Assessment of innovative living and care arrangements for persons with dementia: a systematic review.

BACKGROUND: Alternative forms of housing for persons with dementia have been developed in recent decades. These concepts offer small groups of residents familiar settings combined with efforts to provide normal daily life. The aim of this systematic review is to collate and analyze these more innovative forms of housing regarding residents' quality of life, behavioral aspects, as well as functional, cognitive and emotional aspects. METHODS: Searches were conducted in PubMed, EMBASE and PsycInfo in November 2020. Studies comparing traditional and more innovative living environments for persons with dementia were eligible. Concepts are described based on the results of additional searches. Risk of bias of included studies was assessed using checklists from the Joanna Briggs Institute. RESULTS: A total of 21 studies corresponding to 11 different concepts were included, namely Green Houses (USA), Group Living (Sweden), Cantou (France), Group Homes (Japan), Small-scale Group Living (Austria), Special Care Facilities (Canada), Shared-housing Arrangements (Germany), Residential Groups (Germany), Residential Care Centers / Woodside Places (USA/Canada), Small-scale Living (Netherlands/ Belgium), and Green Care Farms (Netherlands). The concepts are broadly similar in terms of care concepts, but partly differ in group sizes, staff qualifications and responsibilities. Several studies indicate that innovative forms of housing may encourage social behavior, preserve activity performance and/or positively influence emotional status compared to more traditional settings, while other studies fail to demonstrate these effects. Some studies also show increased behavioral and psychological symptoms of dementia (BPSD) in residents who live in more innovative housing concepts. The effect on cognition remains indistinct. DISCUSSION: The positive effects may be attributable to the inherent characteristics, including small group sizes, a stimulating design, and altered staff roles and responsibilities. Arguably, some of these characteristics might also be the reason for increased BPSD. Studies had variable methodological quality and results have to be considered with caution. Future research should examine these effects more closely and should investigate populations' preferences with regards to housing in the event of dementia.

Hyperhidrosis Quality of Life Index (HidroQoL©): further validation and clinical application in patients with axillary hyperhidrosis using data from a phase III randomized controlled trial.

BACKGROUND: The Hyperhidrosis Quality of Life Index (HidroQoL©) is a validated patient-reported outcome measure capturing the quality of life of people affected by hyperhidrosis. OBJECTIVES: We aimed to extend the validity evidence to physician-confirmed diagnosis of primary axillary hyperhidrosis. METHODS: Data from a phase III randomized placebo-controlled clinical trial were used (n = 171). Confirmatory factor analysis was carried out to confirm the a priori two-factor structure of the HidroQoL. Internal consistency was assessed using Cronbach's α. Intraclass correlation coefficients (ICCs) were calculated to evaluate test-retest reliability after days -7 to -4. Convergent validity was assessed using correlations with the Dermatology Life Quality Index (DLQI), the Hyperhidrosis Disease Severity Scale (HDSS) and gravimetric sweat production. Known groups were analysed to evaluate discriminative validity. Responsiveness after 29 days was assessed and minimal important difference (MID) values were calculated using both anchor- and distribution-based approaches. All analyses were carried out for total HidroQoL and its two domains. RESULTS: The two-factor structure of the HidroQoL was confirmed. Internal consistency and test-retest reliability were strong (Cronbach's α 0·81-0·90; ICCs 0·89-0·93). Correlations with other outcome measures were in line with a priori hypotheses. The HidroQoL discriminated between different severity groups (P ≤ 0·001) and showed sensitivity to change towards improvement (P < 0·001). An MID value of 4 is proposed for the total scale. CONCLUSIONS: This study supports excellent measurement properties including clinical applicability of the HidroQoL in primary axillary hyperhidrosis and suggests a MID of 4 be applied to clinical trial data.

A glycopyrronium bromide 1% cream for topical treatment of primary axillary hyperhidrosis: efficacy and safety results from a phase IIIa randomized controlled trial.

BACKGROUND: Effective topical treatment options for patients with primary axillary hyperhidrosis (PAHH) are limited. A phase I trial showed promising results regarding the efficacy and safety of a topical cream containing glycopyrronium bromide (GPB). OBJECTIVES: To assess the efficacy, safety and tolerability of a 4-week topical treatment of GPB 1% cream in patients with PAHH vs. placebo. METHODS: In total, 171 patients (84 receiving placebo; 87 receiving GPB 1%) with PAHH were included in the 4-week, multicentre, randomized, double-blind, placebo-controlled phase IIIa part of the pivotal study. Sweat production was measured by gravimetry. Patients rated the impact of disease with the Hyperhidrosis Disease Severity Scale (HDSS) and Hyperhidrosis Quality of Life Index (HidroQoL© ). RESULTS: Absolute change in sweat production from baseline to day 29 in logarithmic values was significantly larger in the GPB 1% group compared with the placebo group (P = 0·004). The improvement in HidroQoL exceeded the minimal clinically important difference of 4. The proportion of responders was twofold higher for sweat reduction (-197·08 mg GPB 1% vs. -83·49 mg placebo), HDSS (23% GPB 1% vs. 12% placebo) and HidroQoL (60% GPB 1% vs. 26% placebo). Treatment was safe: most treatment-emergent adverse effects were mild or moderate, and transient. Local tolerability was very good, with 9% of patients having only mild or moderate application-site reactions. The most reported adverse drug reaction was dry mouth (16%), an expected anticholinergic effect of the treatment. CONCLUSIONS: GPB 1% cream may provide an effective new treatment option exhibiting a good safety profile for patients with PAHH. The long-term open-label part (phase IIIb) is ongoing.

Accelerated barrier recovery and enhancement of the barrier integrity and properties by topical application of a pH 4 vs. a pH 5·8 water-in-oil emulsion in aged skin.

BACKGROUND: Increased skin-surface pH is an important host-related factor for deteriorated barrier function in aged skin. OBJECTIVES: We investigated whether restoration of skin pH through topical application of a water-in-oil emulsion with pH 4 improved the barrier homeostasis in aged skin, and compared the effects with an identical galenic formulation with pH 5·8. METHODS: The effects of the test formulations on barrier recovery were investigated by repeated measurements of transepidermal water loss (TEWL) and skin pH 3 h, 6 h and 24 h after acetone-induced impairment of barrier function in aged skin. The long-term effects of the pH 4 and pH 5·8 emulsions were analysed by investigation of the barrier integrity and cohesion, the skin-surface pH and the skin roughness and scaliness before and after a 4-week, controlled application of the formulations. RESULTS: The application of the pH 4 emulsion accelerated barrier recovery in aged skin: 3 h and 6 h after acetone-induced barrier disruption the differences in the TEWL recovery between the pH 4 treated and acetone control fields were significant. Furthermore, long-term application of the pH 4 formulation resulted in significantly decreased skin pH, enhanced barrier integrity and reduced skin-surface roughness and scaliness. At the same time points, the pH 5·8 formulation exerted only minor effects on the barrier function parameters. CONCLUSIONS: Exogenous acidification through topical application of a water-in-oil emulsion with pH 4 leads to improvement of the skin barrier function and maintenance of the barrier homeostasis in aged skin.

Corrigendum: Integration of digital health applications into the German healthcare system: development of "The DiGA-Care Path".

[This corrects the article DOI: 10.3389/frhs.2024.1372522.].

Integration of digital health applications into the German healthcare system: development of "The DiGA-Care Path".

Introduction: Since 2019 people who have insured in the German statutory health insurance are entitled to use certified apps called the Digitale Gesundheitsanwendungen [Digital Health Applications (DiGAs)]. The prerequisite for this is that an app certified as DiGA and suitable for their diagnosis exists. The DiGA can then either be prescribed by a physician or psychotherapist or requested by the patient from the statutory health insurance fund. Given the novelty of this type of healthcare, the implementation of a DiGA should be closely monitored to identify potential weaknesses and achieve quality improvements. To enable an analysis of the supply of DiGAs step-by-step, we aimed to create the DiGA-Care Path. Methods: We conducted three steps to create the DiGA-Care Path. First, a knowledge base was created based on a structured literature research matched with knowledge gathered from the superordinate research project "QuaSiApps" funded by the German Federal Joint Committee. Second, we aimed to create an "ideal-typical" DiGA-Care Path using a flowchart. Third, based on the first path, a final path was developed using the graphical modeling language "Event-Driven Process Chain." Results: The DiGA-Care Path was developed to depict the supply of DiGAs in Germany. The final path is constituted by a "main path" as well as a corresponding "sub-path". While the "main path" focuses more on the supply environment in which a DiGA is used, the "sub-path" depicts the supply delivered by the DiGA itself. Besides the process itself, the paths include relevant actors to indicate responsibilities for individual process steps. Discussion: The DiGA-Care Path helps to analyze the current supply of DiGAs step-by-step. Thereby, each step can be investigated in detail to identify problems and to detect further steps where quality improvements can be enabled. Depending on the perspective, focused either on the supply environment, or the supply delivered by the DiGA itself, the "main path" or the "sub-path" can be used, respectively. Besides the potential of the DiGA-Care Path to improve the current supply of DiGAs, it can help as an orientation for international policymakers or further stakeholders either to develop their own integration of apps into healthcare systems or for international manufacturers to consider entering the German market.

The impact of 10% α-hydroxy acid emulsion on skin pH.

BACKGROUND/AIMS: The effects of a 10% α-hydroxy acid (AHA) oil/water (O/W) emulsion on the pH of human skin surface (pH(ss)) and stratum corneum (SC; pH(sc)) were evaluated in vivo. METHODS: The AHA O/W emulsion was applied to an area on the volar forearm of male volunteers (n = 12), and then wiped off after 10 min. Prior to application and over the following 3 h, the pH(ss) was measured. We used glass electrode measurements and time domain dual lifetime referencing (tdDLR) with luminescent sensor foils. In another experiment (n = 5), the impact of the AHA O/W emulsion on the pH(sc) gradient was measured by tape stripping of the SC of the volar forearm after application of the AHA O/W emulsion. RESULTS: Compared with pH(ss) values prior to treatment [5.2 ± 1.7 (tdDLR) or 4.8 ± 0.5 (electrode)], the pH(ss) was significantly reduced 10 min after application [4.0 ± 0.3 (tdDLR) or 4.1 ± 0.1 (electrode)] and the pH(ss) remained significantly reduced over the measurement period of 3 h [after 3 h: 4.4 ± 0.2 (tdDLR) or 4.5 ± 0.3 (electrode)]. The AHA O/W emulsion significantly reduced the pH(sc) even down to deep layers of the SC. CONCLUSION: After a 10-min application time, the 10% AHA O/W emulsion reduces the pH(ss) (for at least 3 h) and pH(sc) in deep layers of the SC.

Evaluation of a novel polihexanide-preserved wound covering gel on dermal wound healing.

OBJECTIVE: Daily wound assessment, including dressing changes and the removal of old ointments causes discomfort for the patient. We therefore developed a new thermoreversible and transparent gel formulation that allows for filling wounds of different shapes and depths. The aim of the study was to investigate the effect of a wound covering gel on wound healing and the skin's microcirculation. MATERIALS AND METHODS: Investigations were carried out in a standardized and reproducible wound model (hairless mice SKH1/hr, n = 30). Three groups were studied by intravital fluorescence microscopy: treatment with polihexanide-preserved wound covering gel, a formulation containing 3% povidone (PVP)-iodine, and physiological saline for control. Microcirculatory standard parameters were analysed. RESULTS: The non-perfused area vanished within 14 days due to angiogenesis. The venular diameter, oedema formation and functional capillary density showed no significant differences between the three groups. CONCLUSION: The use of the newly developed wound covering gel has no toxic effects on microcirculation and angiogenesis and reveals no significant differences in the overall assessment of microcirculation compared to the control group and the well-established PVP-iodine. The transparent antibacterial wound covering gel allows for direct wound assessment. Due to its thermoreversible gel formulation it enables good wound contact and easy handling.

Clinical safety and efficacy of a novel thermoreversible polyhexanide-preserved wound covering gel.

BACKGROUND: An ideal topical formulation for wound therapy does not exist. The aim of this study was to develop a novel improved therapeutic option for the treatment of acute and chronic wounds. METHODS: A transparent wound gel which is in a liquid state below and in a gel state at or above room temperature was developed. Forty-four patients were included in this open randomized controlled single-center study. Flammazine served as control in the treatment of skin graft donor sites. Wounds were assessed for time of dressing change and overall satisfaction of patients and health care providers. The data were analyzed using the nonparametric Mann-Whitney test. RESULTS: The wound gel proved to be superior in comparison with Flammazine with respect to wound assessment (p = 0.002), staining (p = 0.007), leaking (p = 0.032) and smell (p = 0.034). Flammazine showed favorable results regarding the parameters dehydration of the dressings (p = 0.012) and wound adherence (p = 0.005). The evaluation of the overall dressing change process showed no significant differences. CONCLUSION: The thermoreversible wound gel containing polyhexanide allows for good handling and wound assessment. This study demonstrated a high satisfaction level of patient and health care providers, and the wound gel proved an effective alternative to commonly used treatments.

The alpha-melanocyte stimulating hormone-related tripeptide K(D)PT stimulates human hair follicle pigmentation in situ under proinflammatory conditions.

BACKGROUND: Alpha-melanocyte stimulating hormone (alpha-MSH) is a well-tolerated immunomodulator with cytoprotective and anti-inflammatory effects that is known to stimulate melanogenesis and proliferation of follicular melanocytes. As human hair follicles (HFs) locally synthesize alpha-MSH, pharmacologically more easily handled alpha-MSH-related tripeptides, such as K(D)PT, may imitate this endogenous regulation, and may show a favourable side-effect profile on clinical use. OBJECTIVES: To investigate the effect of the synthetic, alpha-MSH-related peptide K(D)PT [which is identical to interleukin (IL)-1beta(193-195)] on melanogenesis in human anagen HFs, under normal and proinflammatory growth conditions. METHODS: Normal human anagen VI scalp HFs were microdissected and organ cultured with different concentrations of K(D)PT with or without coadministration of a proinflammatory, catagen-inducing stimulus, interferon (INF)-gamma. Masson-Fontana histochemistry and NKI/beteb immunohistochemistry were employed to assess changes in the degree of human HF pigmentation and melanocyte dendricity. RESULTS: As confirmed by quantitative (immuno-)histomorphometry, compared with controls, K(D)PT alone did not affect human HF pigmentation in organ culture. However, in the presence of a strong, prototypic proinflammatory stimulus (IFN-gamma), K(D)PT significantly stimulated HF melanin content and melanocyte dendrite formation in situ. CONCLUSIONS: The IL-1beta- and alpha-MSH-related tripeptide, K(D)PT, displays interesting hair pigmentation-stimulatory activities under proinflammatory conditions. These might become exploitable for innovative antigreying strategies, notably in postinflammatory poliosis (regrowth of white hair, e.g. during recovery from alopecia areata), where no effective clinical therapy is yet available.

Double blinded, vehicle controlled, crossover study on the efficacy of a topical endocannabinoid membrane transporter inhibitor in atopic Beagles.

The endocannabinoid system is important for skin homeostasis and alterations are linked to inflammatory diseases like atopic dermatitis (AD). Importantly, activation of cannabinoid receptor CB2 decreases pruritus and inflammation in mouse models. Reduction of inactivation of endogenous cannabinoids could, therefore, be a therapeutic option for AD. Dogs spontaneously develop AD, which closely mimics the human disease making them suitable to test new therapies. Our study aimed to test the effects of a topical endocannabinoid membrane transporter inhibitor (WOL067-531, 1% gel) on pruritus and dermatitis in a canine model of AD. Nineteen Beagles allergic to dust mites (DM) were randomized to receive either active ingredient or vehicle on inguinal area while challenged epicutaneously with DM twice weekly for 28 days. Treatment was administered twice daily and started after three challenges (day 8). Dermatitis and pruritus were scored weekly by personnel blinded to treatment allocation. Dermatitis was scored using a validated scoring system and pruritus was scored using camera recordings. After a 4-week washout, dogs were crossed over and the study was repeated. On days 15 and 22, dermatitis scores were significantly increased after DM challenge in the vehicle group (16.34, p = 0.0089 and 7.42, p = 0.04845, respectively) but not in the active ingredient group (p = 0.3177 and p = 0.3190, respectively). Significant decrease on pruritus both on inguinal area and overall (p = 0.048 and p = 0.032, respectively) occurred in the active ingredient group. No adverse effects were noted. In conclusion, the newly developed topical endocannabinoid membrane transporter inhibitor (WOL067-531) minimized allergic flares and pruritus in a canine model of AD.

A bio-inspired real-time capable artificial lateral line system for freestream flow measurements.

To enhance today's artificial flow sensing capabilities in aerial and underwater robotics, future robots could be equipped with a large number of miniaturized sensors distributed over the surface to provide high resolution measurement of the surrounding fluid flow. In this work we show a linear array of closely separated bio-inspired micro-electro-mechanical flow sensors whose sensing mechanism is based on a piezoresistive strain-gauge along a stress-driven cantilever beam, mimicking the biological superficial neuromasts found in the lateral line organ of fishes. Aiming to improve state-of-the-art flow sensing capability in autonomously flying and swimming robots, our artificial lateral line system was designed and developed to feature multi-parameter freestream flow measurements which provide information about (1) local flow velocities as measured by the signal amplitudes from the individual cantilevers as well as (2) propagation velocity, (3) linear forward/backward direction along the cantilever beam orientation and (4) periodicity of pulses or pulse trains determined by cross-correlating sensor signals. A real-time capable cross-correlation procedure was developed which makes it possible to extract freestream flow direction and velocity information from flow fluctuations. The computed flow velocities deviate from a commercial system by 0.09 m s(-1) at 0.5 m s(-1) and 0.15 m s(-1) at 1.0 m s(-1) flow velocity for a sampling rate of 240 Hz and a sensor distance of 38 mm. Although experiments were performed in air, the presented flow sensing system can be applied to underwater vehicles as well, once the sensors are embedded in a waterproof micro-electro-mechanical systems package.

Active and higher intracellular uptake of 5-aminolevulinic acid in tumors may be inhibited by glycine.

Topical 5-aminolevulinic acid is used for the fluorescence-based diagnosis and photodynamic treatment of superficial precancerous and cancerous lesions of the skin. Thus, we investigated the kinetics of 5-aminolevulinic acid-induced fluorescence and the mechanisms responsible for the selective formation of porphyrins in tumors in vivo. Using amelanotic melanomas (A-Mel-3) grown in dorsal skinfold chambers of Syrian golden hamsters fluorescence kinetics were measured up to 24 h after topical application of 5-aminolevulinic acid (1%, 3%, or 10%) for 1 h, 4 h, or 8 h by intravital microscopy (n = 54). Maximal fluorescence intensity in tumors after 1 h application (3% 5-aminolevulinic acid) occurred 150 min and after 4 h application (3% 5-aminolevulinic acid) directly thereafter. Increasing either concentration of 5-aminolevulinic acid or application time did not yield a higher fluorescence intensity. The selectivity of the fluorescence in tumors decreased with increasing application time. Fluorescence spectra indicated the formation of protoporphyrin IX (3% 5-aminolevulinic acid, 4 h; n = 3). The simultaneous application of 5-aminolevulinic acid (3%, 4 h) and glycine (20 microM or 200 microM; n = 10) reduced fluorescence in tumor and surrounding host tissue significantly. In contrast, neither decreasing iron concentration by desferrioxamine (1% and 3%; n = 10) nor inducing tetrapyrrole accumulation using 1, 10-phenanthroline (7.5 mM; n = 5) increased fluorescence in tumors. The saturation and faster increase of fluorescence in the tumor together with a reduction of fluorescence by the application of glycine suggests an active and higher intracellular uptake of 5-aminolevulinic acid in tumor as compared with the surrounding tissue. Shorter application (1 h) yields a better contrast between tumor and surrounding tissue for fluorescence diagnosis. The additional topical application of modifiers of the heme biosynthesis, desferrioxamine or 1,10-phenanthroline, however, is unlikely to enhance the efficacy of topical 5-aminolevulinic acid-photodynamic therapy at least in our model.

Wavelength dependency of photodynamic effects after sensitization with 5-aminolevulinic acid in vitro and in vivo.

A promising new therapeutic modality for skin cancer, administration of the heme precursor 5-aminolevulinic acid followed by light irradiation, is known as photodynamic therapy. Photofrin, the only clinically approved sensitizer, has an absorption maximum at 630 nm, the wavelength used in most experimental and clinical trials with 5-aminolevulinic acid. We investigated photodynamic efficacy of irradiation with coherent light at wavelengths ranging from 622 to 649 nm in vitro and in vivo as well as the content and distribution of intracellular porphyrin after administration of 5-aminolevulinic acid. HaCaT immortalized human keratinocytes were sensitized with 30 micrograms/ml 5-aminolevulinic acid for 24 h in vitro. By cell viability determined with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, the best cell-killing effects were observed after irradiation at 635 nm. Using an amelanotic melanoma (A-Mel-3) grown subcutaneously in Syrian Golden hamsters, we confirmed these results in vivo: tumor growth was markedly delayed in animals treated with 100 mg/kg 5-aminolevulinic acid intravenously and irradiated with coherent light at 635 nm as compared to animals irradiated at 630 nm. This photodynamic effect is probably mediated by large amounts of the photosensitizing porphyrin, protoporphyrin IX, localized in cell membranes as visualized by confocal laser scan microscopy and as determined by high pressure liquid chromatography in vitro. The results suggest that irradiation at 635 nm with a coherent light source is more effective than irradiation at 630 nm for photodynamic therapy with 5-aminolevulinic acid.

Impact of dextran on microvascular disturbances and tissue injury following ischemia/reperfusion in striated muscle.

The aim of this study was to evaluate the effect of dextran (Dx) 1 versus Dx 60 (molecular weights 1,000 and 60,000) on microvascular disturbances and tissue injury in striated muscle after ischemia/reperfusion (I/R). Experiments were performed using a 4 h pressure-induced ischemia model in the hamster dorsal skinfold chamber. Three groups (n=6) of animals received a continuous infusion (45 min, 3 microL/min) of either Dx 1 or Dx 60 (total dose 5 mg/kg) or saline solution beginning 15 min before reperfusion. Intravital fluorescence microscopy allowed for quantification of functional capillary density, leukocyte adherence, extravasation of fluorescein isothiocyanate-Dx, and nonviable (propidium-positive) cell count before ischemia and .5, 2, and 24 h after reperfusion. Experiments were terminated with tissue preservation for electron microscopy. Postischemic functional capillary density was significantly improved by Dx 60 (at 24 h, 88% vs. 51% in controls). In animals receiving postischemic Dx 1 or Dx 60, leukocyte adherence was significantly reduced (at .5 h, 44% and 58%, respectively) as compared with controls, whereas macromolecular extravasation was unchanged. Nonviable cell count was significantly decreased by both Dx fractions (at 24 h, Dx 1, 75%; Dx 60, 87%), indicating a reduction of tissue injury, which was also confirmed by electron microscopy. These results provide evidence that Dx 60 at 5 mg/kg attenuates I/R injury more effectively than Dx 1. Leukocytes play a major role in the development of I/R injury, but macromolecular extravasation does not always correlate with the leukocyte-endothelium interaction and the manifestation of I/R injury.

Structure-activity relationships of three differently substituted 2,7,12,17-tetrakis-(beta-methoxyethyl) porphycene derivatives in vitro.

The subcellular localization, efficacy and photooxidative mechanism of three new photosensitizing porphycenes (HexoTMPn, PeloTMPn, CpoTMPn) for photodynamic therapy with different substituents at position 9 of the tetrapyrrole macrocycle were investigated in vitro using different human skin-derived cell lines (HaCaT, SCL I, SCL II) with the aim of customizing the side-chain chemistry to accelerate cellular uptake and so enhance photodynamic activity. Cells were incubated with a porphycene and costained with organelle-specific markers. Subcellular localization was determined by fluorescence microscopy. Also, cells were incubated with different sensitizer concentrations (0-1000 nmol/l) and irradiated by an incoherent light source (lambda(em) = 600-750 nm, 40 mW/cm(2), 24 J/cm(2)) with/without quenchers or enhancers (NaN(3), histidine, mannitol or D(2)O). Cell viability was assessed. All porphycenes were localized in perinuclear lysosomes and induced a decrease in mitochondrial activity following irradiation. HexoTMPn was the most efficient in all three cell lines (EC(50) in HaCaT cells: HexoTMPn 14 nmol/l, CpoTMPn 62 nmol/l, PeloTMPn 89 nmol/l). Addition of either NaN(3) or histidine reduced the phototoxicity significantly. Due to the short lifetime of singlet oxygen, the sites of sensitizer localization are the initial subcellular targets. The cytotoxicity of each sensitizer varied depending on singlet oxygen quantum yield and cell line. Despite the different chemical structures, the biological effects were not very distinct, since they seemed to be mostly determined by the tetrapyrrole ring and only slightly modified by the substituent at position 9. Also, there was only a narrow margin between biological compatibility and efficacy.