Applying machine learning to consumer wearable data for the early detection of complications after pediatric appendectomy.

When children are discharged from the hospital after surgery, their caregivers often rely on subjective assessments (e.g., appetite, fatigue) to monitor postoperative recovery as objective assessment tools are scarce at home. Such imprecise and one-dimensional evaluations can result in unwarranted emergency department visits or delayed care. To address this gap in postoperative monitoring, we evaluated the ability of a consumer-grade wearable device, Fitbit, which records multimodal data about daily physical activity, heart rate, and sleep, in detecting abnormal recovery early in children recovering after appendectomy. One hundred and sixty-two children, ages 3-17 years old, who underwent an appendectomy (86 complicated and 76 simple cases of appendicitis) wore a Fitbit device on their wrist for 21 days postoperatively. Abnormal recovery events (i.e., abnormal symptoms or confirmed postoperative complications) that arose during this period were gathered from medical records and patient reports. Fitbit-derived measures, as well as demographic and clinical characteristics, were used to train machine learning models to retrospectively detect abnormal recovery in the two days leading up to the event for patients with complicated and simple appendicitis. A balanced random forest classifier accurately detected 83% of these abnormal recovery days in complicated appendicitis and 70% of abnormal recovery days in simple appendicitis prior to the true report of a symptom/complication. These results support the development of machine learning algorithms to predict onset of abnormal symptoms and complications in children undergoing surgery, and the use of consumer wearables as monitoring tools for early detection of postoperative events.

Unmet needs in uncomplicated urinary tract infection in the United States and Germany: a physician survey.

BACKGROUND: Uncomplicated urinary tract infections (uUTIs/acute cystitis) are among the most common infections in women worldwide. There are differences in uUTI treatment guidelines between countries and understanding the needs of physicians in diverse healthcare systems is important for developing new treatments. We performed a survey of physicians in the United States (US) and Germany to understand their perceptions of, and management approaches to uUTI. METHODS: This was a cross-sectional online survey of physicians in the US and Germany who were actively treating patients with uUTI (≥ 10 patients/month). Physicians were recruited via a specialist panel and the survey was piloted with 2 physicians (1 US, 1 Germany) prior to study commencement. Data were analyzed with descriptive statistics. RESULTS: A total of 300 physicians were surveyed (n = 200 US, n = 100 Germany). Across countries and specialties, physicians estimated 16-43% of patients did not receive complete relief from initial therapy and 33-37% had recurrent infections. Urine culture and susceptibility testing was more common in the US and among urologists. The most commonly selected first-line therapy was trimethoprim-sulfamethoxazole in the US (76%) and fosfomycin in Germany (61%). Ciprofloxacin was the most selected following multiple treatment failures (51% US, 45% Germany). Overall, 35% of US and 45% of German physicians agreed with the statement "I feel there is a good selection of treatment options" and ≥ 50% felt that current treatments provided good symptom relief. More than 90% of physicians included symptom relief amongst their top 3 treatment goals. The overall impact of symptoms on patients' lives was rated "a great deal" by 51% of US and 38% of German physicians, increasing with each treatment failure. Most physicians (> 80%) agreed that antimicrobial resistance (AMR) is serious, but fewer (56% US, 46% Germany) had a high level of confidence in their knowledge of AMR. CONCLUSIONS: Treatment goals for uUTI were similar in the US and Germany, although with nuances to disease management approaches. Physicians recognized that treatment failures have a significant impact on patients' lives and that AMR is a serious problem, though many did not have confidence in their own knowledge of AMR.

An intrasplenic injection model of pancreatic cancer metastasis to the liver in mice.

Here, we provide a protocol for an intrasplenic injection model to establish pancreatic tumors in the mouse liver. We describe the steps to inject tumor cells into mouse spleen and to perform a splenectomy, followed by animal recovery and end point analysis of tumors in the liver. This model allows rapid and reproducible tumor growth in a clinically relevant metastatic site, providing a platform to evaluate the efficacy of anti-cancer drugs. This technique can be expanded to other cancer cell lines. For complete details on the use and execution of this protocol, please refer to Poh et al. (2022).1.

Rationalising pre-operative trauma bloods can lead to significant cost savings.

BACKGROUND: A full set of pre-operative bloods is being done on nearly all trauma patients who are admitted to our institute for surgery-regardless of variables such as patient age, injury sustained, or co-morbidities. This leads to unnecessary bloods being taken. AIMS: The primary aims are (1) to calculate the costs associated with routine pre-operative bloods and (2) to examine how much money could be saved by retrospectively applying a more pragmatic pre-operative bloods policy. METHODS: Trauma theatre cases over a 5-week period were identified with their pre-operative bloods and post-operative transfusions. Labour, material, and processing costs were estimated for each test. An updated pre-operative blood schedule was proposed and applied retrospectively to see if cost savings could be found. RESULTS: Of the 173 orthopaedic procedures performed, 109 (63%) had a group and screen or crossmatch pre-operatively. Fifteen (8.6%) required a post-operative blood transfusion. One hundred and twenty-eight (74%) patients had a full blood count, and renal profile taken pre-operatively. A full set of bloods costs approximately €51.23 to take and process. When the updated pre-operative blood guidelines were retrospectively applied, it would have led to cost savings of €2496 over the 5-week period of this audit, and if extrapolated up to 1 year, could lead to potential annual savings of €25,960. CONCLUSIONS: We have demonstrated that an excessive amount of unnecessary pre-operative bloods have been taken using the current blood schedule. A pragmatic pre-operative blood schedule can lead to significant actual cost savings.

Tumor Growth Remains Refractory to Myc Ablation in Host Macrophages.

Aberrant expression of the oncoprotein c-Myc (Myc) is frequently observed in solid tumors and is associated with reduced overall survival. In addition to well-recognized cancer cell-intrinsic roles of Myc, studies have also suggested tumor-promoting roles for Myc in cells of the tumor microenvironment, including macrophages and other myeloid cells. Here, we benchmark Myc inactivation in tumor cells against the contribution of its expression in myeloid cells of murine hosts that harbor endogenous or allograft tumors. Surprisingly, we observe that LysMCre-mediated Myc ablation in host macrophages does not attenuate tumor growth regardless of immunogenicity, the cellular origin of the tumor, the site it develops, or the stage along the tumor progression cascade. Likewise, we find no evidence for Myc ablation to revert or antagonize the polarization of alternatively activated immunosuppressive macrophages. Thus, we surmise that systemic targeting of Myc activity may confer therapeutic benefits primarily through limiting Myc activity in tumor cells rather than reinvigorating the anti-tumor activity of macrophages.

Inhibition of HCK in myeloid cells restricts pancreatic tumor growth and metastasis.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a low 5-year survival rate and is associated with poor response to therapy. Elevated expression of the myeloid-specific hematopoietic cell kinase (HCK) is observed in PDAC and correlates with reduced patient survival. To determine whether aberrant HCK signaling in myeloid cells is involved in PDAC growth and metastasis, we established orthotopic and intrasplenic PDAC tumors in wild-type and HCK knockout mice. Genetic ablation of HCK impaired PDAC growth and metastasis by inducing an immune-stimulatory endotype in myeloid cells, which in turn reduced the desmoplastic microenvironment and enhanced cytotoxic effector cell infiltration. Consequently, genetic ablation or therapeutic inhibition of HCK minimized metastatic spread, enhanced the efficacy of chemotherapy, and overcame resistance to anti-PD1, anti-CTLA4, or stimulatory anti-CD40 immunotherapy. Our results provide strong rationale for HCK to be developed as a therapeutic target to improve the response of PDAC to chemo- and immunotherapy.

Physical Activity among U.S. Preschool-Aged Children: Application of Machine Learning Physical Activity Classification to the 2012 National Health and Nutrition Examination Survey National Youth Fitness Survey.

Early childhood is an important development period for establishing healthy physical activity (PA) habits. The objective of this study was to evaluate PA levels in a representative sample of U.S. preschool-aged children. The study sample included 301 participants (149 girls, 3-5 years of age) in the 2012 U.S. National Health and Examination Survey National Youth Fitness Survey. Participants were asked to wear an ActiGraph accelerometer on their wrist for 7 days. A machine learning random forest classification algorithm was applied to accelerometer data to estimate daily time spent in moderate- and vigorous-intensity PA (MVPA; the sum of minutes spent in running, walking, and other moderate- and vigorous-intensity PA) and total PA (the sum of MVPA and light-intensity PA). We estimated that U.S. preschool-aged children engaged in 28 min/day of MVPA and 361 min/day of total PA, on average. MVPA and total PA levels were not significantly different between males and females. This study revealed that U.S. preschool-aged children engage in lower levels of MVPA and higher levels of total PA than the minimum recommended by the World Health Organization.

Therapeutic inhibition of the SRC-kinase HCK facilitates T cell tumor infiltration and improves response to immunotherapy.

Although immunotherapy has revolutionized cancer treatment, many immunogenic tumors remain refractory to treatment. This can be largely attributed to an immunologically "cold" tumor microenvironment characterized by an accumulation of immunosuppressive myeloid cells and exclusion of activated T cells. Here, we demonstrate that genetic ablation or therapeutic inhibition of the myeloid-specific hematopoietic cell kinase (HCK) enables activity of antagonistic anti-programmed cell death protein 1 (anti-PD1), anti-CTLA4, or agonistic anti-CD40 immunotherapies in otherwise refractory tumors and augments response in treatment-susceptible tumors. Mechanistically, HCK ablation reprograms tumor-associated macrophages and dendritic cells toward an inflammatory endotype and enhances CD8+ T cell recruitment and activation when combined with immunotherapy in mice. Meanwhile, therapeutic inhibition of HCK in humanized mice engrafted with patient-derived xenografts counteracts tumor immunosuppression, improves T cell recruitment, and impairs tumor growth. Collectively, our results suggest that therapeutic targeting of HCK activity enhances response to immunotherapy by simultaneously stimulating immune cell activation and inhibiting the immunosuppressive tumor microenvironment.

Anti-CD19 CAR T cells in combination with ibrutinib for the treatment of chronic lymphocytic leukemia.

In chronic lymphocytic leukemia (CLL) patients who achieve a complete remission (CR) to anti-CD19 chimeric antigen receptor T cells (CART-19), remissions are remarkably durable. Preclinical data suggesting synergy between CART-19 and the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib prompted us to conduct a prospective single-center phase 2 trial in which we added autologous anti-CD19 humanized binding domain T cells (huCART-19) to ibrutinib in patients with CLL not in CR despite ≥6 months of ibrutinib. The primary endpoints were safety, feasibility, and achievement of a CR within 3 months. Of 20 enrolled patients, 19 received huCART-19. The median follow-up for all infused patients was 41 months (range, 0.25-58 months). Eighteen patients developed cytokine release syndrome (CRS; grade 1-2 in 15 of 18 subjects), and 5 developed neurotoxicity (grade 1-2 in 4 patients, grade 4 in 1 patient). While the 3-month CR rate among International Working Group on CLL (iwCLL)-evaluable patients was 44% (90% confidence interval [CI], 23-67%), at 12 months, 72% of patients tested had no measurable residual disease (MRD). The estimated overall and progression-free survival at 48 months were 84% and 70%, respectively. Of 15 patients with undetectable MRD at 3 or 6 months, 13 remain in ongoing CR at the last follow-up. In patients with CLL not achieving a CR despite ≥6 months of ibrutinib, adding huCART-19 mediated a high rate of deep and durable remissions. ClinicalTrials.gov number, NCT02640209.

Understanding Preventable Deaths in the Geriatric Trauma Population: Analysis of 3,452,339 Patients From the Center of Medicare and Medicaid Services Database.

BACKGROUND: Patient safety indicators (PSIs) are avoidable complications that can impact outcomes. Geriatric patients have a higher mortality than younger patients with similar injuries, and understanding the etiology may help reduce mortality. We aim to estimate preventable geriatric trauma mortality in the United States and identify PSIs associated with increased preventable mortality. METHODS: A retrospective cohort study of patients aged ≥65 years, in the CMS database, 2017-second quarter of 2020. Risk-adjusted multivariable regression was performed to calculate observed-to-expected (O/E) mortality ratios for failure-to-prevent and failure-to-rescue PSIs with significance defined as P < .05. RESULTS: 3 452 339 geriatric patients were analyzed. Patients aged 75-84 years had 33% higher odds of preventable mortality (adjusted odds ratio [aOR] = 1.33 and 95% confidence interval [CI] = 1.31, 1.36), whereas patients aged ≥85 years had 91% higher odds of preventable mortality (aOR = 1.91 and 95% CI = 1.87, 1.94) compared to patients aged 65-74 years. Failure-to-prevent O/E were >1 for all PSIs evaluated with central line-related blood stream infection having a high O/E (747.93). Failure-to-rescue O/E were >1 for 10/11 (91%) PSIs with physiologic and metabolic derangements having the highest O/E (5.98). United States' states with higher quantities of geriatric trauma patients experienced reduced preventable mortality. CONCLUSION: Odds of preventable mortality increases with age. Perioperative venous thrombotic events, hemorrhage or hematoma, and postoperative physiologic/metabolic derangements produce significant preventable mortalities. United States' states differ in their failure-to-prevent and failure-to-rescue PSIs. Utilization of national guidelines, minimization of central venous catheter use, addressing polypharmacy especially anticoagulation, ensuring operative and procedure-based competencies, and greater incorporation of inpatient geriatricians may serve to reduce preventable mortality in elderly trauma patients.

Achieving the cancer moonshot in Africa.

For decades now, the United States (US) has been a leading contributor in global health with the government, academic institutions, foundations, non-profits and industry investing and partnering with African countries, as seen with the US President's Emergency Plan for AIDS Relief (PEPFAR) program. Now as more people survive HIV/AIDs and other infectious diseases in Africa and live longer, non-communicable diseases like cancer are on the rise, in what can be described as a growing health iceberg, hidden under epidemics of infectious diseases. There is now more urgent need for international collaborations on cancer, which has become a leading cause of death in both Africa and the US, underpinned by poignant disparities in access to care. The re-ignited Cancer Moonshot in the USA and publication of the Lancet Oncology Commission report for sub-Saharan Africa in 2022 provide a timely and valuable framework for growing US-Africa collaborations in the coming years towards attaining the goal of the cancer moonshot both in the US and Africa. This goal is to reduce cancer death rate by at least 50% over the next 25 years, and to improve the experience of those living with and surviving cancer. The US-Africa summit taking place in Washington in December 2022 provides a momentous opportunity to identify recommendations or priority areas, some of them included in this article, and initiating action for win-win collaborations towards achieving the cancer moonshot in Africa.

A novel BH3-mimetic, AZD0466, targeting BCL-XL and BCL-2 is effective in pre-clinical models of malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with treatment limited to Cisplatin and Pemetrexed chemotherapy. Recently, we showed that drugs targeting the BCL-2-regulated apoptosis pathway could kill MPM cell lines in vitro, and control tumor growth in vivo. These studies showed BCL-XL was the dominant pro-survival BCL-2 family member correlating with its high-level expression in cells and patient tumor samples. In this study we show another inhibitor, AZD4320 that targets BCL-XL (and BCL-2), can also potently kill MPM tumor cells in vitro (EC50 values in the 200 nM range) and this effect is enhanced by co-inhibition of MCL-1 using AZD5991. Moreover, we show that a novel nanoparticle, AZD0466, where AZD4320 is chemically conjugated to a PEGylated poly-lysine dendrimer, was as effective as standard-of-care chemotherapy, Cisplatin, at inhibiting tumor growth in mouse xenograft studies, and this effect was enhanced when both drugs were combined. Critically, the degree of thrombocytopenia, an on-target toxicity associated with BCL-XL inhibition, was significantly reduced throughout the treatment period compared to other BCL-XL-targeting BH3-mimetics. These pre-clinical findings provide a rationale for the future clinical evaluation for novel BH3-mimetic formulations in MPM, and indeed, other solid tumor types dependent on BCL-XL.

Host IL11 Signaling Suppresses CD4+ T cell-Mediated Antitumor Responses to Colon Cancer in Mice.

IL11 is a member of the IL6 family of cytokines and signals through its cognate receptor subunits, IL11RA and glycoprotein 130 (GP130), to elicit biological responses via the JAK/STAT signaling pathway. IL11 contributes to cancer progression by promoting the survival and proliferation of cancer cells, but the potential immunomodulatory properties of IL11 signaling during tumor development have thus far remained unexplored. Here, we have characterized a role for IL11 in regulating CD4+ T cell-mediated antitumor responses. Absence of IL11 signaling impaired tumor growth in a sporadic mouse model of colon cancer and syngeneic allograft models of colon cancer. Adoptive bone marrow transfer experiments and in vivo depletion studies demonstrated that the tumor-promoting activity of IL11 was mediated through its suppressive effect on host CD4+ T cells in the tumor microenvironment. Indeed, when compared with Il11ra-proficient CD4+ T cells associated with MC38 tumors, their Il11ra-deficient counterparts displayed elevated expression of mRNA encoding the antitumor mediators IFNγ and TNFα. Likewise, IL11 potently suppressed the production of proinflammatory cytokines (IFNγ, TNFα, IL6, and IL12p70) by CD4+ T cells in vitro, which we corroborated by RNAscope analysis of human colorectal cancers, where IL11RAhigh tumors showed less IFNG and CD4 expression than IL11RAlow tumors. Therefore, our results ascribe a tumor cell-extrinsic immunomodulatory role to IL11 during colon cancer development that could be amenable to an anticytokine-based therapy.See related Spotlight by van der Burg, p. 724.

BCL-XL is an actionable target for treatment of malignant pleural mesothelioma.

Despite having one of the lowest survival rates of all cancers, there have been no new approved treatments for malignant pleural mesothelioma (MPM) in over a decade. Standard-of-care treatment relies on Cisplatin plus Pemetrexed chemotherapy. Here, we tested a suite of BH3-mimetic drugs targeting BCL-2 pro-survival proteins of the intrinsic apoptotic pathway. We found BCL-XL is the dominant pro-survival protein in a panel of cell lines in vitro, though potent, synergistic cell killing occurred with MCL-1 co-targeting. This correlates with high-level expression of BCL-XL and MCL-1 in cell lines and a large cohort of patient tumour samples. BCL-XL inhibition combined with Cisplatin also enhanced cell killing. In vivo BCL-XL inhibition was as effective as Cisplatin, and the combination enhanced tumour growth control and survival. Genetic ablation of MCL-1 also enhanced the effects of BCL-XL inhibitors, in vivo. Combined, these data provide a compelling rationale for the clinical investigation of BH3-mimetics targeting BCL-XL in MPM.

Inhibition of the SRC Kinase HCK Impairs STAT3-Dependent Gastric Tumor Growth in Mice.

Persistent activation of the latent transcription factor STAT3 is observed in gastric tumor epithelial and immune cells and is associated with a poor patient prognosis. Although targeting STAT3-activating upstream kinases offers therapeutically viable targets with limited specificity, direct inhibition of STAT3 remains challenging. Here we provide functional evidence that myeloid-specific hematopoietic cell kinase (HCK) activity can drive STAT3-dependent epithelial tumor growth in mice and is associated with alternative macrophage activation alongside matrix remodeling and tumor cell invasion. Accordingly, genetic reduction of HCK expression in bone marrow-derived cells or systemic pharmacologic inhibition of HCK activity suppresses alternative macrophage polarization and epithelial STAT3 activation, and impairs tumor growth. These data validate HCK as a molecular target for the treatment of human solid tumors harboring excessive STAT3 activity.

Immunoprofiling of Breast Cancer Antigens Using Antibodies Derived from Local Lymph Nodes.

Tumor antigens are responsible for initiating an immune response in cancer patients, and their identification may provide new biomarkers for cancer diagnosis and targets for immunotherapy. The general use of serum antibodies to identify tumor antigens has several drawbacks, including dilution, complex formation, and background reactivity. In this study, antibodies were generated from antibody-secreting cells (ASC) present in tumor-draining lymph nodes of 20 breast cancer patients (ASC-probes) and were used to screen breast cancer cell lines and protein microarrays. Half of the ASC-probes reacted strongly against extracts of the MCF-7 breast cancer cell line, but each with a distinct antigen recognition profile. Three of the positive ASC-probes reacted differentially with recombinant antigens on a microarray containing cancer-related proteins. The results of this study show that lymph node-derived ASC-probes provide a highly specific source of tumor-specific antibodies. Each breast cancer patient reacts with a different antibody profile which indicates that targeted immunotherapies may need to be personalized for individual patients. Focused microarrays in combination with ASC-probes may be useful in providing immune profiles and identifying tumor antigens of individual cancer patients.

Treat the Pain Program.

CONTEXT: Globally, low- and middle-income countries are home to 70% of cancer deaths and 99% of HIV deaths, but they consume just 7% of opioid analgesics. OBJECTIVE: The American Cancer Society's Treat the Pain program partners with governments in low- and middle-income countries to improve access to high-quality essential pain medicines. METHOD: Treat the Pain has developed the MORPHINE Framework to provide a structure to describe challenges to access to pain relief and to group and sequence interventions to address these challenges. RESULTS: Treat the Pain has used the framework to improve access to oral morphine in partner countries in Sub-Saharan Africa, including Nigeria, Ethiopia, Uganda, Kenya, and Swaziland, addressing both supply- and demand-side challenges. CONCLUSION: Treat the Pain is supporting governments in Sub-Saharan Africa to reduce needless suffering and improve access to essential pain medicines for patients in pain by supporting the expansion of locally produced, affordable oral morphine solution and expanding basic training in pain assessment and management.

Nicotine Enhances the Hypnotic and Hypothermic Effects of Alcohol in the Mouse.

BACKGROUND: Ethanol (EtOH) and nicotine abuse are 2 leading causes of preventable mortality in the world, but little is known about the pharmacological mechanisms mediating co-abuse. Few studies have examined the interaction of the acute effects of EtOH and nicotine. Here, we examine the effects of nicotine administration on the duration of EtOH-induced loss of righting reflex (LORR) and characterize the nature of their pharmacological interactions in C57BL/6J mice. METHODS: We assessed the effects of EtOH and nicotine and the nature of their interaction in the LORR test using isobolographic analysis after acute injection in C57BL/6J male mice. Next, we examined the importance of receptor efficacy using nicotinic partial agonists varenicline and sazetidine. We evaluated the involvement of major nicotinic acetylcholine receptor (nAChR) subtypes using nicotinic antagonist mecamylamine and nicotinic α4- and α7-knockout mice. The selectivity of nicotine's actions on EtOH-induced LORR was examined by testing nicotine's effects on the hypnotic properties of ketamine and pentobarbital. We also assessed the development of tolerance after repeated nicotine exposure. Last, we assessed whether the effects of nicotine on EtOH-induced LORR extend to hypothermia and EtOH intake in the drinking in the dark (DID) paradigm. RESULTS: We found that acute nicotine injection enhances EtOH's hypnotic effects in a synergistic manner and that receptor efficacy plays an important role in this interaction. Furthermore, tolerance developed to the enhancement of EtOH's hypnotic effects by nicotine after repeated exposure of the drug. α4* and α7 nAChRs seem to play an important role in nicotine-EtOH interaction in the LORR test. In addition, the magnitude of EtOH-induced LORR enhancement by nicotine was more pronounced in C57BL/6J than DBA/2J mice. Furthermore, acute nicotine enhanced ketamine and pentobarbital hypnotic effects in the mouse. Finally, nicotine enhanced EtOH-induced hypothermia but decreased EtOH intake in the DID test. CONCLUSIONS: Our results demonstrate that nicotine synergistically enhances EtOH-induced LORR in the mouse.

Targeting the androgen receptor in breast cancer.

The androgen receptor (AR) is expressed in the majority of breast cancer and across the three main breast cancer subtypes. Historically, the oncogenic role of AR has best been described in molecular apocrine breast cancers, an estrogen receptor (ER)-/AR+ subtype which has a steroid response signature similar to that in the ER-positive breast cancer. The signalling effect of AR is likely to be different across breast cancer subtypes, and particularly important is its interaction with ER signalling. Despite the high frequency of AR expression in breast cancer, it is still not a standard clinical practice to use AR antagonists as therapy. Older trials of AR-directed therapies in breast cancer have had generally been disappointing. More recently, more potent, next-generation, AR-directed therapies have been developed in the context of prostate cancer. Here, we will review the emerging literature dissecting the role of AR signalling in a context-dependent manner in breast cancer and the renewed interest and wave of clinical trials targeting the AR in breast cancer.