Integration, challenges, and future of artificial intelligence in critical care medicine: comprehensive applications from predictive models to clinical integration.

The immune system development begins in
the fetus during gestation
and continues after birth. Different immune cell types arise from
precursors, which can differentiate and develop in a regulated manner. Environmental exposure to harmful agents such as chemical toxicants
or deficits in nutrition during gestation and infancy can dysregulate
multiple developmental processes influencing health over a lifetime. Among these harmful agents, exposure to per- and polyfluoroalkyl
substances (PFAS) stands out due to their widespread prevalence and
persistence in the environment and their
well-documented associations with several adverse health outcomes
across the lifespan, including impaired reproduction, growth, neurodevelopment,
and liver, kidney and immune dysfunction. PFAS are a group of synthetic chemicals characterized by interconnected
carbon and fluorine (C–F) atom chains. The strong C–F bond makes PFAS resistant to environmental
and physiological breakdown processes and allows them to accumulate
and persist in the environment and human tissues. In the U.S., over 97% of the population has detectable
concentrations of PFAS in their blood, and similar findings have been reported in studies from Spain, Germany, and China. In addition to blood, PFAS have been detected
in human lungs, brain, bone, liver, and kidneys. PFAS have also been detected in the placenta, cord blood,
and breast milk, which further emphasizes the potential for early life exposures.
Transplacental transfer and excretion through
breastfeeding are main routes of early life PFAS exposure, and this transfer occurs
during a critical window of development. One common observation
is an inverse association between PFAS concentrations
and antibody responses to vaccinations. While this inverse association between PFAS and antibodies has been
consistent in children, the evidence for adults is less consistent
across studies, PFAS species and vaccine types. It is unclear which immune system components are affected by PFAS
to generate a net effect of lower humoral responses. The production
of antibodies results from the collaboration between multiple types
of immune cells. When the immune system
is stimulated by vaccinations or infections, cells from the innate
compartment, such as macrophages and neutrophils, trigger inflammatory
processes that activate cells of the adaptive immune system (T and
B-cells), which can then establish immune memory. Immune memory is
the ability of cells to retain antigen-specific information from prior
exposures to facilitate a faster and more targeted response upon subsequent
encounters. Antibody production by B-cells is influenced by CD4+ T-cells,
which consist of different specialized subpopulations tailored to
the immune response needed for a specific pathogen or antigen. These include Th1, Th2, Th17, T follicular helper
cells (Tfh), and T regulatory cells (Treg). Each CD4+ T-cell subset carries a unique set of functions that influence
B-cells by modulating the strength, specificity, and durability of
their produced antibodies. For example,
long-lived B-cells rely on Tfh cells for durable antibody production
because Tfh cells promote germinal center formation in lymph nodes
via IL-21 secretion. This interaction leads to B-cell proliferation, somatic hypermutation,
and isotype class switching, ultimately resulting in high-affinity
antibodies. Other CD4+ T-cell subpopulations
modulate antibody class switching by fine-tuning the context of the
immune response required. How early life exposures to PFAS affects these cell
types is crucial for discovering how PFAS ultimately leads to changes
in immune responses. This longitudinal study aims to identify alterations
in CD4+ T-cell subpopulations related to developmental PFAS exposure
as a first step in understanding pathways implicated in PFAS-related
immune dysfunction. Between December 2015 and April 2019,
first-trimester pregnant women were recruited from outpatient clinics
affiliated with the University of Rochester and enrolled in the Understanding
Pregnancy Signals and Infant Development and Environmental Influences
on Child Health Outcomes (UPSIDE-ECHO) study after informed consent.
UPSIDE-ECHO is an ongoing prospective birth cohort designed to study
prenatal exposures in relation to perinatal and child health outcomes
in the Rochester, NY, area that is part
of the National Institutes of Health (NIH) ECHO program. Eligibility criteria included maternal age 18
years or older, singleton pregnancy, no known substance abuse problems
or history of psychotic illness, and the ability to communicate in
English. Participants with major endocrine disorders (e.g., polycystic
ovary syndrome) and high-risk pregnancies at baseline were not enrolled;
additionally, infants born prior to 37 weeks of gestation or with
congenital anomalies or significant health problems were excluded
( = 9). Study visits, including physical exams,
biospecimen collection, and questionnaire completion, were com