As the world endures the coronavirus disease 2019 (COVID-19) pandemic, the conditions of 35 million vulnerable individuals struggling with substance use disorders (SUDs) worldwide have not received sufficient attention for their special health and medical needs. Many of these individuals are complicated by underlying health conditions, such as cardiovascular and lung diseases and undermined immune systems. During the pandemic, access to the healthcare systems and support groups is greatly diminished. Current research on COVID-19 has not addressed the unique challenges facing individuals with SUDs, including the heightened vulnerability and susceptibility to the disease. In this systematic review, we will discuss the pathogenesis and pathology of COVID-19, and highlight potential risk factors and complications to these individuals. We will also provide insights and considerations for COVID-19 treatment and prevention in patients with SUDs.

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As the world endures the coronavirus disease 2019 (COVID-19) pandemic, conditions of 35 million vulnerable individuals struggling with substance use disorders (SUDs) worldwide have not received sufficient attention for their special health and medical needs. Many of these individuals are complicated by underlying health conditions, such as cardiovascular and lung diseases and undermined immune systems. During the pandemic, access to the healthcare systems and support groups is greatly diminished. Current research on COVID-19 has not addressed the unique challenges facing individuals with SUDs, including the heightened vulnerability and susceptibility to the disease. In this systematic review, we will discuss the pathogenesis and pathology of COVID-19, and highlight potential risk factors and complications to these individuals. We will also provide insights and considerations for COVID-19 treatment and prevention in patients with SUDs.

ALG13‐CDG is a rare X‐linked disorder of N‐linked glycosylation. Given the lack of long‐term outcome data in ALG13‐CDG, we collected natural history data and reviewed individuals surviving to young adulthood with confirmed pathogenic variants in ALG13 in our own cohort and in the literature. From the 14 ALG13‐CDG patients enrolled into our Frontiers of Congenital Disorders of Glycosylation Consortium natural history study only two patients were older than 16 years; one of these two females is so far unreported. From the 52 patients described in the medical literature with confirmed pathogenic variants in ALG13 only five patients were older than 16 years (all females), in addition to the new, unreported patient from our natural history study. Two male patients have died due to ALG13‐CDG, and there were no surviving males older than 16 years with a confirmed ALG13‐CDG diagnosis. Our adolescent and young adult cohort of six patients presented with epilepsy, muscular hypotonia, speech, and developmental delay. Intellectual disability was present in all female patients with ALG13‐CDG. Unreported features included ataxia, neuropathy, and severe gastrointestinal symptoms requiring G/J tube placement. In addition, two patients from our natural history study developed unilateral hearing loss. Skeletal abnormalities were found in four patients, including osteopenia and scoliosis. Major health problems included persistent seizures in three patients. Ketogenic diet was efficient for seizures in three out of four patients. Although all patients were mobile, they all had severe communication problems with mostly absent speech and were unable to function without parental support. In summary, long‐term outcome in ALG13‐CDG includes gastrointestinal and skeletal involvement in addition to a chronic, mostly non‐progressive neurologic phenotype.

Clustered regularly interspaced short palindromic repeats (CRISPR) is a DNA sequence, found in bacteria, that functions as protective system against bacteriophages. CRISPR DNA sequence is characterized by the presence of short, identical nucleotide repeats that are interspaced by spacers. The spacer sequences are unique in that they are records of viral infections experienced by the bacterium and act as an “immunization card”. If the same virus attempts to invade again, the spacer sequence recognizes it via the help of CRISPR‐RNA (crRNA) and CRISPR‐associated (Cas) proteins. Subsequently, Cas proteins cut the viral DNA to eliminate the threat. Thus, CRISPR/Cas system provides an effective mechanism for bacteria, such as Escherichia coli (E. coli), to resist infections from bacteriophage, but it could also pose challenges to phage therapy, which utilizes bacteriophages to kill bacteria. The focus of this research is to examine spacer sequences from soil samples collected around NY/NJ metropolitan area at various timepoints, locations, and weather conditions. To accomplish this goal, the genomic DNA was extracted from E. coli bacteria from the soil and purified. The CRISPR locus was amplified and purified using polymerase chain reaction (PCR) and gel electrophoresis, respectively. The sequences were run through the CRISPR Finder program to identify spacer sequences, and NCBI’s Blast alignment was carried out to determine the specific E. coli strain associated with the sequence. We have identified several new spacer sequences, which could putatively link the history of bacteriophage infections of the E. coli bacteria to the unique environments the bacteria are located. Support or Funding Information We would like to thank the Chemistry Department at NJCU. This research was funded by National Institutes of Health (NIH), grant number R21DA046223.

Clustered regularly interspaced short palindromic repeats (CRISPR) is a defense system found in bacteria (and archaea) against bacteriophages, viruses that infect bacteria. CRISPR DNA sequence consists of short, identical nucleotide repeats that are interspaced by spacers. The spacer sequences are records of viral infections experienced by the bacteria and play the role of an “immunization card”: if the spacer sequences match the infecting viral DNA, the bacteria will cut the viral DNA with CRISPR‐associated (Cas) proteins, eliminating the threat of viral infection. We speculate that the spacer sequences reflect the history of bacteriophage infections, which are unique to the environment bacteria reside in. Environmental factors, such as location and time, weather, local ecosystems, and pollutions, will alter the spacer sequences found in bacteria. This research focuses on investigating and discovering new spacer sequences from soil samples collected around NY/NJ metropolitan area, a historically heavily polluted urban ecosystem, at various locations, timepoints, and weather conditions. To accomplish this goal, the genomic DNA was extracted and purified from the collected soil samples. The CRISPR locus was amplified by using polymerase chain reaction (PCR) and then purified via gel electrophoresis. The purified CRISPR DNA was then ligated into a p‐Drive vector and transformed into M15 competent cells. The cells were cultured to amply the vector containing ligated CRISPR sequence, which was subsequently analyzed by aligning against CRISPR spacer database to identify new space sequence. We expect that the newly discovered spacer sequences reflect the history of viral infections unique to the regions investigated, which can potentially inform the understanding of health risks related to environmental bacteria and viruses.Support or Funding Information‐ U.S. Education Department Minority Science & Engineering Improvement Program grant # P120A160084‐ NIH AREA Grant # CA179410‐ USED Title III Part F, HSI‐STEM & Articulation Grant #P03C160155This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Background: The kinases ataxia-telangiectasia-mutated-and-Rad3-related (ATR), checkpoint kinase 1 (CHK1) and WEE1 participate in the response to replication stress. Inhibitors of ATR, WEE1 and CHK1 are being tested for antineoplastic activity as monotherapies and in combination with chemotherapy. Although these agents impair cell cycle checkpoints, fork stabilization, origin firing and homologous recombination (HR), little is known about the apoptotic pathways that are engaged and the critical mediators activating cell death mechanisms. The present study utilizes high grade serous ovarian cancer (HGSOC) cell lines and patient derived xenografts (PDXs) to identify the primary mechanism of cell death in ovarian cancer and assess changes involved in the resistance setting after treatment with these inhibitors. Methods: A panel of HGSOC cell lines was examined for responses to ceralasertib (ATRi), prexasertib (CHK1i) or adavosertib (WEE1i) using colony forming assays, immunoblotting and assays for apoptosis. Mechanisms involved in acquired resistance and downstream changes in cell fate were evaluated by generating prexasertib-resistant HGSOC cell lines. Subsequent NGS analysis was performed in the sensitive and resistant pairs. Results: Irrespective of the homologous recombination (HR) status, ovarian cell lines and PDXs underwent cell death during prolonged exposure at clinically achievable concentrations. Treatment of ovarian cancer cell lines with ATRi, CHK1i or WEE1i activated the replication checkpoint, consistent with previously published reports. The subsequent apoptotic response involved PMAIP1 and BCL2L11 upregulation rather than the TNFa-induced death receptor-mediated apoptosis we recently described in acute leukemia (Cancer Res. PMID: 33414171). Additionally, ovarian lines selected for CHK1i resistance failed to die in response to either ATRi or WEE1i. Conclusions: Prexasertib, ceralasertib, and adavosertib exhibit monotherapy activity in both HR deficient and proficient HGSOC cell lines and PDX models. Unlike AML, death receptor mediated apoptosis was not observed; instead, the primary mechanism of cell killing in HGSOC lines involves activation of the mitochondrial apoptotic pathway. Cross-resistance of these DNA damage repair modulators is likely multifactorial and mainly involves diminished replication stress response. Citation Format: Annapoorna Venkatachalam, Kevin L. Peterson, Cristina Correia, Karen S. Flatten, Xianon Hou, Paula A. Schneider, Emily Balczewski, Cordelia McGehee, Rachel M. Hurley, Xue W. Meng, Chance Sine, Rameen Shah, Nicole Vincelettte, Husheng Ding, Hu Li, Saravut (John) Weroha, Scott H. Kaufmann. CHK1 inhibitor prexasertib induces NOXA-dependent apoptosis in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1832.