRCC is not supported by this study, with only a minority of participants benefiting from this strategy.

Engaging participants with research findings: A rights-informed approach.

BACKGROUND: Sharing research findings with participants is recognized as an ethical imperative for the research community. However, most discourse on this topic in mainstream public health takes a paternalistic approach, with researchers retaining the power to choose if, when, and how research findings are shared. METHODS: Fieldwork took place from August 2018 to January 2019 and again from August 2019 to December 2019 among two communities in the south Indian state of Kerala. We integrated participant engagement with study findings into the research protocol, using various collaborative strategies identified during the design stage, forming partnerships with participants and determining appropriate forms of dissemination for different participant groups during fieldwork. RESULTS: Findings from previous research projects undertaken with these communities by other researchers had not been shared with them. This was interpreted by the communities as researchers not being interested in making a difference to their situation. In the current study, building reciprocal relationships that minimized power disparities, and providing outputs in tailored formats that promoted active engagement were key factors that enabled participants to engage with results. This engagement added value by enabling us to co-develop study recommendations. This process also enabled the community to have ownership of the results and use them to advocate for health system change to improve access to health care. CONCLUSION: Research should be transformative for participating communities. Participants have a right to know the results of the research they participate in since their knowledge provides the research data which can in turn promote community change. Operationalising this requires researchers to build partnerships with participants and their communities from the outset. The role of participants must be reimagined, and adequate resources should be built into the research process. This is both socially responsible and ethical, but also improves the impact and legitimacy of research for the participants and the communities that they represent. PATIENT OR PUBLIC CONTRIBUTION: Participants of our research contributed to the design of various aspects of the engagement processes including the venue, the formats used for engagement, interpretation of the findings and recommendations from our research.

6-Year-Old Male Drowning Complicated by Cardiac Arrest and Ensuing Metabolic and Respiratory Acidosis: Should Presence of Pulses Lead Clinicians to Pursue Prolonged Cardiopulmonary Resuscitation?

BACKGROUND: Drowning is one of the leading causes of death in the pediatric population. Patients arriving to the emergency department (ED) with submersion injuries are often asymptomatic and well-appearing, but can sometimes present critically ill and require prolonged resuscitation. The question of how long to continue resuscitation of a pediatric patient with a submersion injury is a difficult question to answer. CASE REPORT: We present a case of 6-year-old boy was found by his friends submerged in sea water for 10-15 min. The patient was rescued by lifeguards and evaluated by emergency medical personnel, who found him breathing spontaneously but unresponsive. En route to hospital, the patient became apneic, cardiopulmonary resuscitation (CPR) was started, and the patient was intubated. The patient arrived to the ED in cardiopulmonary arrest, CPR was continued and epinephrine was administered. Return of spontaneous circulation was achieved after 42 min in the ED. Initial laboratory test results showed severe acidosis and chest x-ray study showed diffuse interstitial edema. Ventilator settings were adjusted in accordance with lung protective ventilation strategies and the acidosis began to improve. Over the next several days, the patient was weaned to noninvasive ventilation modalities and eventually made a complete neurologic recovery and continued to be a straight-A student. Why Should an Emergency Physician Be Aware of This?We make the case that, in select drowning patients, duration of CPR longer than 30 min can potentially result in favorable neurologic outcomes. Prolonged CPR should be especially strongly considered in patients with a pulse at any point during evaluation. With the combination of prolonged CPR and judicious use of lung protective mechanical ventilation strategies, we were able to successfully treat the patient in our case.

A Rare Pediatric Case of Cefixime Induced Toxic Epidermal Necrolysis.

Cefixime is a third-generation cephalosporin that has been used for the treatment of a wide range of infections in children and adults. The incidence of cefixime induced toxic epidermal necrolysis (TEN) is less than 2% in adults, but it is infrequent among pediatric patients. We report a rare case of cefixime induced TEN in a 7-year-old boy. In this case, the child presented with symptoms of TEN after 2 days of administration of cefixime. This case highlights the need to select structurally different antibiotics in case of antibiotic-induced severe cutaneous adverse reaction (SCAR) to avoid recurrence of SCAR. Furthermore, concluded that irrational use of antibiotics could be disastrous as it can result in TEN as the incidence of antibiotics induced TEN ranges from 29% to 42%.

Comparison of postoperative analgesia with two different doses of dexmedetomidine as an adjuvant to ropivacaine in adductor canal block for unilateral total knee replacement surgery: A randomized double-blinded study.

Background and Aims: Multimodal analgesia is used to treat severe postoperative pain (POP) in total knee replacement (TKR) surgery. Adjuvants are used with local anesthetics to improve the quality and duration of pain relief. Studies comparing different doses of dexmedetomidine in adductor canal block (ACB) are sparse to date. This study compares postoperative analgesia with two different doses of dexmedetomidine as an adjuvant to 0.2% ropivacaine in ACB for unilateral TKR. Material and Methods: In this prospective, randomized, double-blinded comparative study, sixty patients were divided into two groups: A and B. Postoperatively perineural catheter was inserted and all patients received 0.2% ropivacaine 20 mL bolus followed by an infusion of 0.2% ropivacaine with dexmedetomidine (0.5 µg/Kg in Group A and 1 µg/Kg in Group B) at 8 mL/h. Postoperative pain, motor blockade, rescue analgesia, hemodynamic parameters, sedation, and adverse effects were recorded. Student t, Chi-square, and Mann-Whitney tests were used. Results: Most patients were elderly females (M:15, F:45). Postoperatively, from 2nd to 24th hour, pain score was less in Group B (P < 0.05). The requirement of rescue analgesic was also less in Group B (A:B 330 µg:60 µg; 23%:6%). Motor blockade assessed using modified Bromage scale and sedation using Richmond agitation sedation scale did not show any statistical difference. Conclusion: Dexmedetomidine infusion at 1 µg/Kg is a better adjuvant to 0.2% ropivacaine than 0.5 µg/Kg in ACB. It provides better analgesia without producing sedation, motor blockade, hemodynamic changes, or any adverse effects.

Intraoperative Neuromonitoring for Tethered Cord Surgery in Infants: Challenges and Outcome.

OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of intraoperative neuromonitoring (IONM) in surgery for tethered cord in infants. MATERIALS AND METHODS: The study included 87 infants who underwent surgery for closed spinal dysraphism under IONM. Their preoperative neurological and urological statuses were compared with postoperative status clinically. The study design was prospective, and the study's duration was from January 2011 to February 2020. IONM was performed (TcMEP and direct mapping) with an Xltek Protektor 32 IOM system, Natus Neurology/medical Inc., Middleton, USA. Statistical analysis in the form of χ2 is conducted using SPSS. RESULTS: Overall, among 87 patients, clinical improvement was seen in 28 (28/29) patients with motor deficits, 17 (17/24) with bladder deficits, and 18 (18/24) with bowel deficits. The monitorability for motor and sphincter was 97.3% and 90.7%, respectively. The sensitivity of IONM in predicting new motor deficit was 100%, whereas the specificity was 100%. The negative predictive value of predicting motor deficit was 100%, with a diagnostic accuracy of 100%. There were no complications in this cohort related to the IONM. CONCLUSIONS: The study has highlighted that the use of IONM is sensitive in identifying motor injury in infants with reliable outcome correlation. Assessment, monitoring, and outcome correlation of bladder and sphincteric functions are a challenge in this cohort.

Prognostication of the neurological outcome of tethered cord based on intraoperative neuromonitoring findings: how close can we get?

PURPOSE: To evaluate the correlation of intraoperative neuromonitoring (IONM) data in surgery for tethered cord syndrome (TCS) in children to the neurological outcome at 1-year follow-up. METHODS: 208 consecutive patients operated on for TCS, between January 2011 to February 2020, under electrophysiological monitoring in the Division of Paediatric Neurosurgery, AIMS, Kochi, India, were included. Their preoperative neurological, urological and orthopaedic status were compared with the postoperative status at 1 year follow-up. RESULTS: Our study prospectively collected the IONM data and retrospectively correlated it to the children's neurological outcome on follow-up. Out of 208 children, 28% (n = 59/208) had motor, 35% (n = 73/208) had bladder and 26% (n = 54/208) had bowel disturbances. Postsurgery, at one-year follow-up, 91% (n = 52/57) of the patients who had motor deficits had improvement, 82.3% (n = 51/62) of patients who had bladder deficits showed an improvement, and 88.8% (n = 48/54) with bowel deficits showed improvement. The monitorability for motor and sphincter potentials were 99.4% and 89.3%, respectively. Except for four patients (3 with bladder and 1 with motor worsening), all the patients who were monitorable with no deficits remained intact except for four patients, all the patients who had deficits and were monitorable improved after detethering (at 1 year). Clinical worsening corresponded to those who had a drop in amplitude of baseline TcMEP (n = 4). 18 events showed an increase in amplitude compared to the baseline TcMEP. These patients improved clinically on follow-up (at 1 year). CONCLUSIONS: IONM complements the preoperative clinical details in predicting immediate and long-term outcomes.

A Rare Case of Dapsone Hypersensitivity Syndrome and Leukemoid Reaction With Coexisting Hepatitis E in a Pediatric Patient.

Dapsone is extensively used for a variety of infectious, immunological, and hypersensitivity disorders. Dapsone can cause several adverse effects, the most serious being dapsone hypersensitivity syndrome (DHS), which is potentially fatal. DHS is characterized by triad of eruptions, fever, and organ involvement (including liver, kidney, hematological system, etc.). DHS can develop several weeks to as late as 6 months after treatment initiation with dapsone. Here, we report a case of DHS and leukemoid reaction with coexisting hepatitis E in a 10-year-old girl. Three weeks prior to the current admission, she was treated with dapsone (1 mg/kg/day in two divided doses) for 8 days by a local doctor for lichen nitidus. She was managed successfully for DHS with intravenous (IV) steroids followed by the oral steroid. This case is being reported to highlight the importance to ensure timely diagnosis of DHS and its appropriate management. Patients started on dapsone for various clinical conditions need to be observed carefully for the development of the DHS. If this occurs, DHS can be mistaken for the progression of the primary disease. If dapsone is not withdrawn, it could have deleterious and potentially fatal effects due to major organ dysfunction.

Comparison of performance characteristics of C-MAC video, McCoy, and Macintosh laryngoscopes in elective cervical spine surgery.

Background and Aims: To compare the performance characteristics of C-MAC video, McCoy, and Macintosh laryngoscopes in elective cervical spine surgery. The primary objective was to assess the ease of intubation with the three study devices. The secondary objectives were the time to intubation and hemodynamic responses during intubation. Material and Methods: The prospective observational comparative study was conducted in a tertiary care hospital. Adult ASA 1 and 11 patients who underwent elective cervical spine surgery were included in the study. Patients with unstable spine and trauma were excluded. The analysis of variance, Bonferroni test, Chi square test and multiple comparison tests were used to compare the performance characteristics of laryngoscopes. Results: The C-MAC video laryngoscope improved glottis view by improving the modified Cormack-Lehane (CL) score and the percentage of glottis opening (POGO) score compared to McCoy and Macintosh laryngoscopes. The ease of intubation was better with the C-MAC video laryngoscope compared to the McCoy and Macintosh laryngoscopes. The time to intubation was comparable between the three laryngoscopes. The C-MAC video and McCoy laryngoscopes had 100% successful first attempt intubations while it was 90% for the Macintosh laryngoscope. Hemodynamic variables observed during intubation were comparable between the three groups. Conclusion: The use of C-MAC video laryngoscope resulted in better visualization of the glottis and easier tracheal intubation as compared to the Macintosh and McCoy laryngoscopes in cervical spine surgery. Both C-MAC video and McCoy laryngoscopes had 100% successful first attempt intubation.

"Everything is provided free, but they are still hesitant to access healthcare services": why does the indigenous community in Attapadi, Kerala continue to experience poor access to healthcare?

BACKGROUND: Inequity in access to healthcare services is a constant concern. While advances in healthcare have progressed in the last several decades, thereby significantly improving the prevention and treatment of disease, these benefits have not been shared equally. Excluded communities such as Indigenous communities typically face a lack of access to healthcare services that others do not. This study seeks to understand why the indigenous communities in Attapadi continue to experience poor access to healthcare in spite of both financial protection and adequate coverage of health services. METHODS: Ethnographic fieldwork was carried out among the various stakeholders living in Attapadi. A total of 47 in-depth interviews and 6 focus group discussions were conducted amongst the indigenous community, the healthcare providers and key informants. The data was coded utilising a reflexive and inductive approach leading to the development of the key categories and themes. RESULTS: The health system provided a comprehensive financial protection package in addition to a host of healthcare facilities for the indigenous communities to avail services. In spite of this, they resisted attempts by the health system to improve their access. The failure to provide culturally respectful care, the discrimination of the community at healthcare facilities, the centralisation of the delivery of services as well as the lack of power on the part of the indigenous community to negotiate with the health system for services that were less disruptive for their lives were identified as the barriers to improving healthcare access. The existing power differentials between the community and the health system stakeholders also ensured that meaningful involvement of the community in the local health system did not occur. CONCLUSION: Improving access to health care for indigenous communities would require UHC interventions to be culturally safe, locally relevant and promote active involvement of the community at all stages of the intervention. Continuing structural power imbalances that affect access to resources and prevent meaningful involvement of indigenous communities also need to be addressed.

Community, system and policy level drivers of bovine tuberculosis in smallholder periurban dairy farms in India: a qualitative enquiry.

BACKGROUND: Rapid urbanization has led to expansion of peri-urban fringes, where intensive, industry-style livestock rearing has led to emerging vulnerabilities at the human-animal-environment interface. This study was undertaken to understand the health system and farm-level factors that influenced the risk of transmission of bovine Tuberculosis (bTB) in animals and humans in peri-urban smallholder dairy farms of India. METHODS: Thematic guides were developing through literature review and expert consultation. In-depth interviews were conducted till attainment of saturation. Identification of core themes was followed by etiological enquiry and generation of a conceptual model. RESULTS: Veterinarians were consulted as a last resort after home-remedies and quacks had failed. Damage control measures, especially with respect to- selling or abandoning sick animals, added to the risk of disease transmission. Although civic authorities believed in the adequacy of a functioning laboratory network, end users were aggrieved at the lack of services. Despite the presence of extension services, knowledge and awareness was limited, promoting risky behaviour. The absence of cogent policies in dealing with bTB was a significant barrier. Stakeholders did not consider bTB to be a major concern. It is possible that they underestimate the problem. CONCLUSION: The current study helps to identify gaps which need to be addressed through collaborative research, and OneHealth interventions to build community awareness.

Public health-oriented healthcare systems: Need for a modified typology.

Healthcare systems across the world are dominated by medical care services compared to public health services. Within public health services, individual-oriented interventions dominate compared to population-based interventions perhaps due to the inherent dominance of biomedical approaches within public health. Clarity is needed between diverse approaches, methods and targets of public health as against clinical care services delivered under healthcare systems. Public health has a primary objective of prevention and promotion with the population as the target group with a societal focus, whereas the latter is curative in intent with an individualist orientation and logic and hence reductionist. The implications are important for developing nations such as India, which have a history of neglect towards ensuring public health due to the domination of policies on medical care. The healthcare system should use a modified typology that asserts its differential commitment to address both public health and medical care needs of its citizens.

Probable blueberry-induced haemolysis in a G6PD deficient child: A case report.

BACKGROUND: Blueberry is a North American native fruit increasingly popular as a source of health-promoting bioactive compounds. However, there is evidence in the literature stating that blueberries should be avoided in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. CASE PRESENTATION: We report the first case of a G6PD deficient child who developed haemolysis approximately after half a day following the intake of fresh blueberry. He presented with the complaints of the passage of orange coloured urine and hurried breathing. The child had haemoglobin of 7.9 g/dl on admission day and the laboratory results were indicative of haemolytic process. OUTCOMES AND IMPLICATIONS: During the stay in the hospital, the child was managed conventionally, and he improved both clinically and symptomatically. The child was discharged after four days of treatment and diet counselling was provided to his parents. RECOMMENDATIONS: Our report should encourage further research on this fruit regarding the mechanism behind the development of haemolytic anaemia. Also, it is important in the case of G6PD deficient patients to take lifelong precautions to avoid the foods that can trigger haemolysis.

Broadband waveguide quantum memory for entangled photons.

The reversible transfer of quantum states of light into and out of matter constitutes an important building block for future applications of quantum communication: it will allow the synchronization of quantum information, and the construction of quantum repeaters and quantum networks. Much effort has been devoted to the development of such quantum memories, the key property of which is the preservation of entanglement during storage. Here we report the reversible transfer of photon-photon entanglement into entanglement between a photon and a collective atomic excitation in a solid-state device. Towards this end, we employ a thulium-doped lithium niobate waveguide in conjunction with a photon-echo quantum memory protocol, and increase the spectral acceptance from the current maximum of 100 megahertz to 5 gigahertz. We assess the entanglement-preserving nature of our storage device through Bell inequality violations and by comparing the amount of entanglement contained in the detected photon pairs before and after the reversible transfer. These measurements show, within statistical error, a perfect mapping process. Our broadband quantum memory complements the family of robust, integrated lithium niobate devices. It simplifies frequency-matching of light with matter interfaces in advanced applications of quantum communication, bringing fully quantum-enabled networks a step closer.

'I am doing fine only because I have not told anyone': the necessity of concealment in the lives of people living with HIV in India.

In HIV prevention and care programmes, disclosure of status by HIV-positive individuals is generally encouraged to contain the infection and provide adequate support to the person concerned. Lack of disclosure is generally framed as a barrier to preventive behaviours and accessing support. The assumption that disclosure is beneficial is also reflected in studies that aim to identify determinants of disclosure and recommend individual-level measures to promote disclosure. However, in contexts where HIV infection is stigmatised and there is fear of rejection and discrimination among those living with HIV, concealment of status becomes a way to try and regain as much as possible the life that was disrupted by the discovery of HIV infection. In this study of HIV-positive women and children in India, concealment was considered essential by individuals and families of those living with HIV to re-establish and maintain their normal lives in an environment where stigma and discrimination were prevalent. This paper describes why women and care givers of children felt the need to conceal HIV status, the various ways in which people tried to do so and the implications for treatment of people living with HIV. We found that while women were generally willing to disclose their status to their husband or partner, they were very keen to conceal their status from all others, including family members. Parents and carers with an HIV-positive child were not willing to disclose this status to the child or to others. Understanding the different rationales for concealment would help policy makers and programme managers to develop more appropriate care management strategies and train care providers to assist clients in accessing care and support without disrupting their lives.

Genetic and environmental factors in the aetiology of hypospadias.

This article reviews the current evidence and knowledge of the aetiology of hypospadias. Hypospadias remains a fascinating anomaly of the male phallus. It may be an isolated occurrence or part of a syndrome or field defect. The increasing use of assisted reproductive techniques and hormonal manipulation during pregnancy may have been associated with an apparent rise in the incidence of hypospadias. Genetic studies and gene analysis have suggested some defects that could result in hypospadias. New light has also been thrown on environmental factors that could modulate candidate genes, causing altered development of the male external genitalia.

Spectral multiplexing for scalable quantum photonics using an atomic frequency comb quantum memory and feed-forward control.

Future multiphoton applications of quantum optics and quantum information science require quantum memories that simultaneously store many photon states, each encoded into a different optical mode, and enable one to select the mapping between any input and a specific retrieved mode during storage. Here we show, with the example of a quantum repeater, how to employ spectrally multiplexed states and memories with fixed storage times that allow such mapping between spectral modes. Furthermore, using a Ti:Tm:LiNbO_{3} waveguide cooled to 3 K, a phase modulator, and a spectral filter, we demonstrate storage followed by the required feed-forward-controlled frequency manipulation with time-bin qubits encoded into up to 26 multiplexed spectral modes and 97% fidelity.