Performance Issues in U.S.–China Joint Ventures

Based on an in-depth study of U.S.-China joint ventures, this article offers some insights into the performance of such international business relationships. While the conventional literature treats government as an amorphous aspea of the political-legal environment, in this case government is an active participant and influence in the performance of international joint ventures (UVs). It has both a constraining and enabling effect on LJV structure, strategy, and performance. For example, limits can be placed on ownership shares of joint ventures and on prices of the output. At the same time, government can cooperate with LJVs and foreign parent companies by creating partners for foreign parent companies, acting as major customers, and improving financial performance by lowering taxes

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain–gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials

SARS-CoV-2-specific nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination

BACKGROUND: Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced. METHODS: In this follow up study, plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data. FINDINGS: Strong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months (p < 0.0001). Nasal and plasma anti-S IgG remained elevated for at least 12 months (p < 0.0001) with plasma neutralising titres that were raised against all variants compared to controls (p < 0.0001). Of 323 with complete data, 307 were vaccinated between 6 and 12 months; coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal (1.46-fold change after 10 months, p = 0.011) and the median remained below the positive threshold determined by pre-pandemic controls. Samples 12 months after admission showed no association between nasal IgA and plasma IgG anti-S responses (R = 0.05, p = 0.18), indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination. INTERPRETATION: The decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity. FUNDING: This study has been supported by ISARIC4C and PHOSP-COVID consortia. ISARIC4C is supported by grants from the National Institute for Health and Care Research and the Medical Research Council. Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research. The PHOSP-COVD study is jointly funded by UK Research and Innovation and National Institute of Health and Care Research. The funders were not involved in the study design, interpretation of data or the writing of this manuscript

Prospective Longitudinal Evaluation of Nascent Geographic Atrophy in Age-Related Macular Degeneration.

PURPOSE:Nascent geographic atrophy (nGA) describes features on OCT imaging previously observed to precede the development of atrophy. This study sought to prospectively evaluate the predictive ability of nGA for the conventional clinical endpoint of geographic atrophy (GA) as defined on color fundus photography (CFP). DESIGN:Prospective, longitudinal, observational study. PARTICIPANTS:A total of 284 eyes from 142 participants with bilateral large drusen and without nGA nor late age-related macular degeneration (AMD) at baseline were included. METHODS:OCT volume scans and CFP images were obtained from all participants at baseline and then at 6-month intervals for up to 36 months. OCT and CFP images were graded independently for the presence of nGA and GA, respectively. Eyes that developed neovascular AMD were censored at the day of its detection. MAIN OUTCOME MEASURES:Time to development of GA. RESULTS:A total 12 eyes from 10 participants progressed to GA over 36 months of follow-up, and nGA was detected in 10 of these eyes (83%) at a preceding visit (median, 13 months prior; interquartile range, 6-25 months). A total of 40 eyes from 28 participants developed nGA or GA over 36 months of follow-up, and the probability of progression to nGA and GA after 36 months was 20% (95% confidence interval [CI], 14%-28%) and 9% (95% CI, 6%-13%), respectively. After the detection of nGA, the probability of progression to GA was 38% (95% CI, 15%-55%) after 24 months. The development of nGA was associated with a markedly increased risk of progression to GA compared with when it did not develop (adjusted hazard ratio, 78.1; 95% CI, 13.6-448.0; P < 0.001), and the development of nGA explained 91% of the variance in the time to GA development. CONCLUSIONS:This study prospectively demonstrated that nGA was a strong predictor for the development of GA, providing supportive evidence of the potential value of nGA as a surrogate endpoint in future intervention trials for the early stages of AMD to improve their feasibility substantially.Zhichao Wu, Chi D. Luu, Lauren A.B. Hodgson, Emily Caruso, Nicole Tindill, Khin Zaw Aung, Myra B. McGuinness, Galina Makeyeva, Fred K. Chen, Usha Chakravarthy, Jennifer J. Arnold, Wilson J. Heriot, Shane R. Durkin, Robyn H. Guyme

Subthreshold nanosecond laser intervention in age-related macular degeneration: the LEAD randomized controlled clinical trial

Purpose: There is an urgent need for a more effective intervention to slow or prevent progression of age-related macular degeneration (AMD) from its early stages to vision-threatening late complications. Subthreshold nanosecond laser (SNL) treatment has shown promise in preclinical studies and a pilot study in intermediate AMD (iAMD) as a potential treatment. We aimed to evaluate the safety of SNL treatment in iAMD and its efficacy for slowing progression to late AMD. Design: The Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) study is a 36-month, multicenter, randomized, sham-controlled trial. Participants: Two hundred ninety-two participants with bilateral large drusen and without OCT signs of atrophy. Methods: Participants were assigned randomly to receive Retinal Rejuvenation Therapy (2RT®; Ellex Pty Ltd, Adelaide, Australia) SNL or sham treatment to the study eye at 6-monthly intervals. Main Outcome Measures: The primary efficacy outcome was the time to development of late AMD defined by multimodal imaging (MMI). Safety was assessed by adverse events. Results: Overall, progression to late AMD was not slowed significantly with SNL treatment compared with sham treatment (adjusted hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.33-1.14; P = 0.122). However, a post hoc analysis showed evidence of effect modification based on the coexistence of reticular pseudodrusen (RPD; adjusted interaction P = 0.002), where progression was slowed for the 222 participants (76.0%) without coexistent RPD at baseline (adjusted HR, 0.23; 95% CI, 0.09-0.59; P = 0.002), whereas an increased progression rate (adjusted HR, 2.56; 95% CI, 0.80-8.18; P = 0.112) was observed for the 70 participants (24.0%) with RPD with SNL treatment. Differences between the groups in serious adverse events were not significant. Conclusion: In participants with iAMD without MMI-detected signs of late AMD, no significant difference in the overall progression rate to late AMD between those receiving SNL and sham treatment were observed. However, SNL treatment may have a role in slowing progression for those without coexistent RPD and may be inappropriate in those with RPD, warranting caution when considering treatment in clinical phenotypes with RPD. Our findings provide compelling evidence for further trials of the 2RT® laser, but they should not be extrapolated to other short-pulse lasers.Robyn H. Guymer, Zhichao Wu, Lauren A.B. Hodgson, Emily Caruso, Kate H. Brassington, Nicole Tindill, Khin Zaw Aung, Myra B. McGuinness, Erica L. Fletcher, Fred K. Chen, Usha Chakravarthy, Jennifer J. Arnold, Wilson J. Heriot, Shane R. Durkin, Jia Jia Lek, Colin A. Harper, Sanjeewa S. Wickremasinghe, Sukhpal S. Sandhu, Elizabeth K. Baglin, Pyrawy Sharangan, Sabine Braat, Chi D. Luu, for the Laser Intervention in Early Stages of Age-Related Macular Degeneration Study Grou

Secondary and Exploratory Outcomes of the Subthreshold Nanosecond Laser Intervention Randomized Trial in Age-Related Macular Degeneration: A LEAD Study Report

Purpose:To evaluate the secondary and exploratory outcomesof the Laser Intervention in Early Stages of Age-Related MacularDegeneration (LEAD) study, a 36-month trial of a subthresholdnanosecond laser (SNL) treatment for slowing the progression tolate age-related macular degeneration (AMD) in its early stages.Design:Multicenter, randomized, sham-controlled trial.Participants:Two-hundred ninety-two patients with bilaterallarge drusen.Methods:Participants were randomly assigned to receive SNLor sham treatment to the study eye at 6-month intervals.Main Outcome Measures:The secondary outcome measure ofthe LEAD study was the time to development of late AMD, definedby multimodal imaging in the nonestudy eye. The exploratoryoutcome measures were the rate of change in best-corrected visualacuity (BCVA), low-luminance visual acuity, microperimetric meansensitivity, drusen volume in the study and nonestudy eyes, andparticipant-reported outcomes based on the Night Vision Question-naire and Impact of Vision Impairment questionnaire.Results:Progression to late AMD in the nonestudy eye wasnot significantly delayed with SNL treatment (hazard ratio, 0.83;95% confidence interval, 0.40e1.71;P¼0.611). There was noevidence of effect modification based on the coexistence of retic-ular pseudodrusen; interactionP¼0.065). There was no signifi-cant difference between study groups in the rate of change of low-luminance visual acuity, microperimetric mean sensitivity, anddrusen volume in the study or nonestudy eyes, and Night VisionQuestionnaire and Impact of Vision Impairment questionnaire2 scores (allP 0.167). The rate of BCVA decline was slightlyhigher for participants in the SNL group compared with the shamtreatment group in the study eye (e0.54 and 0.23 letters/year,respectively;P<0.001) but not the nonestudy eye (e0.48 ande0.56 letters/year, respectively;P¼0.628).Conclusions:Subthreshold nanosecond laser treatment of oneeye did not have an effect on delaying progression to late AMD in thefellow eye and did not, in general, have an impact on the exploratorystructural, functional, and participant-reported outcomes.Zhichao Wu, Chi D. Luu, Lauren A.B. Hodgson, Emily Caruso, Kate H. Brassington, Nicole Tindill, Khin Zaw Aung, Colin A. Harper, Sanjeewa S. Wickremasinghe, Sukhpal S. Sandhu, Myra B. McGuinness, Fred K. Chen, Usha Chakravarthy, Jennifer J. Arnold, Wilson J. Heriot, Shane R. Durkin, Maximilian W.M. Wintergerst, Shekoufeh Gorgi Zadeh, Thomas Schultz, Robert P.Finger, Amy C. Cohn, Elizabeth K.Baglin, Pyrawy Sharangan, Robyn H. Guymer, for the LEAD Study Grou