Host Cell Death and Modulation of Immune Response against Mycobacterium tuberculosis Infection.

Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), a prevalent infectious disease affecting populations worldwide. A classic trait of TB pathology is the formation of granulomas, which wall off the pathogen, via the innate and adaptive immune systems. Some key players involved include tumor necrosis factor-alpha (TNF-α), foamy macrophages, type I interferons (IFNs), and reactive oxygen species, which may also show overlap with cell death pathways. Additionally, host cell death is a primary method for combating and controlling Mtb within the body, a process which is influenced by both host and bacterial factors. These cell death modalities have distinct molecular mechanisms and pathways. Programmed cell death (PCD), encompassing apoptosis and autophagy, typically confers a protective response against Mtb by containing the bacteria within dead macrophages, facilitating their phagocytosis by uninfected or neighboring cells, whereas necrotic cell death benefits the pathogen, leading to the release of bacteria extracellularly. Apoptosis is triggered via intrinsic and extrinsic caspase-dependent pathways as well as caspase-independent pathways. Necrosis is induced via various pathways, including necroptosis, pyroptosis, and ferroptosis. Given the pivotal role of host cell death pathways in host defense against Mtb, therapeutic agents targeting cell death signaling have been investigated for TB treatment. This review provides an overview of the diverse mechanisms underlying Mtb-induced host cell death, examining their implications for host immunity. Furthermore, it discusses the potential of targeting host cell death pathways as therapeutic and preventive strategies against Mtb infection.

Characterizing breast cancer incidence and trends among Asian American, Native Hawaiian, and non-Hispanic White women in Hawai'i, 1990-2014.

PURPOSE: To characterize breast cancer (BC) incidence by age at diagnosis and BC subtype among disaggregated Asian American, Native Hawaiian, and Pacific Islander (AANHPI) women and non-Hispanic White (NHW) women in Hawai'i. METHODS: Using 1990-2014 data from the Hawai'i tumor registry, we estimated age-adjusted incidence rates (AAIR) of BC and the annual percent change in BC incidence by age (<50 and ≥50 years) and BC subtype (hormone receptor [HR]+/human epidermal growth factor receptor 2 [HER2]-, HR+/HER2+, HR-/HER2+, triple negative BC) for Filipino American (FA), Japanese American (JA), Native Hawaiian (NH), and NHW women. RESULTS: Among young (<50 years) women, annual BC incidence increased 2.9% (1994-2014) among JA and 1.0% (1990-2014) among NHW women. Incidence was highest among young JA women (2010-2014 AAIR 52.0 per 100,000; 95% confidence interval [CI] 45.6, 58.9). HR+/HER2- BC, the major BC subtype, was similarly highest among young JA women (AAIR 39.5; 95% CI 33.9, 45.4). Among older (≥50 years) women, annual BC incidence increased 1.6% (1990-2014) among FA and 4.2% (2006-2014) for JA women. BC incidence was highest among older NH women (AAIR 137.6, 95% CI 128.2, 147.4), who also displayed highest incidence of two subtypes: HR+/HER2- (AAIR 106.9; 95% CI 98.6, 115.5) and HR+/HER2+ (AAIR 12.1; 95% CI 9.4, 15.1). CONCLUSION: We observed high and increasing BC incidence among JA women ages <50 years and high incidence among NH women ages ≥50 years. These results highlight racial and ethnic differences in BC incidence among disaggregated AANHPI populations in Hawai'i by age and BC subtype.

An epidural brain abscess and thrombus in the superior sagittal sinus in a 12 year-old with sinusitis.

BACKGROUND: Upper respiratory infections can be complicated by acute bacterial sinusitis in pediatric patients, and usually resolve with antibiotic therapy (DeMuri and Wald, 2011). However, intracranial complications such as: epidural abscess, meningitis and more rarely cerebral sinus venous thrombosis (CSVT) can occur (Germiller et al., 2006). We report an unusual case of sinusitis complicated by an epidural abscess and later a CSVT in a young previously healthy patient. CASE DESCRIPTION: A 12-year-old female presented to the emergency department with a 9-day history of headaches and a 3-day history of fevers, rigors, nasal congestion and nonproductive cough. She later tested positive for Covid-19. CT and MRI showed extensive paranasal sinus disease and a right frontal epidural collection. MRV showed no sinovenous thrombosis. Washout and burr hole drainage alongside endoscopic sinus surgery was completed and post-op imaging showed evacuation of the epidural abscess with a small residual collection. Six days after the procedure, she experienced worsening headaches and MRV showed a nonocclusive thrombus in the superior sagittal sinus, which was treated with anticoagulation therapy. Upon follow-up, the patient showed improvement of the sinusitis, abscess and thrombus. CONCLUSION: This specific case encourages clinicians to be aware of complications, though rare, and to diagnose and treat sinusitis cases quickly. It is also important to be aware of any risk factors for thrombus formation, including an inflammatory and hypercoagulable state. In the patient's case, it was perceived that the CSVT was provoked due to the patient's Covid-19 infection, abscess, and sinus disease.

A longitudinal study assessing differences in causes of death among housed and homeless people diagnosed with HIV in San Francisco.

BACKGROUND: San Francisco has implemented several programs addressing the needs of two large vulnerable populations: people living with HIV and those who are homeless. Assessment of these programs on health outcomes is paramount for reducing preventable deaths. METHODS: Individuals diagnosed with HIV/AIDS and reported to the San Francisco Department of Public Health HIV surveillance registry, ages 13 years or older, who resided in San Francisco at the time of diagnosis, and who died between January 1, 2002, and December 31, 2016 were included in this longitudinal study. The primary independent variable was housing status, dichotomized as ever homeless since diagnosed with HIV, and the dependent variables were disease-specific causes of death, as noted on the death certificate. The Cochran-Armitage test measured changes in the mortality rates over time and unadjusted and adjusted Poisson regression models measured prevalence ratios (PR) and 95% confidence intervals (CI) for causes of death. RESULTS: A total of 4158 deceased individuals were included in the analyses: the majority were male (87%), ages 40-59 years old at the time of death (64%), non-Hispanic White (60%), men who have sex with men (54%), had an AIDS diagnosis prior to death (87%), and San Francisco residents at the time of death (63%). Compared to those who were housed, those who were homeless were more likely to be younger at time of death, African American, have a history of injecting drugs, female or transgender, and were living below the poverty level (all p values < 0.0001). Among decedents who were SF residents at the time of death, there were declines in the proportion of deaths due to AIDS-defining conditions (p < 0.05) and increases in accidents, cardiomyopathy, heart disease, ischemic disease, non-AIDS cancers, and drug overdoses (p < 0.05). After adjustment, deaths due to mental disorders (aPR = 1.63, 95% CI 1.24, 2.14) were more likely and deaths due to non-AIDS cancers (aPR = 0.63, 95% CI 0.44, 0.89) were less likely among those experiencing homelessness. CONCLUSIONS: Additional efforts are needed to improve mental health services to homeless people with HIV and prevent mental-health related mortality.

Polyglutamine repeat proteins disrupt actin structure in Drosophila photoreceptors.

Expansions of polygutamine-encoding stretches in several genes cause neurodegenerative disorders including Huntington's Disease and Spinocerebellar Ataxia type 3. Expression of the human disease alleles in Drosophila melanogaster neurons recapitulates cellular features of these disorders, and has therefore been used to model the cell biology of these diseases. Here, we show that polyglutamine disease alleles expressed in Drosophila photoreceptors disrupt actin structure at rhabdomeres, as other groups have shown they do in Drosophila and mammalian dendrites. We show this actin regulatory pathway works through the small G protein Rac and the actin nucleating protein Form3. We also find that Form3 has additional functions in photoreceptors, and that loss of Form3 results in the specification of extra photoreceptors in the eye.

Parental risk factors for oral clefts among Central Africans, Southeast Asians, and Central Americans.

BACKGROUND: Several lifestyle and environmental exposures have been suspected as risk factors for oral clefts, although few have been convincingly demonstrated. Studies across global diverse populations could offer additional insight given varying types and levels of exposures. METHODS: We performed an international case-control study in the Democratic Republic of the Congo (133 cases, 301 controls), Vietnam (75 cases, 158 controls), the Philippines (102 cases, 152 controls), and Honduras (120 cases, 143 controls). Mothers were recruited from hospitals and their exposures were collected from interviewer-administered questionnaires. We used logistic regression modeling to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Family history of clefts was strongly associated with increased risk (maternal: OR = 4.7; 95% CI, 3.0-7.2; paternal: OR = 10.5; 95% CI, 5.9-18.8; siblings: OR = 5.3; 95% CI, 1.4-19.9). Advanced maternal age (5 year OR = 1.2; 95% CI, 1.0-1.3), pregestational hypertension (OR = 2.6; 95% CI, 1.3-5.1), and gestational seizures (OR = 2.9; 95% CI, 1.1-7.4) were statistically significant risk factors. Lower maternal (secondary school OR = 1.6; 95% CI, 1.2-2.2; primary school OR = 2.4, 95% CI, 1.6-2.8) and paternal education (OR = 1.9; 95% CI, 1.4-2.5; and OR = 1.8; 95% CI, 1.1-2.9, respectively) and paternal tobacco smoking (OR = 1.5, 95% CI, 1.1-1.9) were associated with an increased risk. No other significant associations between maternal and paternal factors were found; some environmental factors including rural residency, indoor cooking with wood, chemicals and water source appeared to be associated with an increased risk in adjusted models. CONCLUSION: Our study represents one of the first international studies investigating risk factors for clefts among multiethnic underserved populations. Our findings suggest a multifactorial etiology including both maternal and paternal factors.

Nemaline Myopathy in a Hypotonic Neonate: Diagnostic Approach for Early Detection and Management.

Neonatal hypotonia presents with low muscle tone and an array of symptoms that vary depending on the etiology. The differential diagnosis for this condition is complex. It is crucial to exclude life-threatening causes before following a diagnostic algorithm and performing additional tests. Given the wide range of clinical symptoms and etiologies for neonatal hypotonia, rapid genetic testing has the potential to expedite diagnosis, reduce invasive testing such as muscle biopsy, reduce hospital stays, and guide condition management.  A four-week-old girl was admitted to the emergency department (ED) with a one-day history of lethargy, poor feeding, congestion, cough, and hypoxemia. Given positive rhino-enterovirus testing and high inflammatory markers, antibiotics were administered. Imaging, venous blood gas, and blood cultures were negative, and the patient was admitted to the pediatric intensive care unit (PICU) for hypoxemia. After speech-language pathology (SLP) and occupational therapy (OT) evaluation, weak orofacial muscles and feeding issues resulted in a nasogastric tube placement. A swallow study revealed decreased pharyngeal contraction and post-swallow liquid residue. Laryngoscopy showed mild laryngomalacia and dysphagia with aspiration. Genetic testing identified an ACTA1 mutation and confirmed nemaline myopathy (NM). The patient's oxygen levels dropped further during sleep, resulting in diagnoses of severe obstructive and moderate-severe central sleep apnea. Treatment included oxygen therapy, SLP, physical therapy, albuterol, and cough assists. After discharge, the patient was frequently re-admitted with chronic respiratory failure and bronchiolitis and later had gastrostomy and tracheostomy tubes inserted.  This specific case highlights the importance of implementing a diagnostic algorithm for neonatal hypotonia. It is also important for physicians, especially emergency medicine (EM) providers, to first exclude infection, sepsis, and cardiac and respiratory organ failure before looking into other tests. Then, physicians should evaluate for more rare etiologies. In this patient's case, the hypotonia was due to a rare genetic disease, nemaline myopathy, and a multidisciplinary approach was used for this patient's care.

The Role of Obesity in Breast Cancer Pathogenesis.

Research has shown that obesity increases the risk for type 2 diabetes mellitus (Type 2 DM) by promoting insulin resistance, increases serum estrogen levels by the upregulation of aromatase, and promotes the release of reactive oxygen species (ROS) by macrophages. Increased circulating glucose has been shown to activate mammalian target of rapamycin (mTOR), a significant signaling pathway in breast cancer pathogenesis. Estrogen plays an instrumental role in estrogen-receptor-positive breast cancers. The role of ROS in breast cancer warrants continued investigation, in relation to both pathogenesis and treatment of breast cancer. We aim to review the role of obesity in breast cancer pathogenesis and novel therapies mediating obesity-associated breast cancer development. We explore the association between body mass index (BMI) and breast cancer incidence and the mechanisms by which oxidative stress modulates breast cancer pathogenesis. We discuss the role of glutathione, a ubiquitous antioxidant, in breast cancer therapy. Lastly, we review breast cancer therapies targeting mTOR signaling, leptin signaling, blood sugar reduction, and novel immunotherapy targets.

Impact of housing on the survival of persons with AIDS.

BACKGROUND: Homeless persons with HIV/AIDS have greater morbidity and mortality, more hospitalizations, less use of antiretroviral therapy, and worse medication adherence than HIV-infected persons who are stably housed. We examined the effect of homelessness on the mortality of persons with AIDS and measured the effect of supportive housing on AIDS survival. METHODS: The San Francisco AIDS registry was used to identify homeless and housed persons who were diagnosed with AIDS between 1996 and 2006. The registry was computer-matched with a housing database of homeless persons who received housing after their AIDS diagnosis. The Kaplan-Meier product limit method was used to compare survival between persons who were homeless at AIDS diagnosis and those who were housed. Proportional hazards models were used to estimate the independent effects of homelessness and supportive housing on survival after AIDS diagnosis. RESULTS: Of the 6,558 AIDS cases, 9.8% were homeless at diagnosis. Sixty-seven percent of the persons who were homeless survived five years compared with 81% of those who were housed (p < 0.0001). Homelessness increased the risk of death (adjusted relative hazard [RH] 1.20; 95% confidence limits [CL] 1.03, 1.41). Homeless persons with AIDS who obtained supportive housing had a lower risk of death than those who did not (adjusted RH 0.20; 95% CL 0.05, 0.81). CONCLUSION: Supportive housing ameliorates the negative effect of homelessness on survival with AIDS.

Excessive postextraction bleeding associated with Cordyceps sinensis: a case report and review of select traditional medicines used by Vietnamese people living in the United States.

Many older people who have emigrated from Vietnam to the United States continue to use the traditional medicines that they used in their country of origin. Clinicians trained in the West may not be familiar with these products. We reviewed 6 Asian traditional medicines that are popular among older Vietnamese people living in the United States. Each medicine has significant side effects that can lead to complications in patients undergoing surgery. Here, we present the case of a patient who used Cordyceps sinensis daily as a tonic and experienced prolonged bleeding after dental surgery.

Using a Multitest Algorithm to Improve the Positive Predictive Value of Rapid HIV Testing and Linkage to HIV Care in Nonclinical HIV Test Sites.

BACKGROUND: Use of a rapid HIV testing algorithm (RTA) in which all tests are conducted within one client appointment could eliminate off-site confirmatory testing and reduce the number of persons not receiving confirmed results. METHODS: An RTA was implemented in 9 sites in Los Angeles and San Francisco; results of testing at these sites were compared with 23 sites conducting rapid HIV testing with off-site confirmation. RTA clients with reactive results on more than 1 rapid test were considered HIV+ and immediately referred for HIV care. The positive predictive values (PPVs) of a single rapid HIV test and the RTA were calculated compared with laboratory-based confirmatory testing. A Poisson risk regression model was used to assess the effect of RTA on the proportion of HIV+ persons linked to HIV care within 90 days of a reactive rapid test. RESULTS: The PPV of the RTA was 100% compared with 86.4% for a single rapid test. The time between testing and receipt of RTA results was on average 8 days shorter than laboratory-based confirmatory testing. For risk groups other than men who had sex with men, the RTA increased the probability of being in care within 90 days compared with standard testing practice. CONCLUSIONS: The RTA increased the PPV of rapid testing to 100%, giving providers, clients, and HIV counselors timely information about a client's HIV-positive serostatus. Use of RTA could reduce loss to follow-up between testing positive and confirmation and increase the proportion of HIV-infected persons receiving HIV care.

Changes in causes of death among persons with AIDS: San Francisco, California, 1996-2011.

The increased life expectancy among HIV-infected persons treated with combination antiretroviral therapy (ART), risk behaviors, and co-morbidities associated with ART place HIV-infected persons at risk for non-HIV-related causes of death. We used the San Francisco HIV/AIDS registry to identify deaths that occurred from January 1996 through December 2011. Temporal trends in AIDS- and non-AIDS-related mortality rates, the proportion of underlying and contributory causes of death, and the ratio of observed deaths in the study population to expected number of deaths among California men aged 20-79 (standardized mortality ratio [SMR]) of underlying causes of death were examined. A total of 5338 deaths were identified. The annual AIDS-related death rate (per 100 deaths) declined from 10.8 in 1996 to 0.9 in 2011 (p<0.0001), while the annual death rate from non-AIDS-related causes declined from 2.1 in 1996 to 0.9 in 2011 (p<0.0001). The proportion of deaths due to all types of heart disease combined, all non-AIDS cancers combined, mental disorders resulting from substance abuse, drug overdose, suicide and chronic obstructive pulmonary disease increased significantly over time. The SMRs for liver diseased decreased significantly over time but remained elevated. Our data highlight the importance of age-related causes of death as well as deaths from causes that are, at least in part, preventable.