Cyano disubstituted tetrabenzoindeno[2,1-a]fluorene: open-shell or closed-shell?

Organic diradicaloids have lately emerged as potential spintronic materials. We report the unprecedented synthesis of a near-IR absorbing indeno[2,1-a]fluorene derivative that displays remarkably low LUMO (-4.15 eV) and a small HOMO-LUMO gap (0.85 eV). NMR/EPR studies indicated its open-shell diradical property, which was supported by DFT calculations while suggesting a 30% diradical character and a small singlet (S)-triplet (T) gap (-2.52 kcal mol-1). A large bond length alternation of the as-indacene core for its single-crystals indicated a quinoidal contribution with greater antiaromaticity, which is in line with the small diradical character despite showing a small S-T gap.

A Thiophenoradialene-Embedded Polycyclic Heteroterphenoquinone Exhibiting Dominant Antiaromatic Traits.

A thiophenoradialene-embedded polycyclic heteroterphenoquinone (PHTPQ) derivative of diindeno[1,2-b:2',1'-d]thiophene-2,8-dione, with antiaromatic characteristics, was synthesized by dehydrogenating its fluorescent dihydro PHTPQ precursor. The antiaromatic character was evidenced by the visible absorption band with a weakly intense tail extending to 800 nm in the near-infrared region (forbidden HOMO → LUMO transition) and non-emissive and amphoteric redox properties. Single-crystal and (anti)aromaticity analyses found a non-aromatic thiophene core while suggesting antiaromaticity/paratropicity of the pentafulvene subunits dominating the overall ground state properties.

Constructing 1-Ethoxyphenanthro[9,10-e]acephenanthrylene for the Synthesis of a Polyaromatic Hydrocarbon Containing a Formal Azulene Unit.

peri-Acenoacenes are attractive synthetic targets, but their non-benzenoid isomeric counterparts were unnoticed. 1-Ethoxyphenanthro[9,10-e]acephenanthrylene 8 was synthesized and converted to azulene-embedded 9, which is a tribenzo-fused non-alternant isomeric motif of peri-anthracenoanthracene. Aromaticity and single-crystal analyses suggested a formal azulene core for 9, which showed a smaller highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) energy gap with a charge-transfer absorption band and brighter fluorescence than 8 (quantum yield (Φ): 9 = 41.8%, 8 = 8.9%). The reduction potentials of 8 and 9 were nearly identical, and the observations were further supported by density functional theory (DFT) calculations.

Dominating Antiaromatic Character of as-Indacene Decides Overall Properties of a Formally Aromatic Dicyclopenta[c]fluorenothiophene.

Dicyclopenta[c]fluorenothiophene 5 was synthesized as the isoelectronic polycyclic heteroarene analogue of an as-indacenodifluorene with a (4n + 2)π-electron perimeter. Single-crystal and 1H NMR analyses indicated a quinoidal ground state for 5, which was supported by theoretical calculations while suggesting a degree of antiaromaticity of the as-indacene subunit greater than that for s-indacenodifluorene 3. The dominant antiaromaticity for 5 was evidenced by the broad weakly intense absorption tail reaching the near-IR region, four-stage redox amphotericity, and small HOMO-LUMO energy gap.

Unveiling a Quinoidal 2,3:10,11-Dibenzoheptazethrene.

Parent 2,3:10,11-dibenzoheptazethrene is a singlet diradicaloid polycyclic hydrocarbon in the ground state that did not change its diradical character upon substitution (methyl and triisopropylsilylethynyl). Described herein are the synthesis and characterization of an ethoxy/3,5-(CF3)2C6H3-substituted 2,3:10,11-dibenzoheptazethrene 3 that prefers to retain its p-quinoidal core and shows zero diradical character, as determined by single-crystal analysis and density functional theory calculations. Negative solvatochromism, π-π interactions, Csp2-H···O hydrogen bonding, intramolecular charge transfer, redox amphotericity, and a narrow HOMO-LUMO energy gap make 3 a potential candidate for application in optoelectronics.

Geographic disparities in access to scalp cooling for the prevention of chemotherapy-induced alopecia in the United States.

BACKGROUND: Chemotherapy-induced alopecia is psychologically challenging for patients undergoing cancer treatment, and scalp cooling has been shown to prevent or decrease the hair loss. OBJECTIVE: To evaluate whether access to scalp cooling varies by geographic area in the United States. METHODS: Cancer treatment centers offering scalp cooling were identified using data from the Rapunzel Project. Medicare claims data were queried to evaluate the number of chemotherapy infusions occurring in each zip code in the United States. Geographic distribution of chemotherapy infusions and scalp cooling centers was determined using ArcGIS software. The average distance from the geographic center of all 5-digit zip codes in which chemotherapy infusions occur to the nearest scalp cooling center was calculated in miles. RESULTS: There are 366 chemotherapy infusion centers in the United States that offer scalp cooling. Overall, 43.9% of Medicare-billed chemotherapy infusions in the United States occur in zip codes less than 12.5 miles from a scalp cooling center, 24.8% occur between 12.5 and 49.9 miles away, and 31.3% occur more than 50 miles away. LIMITATIONS: Our results are only generalizable to patients seen at Medicare-accepting institutions in the United States. CONCLUSIONS: Geographic disparities affect which patients can access scalp cooling therapy, and implementation in suburban and rural areas would increase access for patients who wish to preserve their hair while undergoing chemotherapy.

Revisiting indeno[2,1-c]fluorene synthesis while exploring the fully conjugated s-indaceno[2,1-c:6,5-c']difluorene.

Described herein is an alternative synthetic approach for conjugated indeno[2,1-c]fluorene, including the experimental and theoretical investigations of a tetraradicaloid s-indaceno[2,1-c:6,5-c']difluorene that belongs to the rarely explored indacenodifluorene family containing 4n + 2 monocyclic conjugated π-electrons. Expedient synthesis, broad absorption reaching 1150 nm, and small HOMO-LUMO energy gap make [2,1-c:6,5-c']s-IDF a promising candidate for optoelectronic applications.

Abnormal Baseline Lab Results Rarely Lead to Treatment Modification for Patients on Isotretinoin.

BACKGROUND: Treatment modification and clinical course for patients initiating isotretinoin with abnormal baseline lab results is currently unknown, and no recommendations exist for monitoring this patient group. METHODS: We performed a retrospective review of patients prescribed isotretinoin for acne from 2008 to 2016 at Brigham and Women's and Massachusetts General Hospitals to investigate the characteristics, clinical implications, and management of patients initiating isotretinoin for acne with baseline laboratory abnormalities. RESULTS: We identified a low rate (7.2%) of treatment modification, including interruption (3.6%) and early termination (3.6%), during isotretinoin therapy due to lab abnormalities for patients with baseline lab abnormalities. Abnormal baseline total cholesterol, triglyceride, and liver function tests did not predict management changes, as only 2 of 10 total treatment modifications were due to a lab result that was abnormal at baseline. Treatment modification was driven by ALT elevation not present at baseline that occurred in patients with liver comorbidities. CONCLUSION: Emphasizing relevant comorbidities, including hepatic disease or alcohol use, to inform our monitoring may be a superior predictor of abnormalities during treatment, as our work demonstrates that the value of baseline lab data prior to isotretinoin is unclear.

Impact of rainfall variability and anthropogenic activities on streamflow changes and water stress conditions across Tapi Basin in India.

Water security is a major concern in recent years, especially, in semi-arid and arid regions, which are adversely impacted due to extensive anthropogenic and climatic changes across the globe. Present study investigates the long-term changes in streamflows, their quantitative attribution and socio-environmental implications for a climatically sensitive Tapi basin in west central India. The abrupt and gradual changes in streamflows have been detected over the period 1973-2013 using non-parametric Pettit's and Mann-Whitney U tests; and Modified Mann-Kendall, Spearman's Rho and Sen's slope estimator tests respectively. The streamflow analyses revealed heterogeneity across the basin, wherein the tributaries exhibited higher variability in annual runoff compared to the Tapi River. The spatial analyst tool of ArcGIS has been used to graphically demonstrate the spatial variability in rainfall and streamflow trends across the basin. The streamflows exhibited predominantly decreasing trends across the basin, except in the upper reaches of the Tapi River. The decreasing trends in streamflow are largely attributed to anthropogenic activities such as changes in the land use patterns viz., increase in agriculture area, construction of minor and medium hydraulic structures, decrease in forest cover, rapid urbanization, excessive groundwater extraction and streamflow regulations. The anthropogenic activities played a major role in declining streamflow trends in the Tapi basin, contributing about 68%-99% (average 85%) decline in total runoff, compared to rainfall variability, which contributed around 1%-32% (average 15%) decrease in total runoff. The analysis of water stress levels at sub-catchment scale exhibited significant rise in percentage of population living in the basin facing chronic water shortage (i.e., <1000 m3/capita/year), from 34.0% in year 1981 to 63.2% in year 2011, mostly in semi-arid regions. The reduction in water availability clearly highlighted the deteriorating water quality and stream ecology of the Lower Tapi River in Surat city, India.

Augmented reality in dermatology: Are we ready for AR?

Augmented reality (AR) refers to a group of technologies that capture, analyze, and superimpose digital information onto the real world. This information gives health care providers unique and useful perspectives that can enhance patient care. AR has been utilized in selected scenarios in health care for several decades, notably laparoscopic surgery and vein finding. In recent years, improved wireless technologies, computing power, and analytics are leading to rapid growth in the AR industry. Novel health care-specific use cases are rapidly being introduced with the potential to widely affect clinical care, particularly in dermatology because of the visual nature of the field. In this article, we define AR, profile clinical and educational uses of AR in dermatology, and discuss key policy considerations for the safe and appropriate use of this emerging technology.

Psychiatric Adverse Events in Patients Taking Isotretinoin as Reported in a Food and Drug Administration Database From 1997 to 2017.

IMPORTANCE: Isotretinoin is a highly effective medication for severe acne. Although no causal link between isotretinoin and psychiatric adverse effects has been established, widespread media reporting of depression and suicidality with use of isotretinoin have raised concerns in both patients and clinicians and generated numerous cases of costly litigation. OBJECTIVE: To evaluate reports of psychiatric adverse events associated with isotretinoin use submitted to the US Food and Drug Administration from January 1, 1997, through December 31, 2017. DESIGN, SETTING, AND PARTICIPANTS: This retrospective study evaluated reports of psychiatric adverse events with isotretinoin as the primary suspect drug in the US Food and Drug Administration's Adverse Event Reporting System from 1997 through 2017. Publicly available data on number of patients enrolled in the iPLEDGE program were used to calculate rates of completed suicide per 100 000 patients enrolled in iPLEDGE in 2009 and 2010. All data were analyzed between July 1, 2018, and January 31, 2019. MAIN OUTCOMES AND MEASURES: The main outcomes were frequency and type of psychiatric adverse events in patients taking isotretinoin. Secondary analyses were stratification by age and sex and evaluation of completed suicide rates. RESULTS: Between 1997 and 2017, 17 829 psychiatric adverse events with isotretinoin use were reported to the US Food and Drug Administration, with depressive disorders, emotional lability, and anxiety disorders reported most frequently. Of these events, 8936 (50.1%) were reported among men and 8362 (46.9%) among women; the sex of the individual was not reported for 531 events (3.0%). Of the 13 553 reports that included patient age, the mean (SD) age was 22.1 (8.6) years. More than half (52.5%) of all events occurred in 10- to 19-year-old individuals. Whereas depression and anxiety were reported equally between sexes, eating disorders were more common in females (58 of 85 [68.2%]), while attention-deficit/hyperactivity disorder (55 of 83 events [66.3%]) and completed suicides (290 of 368 [78.8%]) were more common in males. The rates of completed suicide were 8.4 and 5.6 suicides per 100 000 patients enrolled in iPLEDGE in 2009 and 2010, respectively. CONCLUSIONS AND RELEVANCE: Although depressive disorders and suicidality were frequently reported with isotretinoin use, these reports must be considered in the context of elevated rates of depression and suicide among patients with acne at large. These data suggest that the rate of completed suicide in patients taking isotretinoin may be lower than that of the general US population. Many psychiatric adverse events unrelated to depression and suicidality were also reported, but it is unclear if they were a result of isotretinoin therapy. Although no causal link between isotretinoin and psychiatric risk has been established, patients taking the drug appear vulnerable to psychiatric concerns. Mandated monthly iPLEDGE visits may provide an opportunity to screen patients for psychiatric conditions and improve outcomes.

US Food and Drug Administration Reports of Pregnancy and Pregnancy-Related Adverse Events Associated With Isotretinoin.

IMPORTANCE: iPLEDGE is a rigorous program initiated in 2006 to reduce fetal exposure to isotretinoin, a disease-modifying medication for acne that carries a risk of teratogenesis. Despite the imposition of iPLEDGE requirements on patients and clinicians, the scope of isotretinoin-related adverse events is unknown. OBJECTIVE: To determine the frequency and rate of pregnancy and pregnancy-related adverse events among women taking isotretinoin reported to the US Food and Drug Administration (FDA). DESIGN, SETTING, AND PARTICIPANTS: Pregnancy reports from the FDA Adverse Event Reporting System, a public database of medication adverse event reports filed by prescribers, consumers, and manufacturers, were used to perform a retrospective analysis of pregnancy-related adverse events associated with isotretinoin from January 1, 1997, to December 31, 2017. Each individual reporting any pregnancy-related adverse event signified 1 pregnancy. Abortions, pregnancies that occurred while contraception was used, and fetal defects were counted as subgroups of total pregnancy events. MAIN OUTCOMES AND MEASURES: The frequency of pregnancy and of pregnancy-related events (abortions, pregnancies that occurred while using contraception, and fetal defects) were stratified by year that the FDA was notified of the event and by age. The rates of adverse events were calculated using isotretinoin prescribing data. RESULTS: There was a total of 6740 pregnancies among women taking isotretinoin reported to the FDA from 1997 to 2017, peaking in 2006 (768 pregnancies) before settling into a range of 218 to 310 annual reports of pregnancy after 2011. The mean (SD) age of the women was 24.6 (7.1) years. The rate of pregnancy for females of childbearing potential was between 0.33% (388 of 115 925) and 0.65% (768 of 117 784), with a peak in 2006. Although pregnancies, abortions, and fetal defects among women taking isotretinoin have decreased since the initiation of iPLEDGE in 2006, all 3 persist. CONCLUSIONS AND RELEVANCE: The number of reports of pregnancies, abortions, and fetal defects among women taking isotretinoin has decreased since peaking around the initiation of iPLEDGE in 2006. Explanations for this trend include a broader national decrease in teenage pregnancies and abortion rates, improvements in access to effective long-term and emergency contraception, stringent iPLEDGE requirements, and reporting fatigue over time. Despite the decrease, persistent reporting of pregnancy-related events in the last decade warrants investigation into the efficacy of iPLEDGE and exploration of new approaches for lowering fetal exposure to isotretinoin.

Teledermatology as a means to improve access to inpatient dermatology care.

Many hospitals have limited inpatient dermatology consultation access. Most dermatologists are outpatient-based and may find the distance and time to complete inpatient consultations prohibitive. Teledermatology may improve access to inpatient dermatology care by reducing barriers of distance and time. We conducted a prospective two-phase pilot study at two academic hospitals comparing time needed to complete inpatient consultations after resident dermatologists initially evaluated patients, called average handling time (AHT), and time needed to respond to the primary team, called time to response (TTR), with and without teledermatology with surveys to capture changes in dermatologist opinion on teledermatology. Teledermatology was only used in the study phase, and patients were seen in-person in both study phases. Teledermatology alone sufficiently answered consultations in 10 of 25 study consultations. The mean AHT in the study phase (sAHT) was 26.9 min compared to the baseline phase (bAHT) of 43.5 min, a 16.6 min reduction (p = 0.004). The 10 study cases where teledermatology alone was sufficient had mean study TTR (sTTR) of 273.3 min compared to a baseline TTR (bTTR) of 405.7 min, a 132.4 min reduction (p = 0.032). Teledermatology reduces the time required for an attending dermatologist to respond and the time required for a primary team to receive a response for an inpatient dermatology consultation in a subset of cases. These findings suggest teledermatology can be used as a tool to improve access to inpatient dermatology care.