Finding one's way.

The following is a meditative reflection on an anecdote from Jeremy Safran's Psychoanalysis and Buddhism. Moving through Safran's description of an important moment in his development as a student of Buddhism, the author weaves images, practices, and ways of being and feeling into an homage to Safran's legacy integrating psychoanalytic and Buddhist praxis and epistemology.

Gender, Race, and Ethnicity of US Academic Ophthalmology Faculty and Department Chairs From 1966 to 2021.

Importance: Workforce diversity is integral to optimal function within health care teams. Objective: To analyze gender, race, and ethnicity trends in rank and leadership among US full-time academic ophthalmology faculty and department chairs between 1966 and 2021. Design, Setting, and Participants: This cohort study included full-time US academic ophthalmology faculty and department chairs registered in the Association of American Medical Colleges. Study data were analyzed in September 2023. Exposure: Identifying with an underrepresented in medicine (URiM) group. Main Outcomes and Measures: The main outcome measures were demographic (ie, gender, race, and ethnicity) changes among academic faculty and department chairs, assessed in 5-year intervals. The term minoritized race refers to any racial group other than White race. Results: There were 221 academic physicians in 1966 (27 women [12.2%]; 38 minoritized race [17.2%]; 8 Hispanic, Latino, or Spanish [3.6%]) and 3158 academic faculty by 2021 (1320 women [41.8%]; 1298 minoritized race [41.1%]; 147 Hispanic, Latino, or Spanish ethnicity [4.7%]). The annual proportional change for women, minoritized race, and Hispanic, Latino, or Spanish ethnicity was +0.63% per year (95% CI, 0.53%-0.72%), +0.54% per year (95% CI, 0.72%-0.36%), and -0.01% (95% CI, -0.03% to 0%), respectively. Women were underrepresented across academic ranks and increasingly so at higher echelons, ranging from nonprofessor/instructor roles (period-averaged mean difference [PA-MD], 19.88%; 95% CI, 16.82%-22.94%) to professor (PA-MD, 81.33%; 95% CI, 78.80%-83.86%). The corpus of department chairs grew from 77 in 1977 (0 women; 7 minoritized race [9.09%]; 2 Hispanic, Latino, or Spanish ethnicity [2.60%]) to 104 by 2021 (17 women [16.35%]; 22 minoritized race [21.15%]; 4 Hispanic, Latino, or Spanish ethnicity [3.85%]). For department chairs, the annual rate of change in the proportion of women, minoritized race, and Hispanic, Latino, or Spanish ethnicity was +0.32% per year (95% CI, 0.20%-0.44%), +0.34% per year (95% CI, 0.19%-0.49%), and +0.05% per year (95% CI, 0.02%-0.08%), respectively. In both faculty and department chairs, the proportion of URiM groups (American Indian or Alaska Native, Black or African American, Hispanic, and Native Hawaiian or Other Pacific Islander) grew the least. Intersectionality analysis suggested that men and non-URiM status were associated with greater representation across ophthalmology faculty and department chairs. However, among ophthalmology faculty, URiM women and men did not significantly differ across strata of academic ranks, whereas for department chairs, no difference was observed in representation between URiM men and non-URiM women. Conclusion & Relevance: Results of this cohort study revealed that since 1966, workforce diversity progressed slowly and was limited to lower academic ranks and leadership positions. Intersectionality of URiM status and gender persisted in representation trends. These findings suggest further advocacy and intervention are needed to increase workforce diversity.

Executive Board Chairs: Examining the Performance Consequences of a Corporate Governance Hybrid.

Traditional agency theory views the proper role of the board chair exclusively as providing independent oversight to monitor and control the CEO. Recently, firms have introduced innovations in board leadership that have confounded these theoretical expectations. One notable innovation is the executive board chair, a corporate governance hybrid responsible for both oversight and strategic decision-making, challenging agency theory's prescription that the two activities remain separate. In this study, we argue that an executive board chair position can resolve the trade-off between independent oversight and involvement in strategy and therefore generate a performance advantage. We also predict that, owing to the blurring of lines between the CEO and board chair roles that the executive board chair position creates, the relationship will be stronger the greater the need to monitor and control the CEO but weaker when organizational complexity and board leadership demands are greater. Analysis of S&P 1500 firms from 2003 to 2017 provides general support for our arguments.

Pulmonary Nodules: Common Questions and Answers.

Pulmonary nodules are often incidentally discovered on chest imaging or from dedicated lung cancer screening. Screening adults 50 to 80 years of age who have a 20-pack-year smoking history and currently smoke or have quit smoking within the past 15 years with low-dose computed tomography is associated with a decrease in cancer-associated mortality. Once a nodule is detected, specific radiographic and clinical features can be used in validated risk stratification models to assess the probability of malignancy and guide management. Solid pulmonary nodules less than 6 mm warrant surveillance imaging in patients at high risk, and nodules between 6 and 8 mm should be reassessed within 12 months, with the recommended interval varying by the risk of malignancy and an allowance for patient-physician decision-making. A functional assessment with positron emission tomography/computed tomography, nonsurgical biopsy, and resection should be considered for solid nodules 8 mm or greater and a high risk of malignancy. Subsolid nodules have a higher risk of cancer and should be followed with surveillance imaging for longer. Direct physician-patient communication, clinical decision support within electronic health records, and guideline-based management algorithms included in radiology reports are associated with increased compliance with existing guidelines.

Chronic Kidney Disease: Prevention, Diagnosis, and Treatment.

Chronic kidney disease (CKD) affects approximately 15% of the U.S. population, and many people are unaware of their diagnosis. Screening may be considered for patients with cardiovascular disease, diabetes mellitus, hypertension, age 60 years and older, family history of kidney disease, previous acute kidney injury, or preeclampsia. Diagnosis and staging of CKD are based on estimated glomerular filtration rate (eGFR), excessive urinary albumin excretion, or evidence of kidney parenchymal damage lasting more than three months. eGFR should be determined using the CKD-EPI creatinine equation without the race variable. Risk calculators are available to estimate the risk of progression to end-stage renal disease. When possible, serum cystatin C should be measured to confirm eGFR in patients with CKD. Blood pressure should be maintained at less than 140/90 mm Hg, with a systolic blood pressure target of 120 mm Hg or less for patients tolerant of therapy, using an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Sodium-glucose cotransporter-2 inhibitors and metformin should be considered in patients with CKD and type 2 diabetes who have not reached their glycemic goal. Intravenous iodinated contrast media temporarily reduces eGFR and should be avoided in patients with advanced CKD. Interdisciplinary management of patients with CKD is important for reducing morbidity and mortality, and patients at high risk of progression to end-stage renal disease should be referred to a nephrologist.

Scrotal Masses.

Scrotal and testicular masses can be broadly categorized into painful conditions, which include testicular torsion, torsion of the testicular appendage, and epididymitis, and painless conditions, which include hydrocele, varicocele, and testicular cancer. Testicular torsion is a urologic emergency requiring prompt surgical intervention to save the testicle, ideally within six hours of presentation when the salvage rate is about 90%. The Testicular Workup for Ischemia and Suspected Torsion score can be used to help physicians identify patients at high risk of torsion and those at lower risk who would benefit from imaging first. Torsion of the testicular appendage presents with gradual onset of superior unilateral pain, is diagnosed using ultrasonography, and is treated supportively with analgesics. Epididymitis is usually caused by infection with Chlamydia trachomatis, Neisseria gonorrhoeae, or enteric bacteria and is treated with antibiotics, analgesics, and scrotal support. Hydroceles are generally asymptomatic and are managed supportively. Varicoceles are also generally asymptomatic but may be associated with reduced fertility. It is uncertain if surgical or radiologic treatment of varicoceles in subfertile men improves the rate of live births. Testicular cancer often presents as a unilateral, painless mass discovered incidentally. Ultrasonography is used to evaluate any suspicious masses, and surgical treatment is recommended for suspected cancerous masses.

Adult Eye Conditions: Ophthalmic Emergencies.

Prompt recognition and referral of patients with ophthalmic emergencies is crucial to preserving vision. Acute angle-closure glaucoma is the result of blockage of the outflow of aqueous humor, which increases intraocular pressure (IOP) and damages the retina. Patients typically report abrupt onset of a unilateral painful red eye with blurry vision and constitutional symptoms. The diagnosis is confirmed by measurement of elevated IOP. Urgent evaluation by an ophthalmologist is required to reduce the IOP before medical and surgical treatment. Retinal detachment occurs when fluid passes through a tear in the retina, lifting the retina away from its blood supply. This can occur spontaneously as a result of trauma or after cataract surgery. Patients may present with sudden onset of floaters or flashes of light followed by a curtainlike shadow in the visual field. Indirect ophthalmoscopy is the preferred modality to evaluate for retinal detachment. Prompt surgical repair is recommended. Mechanical trauma to the eye may cause globe rupture or full-thickness laceration. Antiemetics, pain management, systemic antibiotics, and use of an eye shield are recommended until the patient can be evaluated urgently by an ophthalmologist. Any protruding foreign bodies should not be removed. Ongoing follow-up with an ophthalmologist is recommended for patients with ophthalmic emergencies to assess for later complications.

Hepatitis A.

Hepatitis A is a common viral infection worldwide that is transmitted via the fecal-oral route. The incidence of infection in the United States decreased by more than 90% after an effective vaccine was introduced, but the number of cases has been increasing because of large community outbreaks in unimmunized individuals. Classic symptoms include fever, malaise, dark urine, and jaundice and are more common in older children and adults. People are most infectious 14 days before and seven days after the development of jaundice. Diagnosis of acute infection requires the use of serologic testing for immunoglobulin M anti-hepatitis A antibodies. The disease is usually self-limited, supportive care is often sufficient for treatment, and chronic infection or chronic liver disease does not occur. Routine hepatitis A immunization is recommended in children 12 to 23 months of age. Immunization is also recommended for individuals at high risk of contracting the infection, such as persons who use illegal drugs, those who travel to areas endemic for hepatitis A, incarcerated populations, and persons at high risk of complications from hepatitis A, such as those with chronic liver disease or HIV infection. The vaccine is usually recommended for pre- and postexposure prophylaxis, but immune globulin can be used in patients who are too young to be vaccinated or if the vaccine is contraindicated.

Generation of ordered protein assemblies using rigid three-body fusion.

Protein nanomaterial design is an emerging discipline with applications in medicine and beyond. A long-standing design approach uses genetic fusion to join protein homo-oligomer subunits via α-helical linkers to form more complex symmetric assemblies, but this method is hampered by linker flexibility and a dearth of geometric solutions. Here, we describe a general computational method for rigidly fusing homo-oligomer and spacer building blocks to generate user-defined architectures that generates far more geometric solutions than previous approaches. The fusion junctions are then optimized using Rosetta to minimize flexibility. We apply this method to design and test 92 dihedral symmetric protein assemblies using a set of designed homodimers and repeat protein building blocks. Experimental validation by native mass spectrometry, small-angle X-ray scattering, and negative-stain single-particle electron microscopy confirms the assembly states for 11 designs. Most of these assemblies are constructed from designed ankyrin repeat proteins (DARPins), held in place on one end by α-helical fusion and on the other by a designed homodimer interface, and we explored their use for cryogenic electron microscopy (cryo-EM) structure determination by incorporating DARPin variants selected to bind targets of interest. Although the target resolution was limited by preferred orientation effects and small scaffold size, we found that the dual anchoring strategy reduced the flexibility of the target-DARPIN complex with respect to the overall assembly, suggesting that multipoint anchoring of binding domains could contribute to cryo-EM structure determination of small proteins.

Men's Health: Benign Prostatic Hyperplasia.

Benign prostatic hyperplasia (BPH) commonly causes lower urinary tract symptoms (LUTS) through narrowing of the urethra and disruption of innervation of the gland. BPH is common in older men. Risk factors include Black race, Hispanic ethnicity, obesity, type 2 diabetes, high levels of alcohol consumption, physical inactivity, and a family history of BPH. The degree of LUTS can be assessed using the American Urological Association Symptom Index (AUASI). Watchful waiting is recommended for men with mild symptoms. Alpha1-adrenergic blockers or 5-alpha reductase inhibitors can be used to manage more severe symptoms. (This is an off-label use of some alpha1-adrenergic blockers.) Alpha1-adrenergic blockers typically are the initial choice. Combination therapy is more effective than monotherapy. Anticholinergics and beta3-adrenergic agonists can be used to manage irritative LUTS if the postvoiding residual urine volume is low. (This is an off-label use of anticholinergics and beta3-adrenergic agonists.) The phosphodiesterase type 5 inhibitor tadalafil is a second-line pharmacotherapy. There is insufficient evidence to support use of integrative medicine therapies. Physicians should consult with a urology subspecialist when patients do not benefit from medical therapy or have refractory LUTS, recurrent urinary tract infections, gross hematuria, bladder stones, or renal insufficiency.

Men's Health: Scrotal and Testicular Conditions.

Scrotal and testicular conditions include benign masses, infections, testicular torsion, and testicular cancer. Common palpable benign scrotal masses include spermatocele, varicocele, and hydrocele. Most patients with these masses require no treatment. Some varicoceles are associated with impaired fertility, probably due to an increase in scrotal temperature that leads to testicular hyperthermia, oxidative stress, and reduced spermatogenesis. Patients with documented infertility or scrotal pain should be referred to a urology subspecialist for consideration of surgical management. Epididymitis and epididymo-orchitis are caused by infection with Neisseria gonorrhoeae, Chlamydia trachomatis, or enteric bacteria. Antibiotics and supportive measures (eg, scrotal elevation, bed rest) are recommended for management of acute epididymitis. Testicular torsion is a urologic emergency that requires rapid surgical exploration and orchidopexy to reduce the risk of testicular loss due to ischemia. Salvage rates exceed 90% when surgical exploration is performed within 6 hours of symptom onset. Testicular cancer commonly manifests as a painless, incidentally discovered mass in a single testis. Ultrasonography is recommended to confirm the diagnosis. The recommended primary intervention for a suspected malignant testicular tumor is radical inguinal orchiectomy.

De novo design of modular and tunable protein biosensors.

Naturally occurring protein switches have been repurposed for the development of biosensors and reporters for cellular and clinical applications1. However, the number of such switches is limited, and reengineering them is challenging. Here we show that a general class of protein-based biosensors can be created by inverting the flow of information through de novo designed protein switches in which the binding of a peptide key triggers biological outputs of interest2. The designed sensors are modular molecular devices with a closed dark state and an open luminescent state; analyte binding drives the switch from the closed to the open state. Because the sensor is based on the thermodynamic coupling of analyte binding to sensor activation, only one target binding domain is required, which simplifies sensor design and allows direct readout in solution. We create biosensors that can sensitively detect the anti-apoptosis protein BCL-2, the IgG1 Fc domain, the HER2 receptor, and Botulinum neurotoxin B, as well as biosensors for cardiac troponin I and an anti-hepatitis B virus antibody with the high sensitivity required to detect these molecules clinically. Given the need for diagnostic tools to track the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)3, we used the approach to design sensors for the SARS-CoV-2 spike protein and antibodies against the membrane and nucleocapsid proteins. The former, which incorporates a de novo designed spike receptor binding domain (RBD) binder4, has a limit of detection of 15 pM and a luminescence signal 50-fold higher than the background level. The modularity and sensitivity of the platform should enable the rapid construction of sensors for a wide range of analytes, and highlights the power of de novo protein design to create multi-state protein systems with new and useful functions.

Designed protein logic to target cells with precise combinations of surface antigens.

Precise cell targeting is challenging because most mammalian cell types lack a single surface marker that distinguishes them from other cells. A solution would be to target cells using specific combinations of proteins present on their surfaces. In this study, we design colocalization-dependent protein switches (Co-LOCKR) that perform AND, OR, and NOT Boolean logic operations. These switches activate through a conformational change only when all conditions are met, generating rapid, transcription-independent responses at single-cell resolution within complex cell populations. We implement AND gates to redirect T cell specificity against tumor cells expressing two surface antigens while avoiding off-target recognition of single-antigen cells, and three-input switches that add NOT or OR logic to avoid or include cells expressing a third antigen. Thus, de novo designed proteins can perform computations on the surface of cells, integrating multiple distinct binding interactions into a single output.

Conditional Recruitment to a DNA-Bound CRISPR-Cas Complex Using a Colocalization-Dependent Protein Switch.

To spatially control biochemical functions at specific sites within a genome, we have engineered a synthetic switch that activates when bound to its DNA target site. The system uses two CRISPR-Cas complexes to colocalize components of a de novo-designed protein switch (Co-LOCKR) to adjacent sites in the genome. Colocalization triggers a conformational change in the switch from an inactive closed state to an active open state with an exposed functional peptide. We prototype the system in yeast and demonstrate that DNA binding triggers activation of the switch, recruitment of a transcription factor, and expression of a downstream reporter gene. This DNA-triggered Co-LOCKR switch provides a platform to engineer sophisticated functions that should only be executed at a specific target site within the genome, with potential applications in a wide range of synthetic systems including epigenetic regulation, imaging, and genetic logic circuits.

De novo design of modular and tunable allosteric biosensors.

Naturally occurring allosteric protein switches have been repurposed for developing novel biosensors and reporters for cellular and clinical applications 1 , but the number of such switches is limited, and engineering them is often challenging as each is different. Here, we show that a very general class of allosteric protein-based biosensors can be created by inverting the flow of information through de novo designed protein switches in which binding of a peptide key triggers biological outputs of interest 2 . Using broadly applicable design principles, we allosterically couple binding of protein analytes of interest to the reconstitution of luciferase activity and a bioluminescent readout through the association of designed lock and key proteins. Because the sensor is based purely on thermodynamic coupling of analyte binding to switch activation, only one target binding domain is required, which simplifies sensor design and allows direct readout in solution. We demonstrate the modularity of this platform by creating biosensors that, with little optimization, sensitively detect the anti-apoptosis protein Bcl-2, the hIgG1 Fc domain, the Her2 receptor, and Botulinum neurotoxin B, as well as biosensors for cardiac Troponin I and an anti-Hepatitis B virus (HBV) antibody that achieve the sub-nanomolar sensitivity necessary to detect clinically relevant concentrations of these molecules. Given the current need for diagnostic tools for tracking COVID-19 3 , we use the approach to design sensors of antibodies against SARS-CoV-2 protein epitopes and of the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein. The latter, which incorporates a de novo designed RBD binder, has a limit of detection of 15pM with an up to seventeen fold increase in luminescence upon addition of RBD. The modularity and sensitivity of the platform should enable the rapid construction of sensors for a wide range of analytes and highlights the power of de novo protein design to create multi-state protein systems with new and useful functions.

Autoimmune Conditions: Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is the most common autoimmune inflammatory arthritis, and is seen more commonly in women, smokers, and individuals with a family history of RA. It should be considered if unexplained pain and swelling in the metacarpophalangeal and/or metatarsophalangeal joints and morning stiffness of fingers lasting for longer than 30 minutes are present. RA may be present in the lungs, skin, and eyes. It is associated with an increased risk of cardiovascular death independent of other risk factors. Disease activity should be monitored using a validated scale, such as the Disease Activity Score 28 (DAS28), among others. Earlier management to achieve remission or decrease disease activity is associated with less joint damage, better quality of life, and improved survival rates. Methotrexate with consideration of low-dose glucocorticoids is considered first-line therapy for RA. Other disease-modifying antirheumatic drugs, including immunobiologics, may be used for patients who do not benefit from methotrexate. Before undergoing treatment, patients should be screened for tuberculosis and hepatitis B and C infection. Drug dosages may be tapered in patients with remission or decreased disease activity, but drugs should not be discontinued.

Office Spirometry: Indications and Interpretation.

High-quality, office-based spirometry provides diagnostic information as useful and reliable as testing performed in a pulmonary function laboratory. Spirometry may be used to monitor progression of lung disease and response to therapy. A stepwise approach to spirometry allows for ease and reliability of interpretation. Airway obstruction is suspected when there is a decreased forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ratio, but there is no strong evidence to clearly define what constitutes a significant decrease in this ratio. A low FVC is defined as a value below the 5th percentile in adults or less than 80% of predicted in children and adolescents five to 18 years of age. The FEV1/FVC ratio and FVC are used together to identify obstructive defects and restrictive or mixed patterns. Obstructive defects should be assessed for reversibility, as indicated by an improvement of the FEV1 or FVC by at least 12% and 0.2 L in adults, or by more than 12% in children and adolescents five to 18 years of age after the administration of a short-acting bronchodilator. FEV1 is used to determine the severity of obstructive and restrictive disease, although the values were arbitrarily determined and are not based on evidence from patient outcomes. Bronchoprovocation testing may be used if spirometry results are normal and allergen- or exercise-induced asthma is suspected. For patients with an FEV1 less than 70% of predicted, a therapeutic trial of a short-acting bronchodilator may be tried instead of bronchoprovocation testing.

Publisher Correction: Modular and tunable biological feedback control using a de novo protein switch.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.