Incidence, clinical characteristics and prognosis of tumor lysis syndrome following B-cell maturation antigen-targeted chimeric antigen receptor-T cell therapy in relapsed/refractory multiple myeloma

Background aimsB-cell maturation antigen (BCMA)-targeted chimeric antigen receptor-T cell (CAR-T) therapy is used for refractory or relapsed multiple myeloma (r/r MM). However, CAR-T-related tumor lysis syndrome (TLS) has been observed. We aimed to elucidate the incidence, clinical and laboratory characteristics, and prognosis of CAR-T cell-related TLS.MethodsPatients (n=105) with r/r MM treated with BCMA-targeted CAR-T cell therapy were included. Patient characteristics, laboratory parameters, and clinical outcomes were assessed.ResultsEighteen (17.1%) patients developed TLS after BCMA-targeted CAR-T cell therapy. The median time till TLS onset was 8 days. Patients with TLS had steep rise in uric acid (UA), creatinine, and lactate dehydrogenase (LDH) within 6 days following CAR-T cell infusion and presented earlier and persistent escalation of cytokines (C-reactive protein [CRP], interleukin-6 [IL-6], interferon-γ [IFN-γ], and ferritin levels). All 18 patients had cytokine release syndrome (CRS), of which 13 (72.2%) developed grade 3–4 CRS. Three of 18 patients (16.7%) developed immune effector cell-associated neurotoxicity syndrome (ICANS): two patients with grade 1 ICANS and one with grade 2 ICANS. TLS development had a negative effect on the objective response rate (77.8% in the TLS group vs. 95.4% in the non-TLS group, p<0.01). During the median follow-up of 15.1 months, the median PFS was poorer of patients with TLS (median: 3.4 months in the TLS group vs. 14.7 months in the non-TLS group, p<0.001, hazard ratio [HR]=3.5 [95% confidence interval [CI] 1.5–8.5]). Also, TLS development exhibited significant effects on OS (median: 5.0 months in the TLS group vs. 39.8 months in the non-TLS group, p<0.001, hazard ratio [HR]=3.7 [95% CI 1.3–10.3]). TLS was associated with a higher tumor burden, elevated baseline creatinine and UA levels, severe CRS, pronounced CAR-T cell expansion, and corticosteroid use.ConclusionTLS is a frequently observed CAR-T therapy complication and negatively influences clinical response and prognosis. Close monitoring for TLS should be implemented during CAR-T cell therapy, especially for those at high TLS risk

Association of inpatient use of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19

Rationale: Use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) is a major concern for clinicians treating coronavirus disease 2019 (COVID-19) in patients with hypertension. Objective: To determine the association between in-hospital use of ACEI/ARB and all-cause mortality in COVID-19 patients with hypertension. Methods and Results: This retrospective, multi-center study included 1128 adult patients with hypertension diagnosed with COVID-19, including 188 taking ACEI/ARB (ACEI/ARB group; median age 64 [IQR 55-68] years; 53.2% men) and 940 without using ACEI/ARB (non-ACEI/ARB group; median age 64 [IQR 57-69]; 53.5% men), who were admitted to nine hospitals in Hubei Province, China from December 31, 2019 to February 20, 2020. Unadjusted mortality rate was lower in the ACEI/ARB group versus the non-ACEI/ARB group (3.7% vs. 9.8%; P = 0.01). In mixed-effect Cox model treating site as a random effect, after adjusting for age, gender, comorbidities, and in-hospital medications, the detected risk for all-cause mortality was lower in the ACEI/ARB group versus the non-ACEI/ARB group (adjusted HR, 0.42; 95% CI, 0.19-0.92; P =0.03). In a propensity score-matched analysis followed by adjusting imbalanced variables in mixed-effect Cox model, the results consistently demonstrated lower risk of COVID-19 mortality in patients who received ACEI/ARB versus those who did not receive ACEI/ARB (adjusted HR, 0.37; 95% CI, 0.15-0.89; P = 0.03). Further subgroup propensity score-matched analysis indicated that, compared to use of other antihypertensive drugs, ACEI/ARB was also associated with decreased mortality (adjusted HR, 0.30; 95%CI, 0.12-0.70; P = 0.01) in COVID-19 patients with hypertension. Conclusions: Among hospitalized COVID-19 patients with hypertension, inpatient use of ACEI/ARB was associated with lower risk of all-cause mortality compared with ACEI/ARB non-users. While study interpretation needs to consider the potential for residual confounders, it is unlikely that in-hospital use of ACEI/ARB was associated with an increased mortality risk

GJB2 mutation spectrum in 2063 Chinese patients with nonsyndromic hearing impairment

Background: Mutations in GJB2 are the most common molecular defects responsible for autosomal recessive nonsyndromic hearing impairment (NSHI). The mutation spectra of this gene vary among different ethnic groups. Methods: In order to understand the spectrum and frequency of GJB2 mutations in the Chinese population, the coding region of the GJB2 gene from 2063 unrelated patients with NSHI was PCR amplified and sequenced. Results: A total of 23 pathogenic mutations were identified. Among them, five (p.W3X, c.99delT, c.155_c.158delTCTG, c.512_c.513insAACG, and p.Y152X) are novel. Three hundred and seven patients carry two confirmed pathogenic mutations, including 178 homozygotes and 129 compound heterozygotes. One hundred twenty five patients carry only one mutant allele. Thus, GJB2 mutations account for 17.9% of the mutant alleles in 2063 NSHI patients. Overall, 92.6% (684/739) of the pathogenic mutations are frame-shift truncation or nonsense mutations. The four prevalent mutations; c.235delC, c.299_c.300delAT, c.176_c.191del16, and c.35delG, account for 88.0% of all mutantalleles identified. The frequency of GJB2 mutations (alleles) varies from 4% to 30.4% among different regions of China. It also varies among different sub-ethnic groups. Conclusion: In some regions of China, testing of the three most common mutations can identify at least one GJB2 mutant allele in all patients. In other regions such as Tibet, the three most common mutations account for only 16% the GJB2 mutant alleles. Thus, in this region, sequencing of GJB2 would be recommended. In addition, the etiology of more than 80% of the mutant alleles for NSHI in China remains to be identified. Analysis of other NSHI related genes will be necessary

Redefining Cardiac Biomarkers in Predicting Mortality of Inpatients With COVID-19

The prognostic power of circulating cardiac biomarkers, their utility, and pattern of release in coronavirus disease 2019 (COVID-19) patients have not been clearly defined. In this multicentered retrospective study, we enrolled 3219 patients with diagnosed COVID-19 admitted to 9 hospitals from December 31, 2019 to March 4, 2020, to estimate the associations and prognostic power of circulating cardiac injury markers with the poor outcomes of COVID-19. In the mixed-effects Cox model, after adjusting for age, sex, and comorbidities, the adjusted hazard ratio of 28-day mortality for hs-cTnI (high-sensitivity cardiac troponin I) was 7.12 ([95% CI, 4.60-11.03] P\u3c0.001), (NT-pro)BNP (N-terminal pro-B-type natriuretic peptide or brain natriuretic peptide) was 5.11 ([95% CI, 3.50-7.47] P\u3c0.001), CK (creatine phosphokinase)-MB was 4.86 ([95% CI, 3.33-7.09] P\u3c0.001), MYO (myoglobin) was 4.50 ([95% CI, 3.18-6.36] P\u3c0.001), and CK was 3.56 ([95% CI, 2.53-5.02] P\u3c0.001). The cutoffs of those cardiac biomarkers for effective prognosis of 28-day mortality of COVID-19 were found to be much lower than for regular heart disease at about 19%-50% of the currently recommended thresholds. Patients with elevated cardiac injury markers above the newly established cutoffs were associated with significantly increased risk of COVID-19 death. In conclusion, cardiac biomarker elevations are significantly associated with 28-day death in patients with COVID-19. The prognostic cutoff values of these biomarkers might be much lower than the current reference standards. These findings can assist in better management of COVID-19 patients to improve outcomes. Importantly, the newly established cutoff levels of COVID-19-associated cardiac biomarkers may serve as useful criteria for the future prospective studies and clinical trials

Redefining cardiac biomarkers in predicting mortality and adverse outcomes of inpatients with COVID-19

The prognostic power of circulating cardiac biomarkers, their utility and pattern of release in coronavirus disease 2019 (COVID-19) patients have not been clearly defined. In this multi-centered retrospective study, we enrolled 3,219 patients with diagnosed COVID-19 admitted to 9 hospitals from December 31, 2019 to March 4, 2020, to estimate the associations and prognostic power of circulating cardiac injury markers with the poor outcomes of COVID-19. In the mixed-effect Cox model, after adjusting for age, gender and comorbidities, the adjusted hazard ratios of 28-day mortality for high-sensitivity cardiac troponin I (hs-cTnI) was 7.12 (95%CI, 4.60-11.03; P<0.001), NT-proB-type natriuretic peptide (NT-proBNP) was 5.11 (95%CI, 3.50-7.47; P<0.001), CK-MB was 4.86 (95%CI, 3.33-7.09; P<0.001), myoglobin was 4.50 (95%CI, 3.18-6.36; P < 0.001), and CK was 3.56 (95%CI, 2.53-5.02; P < 0.001). The cutoffs of those cardiac biomarkers for effective prognosis of 28-day mortality of COVID-19 were found to be much lower than for regular heart disease at about 49% of the currently recommended thresholds. Patients with elevated cardiac injury markers above the newly established cutoffs were associated with significantly increased risk of COVID-19 death. In conclusion, cardiac biomarker elevations are significantly associated with 28-day death in patients with COVID-19. The prognostic cutoffs for of these values might be much lower than the current reference standards. These findings can assist better management of COVID-19 patients to improve outcomes. Importantly, the newly established cutoff levels of COVID-19 associated cardiac biomarkers may serve as useful criteria for the future prospective studies and clinical trials

Electrochemical behaviour of the nitrobenzene family in aprotic media

The electrochemical reduction of nitrobenzene, nitrosobenzene, azoxybenzene and azobenzene in aprotic media has been studied by conventional voltammetric and controlled­potential electrolysis techniques. The influence of the following experimental parameters has been investigated: electrode material, solvant, supporting electrolyte, proton donor, temperature, and the concentration of the electroactive substance. The voltammetric reduction of the four compounds in DMF using a quaternary ammonium salt as supporting electrolyte consists of two steps. The first reduction step is a reversible one-electron transfer process ta yield the radical anion and the second reduction step is usually irreversible due oa the fast protonation of the dianion. The total number of electrons involved in the second step depends on the nature of the compound. For nitrobenzene, the second peak (wave) involves a three­electron reduction to yield the phenylhydroxylamine anion. For nitrosobenzene and azobenzene, the second peak (wave) corresponds to an one-electron reduction to the dianion. The reversibility of this step depends on the supporting electrolyte and the temperature. When Me₄ N+ and Bu₄N+ salts are used as supporting electrolyte, the anodic peak corresponding to the oxidation of the dianion to the radical anion increases in intensity upon lowering the temperature. However, with Et₄N+ salt as supporting electrolyte, protonation of the dianion is much faster and the oxidation peak of the dianion is not observed even at -30 °C. For azoxybenzene, the second peak (wave) corresponds to an irreversible two-electron reduction of the azoxybenzene radical anion to the azobenzene radical anion. Further reduction of azobenzene radical anion can be observed at a more negative potential. As a result, three reduction peaks (waves) can be observed in the cyclic voltammogram (polarogram) of azoxybenzene. Partial electrolysis of nitrobenzene at -2.35 V (1.2 F/mole) gave phenylhydroxylamine as the predominant product (= 70% yield). The exhausitive controlled-potential electrolyses of nitrobenzene, nitrosobenzene, and azobenzene at -2.35 V gave similar results: hydrazobenzene was the predominant product. The first electron transfer on nitrobenzene and on azoxybenzene was found to be less reversible on copper and nickel electrodes than on platinum and mercury electrodes due to surface oxides on copper and nickel formed during the conventional polishing process. The surface oxide was removed either by reduction by molecular hydrogen at 280 °c or by cathodic polarization at -2.20 V in TEAP - DMF. On these pretreated copper and nickel electrodes, the anodic to cathodic peak separation was nearly the same as that on platinum and mercury electrodes. With nitrosobenzene and azobenzene, the presence of oxides had no influence on the reversibility of the first electron transfer. ln the presence of lithium perchlorate, only one reduction peak for nitrobenzene, azoxybenzene, and azobenzene, and only two reduction peaks for nitrosobenzene can be observed in their cyclic voltammograms. These peaks decrease rapidly in intensity on the second and subsequent cycles due to the formation of a non-conducting grey film on the electrode surface. At HMDE, a new redox systems which consist of two anodic peaks and two cathodic peaks can be observed at potentials more positive than those due to the parent substances; they could be attributed to the formation (anodic peak) and reduction of organomercury compounds between the azobenzene dianion strongly associated with lithium cations and mercury. A new example of a chain reaction induced electrochemically was found for the reduction of nitrosobenzene in the presence of fluorene or indene. The products of this chain process are N-fluorenyl-N-phenyl nitrone (1) and fluorenone anil (2) for fluorene and N-indenyl-N-phenyl nitrone (3) and indenone anil (4) for indene. At -30 ° C , fluorenone anil was the sole product formed and was isolated in a 97% yield. The mechanism for the chain reactions was proposed and the rate constants of the chain reaction of nitrosobenzene at -30 °c are 3.1 x 10⁵ (k₁) and 4.5 x 10⁴ (k₂) in the presence of five-fold excess of fluorene, and 6.9 x 10⁵ (k₁ ) and 7.4 x 10⁴ (k₂) in the presence of five-fold excess of indene

Housing Choices and Changing Residential Patterns in Transitional Urban China

Aiming to introduce market mechanisms to an administratively managed and heavily subsidized housing system, the ongoing housing reform in urban China has brought dramatic changes in housing provision and consumption. Chinese households have started to enjoy freedom of housing choice that was not possible in socialist China. Yet, their choices are constrained because of the transitional nature of the current housing system where both institutional forces and market mechanisms operate. It is the goal of this research to examine how these two types of forces interact and how households make their housing choices in the transitional housing system. In contrast to the economic and socio-demographic perspectives on housing choices in the Western literature, I argue that a framework incorporating social relationships between the state, work units and employees is needed to understand households’ housing choice in transitional urban China. Associated with housing choices, the homogenous residential pattern in socialist China is gradually changing and a residential sorting is in process. It is also my goal to study the change of residential patterns and its dynamics in urban China.Four research questions are proposed: (1) What kinds of individual and household characteristics affect housing choice, and how relevant are the existing Western theories? (2) What are the roles of work units in housing choice in transitional urban China? (3) What is the role of the central state in constraining housing choice in transitional urban China? (4) Is a new form of residential pattern emerging? What factors contribute to the change of residential patterns and how relevant are the existing Western theories? A complementary methodology combining both quantitative and qualitative analyses, both national studies and case studies will be employed. The data include a national survey data, in-depth interviews in three cities, and archival data such as housing policies and housing statistics. A multi-level logistic model will be used to examine individual, household, work unit level and state level factors affecting households’ housing choices, and maps on residential patterns will be created

Electrochemical behaviour of the nitrobenzene family in aprotic media

The electrochemical reduction of nitrobenzene, nitrosobenzene, azoxybenzene and azobenzene in aprotic media has been studied by conventional voltammetric and controlled­potential electrolysis techniques. The influence of the following experimental parameters has been investigated: electrode material, solvant, supporting electrolyte, proton donor, temperature, and the concentration of the electroactive substance. The voltammetric reduction of the four compounds in DMF using a quaternary ammonium salt as supporting electrolyte consists of two steps. The first reduction step is a reversible one-electron transfer process ta yield the radical anion and the second reduction step is usually irreversible due oa the fast protonation of the dianion. The total number of electrons involved in the second step depends on the nature of the compound. For nitrobenzene, the second peak (wave) involves a three­electron reduction to yield the phenylhydroxylamine anion. For nitrosobenzene and azobenzene, the second peak (wave) corresponds to an one-electron reduction to the dianion. The reversibility of this step depends on the supporting electrolyte and the temperature. When Me? N+ and Bu?N+ salts are used as supporting electrolyte, the anodic peak corresponding to the oxidation of the dianion to the radical anion increases in intensity upon lowering the temperature. However, with Et?N+ salt as supporting electrolyte, protonation of the dianion is much faster and the oxidation peak of the dianion is not observed even at -30 °C. For azoxybenzene, the second peak (wave) corresponds to an irreversible two-electron reduction of the azoxybenzene radical anion to the azobenzene radical anion. Further reduction of azobenzene radical anion can be observed at a more negative potential. As a result, three reduction peaks (waves) can be observed in the cyclic voltammogram (polarogram) of azoxybenzene. Partial electrolysis of nitrobenzene at -2.35 V (1.2 F/mole) gave phenylhydroxylamine as the predominant product (= 70% yield). The exhausitive controlled-potential electrolyses of nitrobenzene, nitrosobenzene, and azobenzene at -2.35 V gave similar results: hydrazobenzene was the predominant product. The first electron transfer on nitrobenzene and on azoxybenzene was found to be less reversible on copper and nickel electrodes than on platinum and mercury electrodes due to surface oxides on copper and nickel formed during the conventional polishing process. The surface oxide was removed either by reduction by molecular hydrogen at 280 °c or by cathodic polarization at -2.20 V in TEAP - DMF. On these pretreated copper and nickel electrodes, the anodic to cathodic peak separation was nearly the same as that on platinum and mercury electrodes. With nitrosobenzene and azobenzene, the presence of oxides had no influence on the reversibility of the first electron transfer. ln the presence of lithium perchlorate, only one reduction peak for nitrobenzene, azoxybenzene, and azobenzene, and only two reduction peaks for nitrosobenzene can be observed in their cyclic voltammograms. These peaks decrease rapidly in intensity on the second and subsequent cycles due to the formation of a non-conducting grey film on the electrode surface. At HMDE, a new redox systems which consist of two anodic peaks and two cathodic peaks can be observed at potentials more positive than those due to the parent substances; they could be attributed to the formation (anodic peak) and reduction of organomercury compounds between the azobenzene dianion strongly associated with lithium cations and mercury. A new example of a chain reaction induced electrochemically was found for the reduction of nitrosobenzene in the presence of fluorene or indene. The products of this chain process are N-fluorenyl-N-phenyl nitrone (1) and fluorenone anil (2) for fluorene and N-indenyl-N-phenyl nitrone (3) and indenone anil (4) for indene. At -30 ° C , fluorenone anil was the sole product formed and was isolated in a 97% yield. The mechanism for the chain reactions was proposed and the rate constants of the chain reaction of nitrosobenzene at -30 °c are 3.1 x 10? (k?) and 4.5 x 10? (k?) in the presence of five-fold excess of fluorene, and 6.9 x 10? (k? ) and 7.4 x 10? (k?) in the presence of five-fold excess of indene