Newborn weight change and predictors of underweight in the neonatal period in Guinea‐Bissau,Nepal, Pakistan and Uganda

In low‐ and middle‐income countries (LMIC), growth impairment is common; however, the trajectory of growth over the course of the first month has not been well characterised. To describe newborn growth trajectory and predictors of growth impairment, we assessed growth frequently over the first 30 days among infants born ≥2000 g in Guinea‐Bissau, Nepal, Pakistan and Uganda. In this cohort of 741 infants, the mean birth weight was 3036 ± 424 g. For 721 (98%) infants, weight loss occurred for a median of 2 days (interquartile range, 1–4) following birth until weight nadir was reached 5.9 ± 4.3% below birth weight. At 30 days of age, the mean weight was 3934 ± 592 g. The prevalence of being underweight at 30 days ranged from 5% in Uganda to 31% in Pakistan. Of those underweight at 30 days of age, 56 (59%) had not been low birth weight (LBW), and 48 (50%) had reached weight nadir subsequent to 4 days of age. Male sex (relative risk [RR] 2.73 [1.58, 3.57]), LBW (RR 6.41 [4.67, 8.81]), maternal primiparity (1.74 [1.20, 2.51]) and reaching weight nadir subsequent to 4 days of age (RR 5.03 [3.46, 7.31]) were highly predictive of being underweight at 30 days of age. In this LMIC cohort, country of birth, male sex, LBW and maternal primiparity increased the risk of impaired growth, as did the modifiable factor of delayed initiation of growth. Interventions tailored to infants with modifiable risk factors could reduce the burden of growth impairment in LMIC.     

[3+2] click chemistry approach to tetrazine containing polymers

We report a [3+2] cycloaddition using 3,6-bis-propargyloxy-1,2,4,5-tetrazine and azides to synthesize energetic polymers containing 1,2,4,5-tetrazine within the scaffold. This work also includes [3+2] cycloaddition to crosslink azide containing glycidyl azide polymer (GAP). These reactions provide pathways for incorporation of 1,2,4,5-tetrazine into novel energetic materials using click-chemistry and provide an alternative polymer curing approach.

We report a [3+2] cycloaddition using 3,6-bis-propargyloxy-1,2,4,5-tetrazine and azides to synthesize energetic polymers containing 1,2,4,5-tetrazine within the scaffold.

Due to their versatility and unique chemical and physical properties, tetrazines have found utility in organic solar cells,^1,2 sensors,^3,4 on/off fluorescence^5–8 and energetic materials applications.^9,10 A significant increase in 1,2,4,5-tetrazine chemistry synthesis has also occurred over the past several years.^11–14 A number of investigations have focused in large part on bioorthogonal, inverse electron demand hetero-Diels–Alder reactions with 1,2,4,5-tetrazines for numerous applications, such as in situ synthesis of fluorogenic probes for live cell imaging, and near infrared fluorogenic probes.⁸ Unfortunately, the inverse electron demand hetero-Diels–Alder reaction of 1,2,4,5-tetrazines is not a promising pathway in energetic materials chemistry as a concomitant reduction in the inherent energy of the molecule results during these types of transformations due to the loss of N₂. Thus alternative pathways for the incorporation of 1,2,4,5-tetrazine into novel energetic materials are warranted.One very interesting possibility for the preparation of new energetics is to employ a [3+2] cycloaddition (click-chemistry) strategy. In this case, a Huisgen 1,3-dipolar cycloaddition between 1,3-dipoles such as azides, and 1,2-dipolarophiles such as acetylenes could be incorporated onto the tetrazine ring system at the 3 and 6 positions either directly or through linkers of varying length. The challenge presented with this approach is the possibility for the 1,2,4,5-tetrazine system to undergo competitive inverse electron demand [4+2] hetero-Diels–Alder chemistry with acetylene functional groups. Indeed, Rusinov and co-workers found that the reaction of but-3-yn-1-ol with 3,6-bis(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (1) in the presence of triethylamine in acetonitrile led to the two products 2 and 3 (5 : 1) as shown in Scheme 1.¹⁵ These two products both are a result of inverse electron demand hetero-Diels–Alder processes. Changing the leaving group from 3,5-dimethylpyrazole to imidazole led to the exclusive isolation of the bicyclic product 2.Open in a separate windowScheme 1But-3-yn-1-ol reaction with 1 in the presence of TEA^.While these literature results were not encouraging, we decided to pursue the synthesis of 3,6-bispropargyloxy-1,2,4,5-tetrazine (4). We found that shortening the distance between the alcohol group and the acetylene moiety allowed for nucleophilic addition to proceed exclusively with no evidence of inter- or intramolecular hetero-Diels–Alder cyclization occurring. Thus propargyl alcohol reacted with 1 in the presence of potassium carbonate to provide 4 in excellent yield (Scheme 2). Ultimately, we were able to perform the reaction neat, using propargyl alcohol as the solvent, although only in minimal amounts.Open in a separate windowScheme 2The synthesis of 4.To confirm the structure of 4, X-ray quality crystals were obtained from slow diffusion of diethyl ether into a solution of 4 in acetone. The compound was found to have the monoclinic crystal system with a P2₁/c space group.⁷ It displayed a density of 1.46 g cm⁻³ at 293 K (see ESI^†). The Ortep representation of the crystal structure is displayed in Fig. 1. Overall, the transformation resulting in 4 is unprecedented and allowed for a “click” chemical approach to make energetic, tetrazine containing polymers.Open in a separate windowFig. 1Molecular conformation of 4, nonhydrogen atoms are shown as 50% probability displacement ellipsoids. Ellipsoids of 4 shown at 50% probability.With 4 in hand, we attempted to perform the Huisgen cycloaddition reaction with azide containing materials employing the Cu(i)-catalyzed azide/alkyne cycloaddition approach (CuAAC) to accomplish prepolymer curing, polymerization and self-polymerization.⁸ We first investigated a [3+2] cross-linking strategy using 4 as a curing agent for azide containing prepolymers, such as the glycidyl azide (GAP) prepolymer. A similar approach has been described with other polyacetylene compounds.⁹ Typically GAP is cured using a urethane crosslinking approach, but this method presents challenges, such as sensitivity to moisture and the use of reactive isocyanates. A [3+2] curing approach with a high energy cross linker could provide higher energy GAP polymers. Initial results found that 5 wt% 4 was successful at curing the GAP prepolymer (5) in the presence of a catalytic amount of CuCl, to produce polymer 6 (Scheme 3).Open in a separate windowScheme 3Curing of glycidyl azide prepolymer.These results were expanded on to include a curing study of GAP (5) and GAP plasticizer (GAPp, 5p) with varying weight percentages of 4 in the presence of a copper halide species to produce polymer 6 and 6p, respectively. The GAP (also called GAP 5527-Polyol) is a high molecular weight prepolymer with a hydroxyl equivalent between 2.5–3 used in urethane cures, while the GAPp is a lower viscosity prepolymer with an average MW of 700, and a hydroxyl equivalent close to 1. As the click-chemistry cure for these GAP pre-polymers is independent of hydroxyl terminal group content, the two materials were utilized to evaluate rheological properties over the course of reaction. Rheometry measurements were conducted on samples containing 3% of 4 for both polymers (see ESI^†). The transition from liquid to solid, or gel point, for 6 occurred at roughly 83 minutes compared to 6p at about 4 hours.After demonstrating that 4 could be used to cure GAP, we turned our attention to polymerization studies of 4 with diazide compounds. One such material was 2,2-bisazidomethyl-1,3-propanediol (7).¹⁶ Since 7 is a liquid, we performed the cycloaddition neat by thoroughly mixing 4, 7 with a catalytic amount of a copper halide (CuCl or CuI). Heating for several hours at 60 °C led to the polymerized product (8) (Scheme 4). Similarly, when 4 was reacted with 2-hydroxy-1,3-diazidopropane (9)^17,18 in the presence of a catalytic amount of CuCl, the desired polymerization product (10) was observed (Scheme 4).Open in a separate windowScheme 4Polymerization of 4 with diazides.Polymers 8 and 10 were found to have molecular weights of 3602 ± 136.71 g mol⁻¹ and 6796 ± 132.17 g mol⁻¹, respectively. As expected, Fourier transform infrared spectroscopy (FT-IR) comparisons of 4 to both polymers showed significant reduction in the intensity of the terminal acetylene stretch at 3261 cm⁻¹ (C–H) and 2126 cm⁻¹ (C C) (see ESI^†).Further studies for single compound self-polymerization were explored by incorporation of the azide group and an acetylene group on the same tetrazine ring. We began with the reaction of propargyl alcohol with 3,6-dichloro-1,2,4,5-tetrazine (11) in the presence of 2,4,6-collidine, using tert-butyl methyl ether as a solvent. This provided 12 in good yield (Scheme 5). Subsequent treatment of 12 with sodium azide in acetone provided the 3-azido-6-propargyloxy-1,2,4,5-tetrazine (13).¹⁰ This material melts at 50 °C and begins to polymerize if left in the melt for several hours to provide polymer 14. Unfortunately, the extreme sensitivity of 13 precluded further studies on the properties of the resultant polymer.Open in a separate windowScheme 5Synthesis of 13 and subsequent thermal polymerization to 14.Calculations for compounds 4, 7, and 9 are provided in 19–21Theoretical calculations

Symptom Clusters Seen in Adult COVID-19 Recovery Clinic Care Seekers

BackgroundCOVID-19 symptom reports describe varying levels of disease severity with differing periods of recovery and symptom trajectories. Thus, there are a multitude of disease and symptom characteristics clinicians must navigate and interpret to guide care.ObjectiveTo find natural groups of patients with similar constellations of post-acute sequelae of COVID-19 (PASC) symptoms.DesignCohortSettingOutpatient COVID-19 recovery clinic with patient referrals from 160 primary care clinics serving 36 counties in Texas.PatientsAdult patients seeking COVID-19 recovery clinic care between November 15, 2020, and July 31, 2021, with laboratory-confirmed mild (not hospitalized), moderate (hospitalized), or severe (hospitalized with critical care) COVID-19.Main MeasuresDemographics, COVID illness onset, and duration of persistent PASC symptoms via semi-structured medical assessments.Key ResultsFour hundred forty-one patients (mean age 51.5 years; 295 [66.9%] women; 99 [22%] Hispanic, and 170 [38.5%] non-White, racial minority) met inclusion criteria. Using a k-medoids algorithm, we found that PASC symptoms cluster into two distinct groups: neuropsychiatric (N = 186) (e.g., subjective cognitive dysfunction) and pulmonary (N = 255) (e.g., dyspnea, cough). The neuropsychiatric cluster had significantly higher incidences of otolaryngologic (X² = 14.3, p < 0.001), gastrointestinal (X² = 6.90, p = 0.009), neurologic (X² = 441, p < 0.001), and psychiatric sequelae (X² = 40.6, p < 0.001) with more female (X² = 5.44, p = 0.020) and younger age (t = 2.39, p = 0.017) patients experiencing longer durations of PASC symptoms before seeking care (t = 2.44, p = 0.015). Patients in the pulmonary cluster were more often hospitalized for COVID-19 (X² = 3.98, p = 0.046) and had significantly higher comorbidity burden (U = 20800, p = 0.019) and pulmonary sequelae (X² = 13.2, p < 0.001).ConclusionsHealth services clinic data from a large integrated health system offers insights into the post-COVID symptoms associated with care seeking for sequelae that are not adequately managed by usual care pathways (self-management and primary care clinic visits). These findings can inform machine learning algorithms, primary care management, and selection of patients for earlier COVID-19 recovery referral.Trial RegistrationN/ASupplementary InformationThe online version contains supplementary material available at 10.1007/s11606-022-07908-4.     

Cumulative Table of Contents

The complications of blepharoplasty are infrequent, most often minor and transient, and rarely major and permanent with functional or aesthetic consequences. Treatment is above all preventive with screening of “at risk” patients in whom blepharoplasty would be contra-indicated. Patients must be informed of possible risks through informative booklets stressing the most important points.

The complications may affect vision. Partial or complete visual loss due to ischemic optic neuropathy, or rarely to compression of the ocular globe by intraorbital hemorrhage, is the most serious complication. Other visual complications include oculomotor disorders, keratoconjunctivitis sicca, epiphora, and chemosis of lymphatic origin. Eyelid complications are more frequent: ptosis of the upper eyelid or lagophthalmia caused by incorrect resection of the skin, scarring, and eyelid fold anomalies. The most severe aesthetic complication is the malposition of the lower eyelid resulting in retraction, lagophthalmia, ectropion, deformation of the external canthus, or lower eyelid tissue relaxation. These malpositions are often minor, sometimes reversible, but they can be major, with psychological, aesthetic, and functional consequences. Other local complications include enophthalmia and hypo- or hypercorrection. General complications may include pigmentation anomalies or infections extending as far as the orbital fat tissue. Finally, complications observed after the newer procedures of laser surgery include ectropion, burns and residual redness. Complications related to periocular injections of filling material are also mentioned.

The discussion of these complications is followed by a comprehensive review of the prevention, diagnosis and management of the complications after blepharoplasty.     

Characteristics and clinical outcomes of patients undergoing fertility treatment by double gamete donation

The number of women receiving in vitro fertilization cycles with both oocyte and sperm donation (double donation; DD) has grown globally in the last decade. The aim of this retrospective study, which included 1139 DD cycles, was to describe the characteristics of patients receiving DD and the outcomes of this assisted reproductive treatment. A cluster analysis identified couple ‘status’ as the main variable in dividing patients into categories. Three such status groups were identified for further analysis: (i) single women (SW), that is women without a partner either male or female; (ii) women with a male partner (MP); (iii) women with a female partner (FP). SW were significantly older (43.9) than patients with a MP (40.4) and a FP (41.3). Women with a male or FP comprised fewer patients with no previous assisted reproductive technology cycles (18.4% and 25.7%, respectively) compared to SW (43.5%). The proportion of patients without children before treatment was significantly different between SW (94.7%) and women with a MP (87.2%). There were no differences in clinical outcomes among the three groups studied. Biochemical pregnancy rate was 58.2% in SW, 58.4% in women with a MP and 64.9% in women with a FP. For the same groups, clinical pregnancy rates were 50.2%, 49.4% and 55.4%, while ‘take-home baby’ rates were 36.6%, 38.9% and 40.3%. Multiple birth and caesarean section rates were not different among the groups, with twinning rates 21.1%, 30.4% and 36%, and caesarean section rates 25.6%, 24% and 26.4% for SW, women with MP and women with FP, respectively.     

Intravenous Therapy for Women in Labor: Implementation of a Practice Change

Background: Intravenous therapy for women in labor has been routinely administered in many North American hospitals since the 1950s. The purpose of this study was to evaluate a change in intravenous therapy practice. Methods: The evaluation study, using a posttest, quasi-experimental design, examined the responses of women in labor and nurses to a questionnaire. Proxy prestudy cohort data were used for comparison of some patient outcomes. The convenience sample comprised 219 women admitted to the labor and delivery unit of a community hospital in Toronto, Ontario, between August and October 1997. Results: Under the new intravenous therapy protocol, 26 percent of the women in labor did not receive intravenous therapy compared with 100 percent under the old protocol. The primary reasons for therapy were to enable administration of prescribed medication and bolus intravenous administration associated with epidural anesthesia. At the first after-delivery void, 61 percent of study women—65 percent of those who received intravenous therapy and 50 percent of those who received no intravenous therapy—tested negative for ketonuria. All 119 comments from nurses indicated comfort with their judgments related to the initiation of intravenous therapy. Conclusions: The change in the intravenous therapy protocol was supported by the study findings. Nurses should increase patient education about drinking and eating adequately throughout labor if appropriate, and resuming adequate fluid and food intake as quickly as possible after childbirth.     

First report of Creutzfeldt-Jakob disease occurring in 2 siblings unexplained by PRNP mutation

Sibling concurrence of pathologically confirmed prion disease has only been reported in association with pathogenic mutation of the prion protein gene (PRNP). Here, we report 2 siblings with classic neuropathologic features of sporadic Creutzfeldt-Jakob disease unexplained by PRNP mutation or known risk factors for iatrogenic transmission of prion infection. Possible explanations include coincidental occurrence, common exposure to an unidentified environmental source of prions, horizontal transmission of disease, or the presence of unknown shared genetic predisposition.     

Matched and mismatched metabolic fuels in lymphocyte function

Immunological function requires metabolic support to suit the needs of lymphocytes at a variety of distinct differentiation and activation states. It is now evident that the signaling pathways that drive lymphocyte survival and activity can directly control cellular metabolism. This linkage provides a mechanism by which activation and specific signaling pathways provide a supply of appropriate and required nutrients to support cell functions in a pro-active supply rather than consumption-based metabolic model. In this way, the metabolism and fuel choices of lymphocytes are guided to specifically match the anticipated needs. If the fuel choice or metabolic pathways of lymphocytes are dysregulated, however, metabolic checkpoints can become activated to disrupt immunological function. These changes are now shown in several immunological diseases and may open new opportunities to selectively enhance or suppress specific immune functions through targeting of glucose, lipid, or amino acid metabolism.