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Background: The transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is complex and multifactorial. We aimed to identify the risk factors for infection among the household contacts of index patients and to determine the incubation period, serial interval, and estimates of secondary infection rate. Methods: We conducted a study in three districts of Kerala among the inhabitants of households of reverse transcriptase polymerase chain reaction (RT-PCR)-positive coronavirus disease (COVID-19) patients between January and July 2021. COVID-19-positive patients and corresponding contacts were enrolled and followed up for 28 days to determine RT-PCR positivity and the presence of total antibodies against SARS-CoV-2 on days 1, 7, 14, and 28 from the date of enrolment. Results: The mean incubation period, serial interval, and generation time were 1.6, 3, and 3.9 days, respectively. The secondary infection rate was 43.0%. Individuals who worked outside the home were protected, whereas those who had kissed the COVID-19-positive patients during illness were more than twice at risk of infection than those who had not kissed the COVID-19-positive patients. Similarly, the contacts who had shared a toilet with the COVID-19-positive patients were more at risk than those who had not shared a toilet. However, the contacts who reported using masks were at a higher risk of infection in household settings. Conclusions Assessment of SARS-CoV-2 transmission in household settings is important, considering its high secondary infection rate. Close physical contact and toilet sharing increase the risk of infection. This study demonstrates shorter incubation period and serial interval.

S1. Combination of lenalidomide (1uM) and bortezomib (different concentrations) induces apoptosis in myeloma cell lines (MM.1S and U266) compared to bortezomib alone treated cells (n=3) at the end of 48 hours. S2. Representative Immunoblot showing induction of apoptosis in MM.1S cell line upon treatment with lenalidomide (1uM) and bortezomib (5nM), lysates were collected the end of 24 and 48 hours post treatment with drugs (n=3). The proteins analysed were mentioned in the image. S3. a) Immunoblot showing that the combination of lenalidomide and bortezomib degraded IKZF1 in U266 cell line (n=3). b) Immunofluorescence assays showing degradation of IKZF1 in U266 cell line upon treatment with Lenalidomide and bortezomib (n=3). S4. Immunoprecipitation of Ubiquitin after treatment with lenalidomide (1uM) and bortezomib (5nM) revealed an interaction with IKZF1 at 8 hours. S5. Inhibition of autophagy by hydroxycholoroquine (HCQ) and bafilomycin A1 (BAFA1) in MM1.S cell line was confirmed using cyto-ID stain, where accumulation of autophagosome was observed (n=3) which was further confirmed by western blot (n=3). S6. Inhibition of autophagy by hydroxycholoroquine (HCQ) and bafilomycin A1 (BAFA1) did not inhibit the degradation of IKZF1 in U266 cell line (n=3). S7. Inhibition of calpain and caspase by PD150606 and zVAD.fmk inhibited the degradation of IKZF1 in U266 cell line (n=3). S8. Inhibition of calpain and chelation of calcium resulted in inhibition of PARP cleavage and IKZF3 degradation in MM1.S cell line (n=3) at the end of 24 hours of drug treatments. S9. Immunoblot representing modulation of calcium flux with ionomycin in MM.1S cell line enhanced IKZF1 degradation only in Ionomycin alone or in combination with LEN treated cells for 12 hours (n=3). S10. Viability of MM1.S cell line at post LEN (1uM) and BTZ (5nM) treatment after 48 hours (n=3). Viability was assessed by Annexin V- and 7 AAD - viability assay.

Key Points Metabolic rewiring promotes ATO resistance in APL, independent of PML mutation status.Inhibition of mitochondrial respiration combined with ATO is a potential therapeutic option for relapsed APL and non-M3 AML., Visual Abstract, Acquired genetic mutations can confer resistance to arsenic trioxide (ATO) in the treatment of acute promyelocytic leukemia (APL). However, such resistance-conferring mutations are rare and do not explain most disease recurrence seen in the clinic. We have generated stable ATO-resistant promyelocytic cell lines that are less sensitive to all-trans retinoic acid (ATRA) and the combination of ATO and ATRA compared with the sensitive cell line. Characterization of these resistant cell lines that were generated in-house showed significant differences in immunophenotype, drug transporter expression, anti-apoptotic protein dependence, and promyelocytic leukemia-retinoic acid receptor alpha (PML-RARA) mutation. Gene expression profiling revealed prominent dysregulation of the cellular metabolic pathways in these ATO-resistant APL cell lines. Glycolytic inhibition by 2-deoxyglucose (2-DG) was sufficient and comparable to the standard of care (ATO) in targeting the sensitive APL cell line. 2-DG was also effective in the in vivo transplantable APL mouse model; however, it did not affect the ATO-resistant cell lines. In contrast, the resistant cell lines were significantly affected by compounds targeting mitochondrial respiration when combined with ATO, irrespective of the ATO resistance-conferring genetic mutations or the pattern of their anti-apoptotic protein dependency. Our data demonstrate that combining mitocans with ATO can overcome ATO resistance. We also show that this combination has potential for treating non-M3 acute myeloid leukemia (AML) and relapsed APL. The translation of this approach in the clinic needs to be explored further.