Impact of metagenomic next-generation sequencing on clinical decision-making at an academic medical center, a retrospective study, Iowa, 2020-2022.

We assessed the impact of metagenomic next-generation sequencing (mNGS) on patient care using previously established criteria. Among 37 patients receiving mNGS testing, 16% showed results that had a positive clinical impact. While mNGS results may offer valuable supplementary information, results should be interpreted within the broader clinical context and evaluation.

Use of subgroup-specific hematopoietic stem cell collection efficiencies to improve truncation calculations for large-volume leukapheresis procedures.

PURPOSE: A critical component of optimizing peripheral blood (PB) hematopoietic stem cell (HSC) collections is accurately determining the processed blood volume required to collect the targeted number of HSCs. Fundamental to most truncation equations employed to determine this volume is the procedure's estimated collection efficiency (CE), which is typically applied uniformly across all HSC collections. Few studies have explored the utility of using different CEs in subpopulations of donors that have substantially different CEs than the institutional average. METHODS: Initial procedures from 343 autologous and 179 allogeneic HSC collections performed from 2018 to 2021 were retrospectively analyzed. Predictive equations were developed to determine theoretical truncation rates in various donor subgroups. RESULTS: Quantitative variables (pre-procedure cell counts) and qualitative variables (relatedness to recipient, gender, method of venous access, and mobilization strategy) were found to significantly impact CE. However, much of the variability in CE between donors could not be explained by the variables assessed. Analyses of procedures with high pre-collection PB cell counts identified lower CE values for these donors' truncation equations which still allow truncation but minimize risk of collecting less CD34+ cells than requested. CONCLUSIONS: Individualized CE does not substantially improve truncation volume calculations over use of a fixed CE and adds complexity to these calculations. The optimal fixed CE varies between autologous and allogeneic donors, and donors with high pre-collection PB cell counts in either of these groups. This model will be clinically validated and continuously refined through analysis of future HSC collections.

What Is New in Fungal Infections?

Invasive fungal infections are an increasingly important cause of morbidity and mortality. We provide a summary of important changes in the epidemiology of invasive fungal infections, citing examples of new emerging pathogens, expanding populations who are at-risk, and increasing antifungal resistance. We review how human activity and climate change may play a role in some of these changes. Finally, we discuss how these changes create the need for advances in fungal diagnostics. The limitations of existing fungal diagnostic testing emphasize the critically important role of histopathology in the early recognition of fungal disease.

Pelvic and central nervous system tuberculosis complicated by a paradoxical response manifesting as a spinal tuberculoma: a case report.

BACKGROUND: The post-partum period is a risk factor for tuberculosis (TB), possibly including the period after miscarriage as illustrated here. This case demonstrates how non-specific symptoms can hide widely disseminated TB. CASE PRESENTATION: A healthy 26-year-old female with a history of recent miscarriage presented to the emergency department with non-specific symptoms of headache, abdominal pain, and sub-acute fevers. She had immigrated to the United States from the Marshall Islands 9 years prior. Two months prior to presentation she had a miscarriage at 18 weeks of pregnancy. On admission, transvaginal ultrasound revealed retained products of conception and abdominal computed tomography revealed findings consistent with tubo-ovarian abscesses and peritonitis. The obstetrics and gynecology service performed dilation and curettage (D&C) to remove retained products of conception. Acid-fast bacilli cultures from cerebrospinal fluid as well as specimens from D&C and intra-abdominal abscesses subsequently all grew TB. She was diagnosed with TB meningitis, peritonitis, endometritis, and tubo-ovarian abscesses. Her treatment course was complicated by a paradoxical response resulting in a spinal tuberculoma causing lower extremity weakness. The tuberculoma was treated with surgical decompression as well as continuation of treatment with anti-tubercular chemotherapy and steroids. CONCLUSION: Disseminated and extrapulmonary TB can present with non-specific symptoms. Recognition of risk factors for TB is critical for prompt diagnostic evaluation and treatment of this deadly disease. A paradoxical reaction needs to be taken into consideration when any new neurological symptoms occur during TB treatment.

Targeted sequencing of the LRRTM gene family in suicide attempters with bipolar disorder.

Glutamatergic signaling is the primary excitatory neurotransmission pathway in the brain, and its relationship to neuropsychiatric disorders is of considerable interest. Our previous attempted suicide genome-wide association study, and numerous studies investigating gene expression, genetic variation, and DNA methylation have implicated aberrant glutamatergic signaling in suicide risk. The glutamatergic pathway gene LRRTM4 was an associated gene identified in our attempted suicide genome-wide association study, with association support seen primarily in females. Recent evidence has also shown that glutamatergic signaling is partly regulated by sex-related hormones. The LRRTM gene family encodes neuronal leucine-rich transmembrane proteins that localize to and promote glutamatergic synapse development. In this study, we sequenced the coding and regulatory regions of all four LRRTM gene members plus a large intronic region of LRRTM4 in 476 bipolar disorder suicide attempters and 473 bipolar disorder nonattempters. We identified two male-specific variants, one female- and five male-specific haplotypes significantly associated with attempted suicide in LRRTM4. Furthermore, variants within significant haplotypes may be brain expression quantitative trait loci for LRRTM4 and some of these variants overlap with predicted hormone response elements. Overall, these results provide supporting evidence for a sex-specific association of genetic variation in LRRTM4 with attempted suicide.

Targeted Sequencing of FKBP5 in Suicide Attempters with Bipolar Disorder.

FKBP5 is a critical component of the Hypothalamic-Pituitary-Adrenal (HPA) axis, a system which regulates our response to stress. It forms part of a complex of chaperones, which inhibits binding of cortisol and glucocorticoid receptor translocation to the nucleus. Variations in both the HPA axis and FKBP5 have been associated with suicidal behavior. We developed a systematic, targeted sequencing approach to investigate coding and regulatory regions in or near FKBP5 in 476 bipolar disorder suicide attempters and 473 bipolar disorder non-attempters. Following stringent quality control checks, we performed single-variant, gene-level and haplotype tests on the resulting 481 variants. Secondary analyses investigated whether sex-specific variations in FKBP5 increased the risk of attempted suicide. One variant, rs141713011, showed an excess of minor alleles in suicide attempters that was statistically significant following correction for multiple testing (Odds Ratio = 6.65, P-value = 7.5 x 10-4, Permuted P-value = 0.038). However, this result could not be replicated in an independent cohort (Odds Ratio = 0.90, P-value = 0.78). Three female-specific and four male-specific variants of nominal significance were also identified (P-value < 0.05). The gene-level and haplotype association tests did not produce any significant results. This comprehensive study of common and rare variants in FKBP5 focused on both regulatory and coding regions in relation to attempted suicide. One rare variant remained significant following correction for multiple testing but could not be replicated. Further investigation is required in larger sample sets to fully elucidate the association of this variant with suicidal behavior.