Publications by authors named "H Kiran K Reddy"

350 Publications

Weight Bearing as Tolerated After Intramedullary Nailing of the Femur: A Retrospective Analysis of Clinical and Radiographic Outcomes.

Orthopedics 2022 Jan 12:1-6. Epub 2022 Jan 12.

Intramedullary nailing of femur fractures has become the standard of care, with high union rates. Few high-level studies have discussed the effect that early weight bearing has on the healing of these fractures, regardless of nail size or fracture pattern. The goal of this study was to determine the clinical and radiographic outcomes of femoral shaft fractures for patients allowed immediate weight bearing after intramedullary nailing. We performed a retrospective review of 341 femoral shaft fractures, with 131 allowed immediate weight bearing, 99 allowed partial weight bearing, and 111 kept non-weight bearing. Demographic, intraoperative, and postoperative variables were collected and analyzed. Increased fracture complexity was associated with higher likelihood of delayed weight bearing. No significant difference was found for nail size or rate of failure with different nail sizes. A total of 50 nonunions were noted (14.7%), with no difference in nonunion rates between weight bearing cohorts. The only significant predictor of nonunion was Orthopaedic Trauma Association (OTA) classification of OTA32B fractures (=.02), which were 2 times and 4 times as likely to occur compared with OTA32A and OTA32C fractures, respectively. Failure of interlocking screws occurred among 15 patients (4.4%) and was more common with older patients, osteoporotic bone, and larger diameter nails. In summary, unilateral intramedullary nailing of adult femoral shaft fractures does not show a difference in fracture union rates or implant failure with unrestricted, immediate weight bearing, regardless of nail characteristics. [. 20XX;XX(X):xx-xx.].
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http://dx.doi.org/10.3928/01477447-20220105-10DOI Listing
January 2022

A revised mechanism of action of hyperaldosteronism-linked mutations in cytosolic domains of GIRK4 (KCNJ5).

J Physiol 2021 Dec 26. Epub 2021 Dec 26.

Department of Physiology and Pharmacology, School of Medicine, and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.

G protein-gated, inwardly rectifying potassium channels (GIRK) mediate inhibitory transmission in brain and heart, and are present in the adrenal cortex. GIRK4 (KCNJ5) subunits are abundant in the heart and adrenal cortex. Multiple mutations of KCNJ5 cause primary aldosteronism (PA). Mutations in the pore region of GIRK4 cause loss of K selectivity, Na influx and depolarization of zona glomerulosa cells followed by hypersecretion of aldosterone. The concept of selectivity loss has been extended to mutations in cytosolic domains of GIRK4 channels, remote from the pore. We expressed aldosteronism-linked GIRK4 , GIRK4 and GIRK4 mutants in Xenopus oocytes. Whole-cell currents of heterotetrameric GIRK1/4 and GIRK1/4 channels were greatly reduced compared with GIRK1/4 . Nevertheless, all heterotetrameric mutants retained full K selectivity and inward rectification. When expressed as homotetramers, only GIRK4 , but none of the mutants, produced whole-cell currents. Confocal imaging, single-channel and Förster Resonance Energy Transfer (FRET) analyses showed: (1) reduction of membrane abundance of all mutated channels, especially as homotetramers, (2) impaired interaction with Gβγ subunits, and (3) reduced open probability of GIRK1/4 . VU0529331, a GIRK4 opener, activated homotetrameric GIRK4 channels, but not GIRK4 or GIRK4 . In the human adrenocortical carcinoma cell line (HAC15), VU0529331 and overexpression of heterotetrameric GIRK1/4 , but not overexpression of GIRK1/4 mutants, reduced aldosterone secretion. Our results suggest that, contrary to pore mutants of GIRK4, non-pore mutants R52H and E246K mutants are loss-of-function rather than gain-of-function/selectivity-loss mutants. Hence, GIRK4 openers may be a potential course of treatment for patients with cytosolic N- and C-terminal mutations. KEY POINTS: Mutations in GIRK4 (KCNJ5) G protein-gated channels cause primary aldosteronism, a major cause of secondary hypertension. The primary mechanism is believed to be loss of K selectivity. R52H and E246K, aldosteronism-causing mutations in cytosolic N- and C- termini of GIRK4, were reported to cause loss of K selectivity. We show that R52H, E246K and G247R mutations render homotetrameric GIRK channels non-functional. In heterotetrameric context with GIRK1, these mutations impair membrane expression, interaction with Gβγ and open probability, but do not alter K selectivity or inward rectification. In the human aldosterone-secreting cell line, a GIRK4 opener and overexpression of heterotetrameric GIRK1/4 , but not overexpression of GIRK1/4 mutants, reduced aldosterone secretion. Aldosteronism-causing mutations in the cytosolic domain of GIRK4 are loss-of-function mutations rather than gain-of-function, selectivity-loss mutations. Deciphering of exact biophysical mechanism that impairs the channel is crucial for setting the course of treatment.
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http://dx.doi.org/10.1113/JP282690DOI Listing
December 2021

Who funded the research behind the Oxford-AstraZeneca COVID-19 vaccine?

BMJ Glob Health 2021 12;6(12)

Epidemiology and Data Science, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands

Objectives: The Oxford-AstraZeneca COVID-19 vaccine (ChAdOx1 nCoV-19, Vaxzevira or Covishield) builds on two decades of research and development (R&D) into chimpanzee adenovirus-vectored vaccine (ChAdOx) technology at the University of Oxford. This study aimed to approximate the funding for the R&D of ChAdOx and the Oxford-AstraZeneca vaccine and to assess the transparency of funding reporting mechanisms.

Methods: We conducted a scoping review and publication history analysis of the principal investigators to reconstruct R&D funding the ChAdOx technology. We matched award numbers with publicly accessible grant databases. We filed freedom of information (FOI) requests to the University of Oxford for the disclosure of all grants for ChAdOx R&D.

Results: We identified 100 peer-reviewed articles relevant to ChAdOx technology published between January 2002 and October 2020, extracting 577 mentions of funding bodies from acknowledgements. Government funders from overseas (including the European Union) were mentioned 158 times (27.4%), the UK government 147 (25.5%) and charitable funders 138 (23.9%). Grant award numbers were identified for 215 (37.3%) mentions; amounts were publicly available for 121 (21.0%). Based on the FOIs, until December 2019, the biggest funders of ChAdOx R&D were the European Commission (34.0%), Wellcome Trust (20.4%) and Coalition for Epidemic Preparedness Innovations (17.5%). Since January 2020, the UK government contributed 95.5% of funding identified. The total identified R&D funding was £104 226 076 reported in the FOIs and £228 466 771 reconstructed from the literature search.

Conclusion: Our study approximates that public and charitable financing accounted for 97%-99% of identifiable funding for the ChAdOx vaccine technology research at the University of Oxford underlying the Oxford-AstraZeneca vaccine until autumn 2020. We encountered a lack of transparency in research funding reporting.
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http://dx.doi.org/10.1136/bmjgh-2021-007321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8704023PMC
December 2021

Phase III, Randomized, Double-blind, Placebo controlled trial of Efficacy, Safety and Tolerability of Antiviral drug Umifenovir vs Standard care of therapy in non-severe COVID-19 patients.

Int J Infect Dis 2022 Feb 19;115:62-69. Epub 2021 Nov 19.

CSIR-Central Drug Research Institute, Lucknow. Electronic address:

Objective: To test efficacy, safety and tolerability of Umifenovir in non-severe COVID-19 adult patients.

Methods: We carried out randomized, double-blind, placebo-controlled, multicenter, phase III trials involving adult (18-75 years), non-severe COVID19 patients, randomized 1:1 on placebo or Umifenovir (800 mg BID, maximum 14 days) respectively along with standard-of-care. The primary endpoint for Asymptotic-mild patients was time to nasopharyngeal swab RT-PCR test negativity. For Moderate patients, the average change in the ordinal scale from the baseline scores on the eight-point WHO ordinal scale was assessed.

Results: 132 patients were recruited between 3 October to 28 April 2021, of which 9 discontinued due to various reasons. In Mild-asymptomatic patients (n=82), we found that 73% patients in the Umifenovir arm were RT-PCR negative, while 40% patients in the placebo arm were negative (P=0.004) on day 5. However, in the moderate group (n=41), the WHO scores for the Umifenovir arm was not statistically significant (P=0.125 on day 3), while it was statistically significant in the Mild-asymptomatic group (P=0.019 on day 5).

Conclusion: Umifenovir meets the primary and secondary endpoint criteria and exhibits statistically significant efficacy for Mild-asymptomatic patients. It is efficacious, safe and well-tolerated at the tested dosage of 800mg BID, maximum 14 days.
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http://dx.doi.org/10.1016/j.ijid.2021.11.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8603331PMC
February 2022
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