The relationship between mental health reforms and general population suicide rates in Australia over the past three and a half decades: 1987-2021.

Nearly 3,000 Australians tragically end their lives by suicide each year, underscoring a major national public health challenge with substantial socio-economic ramifications. Australia's National Mental Health Plans (NMHPs) aim to improve mental health and reduce suicide rates. This study investigates their effectiveness by analyzing how age-standardized suicide rates across Australian jurisdictions have fluctuated alongside the implementation of five NMHPs from 1987 to 2021. Findings reveal mixed impacts, with some plans linked to decreases and others associated with increases in suicide rates across different periods and regions. Notably, the recent decline in 2020 requires careful consideration amidst COVID-19 pandemic influences. These insights not only provide valuable evidence for shaping future mental health policies and initiatives but also for future health services research.

Lessons Learned from a Multi-Site, Team-Based Serious Illness Care Program Implementation at an Academic Medical Center.

Background: Patients with serious illness benefit from conversations to share prognosis and explore goals and values. To address this, we implemented Ariadne Labs' Serious Illness Care Program (SICP) at Stanford Health Care. Objective: Improve quantity, timing, and quality of serious illness conversations. Methods: Initial implementation followed Ariadne Labs' SICP framework. We later incorporated a team-based approach that included nonphysician care team members. Outcomes included number of patients with documented conversations according to clinician role and practice location. Machine learning algorithms were used in some settings to identify eligible patients. Results: Ambulatory oncology and hospital medicine were our largest implementation sites, engaging 4707 and 642 unique patients in conversations, respectively. Clinicians across eight disciplines engaged in these conversations. Identified barriers that included leadership engagement, complex workflows, and patient identification. Conclusion: Several factors contributed to successful SICP implementation across clinical sites: innovative clinical workflows, machine learning based predictive algorithms, and nonphysician care team member engagement.

Activation of the CA2-ventral CA1 pathway reverses social discrimination dysfunction in Shank3B knockout mice.

Mutation or deletion of the SHANK3 gene, which encodes a synaptic scaffolding protein, is linked to autism spectrum disorder and Phelan-McDermid syndrome, conditions associated with social memory impairments. Shank3B knockout mice also exhibit social memory deficits. The CA2 region of the hippocampus integrates numerous inputs and sends a major output to the ventral CA1 (vCA1). Despite finding few differences in excitatory afferents to the CA2 in Shank3B knockout mice, we found that activation of CA2 neurons as well as the CA2-vCA1 pathway restored social recognition function to wildtype levels. vCA1 neuronal oscillations have been linked to social memory, but we observed no differences in these measures between wildtype and Shank3B knockout mice. However, activation of the CA2 enhanced vCA1 theta power in Shank3B knockout mice, concurrent with behavioral improvements. These findings suggest that stimulating adult circuitry in a mouse model with neurodevelopmental impairments can invoke latent social memory function.

Teaching Anti-Racism in the Clinical Environment: The Five-Minute Moment for Racial Justice in Healthcare.

Dismantling racism in health care demands that medical education promote racial justice throughout all stages of medical training. However, racial bias can be fostered unintentionally, influencing the way we make decisions as clinicians with downstream effects on patient health and health equity. The development of any anti-racism curriculum in medicine requires the ability to identify racial bias in practices we have not previously recognized as explicitly racist or unjust. This has limited the creation and delivery of effective anti-racism education in health care.

Considerations in the reliability and fairness audits of predictive models for advance care planning.

Multiple reporting guidelines for artificial intelligence (AI) models in healthcare recommend that models be audited for reliability and fairness. However, there is a gap of operational guidance for performing reliability and fairness audits in practice. Following guideline recommendations, we conducted a reliability audit of two models based on model performance and calibration as well as a fairness audit based on summary statistics, subgroup performance and subgroup calibration. We assessed the Epic End-of-Life (EOL) Index model and an internally developed Stanford Hospital Medicine (HM) Advance Care Planning (ACP) model in 3 practice settings: Primary Care, Inpatient Oncology and Hospital Medicine, using clinicians' answers to the surprise question ("Would you be surprised if [patient X] passed away in [Y years]?") as a surrogate outcome. For performance, the models had positive predictive value (PPV) at or above 0.76 in all settings. In Hospital Medicine and Inpatient Oncology, the Stanford HM ACP model had higher sensitivity (0.69, 0.89 respectively) than the EOL model (0.20, 0.27), and better calibration (O/E 1.5, 1.7) than the EOL model (O/E 2.5, 3.0). The Epic EOL model flagged fewer patients (11%, 21% respectively) than the Stanford HM ACP model (38%, 75%). There were no differences in performance and calibration by sex. Both models had lower sensitivity in Hispanic/Latino male patients with Race listed as "Other." 10 clinicians were surveyed after a presentation summarizing the audit. 10/10 reported that summary statistics, overall performance, and subgroup performance would affect their decision to use the model to guide care; 9/10 said the same for overall and subgroup calibration. The most commonly identified barriers for routinely conducting such reliability and fairness audits were poor demographic data quality and lack of data access. This audit required 115 person-hours across 8-10 months. Our recommendations for performing reliability and fairness audits include verifying data validity, analyzing model performance on intersectional subgroups, and collecting clinician-patient linkages as necessary for label generation by clinicians. Those responsible for AI models should require such audits before model deployment and mediate between model auditors and impacted stakeholders.

Simultaneous Cases of Carfilzomib-Induced Thrombotic Microangiopathy in 2 Patients With Multiple Myeloma.

Background: In patients with multiple myeloma, thrombotic microangiopathy is a rare adverse event associated with proteasome inhibitors, such as bortezomib, carfilzomib, and ixazomib. Case Presentation: Two patients with multiple myeloma who presented with carfilzomib-induced thrombotic microangiopathy received eculizumab with subsequent stabilization of renal function. Conclusions: Given the overall rarity of this adverse event, the simultaneous presentation of these 2 cases was unexpected. These cases underscores the need for heightened awareness in clinical practice of thrombotic microangiopathy. The potential role of eculizumab as a therapeutic treatment in the setting of thrombotic microangiopathy requires further investigation.

Severe Posaconazole-Induced Glucocorticoid Deficiency with Concurrent Pseudohyperaldosteronism: An Unfortunate Two-for-One Special.

A 56-year-old Hispanic man with a history of disseminated coccidioidomycosis was diagnosed with persistent glucocorticoid insufficiency and pseudohyperaldosteronism secondary to posaconazole toxicity. This case was notable for unexpected laboratory findings of both pseudohyperaldosteronism and severe glucocorticoid deficiency due to posaconazole's mechanism of action on the adrenal steroid synthesis pathway. Transitioning to fluconazole and starting hydrocortisone resolved the hypokalemia but not his glucocorticoid deficiency. This case highlights the importance of recognizing iatrogenic glucocorticoid deficiency with azole antifungal agents and potential long term sequalae.

Case series of MET exon 14 skipping mutation-positive non-small-cell lung cancers with response to crizotinib and cabozantinib.

The mesenchymal-to-epithelial transition (MET) gene is altered and becomes a driver mutation in up to 5% of non-small-cell lung cancer (NSCLC). We report our institutional experience treating patients with MET exon 14 skipping (METex14) mutations, including responses to the MET inhibitors crizotinib and cabozantinib. We identified cases of NSCLC with METex14 mutations using an institutionally developed or commercial next-generation sequencing assay. We assessed patient and disease characteristics by retrospective chart review. Some patients were treated off-label by the physician with crizotinib or cabozantinib, and tumor responses to these agents were assessed. A total of 15 patients with METex14-mutated NSCLC were identified, predominantly male (n=10) with a smoking history (60%) and a median age of 74.0 years. No other actionable somatic mutations were detected. Stage distribution included 26.7% stage I, 6.7% stage II, 6.7% stage III, and 60.0% stage IV. Among patients treated with crizotinib or cabozantinib (n=6), three patients showed partial response and one patient showed stable disease on the basis of RECIST criteria. Four patients experienced side effects requiring drug holiday, reduction, or cessation. Our findings highlight the diversity in presentation and histology of NSCLC with METex14 mutations, which were found in the absence of other actionable driver mutations. We observed evidence of tumor response to crizotinib and cabozantinib, supporting the previous reports that METex14 mutations in NSCLC are actionable driver events.

Larger Pore Size Hollow Fiber Membranes as a Solution to the Product Retention Issue in Filtration-Based Perfusion Bioreactors.

Tangential flow filtration (TFF) and alternating tangential flow (ATF) filtration technologies using hollow fiber membranes are commonly utilized in perfusion cell culture for the production of monoclonal antibodies; however, product retention remains a known and common problem with these systems. To address this issue, commercially available hollow fibers ranging from several hundred kilo-Daltons (kDa) to 0.65 µm in nominal pore size are tested and are all demonstrated to undergo moderate to severe product retention. Further investigation revealed accumulation of particles in the same size range (≈20-200 nm) as the pores. Based on the assumption that these particles contribute to product retention and membrane plugging, a hollow fiber with an unconventionally larger pore size is subsequently identified and demonstrated to drastically reduce product retention with no impact to cell clarification. Furthermore, these hollow fibers demonstrate surprisingly high membrane capacities, making them an attractive solution to the problem of product retention in perfusion reactors.

Synchronous primary lung adenocarcinomas harboring distinct MET Exon 14 splice site mutations.

When a patient is found to have multiple lung tumors, distinguishing whether they represent metastatic nodules or separate primary cancers is crucial for staging and therapy. We report the case of a 79-year-old patient with two surgically resected synchronous left upper lobe adenocarcinomas initially pathologically staged as T3 (IIB), indicating adjuvant chemotherapy should be recommended. However, the tumors appeared radiographically distinct, so next-generation sequencing was performed on each nodule. Each tumor harbored a different mesenchymal-to-epithelial transition (MET) exon 14 skipping mutation, an emerging targetable mutation, suggestive of distinct clonality. While the in frame protein deletion was the same in each tumor, the nucleotide base substitutions were different. Thus, the patient was down-staged to having two separate IA tumors, spared of adjuvant chemotherapy, and routine surveillance was recommended. This case highlights the utility of using molecular analysis in diagnosing and treating multifocal lung tumors, and the process of convergent molecular evolution toward a common oncogenic driver mutation. This is the first case of multiple synchronous lung tumors each harboring a distinct MET exon 14 splice site mutation.

Manipulation of the sodium-potassium ratio as a lever for controlling cell growth and improving cell specific productivity in perfusion CHO cell cultures.

Perfusion processes typically require removal of a continuous or semi-continuous volume of cell culture in order to maintain a desired target cell density. For fast growing cell lines, the product loss from this stream can be upwards of 35%, significantly reducing the overall process yield. As volume removed is directly proportional to cell growth, the ability to modulate growth during perfusion cell culture production thus becomes crucial. Leveraging existing media components to achieve such control without introducing additional supplements is most desirable because it decreases process complexity and eliminates safety and clearance concerns. Here, the impact of extracellular concentrations of sodium (Na) and potassium (K) on cell growth and productivity is explored. High throughput small-scale models of perfusion revealed Na:K ratios below 1 can significantly suppress cell growth by inducing cell cycle arrest in the G0/1 phase. A concomitant increase in cell specific productivity was also observed, reaching as high as 115 pg/cell/day for one cell line studied. Multiple recombinant Chinese hamster ovary (CHO) cell lines demonstrated similar responses to lower Na:K media, indicating the universal applicability of such an approach. Product quality attributes were also assessed and revealed that effects were cell line specific, and can be acceptable or manageable depending on the phase of the drug development. Drastically altering Na and K levels in perfusion media as a lever to impact cell growth and productivity is proposed.

Retrospective review of ceftriaxone versus levofloxacin for treatment of E. coli urinary tract infections.

Background Urinary tract infections (UTIs) are among the most common bacterial infections. Options for initial treatment of pyelonephritis or UTI requiring hospitalization include levofloxacin (LVF) or extended-spectrum cephalosporins. Globally, uropathogenic Escherichia coli resistance rates to fluoroquinolones have increased in recent years. Objective To compare clinical outcomes of patients receiving ceftriaxone (CTX) to those who received LVF empirically for the treatment of E. coli UTI. Setting 433-bed community hospital in Lexington, KY. Methods Retrospective, single center, cohort study of adults with a urine culture positive for E. coli who received either IV LVF or CTX empirically for the treatment of UTI. Main outcome measure The primary outcome was hospital length of stay. Secondary outcomes include time to susceptible therapy (TsT), hospital cost, and susceptibility to empiric therapy. Results There was no statistically significant difference in LOS or hospital cost. Subgroup analysis compared patients that received concordant CTX treatment and patients that received discordant LVF treatment. Patients that received concordant CTX treatment had a nonsignificant shorter median LOS (4.16 vs. 6.34 days). Median hospital cost was lower ($4345 vs. $8462, p = 0.004) and median TsT was shorter (5.83 vs. 64.46 h, p < 0.001) in the concordant CTX group. Conclusion Choice of empiric antibiotic therapy should be based on local antibiogram data. For patients with UTI requiring hospitalization, CTX seems to be an effective empiric therapy for most patients. More data is required to examine the effectiveness of local and source specific antibiograms on clinical outcomes when guiding treatment of patients with UTI.

Principles and approach to developing mammalian cell culture media for high cell density perfusion process leveraging established fed-batch media.

Perfusion medium was successfully developed based on our fed-batch platform basal and feed media. A systematic development approach was undertaken by first optimizing the ratios of fed-batch basal and feed media followed by targeted removal of unnecessary and redundant components. With this reduction in components, the medium could then be further concentrated by 2× to increase medium depth. The medium osmolality was also optimized where we found ∼360 mOsm/kg was desirable resulting in a residual culture osmolality of ∼300 mOsm/kg for our cell lines. Further building on this, the amino acids Q, E, N, and D were rebalanced to reduce lactate and ammonium levels, and increase the cell-specific productivity without compromising on cell viability while leaving viable cell density largely unaffected. Further modifications were also made by increasing certain important vitamin and lipid concentrations, while eliminating other unnecessary vitamins. Overall, an effective perfusion medium was developed with all components remaining in the formulation understood to be important and their concentrations increased to improve medium depth. The critical cell-specific perfusion rate using this medium was then established for a cell line of interest to be 0.075 nL/cell-day yielding 1.2 g/L-day at steady state. This perfusion process was then successfully scaled up to a 100 L single-use bioreactor with an ATF6 demonstrating similar performance as a 2 L bioreactor with an ATF2. Large volume handling challenges in our fed-batch facility were overcome by developing a liquid medium version of the powder medium product contained in custom totes for plug-and-play use with the bioreactor. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:891-901, 2017.

Use of subconjunctival injections of 5-fluorouracil to rescue and prolong intraocular pressure reduction for a failing Ahmed glaucoma implant.

PURPOSE: 5-Fluorouracil (5-FU) has been well described for a failing trabeculectomy bleb, but not for aqueous shunts. We sought to determine whether subconjunctival 5-FU prolongs the intraocular pressure (IOP) efficacy of Ahmed shunts. METHODS: We included all patients with Ahmed FP-7 implantation by one surgeon at Yale University. Patients with <3 months follow-up were excluded. Injections were done on a case-by-case basis, usually for IOP > 21 on >2 medications. Five-milligram (0.1 cc) injections were made over the plate. The control group consisted of Ahmed FP-7 patients without injections. The main outcome measure was IOP. Secondary outcome was success (IOP <21 mmHg, 20% decrease from preoperative IOP, and no reoperation). RESULTS: The average age of controls was 72.5 ± 16.6 years, and 63.7 ± 18.8 with 5-FU (p = 0.02). Forty-four patients received 5-FU and 45 did not. Mean preoperative IOP in controls was 31.5 ± 11 mmHg on 3.1 ± 1 medications, and 31.9 ± 9.0 mmHg (p = 0.86) on 3.3 ± 0.9 medications with 5-FU (p = 0.18). At a mean 137 days after surgery, mean pre-injection IOP was 25.3 ± 7.7 mmHg on 2.0 ± 1.3 medications. Five years following implantation, control IOPs averaged 12.9 ± 7.1 mmHg (53% decrease from preoperative IOP, p < 0.001) on 1.4 ± 1.1 medications versus 17.2 ± 4.9 mmHg (46% decrease from preoperative, 32% decrease from pre-5FU IOP, p < 0.001) on 2.7 ± 0.8 medications with 5-FU. The IOP at 5 years was statistically similar in both groups (p = 0.23). Five-year success rates trended higher with 5-FU (77 vs. 67%, p = 0.38). CONCLUSIONS: Subconjunctival injection of 5-FU sustained a significant long-term decline in intraocular pressures in eyes with failing Ahmed shunts. Outcomes between eyes receiving injections and controls were statistically similar.

Shear contributions to cell culture performance and product recovery in ATF and TFF perfusion systems.

Achievement of a robust and scalable cell retention device remains a challenge in perfusion systems. Of the two filtration systems commonly used, tangential flow filtration (TFF) systems often have an inferior product sieving profile compared to alternating tangential flow filtration (ATF) systems, which is typically attributed to the ATF's unique alternating flow. Here, we demonstrate that observed performance differences between the two systems are a function of cell lysis and not the alternating flow as previously thought. The peristaltic pump used in typical TFF perfusion systems is shown to be the single major contributor to shear stress and cell lysis. Replacing the peristaltic pump with a low shear centrifugal pump brought cell growth, cell lysis, particle concentration, and product sieving in a TFF perfusion system to levels comparable with that of an ATF. These results provide a correlation where poor product sieving can be partially explained by high shear in cell retention systems and demonstrate that low shear TFF systems are a feasible alternative to ATF systems.

Randomized Controlled Comparison of Titanium-Sapphire Versus Standard Q-Switched Nd: YAG Laser Trabeculoplasty.

PURPOSE: To evaluate the clinical effects of laser trabeculoplasty using a novel 790 nm wavelength titanium-sapphire laser (TLT) compared with a 532 nm Q-switched Nd:YAG laser used in standard selective laser trabeculoplasty (SLT). METHODS: Single institution prospective clinical trial of open-angle glaucoma patients randomized to TLT or SLT at the Yale Eye Center from 2011 to 2012. Patients with previous glaucoma surgery or trabeculoplasty were excluded. Trabeculoplasty was performed by a single surgeon unmasked to treatment group. All patients received 360 degrees of treatment. The main outcome measure was intraocular pressure (IOP) at 2 years. RESULTS: Thirty-seven patients were enrolled. The mean baseline IOPs were 19.7 in TLT (n=18) and 20.4 mm Hg in SLT (n=19, P=0.69).At 2 years, the mean IOP was 12.9 mm Hg (35% decrease, P<0.001) in the TLT group and 15.4 mm Hg (25% decrease, P=0.006) in the SLT group. The 2 groups did not differ in glaucoma medication use. Success, defined as IOP<21 mm Hg with >20% reduction from baseline without the need for secondary glaucoma procedures, occurred in 44% of TLT patients and 61% of SLT patients at 1 year and in 22% of TLT patients and 46% of SLT patients at 2 years (P=0.11). No patients experienced significant pain, anterior chamber reaction, corneal edema, or loss of vision. CONCLUSIONS: TLT may be a safe and effective alternative to SLT to lower IOP in patients with open-angle glaucoma.

Peripheral neuropathy in primary HIV infection associates with systemic and central nervous system immune activation.

BACKGROUND: Peripheral neuropathy (PN) is a frequent complication of chronic HIV infection. We prospectively studied individuals with primary HIV infection (<1 year after transmission) to assess the presence of and laboratory associations with PN in this early stage. METHODS: Standardized examination and analysis of blood and cerebrospinal fluid (CSF) was performed in participants with laboratory-confirmed primary HIV infection. PN was defined as ≥1 of the following unilateral or bilateral signs: decreased distal limb position, vibration, or temperature sense or hyporeflexia; symptomatic PN (SPN) was defined as the presence of these signs with symptoms. Analysis used nonparametric statistics. RESULTS: Overall, 20 (35%) of 58 antiretroviral-naive male subjects without diabetes evaluated at a median of 107 days post HIV transmission met criteria for PN. Thirteen (65%) of 20 PN subjects met criteria for SPN; 6 (30%) of 20 had bilateral findings. PN subjects and no PN subjects (NPN) did not differ in median age, days post HIV transmission, blood CD4 or CD8 counts, CSF or plasma HIV RNA levels, CSF white blood cell counts, or CSF to blood albumin ratio. PN and SPN subjects had elevated CSF neopterin (P = 0.003 and P = 0.0005), CSF monocyte chemoattractant protein-1 (P = 0.006 and P = 0.01), and blood neopterin (P = 0.006 and P = 0.009) compared with NPN subjects. PN subjects had a higher percentage of activated phenotype CSF CD8 T lymphocytes than NPN subjects (P = 0.009). CONCLUSIONS: Signs of PN were detected by detailed neurologic examination in 35% of men enrolled in a neurological study at a median of 3.5 months after HIV transmission. PN during this early period may be mediated by systemic and nervous system immune responses to HIV.